MXPA06009346A - Novel azabicyclic derivatives, preparation method thereof and pharmaceutical compositions containing same - Google Patents

Abstract

The invention relates to compounds having general formula (I), the enantiomers and diastereoisomers thereof, as well as their addition salts with one or more acids or one or more pharmaceutically-acceptable bases. The inventive compounds are of particular interest for their interaction with central histaminergic systems.

Description

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AZABICICLIC NOVEDIUM DERIVATIVES, METHOD OF PREPARATION t > THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME FIELD OF THE INVENTION The present invention relates to novel azabicyclic compounds, to a process for their preparation and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION The compounds of the present invention are of particular interest from a pharmacological point of view - for the interaction with the central histaminergic systems in vivo, and can be used - in the treatment of neuropathologies associated with brain aging, disorders of behavior, eating behavior disorders and disturbances of the sleep / wake cycle, as well as attention deficit hyperactivity disorder. The aging of the population as a result of the increase in life expectancy at birth has led to a substantial increase in the incidence of neuropathologies associated with age, and especially Alzheimer's disease. The main clinical manifestations of brain aging and especially the neuropathologies associated with age are deficiencies in the mnesic and cognitive function which can lead to dementia. With respect to the central nervous system, recent neuropharmacological studies have shown that histamine, via central histaminergic systems, plays the role of a neurotransmitter or neuromodulator in physiological or pathophysiological scenarios (Pell and Green, Annu Rev. Neurosci., 1986 , 9, 209-254; Schwartz et al., Physiol. Rev., 1991, 71, 1-51). Thus, it has been shown that histamine plays a part in various physiological and behavioral processes such as thermoregulation, neuroendocrine regulation, circadian rhythm, cataleptic states, motor function, aggression, feeding behavior, learning and memory function, and also synaptic plasticity (Hass et al., Histaminergic neurons: morphology and function, Boca Raton, FL: CRC Press, 1991, pp. 196-208; Brown et al., Prog. Neurobiology, 2001, 63_, 637-672). Studies carried out on animals showed that an increase in endogenous extrasynaptic histamine levels allows for the promotion of alertness, the promotion of learning and memory processes and the regulation of food consumption and allows for convulsive attacks to be counteracted. (Brown et al., Prog. Neurobiol., 2000, _63, 637-672, Passani et al., Neurosci.Biobehav, Rev., 2000, 24, 107-113) .- As a result, potential therapeutic indications for compounds capable of increasing histamine turnover or release centrally are the treatment of cognitive deficiencies associated with brain aging and with neurodegenerative diseases, such as Alzheimer's disease, Pick's disease, Korsakoff's disease and frontal or subcortical dementias of vascular origin. another, as well as the treatment of behavioral disorders, seizures and hyperactivity syndrome due to attention deficit. In addition, studies have shown that an injection of histamine at the level of the central hypothalamic nuclei involved in the regulation of satiety reduces feeding in rats. In addition, hypeminergic transmission has been shown to be hypofunctional in genetically obese rats (Machidori et al., Brain Research, 1992, 590, 180-186). As a result, eating and obesity behavior disorders are also potential therapeutic indications for the compounds of the present invention. A number . of documents describes compounds comprising a portion of octahydrocyclopenta- [b] pyrrole or octahydrocyclopenta [c] pyrrole [US 2,962,496; J. Chem. Soc., Chem. Commun. , 1995. 10, 1009-1010; Tetrahedron, 1991, 47 (28), 5161-5172; Tetrahedron Lett. , 1988, 29 (28), 3481-3482; J. Med. Chem. , 1973, 16 (4), 394-397]. Some of these compounds are known for their use in the treatment of cardiovascular diseases, especially hypertension, or as a local anesthetic, and others have been studied from the point of view of. mechanism in relation to chemical reactions of the type of cyclization or catalyzed intramolecular cycloaddition. On the other hand, there is no document describing or suggesting that compounds have in vivo activity as activators of the central histaminergic systems, a novel property of the compounds claimed by the Applicant.

THE INVENTION More specifically, the present invention relates to the compounds of formula (I): where: • myn, which may be the same or different, each represent an integer from 0 to 2 inclusive, with the sum of the two integers being from 2 to 3 inclusive, • p and q, which may be identical or different, represent each an integer from 0 to 2 inclusive, • alq represents a chain of alkyl.eno; alkenylene or alkynylene, and Y which may be identical or different, each represents a hydrogen atom, a halogen atom or an alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, mercapto, hydroxy, perhaloalkyl, nitro, amino (unsubstituted or substituted by one or two alkyl groups), acyl, aminocarbonyl (optionally substituted on the nitrogen atom by one or two alkyl groups), acylamino (optionally substituted on the nitrogen atom by an alkyl group), alkoxycarbonyl , carboxy, sulfo or cyano. "X represents an oxygen atom, a sulfur atom or a group -N (R) - where R represents a hydrogen atom or an alguyl group, • W represents a group selected from cyano (when X represents an oxygen atom or a group NR), -N (R1) -Z1-R2 and -Z2-NR? R2, where: - Zi represents -C (O) -, -C (S) -, -C (NR4) -, * - C (0) -N (R3)) -, * -C (S) -N (R3) -, * -C (NR4) -N (R3) -, * -C (0) -0-, * - C (S) -0- or -S (0) r-, in which r = 1 or 2 and * corresponding to the union to N (Ri), - Z2 represents -C (0) -, -C (S) ) -, -C (NR4) -, -S (0) r- or a bond, - R1 R2, R3 and R4, which may be identical or different, each represents a hydrogen atom, an alkyl group optionally substituted, an optionally substituted alkenyl group, an optionally substituted alkenyl group, an alkoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, - or Ri and R2 or R2 and R3, together with the atom or atoms containing them, form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl group, with its enantiomers, diastereoisomers, and also addition salts thereof with one or more acids or bases pharmaceutically acceptable, wherein: - the term "alkyl" denotes a straight or branched hydrocarbon chain containing from 1 to 6 carbon atoms, the term "alkenyl" denotes a straight or branched group containing from 3 to 6 carbon atoms and from 1 to 3 double bonds, the term "alkynyl" denotes a linear or branched group containing from 3 to 6 carbon atoms and from 1 to 3 triple bonds, the term "alkoxy" denotes an alkyloxy group in which the chain linear or branched alkyl containing from 1 to 6 carbon atoms, the expression "optionally substituted aryloxy" denotes a group of which the aryl group is optionally substituted, - the term "acyl" denotes a RaC (O) group in which Ra represents a hydrogen atom or an alkyl group, - the term perhaloalkyl denotes a linear or branched carbon chain containing from 1 to 3 carbon atoms and from 1 to 7 halogen atoms, - the term "alkylene" denotes a linear or branched bivalent radical containing from 1 to 6 carbon atoms, the term "alkenylene" denotes a linear or branched bivalent radical containing from 2 to 6 carbon atoms and from 1 to 3 carbon atoms doubles, the term "alkynylene" denotes a linear or branched bivalent radical containing from 2 to 6 carbon atoms and from 1 to 3 triple bonds. the term "aryl" denotes a phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl or tetrahydro-naphthyl group, the term "heteroaryl" denotes a monocyclic or bicyclic group in which at least one of the rings is aromatic, containing the group of 5 to 11 members in the ring and from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, the term "cycloalkyl" denotes a monocycle or hydrocarbon bicyclo containing from 3 to 11 carbon atoms and optionally unsaturated by 1 or 2 unsaturated bonds, - the term "heterocycloalkyl" denotes a mono- or bicyclic group, saturated or unsaturated by 1 or 2 unsaturated bonds, containing from 4 to 11 members in the ring and having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, the term "optionally substituted" applied to the terms cycloalkyl, aryl, heteroaryl and heterocycloalkyl denotes i) those groups which may be substituted by 1 to 3 identical or different substituents, substituents selected from alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halogen, hydroxy, mercapto-, perhaloalkyl, nitro, amino (unsubstituted or substituted by one or two alkyl groups), acyl, aminocarbonyl (optionally substituted on the nitrogen atom by one or two alkyl groups), acylamino ( optionally substituted on the nitrogen atom by an alkyl group), alkoxycarbonyl, carboxy, sulfo and cyano; or ii) that those groups may be substituted by an aryl, heteroaryl, cycloalguyl, heterocycloalkyl or benzyl group; it being understood that the aryl or heteroaryl groups may further be substituted by one or two oxo groups on the non-aromatic portion of a group having both non-aromatic and aromatic portions and that the cycloalkyl and heterocycloalkyl groups may likewise be substituted by one or two oxo groups, the term "optionally substituted" applied to the term "alkyl, alkenyl or alkynyl" denotes that those groups may be substituted by one or two identical or different groups selected from alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halogen, hydroxy, mercapto, nitro, amino, acyl, aminocarbonyl, acylamino, alkoxycarbonyl, carboxy, sulfo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted aryloxy .- Among pharmaceutically acceptable acids may be mentioned, - without implying any lim to hydrochloric acid, hydrobromic acid, sulfuric acid,. Phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, oxalic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, etc. Among pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, etc. " Preferred aryl groups are the phenyl group. Advantageously, the compounds of the invention are those where, in the formula (I), q-is 1 ..

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES OF THE INVENTION An advantageous embodiment of the invention relates to compounds where n represents 1. Preferred compounds of the invention are those where m is 1. Other preferred compounds of the invention are those where m is 2. Preferred compounds of the invention are those where p is 1. Other preferred compounds of the invention are those where p is 2. A particularly advantageous embodiment of the invention relates to compounds of formula (I) wherein X represents an oxygen atom or a sulfur atom (more advantageously an oxygen atom).

