TW201144279A - New azabicyclo[3.2.0]hept-6-yl compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Compounds of formula (I): wherein: ALK represents an alkylene chain, W represents a group or, wherein R and R' are as defined in the description. Medicament.

Description

201144279 VI. Description of the Invention: [Technical Field] The present invention relates to a novel azabicyclo[3.2.0]hept-6-yl compound, a process for the preparation thereof and a pharmaceutical composition comprising the same. From a pharmacological point of view, the compounds of the present invention are of particular value because they can interact with the central histamine system in vivo. [Prior Art] The aging of the population due to an increase in life expectancy at birth has greatly increased the incidence of age-related neuropathology and the specific case of Alzheimer's disease. The main clinical manifestations of brain aging and, in particular, age-related neuropathology are the lack of memory and cognitive function, which can lead to dementia. Neuropharmacological studies have shown that in the central nervous system, histamine exerts neurotransmitters or neuromodulators in physiological or physiological pathologies via the central histaminergic system (Pell and Green ' Annu. Rev. Neurosci. ' 1986, 9, 209-254; Schwartz et al., Physiol. Rev. '1991, 71, 1 -5 1). Thus, histamine has been shown to be involved in a variety of physiological and behavioral processes such as thermoregulation, neuroendocrine regulation, nociceptive perception, night rhythm, tonic state 'exercise, encroachment, eating behavior, learning and memory, and synaptic plasticity ( Hass et al, Histaminergic neurones: morphology and function, Boca Raton, FL: CRC Press, 1991, pp. 196-208; Brown et al, Prog. Neurobiology, 2001, 63 >637-672; Smith et al, Neuroimmunomodulation 2007, 14 317-325). 152492.doc 201144279 Animal studies have shown that increasing the endogenous extrasynaptic content of histamine promotes alertness, learning and sufficiency processes and regulates feeding (Br〇wn et al., pr〇g.

Neurobiol., 2000, 63, 637-672; Passani et al, Neurosci. Biobehav· Rev. ’ 2000, 24, 107-113). Therefore, potential therapeutic indications for compounds that increase the release or release of histamine's central content are associated with treatment and emotions associated with 'cerebral aging, associated with acute and chronic neurodegenerative diseases, and cognitive deficits associated with schizophrenia. Obstacle, Tourette's Syndrome (Gulhan Ercan-Sencicek et al, New England Journal of Medicine, May 20, 2010, 1901- 1908), schizophrenia, sleep disorders, sleep-wake rhythm disorders, and lack of attention Treatment of hyperactivity. In addition, studies have shown that inhalation of histamine into the subthalamic nucleus involved in satiety regulation attenuates rat feeding. In addition, the insufficiency of histamine conduction has been demonstrated in hereditary obese rats (Machidod et al, Brain Research, 1992, 590, 180-186). Therefore, eating behavioral disorders and obesity are also potential therapeutic indications for the compounds of the invention. SUMMARY OF THE INVENTION The present invention relates to a novel azabicyclo compound which differs from the compound described in the application. W〇2〇〇5/089747 in the azabicyclo ring. [3.2·0]heptane ring system Existence. (4) The new level of psychology provides novel treatments related to brain aging, neurodegenerative diseases or cognitive impairments associated with head injury, and with, for example, sleep disorders, hyperinflammation, and/or t-state Solutions to the treatment of pathologically relevant psycho-behavioral disorders. In addition, 152492.doc 201144279 The present invention can also be used to envisage a novel treatment of sleep disorders in the spiritual field for Tori's syndrome, schizophrenia, affective disorder or more specifically, and &4; The addition of a compound of formula (I) to its enantiomers and diastereomers to a pharmaceutically acceptable acid or base: ALK-0

\«-·— 1, where: ALK stands for the base chain of the hospital.

