TW201144280A - New compounds of the hexahydrocyclopenta[b]pyrrole type, 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

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel hexahydrocyclopenta[b]pyrrole compound, a process for the preparation thereof, and a pharmaceutical composition comprising the same. The compounds of the invention are of particular value from the pharmacological point of view of the in vivo interaction of the compounds of the invention with the central histamine system. [Prior Art] The ageing of the population due to an increase in the life expectancy at birth leads to an increase in the incidence of age-related neuropathy and especially Alzheimer's disease. The main clinical manifestations of brain aging and, in particular, age-related neuropathy are defects in memory and cognitive function that can lead to dementia. Neuropharmacological studies have shown that in the central nervous system, histamine (via the central histamine system) has neurotransmitters or neuromodulators in physiological or pathophysiological conditions (Pell and Green, iVewroicz., 1986) , 9, 209-254; Schwartz et al., 1991, 71, 1 -5 1). Thus, histamine has been shown to be involved in a variety of physiological and behavioral processes such as thermoregulation, neuro-endocrine regulation, nociceptive sensation, circadian rhythm, stiffness, motility, aggression, eating behavior, learning and memory, and synaptic plasticity ( Hass et al.: morphology and function > Boca Raton » FL: CRC Press 5 1991, pp. 196-208; Brown et al, Prog. Neurobiology, 2001, 63 > 637-672 i Smithy AJ Neuroimmunomodulation 2007, 14, Pages 317 to 325). 152491.doc 201144280 Studies in animals have shown that increased endogenous extra synaptic concentrations of histamine can promote alertness, learning and memory, and regulate food intake (Brown et al. WewroZH'o/., 2000, 63, 637-672, Passani et al., Biobehav. Rev. f 2000 » 24 » 107-113). Thus, for compounds that increase the conversion or release of histamine in the middle class, potential therapeutic indications are treatments for brain aging, acute and chronic neurodegenerative diseases, and cognitive deficits associated with schizophrenia, and Treatment of mood disorders, Tourette's syndrome (Gulhan ETcan-Sencicek et al, New England Journal of Medicine, May 20, 2010 '1901-1908), schizophrenia, sleep disorders, sleep awakening disorder And pay attention to the lack of hyperactivity syndrome. In addition, studies have shown that injecting histamine into rats to participate in the regulation of satiety in the hypothalamic nucleus inhibits feeding. In addition, 'gene-obese rats have confirmed that the function of histamine delivery is abolished (Machidori et al., /Jeiearc/z, 1992, 590, 180-1 86). Thus, eating disorders and obesity are also potential therapeutic indications for the compounds of the invention. SUMMARY OF THE INVENTION The present invention is directed to a novel azabicyclic compound which differs from the compounds described in the application WO 2005/089747 in the presence of a hexahydrocyclopenta[b]pyrrole-1.yl ring system. On a neurological level, these novel compounds not only open the way to treating cognitive disorders associated with brain aging, neurodegenerative diseases or intracranial trauma, but also open up treatments such as sleep disorders, sluggishness and/or depression. State-related pathology-related psychological-behavioural barriers. In addition, this 152491.doc 201144280

Novel treatments for sleep disorders). More specifically, the present invention relates to a compound of formula (1):

The enantiomers and diastereomers thereof, and the present invention are also directed to addition salts thereof with pharmaceutically acceptable acids or bases, wherein: ♦ ALK represents an alkyl chain,