Another particularly advantageous embodiment of the invention relates to compounds of formula (I) wherein X represents a group -N (R) - (more advantageously - NH) '.; A preferred embodiment is one in which the groups Y and Y 'in the compounds of the invention of formula (I) each represents a hydrogen atom. Another preferred embodiment of the invention is that in which, in the compounds of the invention of formula (I), the group Y represents a hydrogen atom and the group Y 'represents a halogen atom or an alkyl group, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, mercapto, hydroxy, perhaloalkyl, nitro, amino, (unsubstituted or substituted by one or two alkyl groups), acyl, aminocarbonyl, (optionally substituted on the nitrogen atom with one or two alkyl groups), acylamino (optionally substituted on the nitrogen atom by an alkyl group), alkoxycarbonyl, formyl, carboxy, sulf? or cyano. More preferably, Y 'represents a halogen atom. Especially advantageous compounds include the compounds of the invention wherein Alk represents, x? N'á alkylene chain (more especially propylene). - A particularly advantageous embodiment of the invention relates to compounds of formula (I), where it is located on the phenyl group in the 4-position. Another advantageous embodiment of the invention relates to compounds of formula (I) where represents a group cyano. Advantageously, the compounds of formula (I) are those where W represents a group -N (R?) - Zi ~ R2. Also, advantageously, the compounds of formula (I) are those comprising W which represents a group -Z2-NR? R2. . ' Y, The preferred Z2 groups are selected from -C (O) -, -C (S) -, -C (NR4) - and -S (0) r-. More preferably, Z2 represents a group -C (O) -. Other preferred compounds of the invention are those wherein Z2 represents a bond. Preferred Zi groups are selected from -C (O) -, * -C (S) - * -C (0) -N (R3) -, * -C (S) -N (R3) -, * -C (0) -0- and S (0) 2-, preferably -C (O) - and * -C (O) - (R3) - (more preferably -C (O) -). A particularly advantageous embodiment of the invention relates to compounds of formula (I) wherein Ri, R2, R3 and R4, which may be identical or different, each represent: • a hydrogen atom; • an alkoxy group; A cycloalguyl group (preferably cyclopropyl, cyclobutyl or cyclohexyl);; • • • • • • • • • • • a phenyl group that is optionally substituted (preferably by one or two substituents selected from nitro, halogen, trihaloalkyl, alkyl, and alkoxy) • a naphthyl group • a heteroaryl group preferably selected from thienyl, furyl, pyridyl, benzofuryl and methylenedioxyphenyl); an alkyl group; or a substituted alkyl group: by a phenyl group which is optionally substituted (preferably by one or two substituents selected from halogen, trihaloalkyl, alkyl and alkoxy), - by a cycloalkyl group (preferably cyclopropyl), or by a heterocycloalkyl group (preferably morpholinyl, piperazinyl, piperidinyl), or by a heteroaryl group (preferably thienyl, furyl, pyridyl, imidazolyl), or by one or two groups alkoxy (preferably methoxy), or by a phenyloxy group Another particularly advantageous embodiment of the invention relates to compounds of formula (I) wherein W represents a group selected from -N (Ri) -C (0) -NR2R3; - N (Ra) -C (S) -NR2R3; -C (0) -NR? R2 and -C (S) -NR? R2; where Rx and R2 or. R2 and -3, together with the atom or atoms which contain them, form a heterocycloalkyl group or a piperidinopiperidyl group. Preferred heterocycloalyl groups are saturated monocyclic groups having 6 or 7 members on the ring optionally containing, in addition to the nitrogen atom, another heteroatom selected from nitrogen, oxygen and sulfur; or saturated bicyclic groups which have from 6 to 10 members in the ring which optionally contain, in addition to the nitrogen atom, another heteroatom selected from nitrogen, oxygen and sulfur. Another particularly advantageous embodiment of the invention relates to compounds of formula (I) where represents -Z2-NR? R2 in which Z2 represents a bond; Rx and R2, together with the nitrogen atom containing them, form a heteroaryl group (preferably imidazolyl or triazolyl) or Ri represents a hydrogen atom or an alkyl group and R2 represents an aryl or heteroaryl group (preferably heteroaryl, more preferably preferable a group selected from quinazolyl, isoquinolyl, quinolyl and pyrrhinyl). Advantageously, the compounds' of formula (I) are those in which W represents a group -C (0) -NR? R2 in which Ri and R2, independently, each represent an alkyl group or a hydrogen atom, or Rx and R2, together with the nitrogen atom containing them, form a group selected from piperazinyl optionally substituted with an alkyl or benzyl group; piperidyl optionally substituted by an alkyl- or benzyl group; acepanyl; morpholinyl; thiomorpholinyl; octahydrocyclopentapyrrolyl; dihydroquinolinyl and tetrahydroquinolinyl. A particularly advantageous embodiment of the invention relates to compounds of formula (I) where represents a group -C (0) -NR? R2 in which Rx and R2, independently, each represent an alkyl group or a hydrogen atom. Another particularly advantageous embodiment of the invention relates to compounds of formula (I) wherein represents a group -N (R2) -C (O) -R2 in which Ri and R2, independently, each represent an alkyl group or an hydrogen atom. Among the preferred compounds of the invention, mention may be made, in particular, of 4- (3-hexahydrocyclopenta [c] pyrrole-2 (1H) -proproxy) benzonitrile, 4- [(3-hexahydrocyclopenta [c] pyrrole-2 (1 H) -ylpropoxy) benzamide, 4- [3- (hexahydrocyclopenta [c] -pyrrole-2 (1H) -yl) ropoxy] -N-methylbenzamide, 4- [3 (hexahydrocyclopenta [c] pyrrol-2 (1H) -yl) propoxy] -N, N-dimethylbenzamide and N- [(3-hexahydrocyclopenta- [c] pyrrol-2 (lH) -lproproxy) phenyl] acetamide .

The invention also relates to a process for the preparation of compounds of formula (I), which is characterized in that a compound of formula (II) is used as starting material: where: Alk is as defined for formula (I), Hal represents a halogen atom, X 'represents an oxygen atom, a sulfur atom or a group -N (p) -, in which (p) represents a hydrogen atom, a conventional protecting group for the nitrogen atom, or an alkyl group, and, Y and Y 'are as defined for formula (I), Compound of formula (II), which, after the optional deprotection is condensed in basic medium with a dicyclo of formula (III): Where: n, m, p and q are as defined for formula (I), to produce a compound of formula (I) • compound of formula (I) which, when representing a cyano group, is reacted optionally with hydroxide of sodium or potassium hydroxide to produce a compound of formula (I / b): a particular case of the compounds of formula (I) wherein Alk, n, m, p, q, X, Y and Y 'are as defined for formula I, compounds of formula (I), which, - can , if desired, be purified according to a conventional purification technique, - are optionally separated into stereoisomers according to a conventional separation technique, are converted, if desired, into addition salts with one or more pharmaceutically acceptable acids or bases acceptable, it being understood that: at any time considered appropriate during the course of the process described above, the carbonyl, thiocarbonyl, amino, alkylamino group or groups in the initial reagent (II) can be protected and then, after condensation, unprotected when is required by the synthesis, - the reactants (II) and (III) are prepared according to procedures described in the literature. The present invention relates to pharmaceutical compositions comprising as an active ingredient at least one compound of formula (I), alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers. Among the pharmaceutical compositions of .agreement a. The invention can be more particularly mentioned those which are suitable for oral, parenteral, nasal or transdermal administration, tablets ... or lozenges, sublingual tablets, gelatin capsules, troches, suppositories, creams, ointments, dermal gels, etc. The useful dose varies according to the age and weight of the patient, the nature and severity of the disorder, and also the route of administration, which may be oral, nasal, rectal or parenteral. Generally, the unit dose ranges from 0.05 to 500 mg for a treatment of 1 to 3 administrations per 24 hours. The following Examples illustrate the invention and limit it in any way. The structures of the described compounds were confirmed by customary spectroscopic and spectrometric techniques. The initial materials used are known products or products prepared according to known procedures.

PREPARATION 1: N- (4-Chlorobutyl-β- (4-cyanophenyl) acetamide 9 g (54.1 mmol) of N- (4-cyanophenyl) acetamide were dissolved in 100 ml of THF The mixture was cooled to 0 ° C before Aa addition by dripping 51 ml of a 1.6? solution in nBuli hexane (1.5 eq.) The solution was left for 1 hour to return to room temperature and cooled to 0 ° C before the drip addition of 9.9. ml of 1-chloro-4-iodobutane (81 mmol) The reaction mixture was stirred at room temperature for 18 h and then - hydrolyzed with a saturated aqueous solution of ammonium chloride (100 ml) and extracted with ethyl acetate The organic phases were combined, dried over magnesium sulfate and concentrated, purification by chromatography on silica (eluent: petroleum ether / ethyl acetate: 1/1) yields a yellow oil - containing the expected product.

PREPARATION 2: N- (3-Chloropropyl) -N- (4-cyanophenyl) acetamide The experimental procedure is identical to that of Preparation 1, with the replacement of l-chloro-4-iodobutane with l-chloro-3-iodopropane. PREPARATION 3: N- (2-Chloroethyl) -N- (4-cyanophenyl) acetamide The experimental procedure is identical to that of Preparation 1, with the replacement of l-chloro-4-iodobutane with l-chloro-2- Iodoethane EXAMPLE 1: 4- (3-hexahydrocyclopenta [c] pyrrole-2 (lH) -lproproxy) benzonitrile Oxalate Step 1: 4- (3-Chloropropoxy) benzonitrile A mixture of 0.47 g (0.004 mole) of 4-hydroxybenzonitrile, 0.63 g (0.004 mol) of l-bromo-3-chloropropane and 1.95 g (0.006 mol) of. Cesium carbonate in 10 ml of acetonitrile was heated to reflux for 5 hours.