♦W represents a group -·Ν_ R, C "1—Ν—R, Ο R* wherein R and R· independently of each other represent a hydrogen atom or, if desired, one selected from the group consisting of halogen, thiol and alkoxy A linear or branched (匸^ C6) alkyl group substituted with a plurality of groups, it is understood that: - the term "alkylene" means a straight or branched divalent group having 2 to 6 carbon atoms; - the term "Alkoxy" means an alkyl-oxy group in which the alkyl chain is a straight bond or a bond 'and contains 1 to 6 carbon atoms; among pharmaceutically acceptable acids, mention may be made, but does not mean any Restriction, hydrogen acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid , oxalic acid, sulfonic acid, camphoric acid, etc. 152492.doc 201144279 Among the pharmaceutically acceptable bases, mention may be made of, but not meant to be any limitation, sodium oxyhydroxide, potassium hydroxide, triethylamine, tert-butylamine and the like. Preferred compounds of formula (I) are those in which the w group is in the para position. ALK preferably represents a linear divalent group having 2 to 6 carbon atoms, such as, for example, an ethyl group or a propyl group, and even more preferably a propyl group. A particular embodiment of the invention is directed to a compound of formula (1) wherein the cargo represents a group 1 · a N - R. Ο R· Another specific embodiment of the invention pertains to compounds of formula (1) wherein the rose represents a group -N-~r-R.

R' C Advantageously, R and R, independently of one another, represent a hydrogen atom, a methyl group or an ethyl group, which groups are optionally substituted by a methoxy group. More specifically, W represents a group -CO-NH-CH3, -(:0-Ν((:ϋ3)2, -CO-NH2^-CO-N(CH2CH3)2^-NH-CO-CH3 &gt -N(CH3)-C〇-CH3 or -NH-C〇-CH2-OCH3. Even more specifically, the present invention relates to compounds of the formula (I) below, and their enantiomers, and And pharmaceutically acceptable acid or co-addition salt: -4-[3-(cis_6_azabicyclo[32〇]heptyl)-propoxy]benzamide, -N-(4 -{3_(cis-6-azabicyclo[3 2 fluorene]heptyl-6-yl)propoxy}phenyl)ethinamide, • cis_6_azabicyclo[3 2 〇]g 6•yl)propoxy}Ν,Ν< 曱基笨甲甲胺胺, I52492.doc 201144279 -4-{3-(cis-6-azabicyclo[3.2.0]hept-6-yl)propyl Oxy}·Ν, Ν-diethyl stearamine, -Ν-(4-{3-(cis-6-azabicyclo[3.2.0]hept-6-yl)propoxy} In the case of a pharmaceutically acceptable acid addition salt, it is preferably more specifically referred to as a hydrochloride, an oxalate and a citrate. The invention also relates to a preparation A process for the compound of formula (I), characterized in that a compound of formula (II) is used as starting material: w (II), wherein W is a compound of formula (11) condensed with a compound of formula (111) in an alkaline medium as defined by formula (I): (10),

Br-ALK-~C| wherein ALK is as defined in formula (I) to obtain a compound of formula (IV):

(IV), wherein W and ALK are condensed with a compound of formula (V) as previously defined herein:

(V) to produce a compound of formula (1) as defined before:

152492.doc 201144279 Purification can be carried out according to conventional separation techniques and, if desired, converted to a pharmaceutically acceptable acid or base addition salt; and, where appropriate, separated into its optical isomers according to conventional separation techniques. Compounds of formula (II), (III) and (V) are commercially available or can be prepared by those skilled in the art using conventional chemical reactions described in the literature. Alternatively, a compound of formula (VI) can be used as a synthetic intermediate of a compound of formula (I/a), especially in the case of a compound of formula (I) wherein W represents a -CONRR' group, by virtue of formula NHRR' (wherein R IT as defined by formula (I) amine coupling

Wherein the ALK group is as previously defined herein. Similarly, a compound of the formula (VII) can be utilized as a synthetic intermediate of the compound of the formula (I/a), especially in the case of a compound of the formula (I) wherein W represents a -CONRR' group, by virtue of the formula NHRR' (wherein R R' as defined in formula (I)) amine coupling