♦ W represents a group -Ijl-Jj·-R or a straight bond in which R and R' each independently represent a hydrogen atom or, as the case may be, one or more groups selected from the group consisting of _, hydroxy and alkoxy Or a branching bond (<:丨-(:6) alkyl group, it should be understood that: - the term "alkylene group" means a straight or branched bond divalent group containing 2 to 6 broken atoms, - the term "alkoxy" ” represents an alkyloxy group, wherein the linear or branched bond has from 1 to 6 carbon atoms. The pharmaceutically acceptable acid may be specifically mentioned (but not meant to be any limitation): acid, hydrobromine Acid, sulfuric acid, scaly acid, acetic acid, trifluoroacetic acid, lactic acid, propylene steel 152491.doc 201144280 acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, Oxalic acid, methanesulfonic acid, camphoric acid, etc. The pharmaceutically acceptable base can be specifically mentioned (but does not mean any limitation): sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc. The compound of formula (I) is the one in which the w group is located. The ALK preferably represents a linear chain of 2 to 6 carbon atoms. The group, for example, an ethyl group or a propyl group, more preferably still a propyl group. A specific embodiment of the invention pertains to a compound of the formula (I) wherein w represents a group |j - Ijl - R. * A further specific embodiment of the invention relates to a compound of formula (I) wherein W represents a group -rji-jp-R. R* 〇R and R and each independently represents a gas atom, methyl or ethyl group, These groups are optionally substituted by a methoxy group. More particularly, W represents a group -CO-NH-CH3, -CO-N(CH3)2, -co-nh2, -CO-N(CH2CH3)2. -NH-CO-CH3, -N(CH3)-CO-ch3 or -NH-CO_CH2-OCH3. Preferably, the hexahydrocyclopenta[b]n-pyrrol-1-yl ring system Cis-configured compounds of the invention. More specifically, the invention relates to compounds of the following formula (I): -4-{3-[cis-hexahydrocyclopenta[b]pyrrole_i ( 2H)-yl]propoxy}phenylguanamine, -N-(4-{3-[cis-hexahydrocyclopenta[b]n-pyrrol-1(2H)-yl]propoxy} Stupid 152491.doc 201144280 base) Ethylamine, -4·{3-[cis-hexahydrocyclopenta[b]°-r-U2H)·yl]propoxy}-N,N-dimethyl Benzoylamine, -4-{3-[cis-hexahydrocyclopentane [b]°pyryl]propoxy}_N_methylbenzamide, -N-(4-{3-[cis-hexahydrocyclopenta[bp]-1(2H)-yl ]propoxy}phenyl)-N-methylacetamide, -N-(4-{3-[cis-hexahydrocyclopenta[b].pyrrol-1(2H)-yl]-propyl Oxy}phenyl)-2-methoxyacetamide, and its enantiomers, the invention also relates to its addition salts with pharmaceutically acceptable acids or bases. More preferred addition salts with pharmaceutically acceptable acids are the hydrochloride, oxalate and citrate salts. The invention also relates to a process for the preparation of a compound of formula (I), characterized in that a compound of formula (II) is used as starting material:

0Η (Π), wherein W is a compound of formula (II) condensed with a compound of formula (ΠΙ) in an alkaline medium as defined by formula (I):

Br-ALK——Cl (m)j wherein ALK is as defined in formula (I) to obtain a compound of formula (IV): 152491.doc (IV), 201144280

Wherein W and ALK are as defined above, which are condensed with a compound of formula (V):

(V) to produce a compound of formula (I) as defined above:

It can be purified according to conventional separation techniques, if desired, converted to its pharmaceutically acceptable acid or base addition salt, and, where appropriate, separated into its optical isomerization according to conventional separation techniques. body. The compounds of the formulae (II) and (III) are commercially available or can be obtained by the skilled artisan using the conventional chemical reactions described in the literature. The cis or trans configuration of a compound of formula (IV) is commercially available or can be obtained by conventional techniques described in the literature using those skilled in the art. Alternatively, a compound of formula (VI) can be used:

Wherein the ALK group is as defined above, 152491. doc (VI), 201144280 as a synthetic intermediate for a compound of formula (I/a), in particular a compound of formula (I) wherein W represents a -CONRR' group By coupling with an amine of the formula NHRR' (wherein R and R1 are as defined for formula (I)). Similarly, a compound of formula (VII) can be used:

Wherein the ALK group is as defined above, as a synthetic intermediate for a compound of formula (I/a), in particular a compound of formula (I) wherein W represents a -CONRR' group, by the formula NHRRi ( An amine coupling wherein R and R are as defined in formula (I). Further, a compound of the formula (I/a) (particularly a compound of the formula (I) wherein W represents a -CONRR' group) can also be used by the amine NHRR' (wherein R and R' are as defined in the formula (I)) Condensation of a compound of formula (VIII):

Wherein the ALK group is as defined above and R" represents a straight or branched chain (CVC6) alkyl or benzyl group, the compound of formula (VIII) being via the corresponding carboxylic acid (VI) or hydrazine shown below Base gas (VII) is produced. Finally, the compound of formula (IX) can also be hydrolyzed by: 152491.doc -10- 201144280

Wherein the ALK group is as defined above to obtain a compound of formula (I/a). At a neurological level, the compounds of the invention are useful for the treatment of brain aging or with neurodegenerative diseases such as Alzheimer's disease, Pa Jinsen's disease, Pick's disease, Lewy body dementia, frontal and subcortical dementia, frontotemporal dementia, vascular dementia, Huntington's disease and multiple Cognitive conditions associated with sclerosis are used to novelly treat cognitive conditions associated with intracranial trauma, and also to treat psychological and behavioral disorders associated with their pathology such as sleep disorders, sluggishness, and depressive/depressive conditions. In particular, it is associated with Alzheimer's disease and sleep disorders associated with Parkinson's disease, such as diurnal narcolepsy. At the psychiatric level, these compounds are useful in the treatment of mood disorders, and more particularly in the treatment of anxiety, depression, dysplasia, schizophrenia and related cognitive disorders, and pain, and also For the treatment of sleep disorders, sleep arousal rhythm, and Zhuangyi deficiency hyperactivity disorder syndrome (ADHD). Among these sleep disorders, early sleep moths may specifically address narcolepsy and sleep apnea. Sleep disorders, such as obsessive-compulsive sleep apnea syndrome or narcolepsy in the absence of hyperactivity syndrome, as well as diurnal narcolepsy are also targets. It comprises a combination of compounds of formula (I). The invention also relates to a pharmaceutical composition, and - or more #pharmaceutically acceptable excipients 152491.doc 201144280 In the pharmaceutical compositions of the invention, the active ingredient weight ratio (the active ingredient weights to the total weight of the composition) Line 1 to 50 〇 /. . In the pharmaceutical compositions of the present invention, particularly those suitable for oral, parenteral, nasal, transdermal or transdermal, rectal, translingual, intraocular or respiratory administration, especially for lozenges or icing Pills, sublingual tablets, sachets, sachets, capsules, sublingual tablets, buccal preparations, suppositories, creams, ointments, epidermal gels, and drinkable or injectable ampoules. The applicable dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the indication for treatment and any related treatment, and is administered in a 24-hour treatment for 1 to 3 times a day. The dose range is 〇〇5 mg. Up to 5〇〇mg. The combination of a compound of formula (I) with an acetylcholinesterase inhibitor also forms an integral part of the invention, and more particularly, the compound of formula (I) is associated with donepezil, rivastigmine or Lanantamine combination. A combination of this type can be used to treat cognitive conditions of Alzheimer's disease. [Embodiment] The following examples illustrate the