Step 2: 4- (3-hexahydrocyclopenta [c] pyrrole-2- (1H) -propropoxy) benzonyl triolate. To the reaction mixture from Step 1, at room temperature, 0.44 g (0.004 mol) of octahydro- cyclopenta [c] pyrrole * and 0.30 g (0.002 mol) of sodium iodide and the heating was resumed at reflux for 16 hours. The precipitate was filtered and rinsed with acetonitrile. The filtrate was concentrated to dryness. The residue was removed in dichloromethane. The resulting solution was extracted with sodium hydroxide solution, then with water, dried over magnesium sulfate and concentrated to dryness. The residue was purified by the preparative chromatography technique on Lichroprep RP-1'8 phase. It recrystallized little product of ethanol in the form of oxalate '? * The octahydrocyclopenta [c] pyrrole was synthesized according to the method of Roussi and Zang (Tetrahedron Lett., 1988, 29, 3481). ESI +: [M + H] + 271. 1810 (theory: 271, 1810) EXAMPLE 2: 4- (2-hexahydrocyclopenta [c] pyrrol-2 (1H) -ylethoxy) benzonitrile oxalate The experimental procedure is identical to that of Example 1, with the replacement of l-bromo-3-chloropropane in "'Step 1 with l-bromo-2-chloroethane Elemental microanalysis: C% H% N% Calculated: 62. 42 6. 40 8. 09 Found: 62. 09 6. 38 8. 09 EXAMPLE 3: 4- (4-hexahydrocyclopenta [c] pyrrole-2 (1H) -ylbutoxy) benzonitrile oxalate The experimental procedure is identical to that of Example 1, with the replacement of l-bromo-3-chloropropane in Step 1 with l-bromo-4-chlorobutane.

Elementary microanalysis C% H% N% Calculated: 63.28 6.89 7.31 Found: 63.14 6.78 6.91 EXAMPLE 4: N- [4- (3-hexahydrocyclopenta [c] pyrrol-2 (lH) -lpropropoxy) -phenyl] acetamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (4-hydroxyphenyl) acetamide. X H NMR (DMSO D6): d (ppm) 1.40-1.80 (m, 6H); 2.00 (s, 3H); 2.10 (quint, 2H); 2.80 (, 4H); 3.25 (t, 2H); 3.60 (m, 2H); 4.00 (t, 2H); 6.90 (d, 2H); 7.50 (d, 2H); 9.80 (s, ÍH).

EXAMPLE 5: N- [3- (3-hexahydrocyclopenta oxalate [c] pyrrol-2 (1 H) -proproxy) -phenyl] acetamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (3-hydroxyphenyl) acetamide. Elemental microanalysis: C% H% N% Calculated: 61.21 7.19 7.14 Found: 61.06 7.28 7.06 EXAMPLE 6: N-Ethyl-4- (3-hexahydrocyclopenta [c] pyrrol-2 (IH) -proproxy) -benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with? -ethyl-4-hydroxybenzamide. '• "Elementary microanalysis: C% H% N% Calculated: 71. 12 8. 92 8. 85 Found: 72. 52 9. 10 8. 80 EXAMPLE 7: N-cyclopentyl-4- (3-hexahydrocyclopenta [c] pyrrol-2- (lH) -lproproxy) -Jaenzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N-cyclopentyl-4-hydroxybenzamide.

EXAMPLE 8: N-cyclopentyl-N-ethyl-4- (3-hexahydrocyclopenta [c] pyrrol-2- (1H) -proproxy) -benzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4- hydroxybenzonitrile in Step 1 with W-cyclopentyl-N-ethyl-4-hydroxybenzamide.

EXAMPLE 9: N, N-Diethyl-4- (3-hexahydrocyclopenta [c] pyrrol-2 (IH) -propropoxy) -benzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N, N-diethyl-4-hydroxybenzamide. • "> Elemental microanalysis: C ~ 6 H'S N ~ s Calculated: 63. 57 7. 89 6. 45 Found: 63. 37 7. 93 6. 34 EXAMPLE 10: N, N-Dicyclopropyl-4- (3-hexahydrocyclopenta [c] pyrrole-2 (lH) -lproproxy) benzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N, N-dicyclopropyl-4-hydroxybenzamide.

EXAMPLE 11: oxalate of 2-. { 3- [4- (1-Acelanyl-carbonyl) phenoxy] propyl} Octahydrocyclopenta- [c] pyrrole The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (1-acetanylcarbonyl) phenol.

EXAMPLE 12: oxalate of 2-. { 3- [4- (1-Tiomorpholinocarbonyl) phenoxy] ropil} Octahydrocyclopenta- [c] pyrrole The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (thiomorpholinocarbonyl) phenol.

EXAMPLE 13: oxalate of 2-. { 3- [4- (Morphonyl carbonyl) phenoxy] ropil} Octahydrocyclopenta- [c] pyrrole The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (Morpholinocarbonyl) phenol. Elemental microanalysis: Calculated: 61. 59 7. 19 6. 25 Found: 61. 50 7. 21 6. 30 EXAMPLE 14: oxalate of 2-. { 3- [4- (1-piperazinylcarbonyl) phenoxy] propyl} Octahydrocyclopenta [c] pyrrole The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (1-piperazinylcarbonyl) phenol.

EXAMPLE 15: 2- [4- (3-Hexahydrocyclopenta [c] pyrrol-2 (lH) -lproproxy) benzoyl] -isoindoline oxalate The experimental procedure is identical to that of the Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4 ~ (1, 3-dihydro-2i-isoindol-2-ylcarbonyl) phenol.

EXAMPLE 16: 5-Bromo-2- [4- (3-hexahydro-cyclopenta [c] pyrrole-2 (1-yl) -ylpropoxy) -benzonyl] isoindoline oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile 'in Step 1 with 4- [(5-bromo, 1,3-dihydro-2H-isoindol-2-yl) -carbonyl] -phenol.

EXAMPLE 17: oxalate of 2-. { 3- [4 (Hexahydrocyclopenta [c] pyrroi-2 (lfl) -ylcarbonyl) phenoxy] -propyl} Octahydrocyclopenta [c] pyrrole The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (hexahydrocyclopenta [c] pyrrole-2 (IfI) -ylcarbonyl) -phenol. Elemental microanalysis: -.

C% H% N% Calculated: 62.65 7.21 '5.41 Found: 63.14 7.30 5.47 EXAMPLE 18: 4- [(4- (Hexahydrocyclopenta [c] pyrrol-2 (lH) -ylbutyl) amino] -benzonitrile oxalate Step 1: N- (4-Cyanophenyl) -N- (4-hexahydrocyclo-penta [c] pyrrol-2 (1H) -ylbutyl) -acetamide 2 g (8 mmol) of the chlorine compound synthesized in Preparation 1 are dissolved in 65 ml of ethanol with 1.5 g of octahydrocyclopenta [c] pyrrole (2 eq.) and 12 mg of Nal (0.01 eq.). The mixture is heated at reflux for 18 hours before being evaporated to dryness in vacuo. The residue is taken up in ethyl acetate and then washed with sodium hydroxide solution N. The organic phase is dried over magnesium sulfate, concentrated and purified by column chromatography over silica (eluent: dichloromethane / ethanol: 9/1) give 1.4 g of the expected product.

Step 2: 4- [(4-Hexahydrocyclopenta [c] pyrrol-2 (lH) -ylbutyl) amino] benzonitrile oxalate 133 mg (1.5 eq.) Of sodium ethanolate was added to a solution of compound prepared in the previous Step (423 mg) in 2.6 ml of ethanol. The mixture was refluxed for 5 hours and then concentrated in vacuo. The residue was taken up in dichloromethane, washed with water and then dried over magnesium sulfate before evaporation of the solvent. Purification by column chromatography (eluent: dichloromethane / ethanol / ammonium hydroxide: 10 / 0.5 / 0.25) gave 330 mg of the product to be obtained. 260 mg of that compound was dissolved in ethanol and then the addition of 2.5 equivalents of oxalic acid in solution in ethanol results in the precipitation of the salt. ESI *: [M + H] '' 284.2085 (theoretical: 284. 2127) EXAMPLE 19: 4- [(3-Hexahydrocyclicpenta [c] pyrrol-2 (lfl) -ylpropyl) amino] benzonitrile oxalate The experimental procedure is identical to that of Example 18, with the replacement of the reagent of Preparation 1 with that of Preparation 2. Elemental microanalysis: EXAMPLE 20: 4- [(2-Hexahydrocyclopenta [c] pyrrol-2 (1-yl) -ylethyl) amino] benzonitrile oxalate The experimental procedure is identical to that of Example 18, with the replacement of the reagent of Preparation 1 with that of the Preparation 3. Elementary microanalysis: C% H% N% Calculated: 60. 81 6. 49 11. 56 Found: 60. 60 6. 00 11. 30 EXAMPLE 21: 4- [(4-Hexahydrocyclopenta [c] pyrrole-2 (IfI) -ylbutyl) amino] benzamide oxalate 436. g of the compound of Example 18 are dissolved in 4 ml of ethanol. 86 mg of potassium hydroxide (1 eq.) Are dissolved in 1.5 ml of water before being added to the alcohol solution. The mixture is heated at reflux for 1.5 hours and then evaporated to dryness. The residue was removed in dichloromethane. The result was: the solution was washed with water and then dried over magnesium sulfate and concentrated in vacuo.The product is crystallized in the form of oxalate ESlX [M + H] * 302.2212 (theoretical: 302.2232) EXAMPLE 2: 4- (3-Hexahydrocyclopenta [c] pyrrole-2 (lH) -lproproxy) benzamide oxalate The experimental procedure is identical to Example 21, using the compound of Example 1 as starting material. Elemental microanalysis: c% H% N% Calculated: 60. 30 6. 93 7. 40 Found: 60. 21 6. 65 7. 31 EXAMPLE 23: 4- [(3-Hexahydrocyclopenta [c] pyrrol-2 (1H) -ylpropyl) aminojbenzamide oxalate The experimental procedure is identical to Example 21, using the compound of Example 19 as starting material.