Wherein the ALK group is as previously defined herein. Further, a compound of the formula (VIII) can also be used to obtain a compound of the formula (I/a) by condensation of an amine NHRR' (wherein R and R' are as defined in the formula (I)), in particular, W represents a -CONRR' group. For the compound of formula (I):

152492.doc 201144279 wherein the ALK group is as previously defined and R" represents a linear or branched (CrC6) alkyl or phenyl fluorenyl group, and the compound of formula (VIII) is via the corresponding carboxylic acid previously shown herein ( VI) or bismuth based gas (VII). Finally, the compound of the formula (I/a) can also be obtained by hydrolyzing the compound of the formula (IX):

Wherein the ALK group is as previously defined herein. The psychiatric level of the compounds of the invention can be used in conjunction with brain aging or with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Pick's disease, Levi. Knowledge of Lewy body dementias, frontal and subcortical dementia, frontotemporal dementia, vascular dementia, Huntington's disease (Downase, disease) and multiple sclerosis Obstacle

Sjogren's disease-related sleep disorders, such as excessive daytime sleepiness

Pain, and treatment of sleep disorders, v-shaped heart, female syndrome (Tourette's 1 and its associated cognitive impairment, and pain sleep-wake rhythm disorder and attention deficit 152492.doc 201144279 hyperactivity (pass D). Difficulty can be (4) mentioning narcolepsy and (4) snoring. It is also directed to (4) dysfunction, such as apnoea in obstructive sleep apnea syndrome or attention deficit hyperactivity disorder, and diurnal narcolepsy. Also contemplated is a pharmaceutical group of persons comprising a compound of formula (1) in combination with one or more pharmaceutically acceptable excipients. The weight ratio of active ingredient in the pharmaceutical composition of the invention ( The weight of the active ingredient divided by the total weight of the composition is from 1 to 5% by weight. The pharmaceutical composition of the present invention can be specifically mentioned for oral, parenteral, nasal, transdermal or transdermal, transrectal, menstrual. Tongue, eye or inhalation of them, especially key agents or sugar coatings, sublingual tablets, sachets, sachets, sublingual labels, lozenges, suppositories, creams, ointments, skin gels, and Drinkable or injectable ampoules. Dosage The patient's gender, age and weight, the route of administration, the characteristics of the treatment indication, and any related treatment changes; and in the treatment, within the range of 5 mg to other mg per 24 small items. Compound of formula (I) and acetaminophen The combination of an alkali esterase inhibitor also forms a combination of a compound of the invention 'and more specifically a compound of formula (1) with donepezil nvastigmine or galantamine (10)-(10)). This type of combination can be used to treat cognitive impairment of Alzheimer's disease. [Embodiment] &quot; By way of example, the invention is described, but is not limited in any way. The structure of the compound described in the example 152492.doc 201144279 is determined according to the general photo 4 photometric technique (infrared method, NMR, mass spectrometry, etc.).歪由-贝Λ *F-form compound corresponds to the cis-configured racemate; in other words, these compounds correspond to (1/?,5/〇_6_azabicyclo[3 2川庚_6 base Framework and (1(tetra)-6-azabicyclo[3.2.]]g-6-yl framework "racemic mixture. As described in the following examples, it can be by HPLC column (eg chiralcel OF, CHIRALPACK AS-H or The chiral separation technique of CHIRALPACK AD-H) separates the racemic mixture to obtain the pure enantiomer. Example 1, Scheme A: 4-[3-(cis-6-azabicyclo[3.2.0]heptane- 6-yl)-propoxy]benzamide A Step 1 : 4-(3-Actyloxy)benzamide is heated under reflux, containing 1 〇ml of acetonitrile containing 〇〇〇4 m〇l 4_ a mixture of hydroxybenzamide, 0.004 mol of 1-bromo-3-aeropropane and 〇.006 m〇i carbonate for 5 hours. Step 2: 4-[3-(cis-6-azabicyclo[3.2. 0]hept-6-yl)propoxy]benzoquinone at a temperature of 0.004 mol cis-6-azabicyclo[3.2.0]heptane (published J. Chem. Soc· Perkin Trans 1 1979, 1770-1773 describes its synthesis) and 0.002 mol of sodium iodide is added to the reaction mixture of step 1. Subsequently, Heating was continued under reflux for 16 hours. The precipitate was filtered off and washed with acetonitrile. The filtrate was concentrated to dryness. The residue was dissolved in methane methane. Dry and concentrate to dryness. Purify the residue on a Lichroprep RP-18 phase using preparative chromatographic techniques. 