invention 'but are not intended to limit the invention in any way. The structures of the compounds described in these examples were determined according to conventional spectrophotometric techniques (infrared, NMR, mass spectrometry, etc.). By way of information, these compounds are equivalent to the cis or trans configuration racemates below; in other words, the compounds π ^ hereinafter are equivalent to (3aR, 6aR)-hexahydrocyclopentane [ b]pyrrole λ-based skeleton with (3aS,6aS)-hexahydrocyclopenta[b]pyrrole·1(2Η)_其Α Α ,, the racemic mixture of J i lunar 152491.doc -12- 201144280 And (3aR,6aS)-hexahydrocyclopenta[b]npyr-1(2H)-yl skeleton and (3aS,6aR)-hexahydrocyclopentane[bp ratio_1( 2H)- Racemic mixture of the base skeleton. As described in certain examples below, the racemic mixture can be isolated by a palmar separation technique on a HPLC column such as CHIRALCEL OF, CHIRALPACK AS-H or CHIRALPACK AD-H to obtain pure Enantiomer. Example 1 'Synthesis Path A: 4·{3-[cis-hexa-Hexanecyclopenta[b]pyrrole-1(2H)-yl]propoxy}benzamide> Step 1: 4-(3-Chlorine Propyl phenyl hydrazine is composed of 0 004 mol of 4-hydroxybenzamide, 0.004 mol of 1-bromo-3-chloropropane and 0.006 mol of carbonic acid in 1 ml of acetonitrile under reflux. The mixture was heated for 5 hours. Step 2: 4-{3-[cis-hexahydrocyclopenta[a]. Bis-l-(2H)-yl]propoxy}benzamide at 0.004 mol of cis-octahydrocyclopentane [b]pyrrole at ambient temperature (the synthesis method is described in publication j. 〇rg Chem. 1996, 61,5813-5817), and 0.002 mol of sodium hydride were added to the reaction mixture of step 1. The heating was restarted for 16 hours. The precipitate was filtered off and rinsed with acetonitrile. The filtrate was concentrated to dryness. The residue was dissolved in di-methane. The resulting solution was extracted successively with sodium hydroxide solution and water, then dried over magnesium sulfate and evaporated to dryness. The residue was purified by preparative chromatography on a Lichroprep RP-18 phase. Elemental microanalysis · 152491.doc 13 201144280 % c % Η % Ν 70.80 8.39 9.71 70.80 8.29 9.70 The theoretical value of the measured value example 1, Lu Jiang 13⁄4. d, live B · 4-{3-[cis-hexahydrocyclopentane Alkano[b]pyrrole-i(2H)-yl]propoxy}benzamide oxime step 1 : benzyl}benzonitrile 4_(3-[cis-hexahydrocyclopentane[bp-1] The reaction procedure was the same as in Example 1, the synthesis route A, and the 4-hydroxybenzonitrile was replaced by 4-hydroxybenzonitrile. Step 2: 4-{3-[Shun · hexahydrocyclopenta[B]D-pyrrol-1(2H)-yl]propoxy}benzamide The compound obtained in the above step (2.2 g) was dissolved in 90 ml of ethanol and The mixture was heated under reflux for 8 hours in the presence of 5.1 g of KOH. The mixture was poured into 90 ml of water and then concentrated to half volume under vacuum. The obtained solid was filtered, washed with isopropyl ether and then dried. Microanalysis: % C % Η % Ν Theoretical value 70.80 8.39 9.71 Measured value 70.32 8.28 9.40 Example 1, path C: 4-{3-[cis-hexahydrocyclopenta[b]pyrrole-1(2H)-yl ] propoxy}benzamide 步骤 Step 1: 4-{3-[cis-hexahydrocyclopentane [b]Methyl pyrrole-1(2H)-yl]propoxy}benzoate This test procedure is the same as in Example 1, the synthesis route A, from 4-hydroxybenzene 152491.doc -14- 201144280 methyl ester Replace 4-hydroxybenzamide in step 1. Step 2: 4-{3-[cis-hexahydrocyclopenta[b].pyr-l-(2H)-yl]propoxy}benzoic acid A mixture of 3.5 g of the compound of Step 1, 12.7 ml of 2 N sodium hydroxide solution and 8 ml of decyl alcohol was heated under reflux for 1 hour. The reaction mixture was cooled in an ice bath and 12.7 ml of 2 N HCl was added. Precipitate and dry under vacuum. Step 3: 4-{3-[cis-Hexahydrocyclopenta[b]«pyrrole-i(2H)-yl]propoxy}benzimidium chloride hydrochloride The mixture of 1.8 g of the product described in Step 2 and 20 ml of sulphur-brewed chlorobenzene was heated under reflux for 2 hours. The reaction mixture was concentrated in vacuo and evaporated twice with