EXAMPLE 24: 4- [(2-Hexahydrocyclopenta [c] pyrrol-2 (1H) -ethyl) aminoj-benzamide oxalate The experimental procedure is identical to Example 21, using the compound of Example 20 as starting material.

EXAMPLE 25: N- oxalate. { 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (ÍH) -yl) propoxy] phenyl} -2-methylpropanamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with 2-methylpropanoyl chloride. Elementary Microanalysis C% H% N% Calculated: 61. 20 7. 66 6. 45 Found: 61. 32 7. 47 6.24 EXAMPLE 26: N-. { 4- [3 (Hexahydrocyclopent [c] pyrrole-2 (1H) -yl) propoxy] phenyl} -2,2-dimethylpropanamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with 2, 2-dimethylpropanoyl chloride. Elemental Microanalysis C% H% N% Calculated: 73. 22 9. 36 8. 13 Found: 73. 69 9. 33 8. 20 EXAMPLE 27: N-. { 4- [3 (Hexahydrocyclopenta [c] irrol-2 (1H) -yl) propoxy] phenyl] cyclopropanecarboxamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with cyclopropanecarbonyl chloride. Elemental Microanalysis C% H% N% Calculated: 73.14 8.59 8.53 Found: 72.04 8.67 8.31 EXAMPLE 28: N-. { 4- [3 (Hexahydrocyclopenta [c] pyrrol-2 (1 H) -yl) propoxy] phenyl} Cyclobutanecarboxamide • > The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with cyclobutanecarbonyl chloride. Elemental Microanalysis c * H% N% Calculated: 73.65 8.83 8.18 Found: 73.24 8.68 8.12 EXAMPLE 29: N-. { 4- [3 (Hexahydrocyclopenta [c] pyrrol-2 (1H) -yl) ropoxy] phenyl} Cyclohexanecarboxamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with cyclohexanecarbonyl chloride.

Elemental Microanalysis C% H% N Calculated: 74. 56 9. 25 7. 56 Found: 74. 20 9. 38 7. 40 '5 EXAMPLE 30: N-. { 4- [3 (Hexahydrocyclopenta [c] pyrrol-2 (1 H) -yl) propoxy] phenyl} -4-nitrobenzamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride 10 in Step 2 with 4-nitrobenzoyl chloride. Elemental microanalysis C 'or H% N% Calculated: 67. 46 6. 65 10. 26 Found: 68. 18 6. 60 10. 31 15 • "EXAMPLE 31: N- { 4- [3 (-Hexahciclopenta [ c] pyrrole 2 (HH) -yl) propoxy] phenyl.}. 4-fluorobenzamide Step 1: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (HH) -yl) propoxy] aniline The title compound is obtained by acid hydrolysis of 1.5 g of the compound of Example 4 by refluxing in 6? hydrochloric acid. The mixture is then concentrated and basified in 20 ml of water and 10 ml of sodium hydroxide solution 1? and subsequently extracted with dichloromethane A white solid is obtained by concentrating the organic phase (1.08 g).

Step 2: N-. { 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (1 H) -yl) propoxy] phenyl} -4-fluorobenzamide 0.24 g (ImM) of the compound synthesized in the previous step are dissolved in 2.5 ml of anhydrous tetrahydrofuran and then cooled in an ice bath. Drill, in succession, 0.21 ml (1.5 mM) of triethylamine and 0.26 g (1 mM) of 4-fluoro-benzoyl chloride. The mixture is kept in an ice bath, with stirring, and then left at room temperature, with stirring, for 16 h. the solution is diluted with ethyl acetate and extracted with sodium hydroxide solution (6N), washed with water and then dried over magnesium sulfate and concentrated. The product of the title can be obtained in a for. of oxalate by recrystallization from ethanol (see Step 2 of Example 18).

My croaná lisis Elemen tal C% H% N% Calculated: 72. 23 7. 12 7. 32 Found: 72. 26 7. 10 7. 34 EXAMPLE 32: N-. { 4- [3 (Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) ropoxy] phenyl} -2-fluorobenzamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with 2-fluorobenzoyl chloride. Elementary Microanalysis C ~ s H s N ~ $ Calculated: 72.23 7.12 7.32 Found: 72.01 7.03 7.28 EXAMPLE 33: N-. { 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (ÍH) -yl) propoxy] phenyl} -2,4-difluorobenzamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with 2,4-difluorobenzoyl chloride. Elemental Microanalysis C% H% N% Calculated: 68.98 6.54 7.00 Found: 69.02 6.72 6.99 EXAMPLE 34: N-. { 4- [3 (Hexahydrocyclopenta [c] pyrrol-2 (1 H) -yl) propoxy] phenyl} -4-trifluoromethylbenzamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with 4-trifluoromethylbenzoyl chloride.

Elemental Microanalysis C% H% N% Calculated: 66.65 6.29 6.48 Found: 66.64 6.39 6.51 EXAMPLE 35: N-. { 4- [3 (Hexahydrocyclopenta [c] pyrrol-2 (ÍH) -yl) propoxy] phenyl} -2-trifluoromethylbenzamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with 2-trifluoromethylbenzoyl chloride. Elemental Microanalysis c% H% N% Calculated: 66.65 6.29 6.48 Found: 66.36 6.34 6.36 EXAMPLE 36: N- oxalate. { 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) ropoxy] phenyl} -4-methoxybenzamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with 4-methoxybenzoyl chloride. Elemental Microanalysis C% H% N% '. Calculated: 64.45 6.66 5.78 Found: 64.57 6.65 5.78 EXAMPLE 37: N-. { 4- [3 (Hexahydrocyclopenta [c] pyrrolo-2 (1H) -yl) propoxy] phenyl} -2-Naph Amide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzyl chloride in Step 2 with 2-naphthoyl chloride. Elemental Microanalysis c% H% N% Calculated: 78.23 7.29 6.76 Found: 78.36 7.26 6.81 EXAMPLE 38: N- oxalate. { 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (lH) -yl) ropoxy] phenyl} -1-naph amide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with 1-naphthoyl chloride. Elementary Microanalysis c% H% N% Calculated: 69.03 6.39 5.55 Found. 68.57 6.33 5.68 EXAMPLE 39: N-. { 4- [3 (Hexahydrocyclopenta [c] pyrrol-2 (ÍH) -yl) propoxy] phenyl} -2-furancarboxamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with 2-furoyl chloride.

Elemental Microanalysis C% H% N% Calculated: 71.16 7.39 7.90 Found: 70.90 7.44 7.87 EXAMPLE 40: N-. { 4- [3 (Hexahydrocyclopenta [c] irrol-2 (lfl) -yl) ropoxy] phenyl} -2-thiophenecarboxamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with 2-tenoyl chloride. Elemental Microanalysis C% H% N%, S% Calculated: 68.08 7.07 7.56 8.65 Found: 68.21 7.09 7.50 8.52 EXAMPLE 41: N-. { 4- [3 (Hexahydrocyclopenta [c] pyrrol-2 (ÍH) -yl) propoxy] phenyl} isonicotinamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with isonicotinoyl chloride. Elemental microanalysis C% H% N% Calculated: 7722..3300 77..4455 11.50 Found: 7722..6633 77..5577 11.44 EXAMPLE 42: N-. { 4- [3 (Hexahydrocyclopent [c] pyrrol-2 (1H) -yl) ropoxy] phenyl} -2-benzo [b] thiophene-3-carboxamide • The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with benzo [b] thiophene-3-carbonium chloride. Elementary Microanalysis C% H% N% S% Calculated: 71.40 6.71 6.66 7.62 Found: 71.00 6.89 6.57 7.41 EXAMPLE 43: N-. { 4- [3 (Hexahydrocyclopent [c] pyrrole-2 (1H) -yl) ropoxy] phenyl} -2-phenylacetamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with phenylacetyl chloride. Elemental Microanalysis C% H% N% - Calculated: 76.16 7.99 7.40 Found: 76.33 8.00 7.26 EXAMPLE 44: N- oxalate. { 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (ÍH) -yl) propoxy] phenyl} -2 (3, 4-dimethoxyphenyl) acetamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with (3,4-dimethoxyphenyl) acetyl chloride.- Elemental Microanalysis C -ff H s N s Calculated: 63.62 6.86 5.30 Found: 63.32 6.72 5.22 EXAMPLE 45: N-. { 4- [3 (Hexahydrocyclopenta [c] pyrrol-2 (1 H) -yl) propoxy] phenyl} -2 (2-thienyl) cetamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with (2-thienyl) acetyl chloride. Elemental Microanalysis C s H s N s S -o Calculated: 68.72 7.34 7.28 8.34 Found: 68.57 7.45 7.20 8.92 '.

EXAMPLE 46: N- oxalate. { 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) ropoxy] phenyl} -2, 2-diphenylacetamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with diphenylacetyl chloride. Elemental Microanalysis C ~ s H ~ s N s Calculated: 70.57 6.66 5.14 Found: 70.15 6.72 5.18 EXAMPLE 47: N- oxalate. { 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) ropoxy] phenyl} -3-phenylpropanamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride 5 in Step 2 with 3-phenylpropanoyl chloride. Elemental microanalysis C% H% N% Calculated: 67. 20 7. 10 5. 80 Found: 66. 85 7. 14 5. 74 10 EXAMPLE 48: N- oxalate. { 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (ÍH) -yl) propoxy] phenyl} -2-oxyacetamide The experimental procedure is identical to Example 31, with replacement of 4-fluorobenzoyl chloride 15. in Step 2 with methoxyacetyl chloride. Elemental Microanalysis C% H% N% Calculated: 56. 96 6. 98 6. 09 Found: 57. 28 6. 77 6. 05 20. * • EXAMPLE 49: N'-. { 4- [3- (Hexahydrocyclopent [c] pyrrole-2 (1H) -yl) propoxy] phenyl} -N, N-dimethylurea The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride 5 in Step 2 with dimethylamine chloride.