152492.doc 201144279 Elemental microanalysis % C % Η 70·〇4 8.08 70.06 8.1 1 % Ν 10.21 10.00 Calculated value Example 1, route Β: 4_[3_(cis_6_heterobicyclo[3.2()]heptylpropoxy]benzamide Step 1: 4-{3-(cis-aza-bicyclo[ The experimental procedure of 3 2 ()]g _6 yl)propoxy acetonitrile is the same as the synthetic route of the real m, wherein the step 艸 is substituted with 4-hydroxy carbamide by hydroxybenzonitrile. Step 2 : 4- [3-(cis-6-azaindole 丨^ Ί ηΊ Λ 杂 杂 杂 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ 〇. <Chemical substance (2.2g) is dissolved in 9〇ml of ethanol, and added in the presence of 5.1 g KOH under reflux, and the mixture is poured into 90 ml of water and then Concentrate to - Benfeng volume. Filter out the solid obtained, Tiangong g,: "b冼 and steep blush, „ J m isopropyl ether rinse and then dry elemental microanalysis: % C % Η % Ν Calculated value 70.04 8.08 10.21 Measured value 69.64 8.01 10.17 Difficult. 2.01 G to 6-yl)-propoxy] Benzoylamine Step 1: 4-{3-(cis-6-azabicyclodecanoic acid methyl ketone ^3·2 ·0]heptyl + yl)propoxy}benzene 152492.doc 201144279 The experimental procedure is the same as that of the synthetic route A of Example 1, in which the hydrazine 4 hydroxy benzoate is substituted for the 4 hydrazinamide in the step 丨. Step 2: 4-{3-(cis-6-azabicyclo[3.2.0]hept-6-yl)propoxy} benzoic acid 12.7 ml of 2 Ν sodium hydroxide solution containing 3.5 g of the compound of Step 1. The mixture with 8 ml of methanol was heated under reflux for 1 hour. 12.7 ml of 2 N HCL· was added to the reaction mixture which was cooled in an ice bath. Rinse the sinking hall with water and dry in a vacuum. Step 3: 4-{3-(cis-6-azabicyclo[3.2.0]hept-6-yl)propoxy}benzaldehyde-hydrochloric acid hydrochloride 1.8 g of the product described in step 2 A mixture of 〇ml sulfite chloride was heated under ί/IL for 2 hours. The reaction mixture was concentrated in vacuo and evaporated twice with benzene. The solid residue was homogenized in diethyl ether, filtered and dried in vacuo. Step 4: 4-[3-(cis-6-azabicyclo[3 2 fluorene]heptyl-6-yl)propoxy]benzamide can be used to dilute 4 ml of 2 N ammonia in 〇C Add to the dioxazole solution containing the product of step 3 in step 3. Subsequently, the mixture was dropped for 1 hour at ambient temperature and rinsed with a 2 N sodium hydroxide solution followed by water. The organic phase was dried and concentrated. The solid obtained was taken out, and the rinse was washed with isopropyl and then dried. Elemental microanalysis: 〇/〇C % Η % Ν Calculated value 70 04 〇ηο ^ 8-〇8 10.21 Measured value 69 90 〇υ 8·〇5 10.19 152492.doc 201144279 Example 2: 4-{2-(Shun The experimental procedure of the formula-6-azabicyclo[3.2.0]hept-6-yl)ethoxy}benzamide is the same as the synthetic route A of Example 1, wherein the step 1 is bromo-2-chloroethane. Replace 1-bromo-3-aeropropane. Elemental microanalysis: % C % Η % Ν Calculated value 69.21 7.74 10.76 Measured value 68.99 7.71 10.28 Example 3: N-(4-{3-(cis-6-azabicyclo[3.2.〇]g]_6_ The experimental procedure of the phenyloxy}phenyl)acetamide oxalate is the same as that of the synthetic route A of Example 1, in which the hydroxy-(4-hydroxyphenyl)acetamamine is substituted for the 4-hydroxy carbamide in the first step. amine. Then, 36 g of oxalic acid was added to 6 ml of ethanol containing 0.40 g of the obtained compound. The resulting product was filtered off and washed with diethyl ether and then dried in vacuo. Elemental microanalysis: % C % Η % Ν 60.31 6.92 7.40 60.47 6.71 7.26 Phenyl) acetamidine oxalate calculated value Example 4 · Ν·(4-{2·(cis-6-azabicycloindole) 3 2 ()] Gg-6 group) Ethoxy} The experimental procedure is the same as in Example 2, in which step i is filtered with Ν-(4-phenyl)ethyl, and the amine is washed with diethyl ether instead of 4. Then, 0.36 g of oxalic acid was added to 6 ml of ethanol containing 0.38 g of the obtained compound and then dried under vacuum. 152492.doc 201144279 Elemental microanalysis: % C % Η % Ν Calculated value 59.33 6.64 7.69 Measured value 58.89 6.30 7.51 Example 5: 4-{3-(cis-6-azabicyclo[3.2.oxime]hept-6-yl)propoxy}_ N,N-dimethylbenzamide hydrochloride experimental procedure and The synthetic route A of Example 1 is the same, in which the step 丨 is replaced by 4-hydroxy-N,N-dimethylbenzamide as the 4-hydroxybenzamide.