EtOAc. , 遽 遽 and dry in vacuum. Step 4: 4-{3·[cis-hexahydrocyclopenta[b]pyrrole_1(2H)-yl]propoxy}phenylamine in 〇°C Next, add 4 ml of 2 N ammonia in methanol to 1 in methane. g The solution of the product described in Step 3. Subsequently, the mixture was stirred at ambient temperature for 1 hour and washed successively with 2 N sodium hydroxide solution and water. The organic phase was dried over magnesium sulfate and concentrated. The solid obtained was filtered off, rinsed with isopropyl hydrazine, and then dried. Elemental microanalysis: % C % Η % Ν Theoretical value 70.80 8.39 9.71 Measured value 70.69 8.46 9.41 152491.doc 201144280 Example la: 4-{3-[cis-hexahydrocyclopentane[b]"* slightly-1 (2H)-yl]propoxy}benzamide (enantiomer 1) by preparative separation (dissolved at ambient temperature on CHIRALCEL OF, 4.6x250 mm ' 10 μιη), dissolved Mixture: ngengyuan/n-propanol/diethylamine (60/40/0.1), flow rate 1 ml/min, UV detection at 255 nm), enantiomer 1 was obtained. Optical rotation: [aD] 589 (four) 25 ° = +38.72. (c = 1.0; MeOH) Example lb: 4-{:3-[,-hexahydrocyclopenta[b]pyrrole-1(2H)-yl]propoxy}benzamide (enantiomer 2 Separation by preparative type (dissolved at ambient temperature on CHIRALCEL OF, 4.6 χ 250 mm ' 10 μηι, mixture of eliminator: n-heptane / n-propanol / diethylamine (60/40 /0.1), flow rate 1 ml/min, UV detection at 255 nm), enantiomer 2 was obtained. Optical rotation: [aD] 589 nm 25 ° = _36.53. (c=0.9; MeOH) Example 2: 4-{2-[cis-hexahydrocyclopentane 丨b]pyrrole-1(2H)-yl]ethoxy}benzamide The test procedure is Example 1, Synthetic Route A was identical, replacing 1-bromo-3-aeropropane in Step 1 with 1-bromo-2-aeroethane. Elemental microanalysis: % C % Η % Ν Theoretical value 70.04 8.08 10.21 Measured value 69.98 8.16 9.98 Example 3: Ν-(4-{3·丨顺-hexa-argon cyclopentane[b]«比咯-1 (2H )-yl]propoxy}phenyl)ethenol 152491.doc 16 · 201144280 This test procedure is the same as the example 丨, synthetic route A, replacing N_(4-hydroxyphenyl)acetamide with step 1 4-hydroxy stupid amide. Elemental microanalysis: % c % Η % Ν Theoretical value 71.49 8.67 9.26 Measured value 70.89 8.79 8.90 Example 3a: N-(4-{3-[cis-hexahydrocyclopentane[...吼i·i(2H)- Alkyl propyl phenyl acetamide (enantiomer 1) by preparative separation (dissolved at ambient temperature on a CHIRALCEL OF 60X (600 mm ' 20 μηι) column, lysing agent) Mixture: n-heptane/n-propanol/diethylamine (100/5/0.1), flow rate 50 ml/min, UV detection at 255 nm), enantiomer 1 was obtained. Optical rotation: [aD] 589 nm 25 ° = +41.90. (c = 1.0; MeOH) Example 3b: N-(4-{3-indene-hexahydrocyclopenta[b]pyrrole-1(2H)-yl]propoxy}phenyl)acetamide ( Enantiomer 2) by preparative separation (dissolved at ambient temperature on a CHIRALCEL OF 60X (600 mm, 20 μηη) column, the mixture of the eluent: n-heptane / n-propanyl / diethylamine (100/5/0.1), flow rate 50 ml/min, UV detection at 255 nm), enantiomer 2 was obtained. Optical rotation: [aD] 589 nm 25 ° = -42.21 ° (c = 1.0; MeOH) Example 4: N-(4-{2-[cis-hexahydrocyclopenta[b]pyrrole-1(2H)- The procedure of this test procedure was the same as in Example 2, except that 4-hydroxybenzoguanamine in Step 1 was replaced by N-(4-hydroxyphenyl)acetamide. Subsequently, 0.36 g of oxalic acid was added to 152491.doc • 17· 201144280 0.38 g of the compound thus obtained contained in 6 ml of ethanol. The obtained product was passed up, rinsed with a test, and then dried in a vacuum. Elemental microanalysis: % C % Η % Ν Theoretical value 60.31 6.92 7.40 Measured value 59.82 6.79 7.71 Example 5: 4·{3-[cis-hexahydrocyclopentane[b]lax_1(2Η)·yl] Propyloxy}_ Ν, Ν-dimethylbenzyl amide amine hydrochloride This test procedure is the same as in Example 1, the synthetic route ,, replacing step i with 4-hydroxy-N,N-dimethylbenzamide 4-hydroxybenzoguanamine. The product thus obtained was dissolved in 1 〇 ml of ethanol, and a 2 mi 2 N HCl solution was added thereto. The crystalline product was filtered off, rinsed with ethanol and dried in vacuo. Elemental