Elemental Microanalysis c% H% N% Calculated: 68.85 8.82 12.68 Found-, 68.84 9.09 12.29 EXAMPLE 50: N-. { 4- [3 (Hexahydrocyclopenta [c] pyrrol-2 (ÍH) -yl) propoxy] phenyl} -4-morpholinecarboxamide The experimental procedure is identical to Example 31, with the replacement of 4-fluorobenzoyl chloride in Step 2 with 4-morpholinecarbonyl chloride. Elemental Microanalysis C% H% N% Calculated: 67.53 8.37 11.25 Found: 67.67 8.67 11.41 EXAMPLE 51: 4- [3- (Hexahydrocyclopenta-oxalate. [c] pyrrole-2 (HH) -yl) ropoxy] -? - phenylbenzamide The experimental procedure is identical to Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4-hydroxy-N-phenylbenzamide. Elemental Microanalysis C% H% N% Calculated: 75.79 7.74 7.69 Found: 75.46 7.82 7.60 EXAMPLE 52: 4- [3-Hexahydrocyclopenta [c] pyrrole-2 (lfl) -yl) ropoxy] -N- (4-fluorophenyl) benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in the. Step 1 with N- (4-fluorophenyl) -4-hydroxybenzamide. Elemental microanalysis: C% H% N% Calculated: 7-2. 23 7. 12 7. 32 Found: 71. 85 7. 23 7. 31 EXAMPLE 53: 4- [3-Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) propoxy] -N- (1,3-benzodioxol-5-yl) benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (1,3-benzodioxol-5-yl) -4-hydroxybenzamide. Elemental microanalysis: C% H% N% Calculated: 70.57 6. 91 6. 86 Found ': 70. 46 7. 06 7. 08 EXAMPLE 54: 4- [3-Hexahydrocyclopenta [c] pyrrole-2 (IfI) -yl) propoxy] -N-cyclohexylbenzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile n Step 1 with N-cyclohexyl-4-hydroxybenzamide Elemental microanalysis: C% H% N% Calculated: 74.56 9.25 7.56 Found: 74.11 9.30 7.36 EXAMPLE 55: 4- [3-Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) ropoxy] -N-methyl-N-cyclohexylbenzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N-methyl-N-cyclohexyl-4-hydroxybenzamide. Elemental microanalysis: C% H% N% Calculated: 65.80 8.07 5.9 Found: 65.06 7.64 6.07 EXAMPLE 56: 4- [3-Hexahydrocyclopenta] oxalate. [c] pyrrol-2 (lfl) -yl) propoxy] -N, N-dicyclohexylbenzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with Air / iv'-dicyclohexyl-4 -hydroxybenzamide.

Elemental microanalysis: C% H% N% '' • Calculated: 76.95 9.80 6.19 Found: 76.23 9.86 6.11 EXAMPLE 57: 2- [3- [4- (1-Piperidyl-carbonyl) phenoxy] propyl oxalate} Octahydrocyclopenta [c] pyrrole The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4-piperidinocarbonylphenol. Elemental microanalysis: C% H% N% Calculated: 61.09 7.18 5.70 Found: 61.05 7.33 5.60 EXAMPLE 58: Dioxalate of l-. { 4- [3 (Hexahydrocyclopenta [c] pyrrol-2 (ÍH) il) propoxy] benzoyl} -1,2,3,4-tetrahydroquinoline The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (3,4-dihydro, 1 (2H) -quinolylcarbonyl) phenol.

Elemental microanalysis C% H% N% Calculated: 63.33 6.40 5.72 Found: 63.47 '6.61 5.16 EXAMPLE 59: 2- [3- (4- [Piperidino piperidinocarbonylphenoxy) propyl] octahydrocyclopenta [c] irrol dioxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4-piperidinopiperidinocarbonylphenol. '". Elemental microanalysis: C% H% N% Calculated: 57.82 6.98 6.32 Found: 57.51 7.17 6.27 EXAMPLE 60: dioxalate of 2- [3-. { 4- [(4-Methyl-l-piperazinyl) carbonyl] phenoxy} propyl) octahydrocyclopenta [c] pyrrole The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- [(4-methyl-1-piperazinyl) carbonyl] phenol. 'Elementary microanalysis.

C% H% N% Calculated: 54.45 6.26 7.06 Found: 54.82 6.51 7.00 EXAMPLE 61: 2- (3-. {4 - [(4-Benzyl-l-piperazinyl) carbonyl] phenoxy].? Ropil) octahydrocyclopenta [c] pyrrole oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- [(4-benzyl-l-piperazinyl) carbonyl] phenol '. Elemental microanalysis: C% H% N% Calculated: 56.90 6.04 5.85 Found: 58.55 6.39 - 6.43 EXAMPLE 62: 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1-yl) -yl) propoxy] -N- (1-benzylpiperidino) benzamide The experimental procedure is identical. to the Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (1-benzylpiperidino) -4-hydroxybenzamide.- J Elemental microanalysis.

C% H% N% Calculated: 75.45 8.52 9.10 Found: 75.36 8.52 9.07 EXAMPLE 63: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (IfI) -yl) propoxy] -N- (cyclopropylmethyl) benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile. 'in Step 1 with N- (cyclopropylmethyl) -4-hydroxybenzamide. Elemental microanalysis: ': C% H% N% Calculated: 73.65 8.83 8.18 Found: 72.99 8.92 8.80 EXAMPLE 64: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (lfl) -yl) propoxy] -N-benzylbenzamide oxalate The experimental procedure is identical to that of the Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N-benzyl-hydroxybenzamide.

Elemental microanalysis:. • _ ' C% H% N% "'. - -. Calculated: 76.16 7.99 7. 0 Y -!" Found: 76.20 8.06 7.41: EXAMPLE 65: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (IfI) -yl) propoxy] -N-benzyl-N-methylbenzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N-benzyl-N-methyl-4-hydroxybenzamide Elemental microanalysis: C% H% N%. Calculated: 67.20 7.10 5.80 Found: 66.85 7.17 5.82 EXAMPLE 66: 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) propoxy] -N-benzyl-N- (4-methoxyphenyl) benzamide oxalate The experimental procedure is identical to the Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N-benzyl-N- (4-methoxyphenyl) -4-hydroxybenzamide.

Elemental microanalysis: C% H% N% Calculated: 68.97 6.66 4.87 Found: 68.18 6.50 4.86 EXAMPLE 67: 4- [3- (Hexahydrocyclopenta [c] -pyr ol-r 2 (lfí) -yl) propoxy] -N- (4-methylbenzyl) enzamide " The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (4-methylbenzyl) -4-hydroxybenzamide. Elemental microanalysis: C% H% N% Calculated: 76.50 8.22 7.14 Found: 76.28 8.19 7.06 EXAMPLE 68: 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1-yl) -yl) ropoxy] -N- (3-methylbenzyl) benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (3-methylbenzyl) -4-hydroxybenzamide.

Elementary microanalysis C% H% N% Calculated: 76.50 8, .22 7.14 Found: 76.01 8. .31 6.96 EXAMPLE 69: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (IH) -yl) propoxy] -N- (3-methylbenzyl) benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (2-methylbenzyl) -4-hydroxybenzamide. Elemental microanalysis: C% H% N% Calculated: 76.50 8.22 7.14 Found: 76.38 8.32 7.05 EXAMPLE 70: 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1-yl) -yl) propoxy] -N- (4-trifluoromethylbenzyl) benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (4-trifluoromethylbenzyl) -4-hydroxybenzamide.

Elementary microanalysis C% H% N% Calculated: 67.25 6.55 6.27 Found: 67.24 6.47 6.23 EXAMPLE 71: 4- [3- (Hexahydrocyclopenta [cJ Irrol-2 (lfl) -yl) propoxy] -N- (3-trifluoromethylbenzyl) benzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of hydroxybenzoritrile in Step 1 with N- (3-trifluoromethylbenzyl) -4-hydroxybenzamide. Elemental microanalysis: C% H% N% Calculated: 60.44 5.82 5.22 - • '. Found: 59.40 5.77 5.07 '' EXAMPLE 72: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (1-yl) -yl) propoxy] -N- (4-pyridylmethyl) benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile . in Step 1 with N- (4-pyridylmethyl) -4-hydroxybenzamide.

Elemental microanalysis: C% H% N% _ * ' Calculated: 72.79 7.70 11.07 Found: 72.11 7.56 10.81 - EXAMPLE 73: 4- [3- (Hexahydrocyclopenta [cjpyrrol-2 (lf) -yl) propoxy] -N-furfurylbenzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- furfuryl-4-hydroxybenzamide. Elemental microanalysis: '"- C% H% N% Calculated: 71.71 7.66 7.60 Found: 70.68 7.77 7.56 EXAMPLE 74: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (1-yl) -yl) propoxy] -N- [2 (2-thienyl) ethyl] benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- [2- (2-thienylmethyl) ethyl] -4-hydroxybenzamide: Elemental microanalysis: C% H% N% S% '"Calculated: 69.31 7.59 7.03. 8.05 Found:' 69.28 7.63 6.89 8.01 EXAMPLE 75: 4- [3- (Hexahydrocyclopent [c] pyrrole-2 (1-yl) -yl) -ropoxy] -N- (3, 4-dimethoxyphenethyl) benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4 -hydroxybenzonitrile in Step 1 with N- (3,4-dimethoxyphenethyl) -4-hydroxybenzamide. Elemental microanalysis:.