The product was bathed in i〇W ethanol to which 2 ml of 2 N HC(10) solution was added. The transitional crystalline product was rinsed with ethanol and dried under vacuum. Elemental trace analysis % C % Η % Ν % Cl- Calculated value 63.80 8.03 8.27 10.46 Measured value 63.22 7.60 7.94 10.49 Example 6: M3-(cis-6-azabicycloindole 3.2 〇]heptanyl 6-propoxyl Ν,Ν-diethylbenzamide oxalate is the same as in Example 3 in the 4-hydroxy-indole, Ν-two experimental procedure, in which the ethyl cumamine in step j is substituted for Ν-(4-hydroxy stupid) Base) Ethylamine. Elemental trace analysis % C % Η % Ν Calculated value 62.84 7.67 6.66 Measured value 61.97 7.51 6.74 Example 7: 4·{3·(cis-6-azabicyclo[32()]g--6-)propoxy ν _ Methyl benzamide hydrochloride 152492.doc -16- 201144279 The experimental procedure is the same as in Example 5, in which step 1 replaces 4-hydroxy-N,N with 4-hydroxy-N-mercaptophenylamine. _ Dimercaptobenzamide. Elemental trace analysis % C % Η % Ν % Cl* Calculated value 62.86 7.76 8.62 10.91 Measured value 62.58 7.65 8.65 10.87 Example 8: N-(4-{3-(cis-6-azabicyclo[3.2.0]g The experimental procedure of -6-yl)propoxy}phenyl)-fluorenyl-indenyl-ethanoic acid hydrochloride is the same as in Example 5, wherein in step 1, ν·(4-hydroxyphenyl)-hydrazine-methyl Acetamine replaces 4-hydroxy-indole, hydrazine-dimethylbenzamide. Elemental trace analysis % C % Η % Ν % Cl- Calculated value 63.80 8.03 8.27 10.46 Measured value 63.47 7.81 8.00 1 1.09 Example 8a : Ν-(4-{3-(cis-6-azabicyclo[3.2.0] Hept-6-yl)propoxy}phenyl)-indole-methyl-acetamide hydrochloride (enantiomer 1) Enantiomer 1 by chiral column CHIRALCEL OF 60X (600 mm, 20 μιη Prepared by preparative separation. Example 813: 1^(4-{3-(cis-6-azabicyclo[3.2.0]hept-6-yl)propoxy}phenyl)-indole-methylacetamide hydrochloride ( Enantiomer 2) Enantiomer 2 was obtained by preparative separation of a chiral column CHIRALCEL OF 60X (600 mm, 20 μιη). Example 9: Ν-(4-{3-(cis-6-azabicyclo[3.2.〇]heptan-6-yl)propoxy} phenyl)-2-methoxy-acetamide hydrochloride Salt 152492.doc 201144279 The experimental procedure is the same as in Example 5, wherein in step 1, N-(4-hydroxyphenyl)_2_methoxyacetamide is substituted for 4-transyl-N,N-dimercaptobenzamide . Elemental microanalysis (1.2 HCI) % C % Η % Ν % cr Calculated value 59.70 7.57 7.74 11.75 Measured value 58.19 7.83 6.94 12.07 Pharmacological study Example A: Brain content of methyl histamine in NMRI mice according to Tay丨0r et al The method (Biochem. Pharm., 1992, 44 » 1261 _1 267) was conducted to evaluate the in vitro activity of the compounds of the present invention as antagonists of the exogenous central histamine receptor. This activity is shown by measuring the central content of Ντ-methylhistamine (the major metabolite of histamine) after oral administration of the test compound. The increase in brain content of thiol histamine increased histamine conversion due to blockade of the % central histamine receptor. NMRI mice (18-20 g) were treated with the compound of the