microanalysis: % C % Η % Ν % Cl % Cl- Theoretical value 64.67 8.28 7.94 10.05 10.05 Found 64.54 8.25 7.85 9.75 9.76 Example 5a: 4-{3-[cis-hexahydrocyclopentane[b]pyrrole _ι(2Η)_基】propoxy*}·Ν,Ν·dimethylbenzamide hydrochloride (enantiomer)^ by preparative separation (in the CHIRALPAK AS-H, 4.6x250 mm, 5 μηι, dissolved at ambient temperature, mixture of dissolving agent: acetonitrile/diethylamine (100/0.1), flow rate 0.6 ml/min, UV detection at 240 nm), enantiomer 1. Obtaining enantiomers Degree: [aD]589nm2<) = -32.66° (c=〇.6; MeOH) -18- 152491.doc 201144280 Example 5b: 4_{3_丨顺-hexahydrocyclopentane 丨b]咕 _ 1(2H)-yl]propoxyb N,N-dimethyl stupidylamine hydrochloride (enantiomer 2) by preparative separation (in the palm of the tube 枉 CHIRALPAK AS-H, 4.6x250 On the mm ' 5 μιη, dissolved at ambient temperature, the eliminator mixture: acetonitrile / diethylamine (10 0 / 0.1), flow rate 0.6 ml / min, UV detection at 240 nm), to obtain enantiomer 2. Optical rotation: [aD] 589nm2C) ° = +34,93. (c=0.8; MeOH) Example 6: 4-{3·[cis-hexahydrocyclopenta-enylpropane}-indole, fluorene-diethylbenzamide dioxalate This test procedure In the same manner as in Example 4, hydrazine-(4-hydroxyphenyl)acetamide in Step 1 was replaced by 4-hydroxy-indole, hydrazine-diethylbenzamine. Elemental microanalysis: % C % Η % Ν theoretical value 57.24 6.92 5.34 measured value 57.74 6.84 4.72 Example 7: 4-{3-[cis-hexahydrocyclopenta[b]pyrrole-1(2Η)-yl] Propyl}-indole-methylbenzamide hydrochloride This test procedure was the same as in Example 5, replacing 4-hydroxy-indole in step 1 with 4-hydroxy-indolylbenzamide. - Dimercaptobenzamine. Elemental microanalysis: % C % Η % Ν % Cl % Cl- Theoretical value 63.80 8.03 8.27 10.46 10.46 Measured value 63.40 8.02 8.23 9.68 10.12 Example 7a: 4-{3-indole-hexahydrocyclopenta[b]pyrrole 4(211)-yl]propoxy 152491.doc -19· 201144280 base}-...methylbenzamide hydrochloride (enantiomer)!) by preparative separation (in the CHIRALPACK AS -H, 4.6x25 0 mm, 5 μιη, dissolved at ambient temperature, mixture of dissolving agent: acetonitrile / diethylamine (1 〇〇 / 〇 · 1), flow rate 1 ml / min, UV detection at 250 nm) , Enantiomeric 1 » Optical rotation: [aD] 589 nm 2 ° ° = -35.97. (c=0.98; MeOH) Example 7b: 4-{3-[cis-hexahydrocyclopenta[b]pyrrole-jqh)-yl]propoxyindole-N-methylbenzamide hydrochloride Salt (enantiomer 2) by preparative separation (dissolved at ambient temperature on CHIRALPACK AS-H, 4.6 x 250 mm '5 μπι' on the palm tube column, lysing agent mixture. Acetonitrile/diethylamine (10 0 /0.1), flow rate 1 ml/min, UV detection at 250 nm) 'Enantiomer 2 was obtained. Optical rotation: [aD] 589 nm 2 ° ° = +36.41. (c=0.94; MeOH) Example 8: N-(4-{3-[cis-hexahydrocyclopenta[b]pyrrole-1(2H)-yl]propoxy}phenyl)-N- Methylacetamide hydrochloride This test procedure was the same as in Example 5, replacing N-(4-hydroxyphenyl)-N-mercaptoacetamide with 4-hydroxy-N,N-dimethyl in step 1. Benzimidamide. Elemental microanalysis: % C % Η % Ν % Cl- Theoretical value 64.67 8.28 7.94 10.05 Found 64.22 8.14 7.73 10.07 Example 8a: N-(4-{3-[cis-hexahydrocyclopentane[b]咐•咯-1(2H)-yl]propoxy}phenyl)-N-methylacetamide hydrochloride (enantiomer 1) by preparative separation (in the pair of palmar column CHIRALPAK AD-H, 152491 .doc •20- 201144280 4_6x250 mm, 5 μιη on 'dissolve at ambient temperature, eluent mixture: ethanol/acetonitrile/diethylamine (15/85/0.1), flow rate 1.0 ml/min, UV detection at 280 nm ) to obtain the enantiomer i. Optical rotation: [aD] 589 nm 2 ° ° = _28.36. (c=0.53; DMSO) Example 8b: N-(4-{3-[cis-hexahydrocyclopenta[b]pyrrolyl]propoxy}phenyl)-N-methylacetamide hydrochloride Salt (enantiomer 2) by preparative separation (dissolved at ambient temperature on CHIRALPAK AD-H, 4_6x250 mm '5 μιη), eluent mixture. Ethanol/acetonitrile/diethylamine (15 /85/0.1), flow rate 1.0 ml/min, UV detection at 280 nm) to obtain enantiomer 2. Optical rotation: [aD] 589 nm 2 ° ° = +29.38. (c=0.50; DMSO) Example 9: N-(4-{3-[cis-hexahydrocyclopenta[b]pyrrole·W2H-propyl]propoxy}phenyl)-2-methoxy