C% H% N% Calculated: 71.65 8.02 6.19 Found: '71.80 8.09 6.16 EXAMPLE 76: 4- [3- (Hexahydrocyclopenta [c] irrol-2 (lf) -yl) propoxy] -N- [2- (1-piperidyl) ethyl] benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- [2- (1-piperidyl) ethyl] -4-hydroxybenzamide .. XE? MR (DMS0D6): d (ppm): 1.20-1.75 (m , 12H); 1.90 (quint, 2H); 2.15 (m, 2H); 2.30-2.50 (, 8H); 2.60 (m, 4H); 3.55 (quad, 2H); 4.05 (t, 4H); 7.00 (d, 2H); 7.80 (d, 2H); 8.20 (t, lH).

EXAMPLE 77: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (ÍH) -yl) propoxy] -N- (2-morpholinoethyl) benzamide. . The experimental procedure is identical to .del * Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (2-morpholinoethyl) -4-hydroxybenzamide. Elemental microanalysis: C% H% N% Calculated: 68. 80 8. 79 10. 46 Found: 68. 62 8. 84 10. 34 EXAMPLE 78: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (1-yl) yl) propoxy] -N- [3- (1H-imidazol-1-yl) ropil dioxalate} benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- [3- (li-imidazol-1-yl) propyl] -4-hydroxybenzamide. Elemental microanalysis: C% H% N% Calculated: 56. 24 6. 29 9. 72 Found: 55. 99 6. 44 9. 60 EXAMPLE 79: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (Ifi) -il) Ropoxy] -N- (2-phenoxyethyl) enzamide. The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (2-phenoxyethyl) -4-hydroxybenzamide. Elemental microanalysis: C% H% N% • Calculated: 73.50 7.89 6.86 Found: 72.76 7.82 6.85 EXAMPLE 80: 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (IfI) -yl) propoxy] -N- (2-methoxyethyl) benzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (2-methoxyethyl) -4-hydroxybenzamide. Elemental microanalysis: C% H% N% Calculated: 60.54 7.39 6.42 Found: '61.07 7.54 6.49 EXAMPLE 81: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (1-yl) yl) propoxy] -N- [2-methoxy-1- (methoxymethyl) ethyl] benzamide oxalate The experimental procedure is identical to that of Example 1 , with the replacement of 4-hydroxybenzonitrile in Step 1 with N- [2-methoxy-1- (ethoxymethyl) ethyl] -4-hydroxybenzamide. Elemental microanalysis: C% H% N% Calculated: 59.99 7.55 5.83 Found: 59.54 7.44 5.60 EXAMPLE 82: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (lH) -yl) propoxy] -N- (tert-butoxy) benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (tert-butoxy) -4-hydroxybenzamide.

Elemental Microanalysis C% H% N% Calculated: 69.97 8.95 7.77 Found: 70.05 9.00 7.69 EXAMPLE 83: 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) ropoxy] -N- (2-ethylbutyl) benzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4 -hydroxybenzonitrile in Step 1 with? - (2-ethylbutyl) -4-hydroxybenzamide.

Elemental Microanalysis C% H% N% Calculated: 64.91 8.28 6.06 Found: 64.93 8.38 6.00 EXAMPLE 84: 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) propoxy] -N-isopropylbenzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in. Step 1 with? -isopropyl-4-hydroxybenzamide. Elementary Microanalysis C% H% N% - '' Calculated: 72.69 9.15 8.48 Found: 73.10 9.36 8.54 EXAMPLE 85: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (1H) -yl) propoxy] -N- (tert-butyl) benzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N- (tert-butyl) -4-hydroxybenzamide. Elemental Microanalysis C% H% N% Calculated: 63.57 7.89 6.45 Found: 63.82 8.12 6.32 EXAMPLE 86: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (1H) -yl) propoxy] -N-propylbenzamide oxalate The procedure experimental is identical to. of Example 1, with the replacement of 4-hydroxybenzonitrile, in Step 1 with N-propyl-4-hydroxybenzamide. Elemental Microanalysis - "- C% H% N% Calculated: 62. 84 7. 67 6. 66 Found: 63. 24 8. 09 6. 58 EXAMPLE 87: 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) propoxy] -N, N-dimethylbenzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N, N-dimethyl-4-hydroxybenzamide. Elemental Microanalysis C% H% N% Calculated: 58. 53 6. 92 6. 20 Found: 58. 51 6. 99 6. 09 EXAMPLE 88: 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) propoxy] -N, N-dipropylbenzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N, N-dipropyl-4-hydroxybenzamide.

Elemental Microanalysis C% H or, N%. Calculated: 64.91 8. .28 6.06 Found: 64.73 8. 39 5.94 EXAMPLE 89: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (1H) -yl) propoxy] -N-ethyl-N-methylbenzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of hydroxybenzonitrile in Step 1 with N-ethyl-N-methyl-4-hydroxybenzamide. Elemental microanalysis C% H% N% Calculated: 59.34 7.15 6.02 Found: 59.26 7.16 5.91 15 EXAMPLE 90: 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (IH) -yl) ropoxy] -N-propyl- oxalate ? -methylbenzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile at Step 1 with I? J-propyl-N-methyl-4-hydroxybenzamide. Elemental microanalysis C% H% N% Calculated: 63.57 7.89 6.45 Found: 63.62 8.11 6.38 25 EXAMPLE 91: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (IH) -yl) propoxy] -N-isopropyl- oxalate N-methylbenzamide The experimental procedure is identical to. of Example 1, with the replacement of 4-hydroxybenzonitrile in. Step 1 with N-isopropyl-N-methyl-4-hydroxybenzamide. Elemental Microanalysis C% H% N% Calculated: 63. 57 7. 89 6. 45 Found: 63. 95 8. 30 6. 37 EXAMPLE 92: 4- [3- (Hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) propoxy] -N- (tert-butyl) -N-methylbenzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile 'in Step 1 with N- (tert-butyl) -N-methyl-4-hydroxybenzamide. Elemental Microanalysis C% H% N% Calculated: 64. 26 8. 09 6. 25 Found: 63. 81 8. 10 6. 20 EXAMPLE 93: 4- [3- (Hexahydrocyclopenta [c] irrol-2 (1H) -yl) propoxy] -N-methylbenzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with N-methyl-4-hydroxybenzamide.

Elementary Microanalysis C% H% N% Calculated: 71. 49 8. 67 9. 26 Found: 71. 35 8. 85 9. 18 EXAMPLE 94: 4- [3- (Hexahydrocyclopenta [c] pyrrol-2 (lH) -yl) propoxy] -3-bromobenzamide oxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4-hydroxy-3-bromobenzamide. ESI +: [M + H] + 367.1031 (theoretical: 367.1021) EXAMPLE 95: Dioxalate of 2-. { 3- [4- (lH-imidazol-1-yl) phenoxy] propyl} octahydrocyclopenta [c] pyrrole The experimental procedure is identical to that of the Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (1J-imidazol-1-yl) phenol. Elemental Microanalysis C% H% N% - X Calculated: 55. 68 5. 88 8. 40 Found: 55. 81 5. 57 8. 51 EXAMPLE 96: oxalate of 2 ~. { 3- [4- (1-l, 2, 4-triazol- -yl) phenoxy] ropil} Octahydrocyclopenta [c] pyrrolo The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (li? -1, 2,4-triazol-1-yl) phenol. Elemental Microanalysis C% H% N%. Calculated: 59.69 6.51 13.92 '' Found: 58.83 6.39 13.35 EXAMPLE 97: N- [4- (3-Hexahydrocyclo-penta [c] pyrrole-2 (IfI) -propropoxy) phenyl] -N (2-pyrimidinyl) amine oxalate The experimental procedure is identical to that of the Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (2-pyrimidinylamino) phenol. - .. Elemental Microanalysis C% H% N% Calculated: 59.92 6.37 12.42. . Found: 59.43 6.47 11.67 ' EXAMPLE 98:? - [4- (3-Hexahydrocyclo-penta [c] pyrrole-2 (1-yl) -propropoxy) phenyl] -2-quinolyl-amine dioxalate The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (2-quinolylamino) phenol. Microanalysis- Elementary C% H% N% Calculated: 61.37 5.86 7.40 3 Found: 61 49 6. 02 7. 32 - '. "'', EXAMPLE 99: N- [4- (3-Hexahydrocyclopenta [c] pyrrol-2 (l- y) -proproxy) phenyl] -1-isoquinolyl amine The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (1-isoquinolylamino) phenol. Elemental Microanalysis C% H% N% Calculated: 77. 49 7. 54 10. 84 Found: 76. 81 7. 68 10. 68 EXAMPLE 100: N- [4- (3-Hexahydrocyclopenta [c] pyrrole-2 (1-yl) -propropoxy) phenyl] -9-pyrim-6-ylamine The experimental procedure is identical to that of the Example 1, with the replacement of 4-hydroxybenzonitrile in Step 1 with 4- (9f-purin-6-ylamino) phenol. Elementary Microanalysis C% H o. "or N% Calculated: 66. 64 6. 92 22. 20 Found: 66. 84 7. 03 21 .81 EXAMPLE 101: 4- (3-Octahydro-2 (lfl) -isoquinolyl-propoxy) benzonitrile The experimental procedure is identical to that of Example 1, with the replacement of octahydrocyclopenta [c] pyrrole in Step 2 with decahydroisoquinoline. The decahydroisoquinoline was synthesized according to the iktop method. B (J. Am. Chem. Soc., 1948, 70, 2617). Elemental Microanalysis C% H% N% Calculated: 64.93 7.27 7.21 Found: 63.93 7.03 7.01 EXAMPLE 102: 4- (3-Octahydro-2H-isoindol-2-ylpropoxy) benzonitrile oxalate The experimental procedure is identical to that of Example 1, with the replacement of octahydrocyclopenta [c] pyrrole in Step 2 with octahydroisoindole. Octahydroisoindole was synthesized according to the method of Matsuki et al.