invention or its vector r^/lcg) via the π route. The animals were sacrificed 1 hour after the pharmacological treatment; the brain was removed, cold; in liquid nitrogen, weighed 4 and homogenized in 〇ι N hcio4. Centrifuge (15 g, 17 min, 4. homogenized product. The supernatant was recovered and divided into several portions. The fraction was taken up in liquid nitrogen and stored under -sot until analyzed. β Ντ-methyl Determination of brain content of N:_P-based histamine by capillary electrophoresis The tissue content of histamine was expressed as _ fresh brain. One-way analysis of variance was used to compare ΝΤ-methylhistamine in animals of vehicle treated with control (control). The brain content was treated with the compound of the invention', if necessary, followed by a cross-J 8 - 152492.doc 201144279 supplemental analysis (Dunnett's test). The results show that the compound of the invention can significantly increase the Ντ- at a dose of 3 mg/kg PO. The endogenous brain content of methyl histamine is more than 80%. By way of example, the compounds of Examples 1, 3, 6, 8, and 5 are endogenous to Ντ-methylhistamine when administered at 3 mg/kg PO. The levels of brain content increase were as follows: Compound of Example 1: +125% Compound of Example 3: +111 % Compound of Example 6: +86% Compound of Example 8: +87% Compound of Example 5: +81% These results Shows that the compound of the present invention is a central histamine receptor of type Η3 An Effective Antagonist. Example Β: Affinity to Mouse Η3 Receptor This objective measures the affinity of a compound of the invention for a histamine receptor of a mouse transfected into Ch〇 cells. Transfected CHO cells In the presence of i〇d〇pr〇Xyfan, which is specific for the % receptor of the radiolabeled ligand, and the scintillation beads, the compounds were cultured at different concentrations for 24 h at room temperature. At the time, the specific binding of the ligands substituted with the test compound was measured, and the affinity constants of the compounds against the mouse oxime; receptor were determined. The results show that the compound of the present invention has a great affinity for the H 3 type histamine receptor (Ki&lt; 40 ηΜ) 〇 For example: Compound of Example 6: Ki=21 ηΜ 152492.doc -19- 201144279 Compound of Example 8: Ki = 14 nM Compound of Example 5: Ki = 35 nM Example C: Preparation of 1000 tablets of pharmaceutical composition Formulation of each lozenge containing 100 mg of active ingredient: Compound of Example 1 .................................. ..................1〇〇g Hydroxypropylcellulose....................... ................................20 g polyvinylpyrrolidine ketone................................................. ...20 g wheat starch........................................... ..................1 50 g ............................. .................................900 g magnesium stearate..... .................................................. .......30 g 152492.doc 20-