B Indoleamine hydrochloride This test procedure was the same as in Example 5, replacing 4-hydroxy-N,N-dimercaptobenzamide in Step 1 with N_(4-hydroxyphenyl)_2-methoxyacetamide. amine. Elemental microanalysis: % c % Η % Ν % cr Theoretical value 61.86 7.92 7.59 9.61 Measured value 62.09 7.69 7.80 10.46 Example 9a · N-(4-{3-[cis-hexahydrocyclopenta[b]pyrrole_1 (2H)yl]propoxy}phenyl)-2-methoxyacetamide hydrochloride is isolated by preparative type (on the CHIRALPAK AD-H, 4·6χ250 mm, 5 μιη, Dissolved at ambient temperature, the eluent mixture·ethanol/acetonitrile/diethylamine (5/95/〇, flow rate i 〇 cent minutes at 152491.doc -21·201144280 25 0 nm for UV detection) gave enantiomer 1. 2 Cyclones: [aD] 589nm = -31.95° (c = l. 〇; DMSO) Example 9b: N-(4-{3-[cis-hexa-hexafluorocyclopenta[b]pyrrole_1 ( 2H-propyl]propoxy}phenyl)-2-methoxyacetamide hydrochloride was isolated by preparative type (on the CHIRALPAK AD-H, 4.6 250 mm, 5 μιη, around the palm tube) Dissolution at temperature, mixture of dissolving agent: ethanol / acetonitrile / diethylamine (5 / 95 / 0.1), flow rate 1. 〇 ml / min, UV detection at 250 nm), to obtain enantiomer 2. Optical rotation: [ClD ]589nm20 = + 32.77〇(C=1.0; DMSO) Example 10, Path A: 4·{3-[Reverse- Hexahydrocyclopenta[b]pyrrole-1(2H)-yl]propoxy}benzamide hydrochloride step 1. 4-(3-propyloxy)benzamide will be contained in a mixture of 0.004 m〇l 4-hydroxybenzamide, 〇·〇〇4 mol 1-bromo-3-propane and 〇·〇〇6 m〇i carbonate planer in 10 ml of acetonitrile. Hour. Step 2: 4-{3-[trans-hexahydrocyclopentanepyrrolyl]propoxy}benzamide at 0.004 mol of trans-octafluorocyclopentene [b]B at ambient temperature Bilo (the synthetic method is described in publication j Chem. Soc. 1959, 1050-1054), and 0.002 mol of sodium iodide are added to the reaction mixture of step 1. The reflux heating is restarted for 6 hours. The precipitate was filtered off and rinsed with acetonitrile. The filtrate was concentrated to dryness. The residue was dissolved in di-methane. The solution was then extracted with sodium hydroxide and water, then dried over magnesium sulfate. Purify the residue by preparative 152491.doc 22· 201144280 chromatography technique on Lichroprep RP-18 phase. Step 3: 4-{3_[trans-hexahydrocyclopentane with n(tetra)yl]propyl Oxygen}benzoquinone hydrochloride Was added 2 ml 2, washed with ethanol The product obtained in Step 2 was dissolved in 10 ml of ethanol, N HC1 solution in diethyl ether thereto. The crystallized product was filtered off and dried in vacuo. Elemental microanalysis: % C % Η % Ν % Cl- Theoretical value 62.86 7.76 8.62 10.91 Measured value 61.89 7.70 8.29 10.63 Example 1 〇 'Path B: 4-(3·[re-hexahydrocyclopenta[b]pyrrole ·ι(2Η)_yl]propoxy}benzamide hydrochloride step 1 : 4-{3-[trans·hexahydrocyclopenta[b]pyrene-1(2Η)yl]-propyl Oxy}benzonitrile This test procedure was carried out in the same manner as in Example 10, Synthetic Route A, Steps 1 and 2, and 4-hydroxybenzonitrile was replaced by 4-hydroxybenzamide in the step. Step 2: 4-{3 -[trans·hexahydrocyclopenta[b]pyrrole_1(2H)yl]propanyl}benzamide The compound obtained in the above step (2.2 g) is dissolved in 90 ml of ethanol, and Heating in the presence of 5.1 g KOH for 18 hours under reflux. The mixture was poured into 90 ml of water and then concentrated to half volume in vacuo. The solid obtained was filtered off, rinsed with isopropyl ether and then dried. Step 3: 4-{3-[trans-hexahydrocyclopenta[b]npyr-1(2H)-yl]propoxy}phenylhydrazine hydrochloride 152491.doc •23- 201144280 The product obtained in step 2 is dissolved in 1 ml of ethanol, and 2 mi 2 N is added. The solution was poured out, the product was crystallized, rinsed with ethanol and dried in vacuo. Elemental analysis: % C % Η % Ν % Cl - Theoretical value 62.86 7.76 8.62 10.91 Measured value 62.59 7.69 8.30 10.75 Example 10, path C. 4-{3-[trans-hexahydrocyclopentane and [b]βpyrole·U2H)-yl]propoxy}benzamide hydrochloride step 1. 