(Chem. Pharm. Bull, 1994, 42 (1), 9-18). Elemental Microanalysis C% H% N% Calculated: 64.15 7.00 7.48 Found: 63.86 6.89 7.55 EXAMPLE 103: 4- (4-Octahydro-2 (lfl) -isoquinolylbutoxy) benzonitrile oxalate The experimental procedure is identical to that of Example 3, with the replacement of octahydrocyclopenta [c] pyrrole in Step 2 with decahydroisoquinoline. . ". ' Elemental Microanalysis '•' ".. C% H% N% '"' .-. Calculated: 68. 98 7. 29. 6. 66 Found: 64. 54 7. 25 6 .. 73 EXAMPLE 104: 4- (3-Octahydro-2-fluoro-isoindol-2-ylpropoxy) benzamide Step 1: 4- (3-Octahydro-2H-isoindol-2-ylpropoxy) benzonitrile The experimental procedure is identical to that of Example 1, with the replacement of octahydrocyclopenta [c] pyrrole in Step 2 with octahydroisoindole. . • Step 2: 4- (3-octahydro-2H-isoindol-2-propoxy) benzamide The experimental procedure is identical to that of Example 21, with the replacement of the compound of Example 18 with the compound of the previous Step. ESI *: [M + H] + 303. 2072 (theoretical: 303. 2073) EXAMPLE 105: N-Methyl-4- (3-octahydro-2-fluoro-isoindol-2-propoxy) benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile with N-methyl-4-hydroxybenzamide in the Step 1, and octahydrocyclopenta [c] pyrrole with octahydroisoindole in Step 2. "ESI *: [M + E] + 31 7. 2240 (theoretical: 31 7. 2229) EXAMPLE 106: N, N-Dimethyl-4 (3-octahydro-2-fluoro-isoindol-2-propoxy) benzamide The experimental procedure is identical to that of Example 1, with the replacement of 4-hydroxybenzonitrile with N, N-dimethyl- 4-hydroxybenzamide in Step 1, and octahydro-cyclopenta [c] pyrrole with octahydroisoindole in Step 2. Elemental Microanalysis C% H% N% Calculated: 72. 69 9. 15 8. 48 Found: 72. 25 9. 21 8. 37 PHARMACOLOGICAL STUDIES OF THE COMPOUNDS OF THE INVENTION "EXAMPLE A: Brain doses of? ^ Methylhistamine in the mouse RM? I The main purpose of this study, carried out according to the method of Taylor et al. (Biochem. Pharm., 1992 , 4_4, 1261-1267), is to evaluate the ex vivo activity of the compounds of the present invention, as antagonists of the H3 central histaminergic receptor.That activity is revealed by measuring the central levels of? T-Methylhistamine, the main metabolite of histamine, after oral administration of the compounds that are being studied, an increase in the "brain concentrations of Nt-methylhistamine means an increase in histamine turnover due to the blockade of central histaminergic receptors of the H3 group . The RMNI mice (18-20 g) are treated via oral administration with the compounds of the present invention or with their support (20 ml / kg). Two hours after drug treatment, the animals are sacrificed, the brains are removed, frozen in liquid nitrogen, weighed and homogenized in HC10 0'1 N'- at 4 ° C. The homogenates are centrifuged (15000 g, 17. min, 4CC). The supernatants are recovered and divided into aliquots. The aliquots are frozen in liquid nitrogen and stored at -80 ° C until analysis. The determination of brain levels of Nt-Methylhistamine is carried out by capillary electrophoresis coupled with laser-induced fluorescence detection (J. Chroma Togr. A., 1996, 755, 99-115). The tissue levels of Nt-Methylhistamine are expressed in ng / g 'of fresh brain. The comparison between the brain levels of Nt-Methylhistamine of the animals treated 'with' the support (control) and the animals treated with the compounds of the present invention (n = 5 / group) is carried out by an analysis of variance of a single factor followed, if necessary, by a complementary analysis (Dunnett's test). The results show that, at doses of 3 to 10 mg / kg p.o., the compounds of the present invention are. able to increase the endogenous brain concentrations of Nt-Methylhistamine by more than 50%. By way of example, at a dose of 3 mg / kg, the compounds of Examples-4, 22 and 93 increase the endogenous brain concentrations of Nt-Methylhistamine by 52%, 33% and 90%, respectively, and, a a dose of 10 mg / kg po, the compound of Example 22 increases the endogenous brain concentrations of Nt-Methylhistamine to I 85%. These results demonstrate that the results of the present invention are potent activators of the central histaminergic systems and are active via the oral route with a duration of action of at least several hours. '•': -. EXAMPLE B: Pharmaceutical compositions The formulation for the preparation of 1000 tablets each of which contains a dose of 100 mg: compound of Example 22 100g hydroxypropyl cellulose 20g polyvinylpyrrolidone. ~ ..20g wheat starch 150g • lactose 900g magnesium stearate, ...: 30g

Claims (36)