Claims (1)

201144279 VII. Scope of application: 1. A compound of formula (1), its enantiomers and diastereomers, and its addition salts with pharmaceutically acceptable acids or bases, ALK stands for alkyl chain, W stands for group N—ΓΓ 丨1R, 〇............ 1 ^ .........^ 赘:R' where R and R 'A straight-chain or branched (c 1 -C6) alkyl group which independently represents a hydrogen atom or is optionally substituted with one or more groups selected from the group consisting of dentate, hydroxyl and alkoxy; "Alkyl" means a straight or branched divalent group having 2 to 6 carbon atoms, and 1 "alkoxy" means an alkyloxy group wherein the alkyl chain is a straight chain or a branch. A chain containing from 1 to 6 carbon atoms. 2. A compound of formula (1) according to claim i, wherein the w group is in the para position. 152492.doc 1 . The compound of the formula (1) of claim 1, the enantiomers and diastereomers thereof, and the addition salts thereof with a pharmaceutically acceptable acid or base, wherein the Alk represents an ethyl or Prolonged propyl. 2 'A compound of the formula (1), such as the enantiomers and diastereomers thereof, and their addition salts with pharmaceutically acceptable acids or bases, wherein the ALK 201144279 represents exopropyl β. Such as the eye 1 &gt; / τ \ , 1 () compound, its enantiomeric bone, and its more with the acceptable acid or alkali added to the drug group - π Μ Q - Q salt The w generation 6. Enantiomeric and diastereomeric addition salts' wherein the % is a compound of the formula (1) of claim 1, which is equivalent to t and a pharmaceutically acceptable acid or test group - μ-__^. R, c are the compounds of the formula (1) of claim 1, and are pharmaceutically pharmaceutically independent of each other and represent a hydrogen atom substituted by a methoxy group. An addition salt of an enantiomer and a diastereomer to an acid or a base, wherein the base and the ruler are methyl or ethyl, and the groups are as desired. 1) a compound, an enantiomer thereof and a diastereomer thereof, and an addition salt thereof with a pharmaceutically acceptable acid or base, wherein w represents a group -C0.2, _C0_NH_CH3, _C0 N(CH3) 2 c〇N(CH2CH3)2^-NH-CO-CH3^-N(CH3)-CO-CH3-NH-CO-CH2-OCH3. 9. A compound of the formula (I) according to claim 1 which is a heart [3-(cis-6-azabicyclo[3.2.0]hept-6-yl)-propoxy]benzamide, hydrazine -(4-{3-(cis-6-azabicyclo[3.2.0]hept-6-yl)propoxy}phenyl)ethinyl, 4-{3-(cis-6-nitrogen Heterobicyclo[3.2.0]hept-6-yl)propoxy}-team:^-two 152492.doc 201144279 Methyl benzamide, heart {guang (cis-6-azabicyclo[3 2 〇 ]g_6•yl)propoxybu N,N-diethylbenzamide, N_(M3-(cis azabicyclo[3.2.0]hept-6-yl)propoxy}phenyl And - anthracene and diastereomers, and their addition salts with pharmaceutically acceptable acids or bases. Ίο. A method of preparing a compound of formula (I) as claimed in Jf 1 &gt; human * item 1, characterized in that a compound of the formula (Π) is used as a starting material: W - \_f~0H (9), wherein W is as requested As defined in Item 1, in a test medium, a compound of the formula (III) is condensed with a compound of the formula (III): Br-~ALK-Cl (HI), wherein the ALK is as defined in the formula (i), Wherein W and ALK are condensed with a compound of formula (V) as previously defined herein: To obtain a compound of formula (IV): (IV), (V) to obtain a compound of formula (1) as defined herein before: 152492.doc 201144279 It can be purified according to conventional separation techniques and, if desired, converted to an addition salt with a pharmaceutically acceptable acid or base, and if desired, separated into its optical isomers according to conventional separation techniques. 11. A compound of the following formula (VI): (VI), wherein the ALK group is as defined in the claim 1 and is used as a synthetic intermediate of the compound of the formula (I/a), specifically in the case of the compound of the formula (I) of claim 1, wherein W represents The group -CONRR;, should be aware that W, R and R are as defined in request 1. 12. - Compounds of formula (VII): (νπ), wherein the ALK group is as defined in the claim 1, which is used as a synthetic intermediate of the compound of the formula (I/a), specifically in the case of the compound of the formula (I) of claim 1, wherein W represents For the group -CONRRi, it should be understood that W, R and R' are as defined in claim 1. 13. - Compound of formula (VIII): 152492.doc -4- 201144279 (vm), wherein the ALK group is as defined by the request and R&quot; is a direct bond or a bond &amp; C6) alkyl or phenyl fluorenyl' which is used as a synthetic intermediate for the compound of formula (IV), specifically as requested In the case of the compound of formula (I) of item 1, wherein the representative group _c〇NRR, it is understood that W, R and R' are as defined in claim 1. 14. A compound of the formula (IX): Wherein the ALK group is as defined in claim 1 and is used as a synthetic intermediate for the compound of formula (I/a), in particular as in the case of the compound of formula (I) of claim 1, wherein W represents a group _C0NRR ,, should understand that W, R and R' are as defined in request 1. 15. A medical composition comprising as an active ingredient a compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable acid or test addition salt thereof, and Or a combination of pharmaceutically acceptable excipients. A pharmaceutical composition according to claim 15 for use in the treatment of cognitive and psycho-behavioral disorders associated with brain aging, degenerative diseases or brain damage. 17. The pharmaceutical composition of claim 16 which is for use in the treatment of Alzheimer's disease, Parkinson's disease '152492.doc 201144279 Pick's disease, Levi Lewy body dementias, frontal and subcortical dementia, frontotemporal dementia, vascular dementia, Huntington's disease and multiple sclerosis Psychological-behavioral barriers. 1 8. The pharmaceutical composition of claim 16, for use in the treatment of psycho-behavioral disorders such as sleep disorders, apathy and anxiety-depression states. 19. The pharmaceutical composition of claim 18 for use in the treatment of Alzheimer's disease and sleep disorders associated with Parkinson's disease. 20. The pharmaceutical composition of claim 15 for use in the treatment of affective disorder, anxiety, barbaric state, Tourette's syndrome, schizophrenia and associated cognitive disorders, and pain, and for Treatment of sleep disorders, sleep-wake rhythm disorders and attention deficit hyperactivity disorder. 21. The pharmaceutical composition of claim 20 for use in the treatment of sleep disorders such as narcolepsy, obstructive sleep apnea syndrome or dyscrasia occurring in attention deficit hyperactivity disorder, and daytime narcolepsy. 22. A combination of a compound of formula (1) and an acetylcholinesterase inhibitor as claimed in any one of claims 1 to 9 . 23. A combination of a compound of formula (1) according to any one of claims 1 to 9 with donepezil, galantamine or remexamine. 24. A combination of claims 22 or 23 for the treatment of cognitive impairment associated with Alzheimer's disease 152492.doc -6 · 201144279 IV. Designated representative map (1) The representative representative of the case is: (None) (2) A brief description of the symbol of the representative figure·· 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 152492.doc