1. CLAIMS 1. Compounds of formula (I) where: myn, which can be the same or different, each represent an integer from 0 to 2 inclusive, with the sum of the two integers being from 2 to 3 inclusive, -pyq, which can be., identical or different, each represents an integer of '0 to 2 inclusive, • alq represents a chain of alkylene, alkenylene or alkynylene, and Y which may be identical or different, each representing a hydrogen atom, a halogen atom or a group alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, mercapto, hydroxy, perhaloalkyl, nitro, amino (unsubstituted or substituted by one or two alkyl groups), acyl, aminocarbonyl (optionally substituted on the nitrogen atom by one or two) alkyl groups), 'acylamino (optionally substituted on the nitrogen atom by an alkyl group), alkoxycarbonyl, carboxy, sulfo or cyano, • X represents an oxygen atom, a sulfur atom or a group -N (R) - where R represents a hydrogen atom or an alkyl group, represents a group selected from cyano (when X represents an oxygen atom or a group NR), -N (R?) - Z? -R2 and -Z2-NR? R2, where : - Zi represents -C (O) -, -C (S) -, -C (NR4) -, '* -C (O) - N (R3)) -, * -C (S) -N (R3 ) -, * -C (NR4) -N (R3) -, * -C (0) -0-, * -C (SJ- 0- or -S (0) r-, in which r = 1 or 2 and * corresponding to the union to N (R1), - Z2 represents -C (0) -, -C (S) -, -C (NR4) -, -S (0) r- or a bond, - Ri , R2, R3 and R, which may be identical or different, each represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group,. an optionally substituted alkynyl group, an alkoxy group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, - or Ri and R2 or R2 and R3, together with the atom or atoms which contain them, form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl group, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases, wherein: the term "alkyl" denotes a chain - linear or branched hydrocarbon containing 1'-. to 6 carbon atoms, - the term "alkenyl" denotes a straight or branched group containing from 3 to 6 carbon atoms and from 1 to 3 double bonds, - the term "alkynyl" denotes a straight or branched group which contains from 3 to 6. carbon atoms and from 1 to 3 triple bonds, - the term "alkoxy" denotes an alkyloxy group in which the linear or branched alkyl chain containing from 1 to 6 carbon atoms, - the expression "optionally substituted aryloxy" denotes a group of which the aryl group is optionally substituted, - the term "acyl" denotes a group RaC (0) in which Ra represents a hydrogen atom or an alkyl group, ".-- the term perhaloalkyl denotes a linear or branched chain of carbon containing 1 to 3 carbon atoms and 1 to 7 halogen atoms, the term "alkylene" denotes a linear or branched bivalent radical containing 1 carbon atom. to 6 carbon atoms, - the term "alkenylene" denotes a bivalent radical linear or branched containing 2 to 6 carbon atoms and -1 to 3 double bonds, - the term "alkynylene" denotes a linear or branched bivalent radical containing. to 6 carbon atoms and from 1 to 3 triple bonds, the term "aryl" denotes a phenyl, naphthyl, indanyl indenyl, dihydronaphthyl or tetrahydronaphthyl group, the term "heteroaryl" denotes a monocyclic or bicyclic group in which at least one of the rings is aromatic, containing the group of 5 to 11 members in the ring and giving; 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, the term "cycloalkyl" denotes a monocycle or hydrocarbon bicyclo containing from 3 to 11 carbon atoms and optionally unsaturated by 1 or 2 unsaturated bonds, - the term "heterocycloalkyl" denotes a mono- or bicyclic group, saturated or unsaturated by 1 or 2 unsaturated bonds, containing from 4 to 11 members in the. ring and having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, - the term "optionally substituted" applied to the terms cycloalkyl, aryl, heteroaryl and heterocycloalkyl denotes i) those groups, which may be substituted by 1 to 3 substituents identical substituents selected from alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halogen, hydroxy, mercapto, perhaloalkyl, nitro, amino (unsubstituted or substituted by one or two alkyl groups), acyl, aminocarbonyl (optionally substituted on the nitrogen atom) by one or two alkyl groups), alkylamino (optionally substituted on the nitrogen atom by an alkyl group), alkoxycarbonyl, carboxy, sulfa and cyano; or ii) that those groups may be substituted by an aryl, heteroaryl, cycloalkyl, heterocycloalkyl or benzyl group; it being understood that the aryl or heteroaryl groups may further be substituted by one or two oxo groups on the non-aromatic portion of a group having both non-aromatic and aromatic portions- and that the cycloalkyl and heterocycloalkyld groups. Alternatively, they may be substituted by one or two groups, oxo, the term "optionally substituted" applied to the term "alkyl, alkenyl or alkynyl denotes that those groups may be substituted by one or two identical or different groups selected from alkylthio. , alkylsuifinyl, alkylsulfonyl, alkoxy, halogen, hydroxy, mercapto, nitro, amino, acyl, aminocarbonyl, acylamino, alkoxycarbonyl, carboxy, sulfo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and aryloxy optionally 2. Compounds of formula (1) according to claim 1, wherein q is 1, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases 3. Compounds of formula (I) ) according to claim 1 or 2, wherein n is 1, its enantiomers-, diastereoisomers, and also salts thereof. ion thereof with one or more pharmaceutically acceptable acids or bases. 4. Compounds of formula (I) according to one of claims 1 to 3, wherein m is 1, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 5. Compounds of formula (I) according to one. of claims 1 to 3, wherein m is 2, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 6. Compounds of formula (I) according to one of claims 1 to 5, wherein p is 1, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 7. Compounds of formula (I) according to one of claims 1 to 5, wherein p is 2, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 8. Compounds of formula (I) according to one of claims 1 to 7, wherein X represents an oxygen atom or a sulfur atom, its enantiomers, diastereoisomers, and also addition salts thereof with one or more acids or pharmaceutically acceptable bases. 9. Compounds of formula (I) according to one. of claims 1 to 7, wherein X represents a group -N (R) -, their enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acid or o-bases. 10. Compounds of formula (I) according to one. from . claims 1 to 9, wherein Y and Y 'represents a hydrogen atom, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. -. 11. Compounds of formula (I) according to any of claims 1 to 9wherein the group Y represents a 'hydrogen atom and the group Y' represents a halogen atom or an alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, mercapto, hydroxy, perhaloalkyl, nitro, amino group, (unsubstituted) or substituted by one or two alkyl groups), acyl, aminocarbonyl, (optionally substituted on the nitrogen atom with one or two alkyl groups), acylamino (optionally substituted on the nitrogen atom by an alkyl group), alkoxycarbonyl, carboxy , sulfo or cyano. its enantiomers, diastereoisomers, and also salts of addition thereof with one or more pharmaceutically acceptable acids or bases. 12. Compounds of formula (I) according to any of claims 1 to 11, wherein Alq represents an alkylene chain, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 13. Compounds of formula (I) according to any of claims 1 to 12, wherein W is located on the phenyl group in position 4, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 14. Compounds of formula (I) according to any of claims 1 to 13, wherein W represents a cyano group, their enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 15. Compounds of formula (I) according to any of claims 1 to 13, wherein it represents. group -N (Ri) -Z? ~ R2, its enantiomers, diastereoisomers,. and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 16. Compounds of formula (I) according to any of claims 1 to 13, wherein W represents a group -Z2-NR? R2, their enantiomers, diastereomers, and also addition salts thereof with one or more acids or bases pharmaceutically acceptable 17. Compounds of formula (I) according to any of claims 1 to 13 or 16, wherein Z2 represents a group selected from -C (O) -, -C (S) -, -C (NR4) - and -S ( 0) r-, their enantiomers, 'diastereoisomers, and also addition salts thereof with one or more acids' or. pharmaceutically acceptable bases. 18. Compounds of formula (I) according to any of claims 1 to 13 or 16, wherein Z2 represents a bond, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids. • - 19. Compounds of formula (I) according to any of claims 1 to 13 or 15, where Za represents a group selected from -C (0) -, -C (S) -, * -C (0) -N (R3) -, * - "C (S) -N (R3) -, * -C (0) -0- and S (0) 2-, their enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases 20. Compounds of formula (I) according to any of claims 1 to 13 or 15 to 19, wherein Ri, R2, R3 and R4, which may be identical or different, represent each a hydrogen atom or a group selected from cycloalkyl, alkoxy, optionally substituted phenyl, naphthyl, a heteroaryl group, and an optionally substituted alkyl group - by an optionally substituted phenyl group, - or by a cycloalkyl group, -or by a heterocycloalkyl group, - or by a heteroaryl group, - or by one or two alkoxy groups, or by a phenyloxy group, their enantiomers, diastereoisomers, and also addition salts of the themselves with one or more pharmaceutically acceptable acids or bases. Compounds of formula (I) according to any of claims 1 to 13 or 15 to 19, wherein it represents a group selected from -N (R?) -C (O) -NR2R3; -N (R?) -C (S) -NR2R3; -C (0) -NR? R2 and ~ C (S) -NR? R2; where R x and R 2 or R 2 and R 3, together with the atom or atoms containing them, form a heterocycloalkyl group or a piperidylpiperidyl group, their enantiomers, diastereoisomers, and also addition salts thereof with one or more acids or. pharmaceutically acceptable bases. 22. Compounds of formula (I) according to any of claims 1 to 13 or 16 to 18, wherein represents -Z2-NR? R2 in which Z2 represents a bond; Ri and R2, together with the nitrogen atom containing them, form a heteroaryl group or Ri represents a hydrogen atom. or an alkyl group and R 2 represents an aryl or Ateroaryl group, their enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 23. Compounds of formula (I) according to any of claims 1 to 13, 16, 17, 19, 20 or 21, wherein; W represents a group -C (0) -NR? R2 in which Rt 'and -R2, independently, each represent an alkyl group or a hydrogen atom, or R2 and R2, together with the nitrogen atom contains, they form a selected group of piperazinyl optionally substituted with an alkyl or benzyl group, piperidyl optionally substituted by an alkyl or benzyl group, acetyl, morpholinyl, thiomorpholinyl, octahydrocyclopentapyrrolyl; dihydroquinolinyl and. tetrahydroquinolinyl, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 24. Compounds of formula (I) according to any one of claims 1 to 13, 16, 17, 20 or 23, wherein Vi represents a group -C (0) -NR? R2 in which Ri, and R2, independently, they each represent an alkyl- or a hydrogen atom, their enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 25. Compounds of formula (I) according to any of claims 1 to 13, 15, 19 or 20, wherein W represents a group -N (R?) -C (O) -R2 in which Ri y. -R2 ,. independently, they each represent an alkyl group or a hydrogen atom, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids or bases. 26. Compound of formula (I) according to any one of claims 1 to 14, which is 4- (3-hexahydrocyclo-penta [c] pyrrol-2 (1H) -l-propoxy) benzonitrile, its enantiomers, diastereoisomers, and also salts of adding them with one or more pharmaceutically acceptable acids. 27. Compound of formula (I) according to any of claims 1 to 13, 16, 17, 20, 23 or 24, which is 4- [(3-hexahydrocyclopenta [c] -pyrrole-2 (1H) - ilpropoxy) benzamide, its enantiomers, diastereoisomers, and also * addition salts thereof with one or more pharmaceutically acceptable t-acids. 28. Compound of formula (I) according to any of claims 1 to 13, 16, 17, 20, 23 or 24, which is 4- [3- (hexahydrocyclopenta [c] -pyrrole-2 (1H) -il ) propoxy] -N-ethylbenzamide, its enantiomers, diastereoisomers, and also addition salts thereof with one or more pharmaceutically acceptable acids. 29. Compound of formula (I) according to any of claims 1 to 13, 16, 17, 20, 23 or 24, which is 4- [3- (hexahydrocyclopenta [c] pyrrole-2 (IH) -yl) propoxy ] - N, N - dimethylbenzamide, its enantiomers, diastereoisomers, and also addition salts of the. same with one or more pharmaceutically acceptable acids. 30. Compound of formula (I) according to any one of claims 1 to 13, 15, 20 or 25, which is N- [4- (3-hexahydrocyclopenta [c] pyrrol-2 (lH) -ylpropoxy) phenyl] -eetamide its enantiomers, diastereoisomers, and also salts of addition thereof with one or more pharmaceutically acceptable acids. Process for the preparation of compounds of formula (I) according to claim 1, characterized in that "a compound of the formula, (II) is used as starting material: where : . • Alq is as defined for formula (I), .Hal represents a halogen atom, X 'represents an atom - and oxygen, a sulfur atom or a group -N (p) -, in which (p) represents a hydrogen atom, a conventional protecting group for the nitrogen atom, or an alkyl group, and, Y and Y 'are as defined for the formula (I), composed of formula (II), which, after optional deprotection, is condensed in basic medium with a bicyclo of formula (III): where: n, m, p and q are as defined for the formula (I), to produce a compound of formula (I), composed of formula (I) which, when represented-a cyano group, is optionally reacted with sodium hydroxide or potassium hydroxide to produce a compound of formula (I / b): a particular case of the compounds of formula (I) wherein Alk, n, m, p, q, X, Y and Y 'are as defined for formula I, compounds of formula (I), which, - can, if desired, be purified according to a conventional purification technique, - are optionally separated into stereoisomers according to H a conventional separation technique, - are converted, if desired, into addition salts with one or more pharmaceutically acceptable acids or bases. acceptable, it being understood that: at any time considered appropriate during the course of the process described above, - the carbonyl, thiocarbonyl, amino, alkylamino group or groups in the initial reagent (II) can be protected and then, after condensation, unprotected when required by the synthesis, - the reagents (II) and (III) are prepared according to procedures described in the literature. 32. Pharmaceutical compositions containing at least one active ingredient according to any one of claims 1 to 30, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers. 33. Pharmaceutical compositions according to claim 32, which contain at least one active ingredient according to any of claims 1 to 30, for use as a medicament in the treatment of cognitive deficiencies associated with cerebral aging and with neurodegenerative diseases, and also in the treatment of behavioral disorders, seizures, hyperactivity syndrome due to attention deficit, obesity and pain. 34. Pharmaceutical compositions according to claim 32, which contain at least one active ingredient according to any of claims 1 to 30, to be used as a medicament in the treatment, of cognitive deficiencies associated with Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoff's disease and frontal or subcortical dementias of vascular or other origin. 35. Use of a pharmaceutical composition according to claim 32, which contains at least one active ingredient according to any of claims 1 to 30, for the manufacture of medicaments to be used in the treatment of associated cognitive deficiencies; - co-brain aging and neurodegenerative diseases, and also in the treatment of behavioral disorders, seizures, hyperactivity syndrome due to attention deficit, obesity and pain. 36. Use of a pharmaceutical composition according to claim 32, which contains at least one active ingredient according to any of claims 1 to 30, for the manufacture of medicaments to be used.- in the treatment of cognitive deficiencies associated with the disease of Alzheimer's, Parkinson's disease, Pick's disease, Korsakoff's disease and frontal or subcortical dementias of vascular or other origin.-