4-{3-[reverse - Hexahydrocyclopentanol [b]. This test procedure is the same as in Example 10 'Synthesis Route A, Steps 1 and 2, replacing the 4-hydroxyl group in Step 1 with methyl 4-hydroxybenzoate. Benzoylamine. Step 2: 4-{3-[trans-hexahydrocyclopenta[^]]11pyr-1(211)-yl]propoxy}benzoic acid 3.5 g of the compound of the above step, 12.7 ml 2 N A mixture of sodium hydroxide solution and 8 ml of decyl alcohol was heated under reflux for a few hours. The reaction mixture was cooled in an ice bath and 12.7 ml 2 N HCl was then added. The precipitate was washed with water and dried in vacuo. Step 3: 4-{3-[trans-hexahydrocyclopenta[b]»pyrrole-i(2H)-yl]propoxy}phenylhydrazine gas hydrochloride will be 1.8 g as described in Step 2. A mixture of the product and 20 ml of sulphur sulphur was heated under reflux for 2 hours. The reaction mixture was concentrated under vacuum and twice with toluene. The solid residue was homogenized in acetonitrile, filtered and dried in the air at 152491.doc -24 - 201144280. Step 4: 4-{3-[trans-hexahydrocyclopenta(8)pyridyl}benzamide A solution of 4 ml of 2% methanol is added to the step 2 contained in the second gas at 〇 °c In the solution of the product described. Subsequently, the mixture was stirred at ambient temperature for 1 hour and washed successively with 2 N sodium hydroxide solution and water/month. The organic phase was dried over magnesium sulfate and concentrated. The solid obtained was filtered off, rinsed with isopropyl ether and then dried. Step 5. 4-{3-[trans-hexahydrocyclopenta[b]D-pyryl i(2H)yl]propoxy}benzamide hydrochloride dissolves the product obtained in step 4. Add 2 ml of 2 N HC1 test solution to 1 〇ml of ethanol. The crystallized product was filtered off, washed with ethanol and dried in vacuo. Elemental microanalysis: % c % Η % Ν % Cl- Theoretical value 62.86 7.76 8.62 10.91 Measured value 62.40 7.50 8.41 10.67 Example 11: 4-{2·[trans-hexahydrocyclopenta[b]pyrrole]6 The test procedure was the same as in Example 1 〇, Synthetic Route A', replacing 1-bromo-3·chloropropane in Step 1 with 1-bromo-2-aeroethane. Elemental microanalysis: % C % Η % Ν % Cl· Theoretical value 61.83 7.46 9.01 11.41 Measured value 61.30 7.38 8.80 10.97 152491.doc -25· 201144280 Example 12: Ν-(4·{3·[reverse. Hex argon cyclopentane (d) 咕 - - l (2H) yl] propoxy} phenyl) acetamidine hydrochloride This test procedure is the same as the example 丨〇, the synthetic route A, from N_(4 phenyl) acetamide Instead of 4-hydroxybenzamine in step 1. Elemental microanalysis: % C % Η % Ν % Cl- Theoretical value 63.80 8.03 8.27 10.46 Measured value 63.53 7.86 7.83 10.14 Example 13: N-(4-{2-[trans-hexahydrocyclopentane 丨b]pyrrole _ 1(2H)-yl]ethoxy}phenyl)acetamide hydrochloride This test procedure was the same as in Example 11, substituting N-(4-hydroxyphenyl)acetamide for the 4-hydroxyl group in Step 1. Benzoylamine. Elemental microanalysis: % C % Η % Ν % Cl- Theoretical value 62.86 7.76 8.62 10.91 Measured value 61.87 7.58 8.49 10.29 Example 14: 4-{3·丨 反-hexa-argon cyclopentane and [b]" 1(2H)-yl]propoxyindole-indole, hydrazine-dimethylbenzamide hydrochloride This test procedure is the same as in Example 10, the synthetic route A, from 4-hydroxy- Ν, Ν·dimethyl The phenylbenzamide replaces the 4-hydroxybenzamide in step 1. Elemental microanalysis: % C % Η % Ν % Cl- Theoretical value 64.67 8.28 7.94 10.05 Found 64.64 7.97 7.64 10.35 152491.doc •26· 201144280 Example 15: 4-{3-[trans-hexahydrocyclopentane[ b]pyrrole_1(2H) group]propane group}-N,N-diethylbenzamide hydrochloride This test procedure is the same as in Example 1 〇, the synthetic route A is the same, from 4-hydroxy-N, N-diethylbenzamide replaces 4-hydroxylamine in step i. Elemental microanalysis: % C % Η % Ν % cr Theoretical value 66.21 8.73 7.35 9.31 Measured value 66.42 8.61 7.26 9.22 Example I6: 4-{3·[trans-hexahydrocyclopentane and [b]pyrrole_1 (2Η) ·Based] Propionyl hydrazine-N-mercaptobenzamide citrate This test procedure is the same as in Example 10, the synthetic route ,, 4_ hydroxymethyl benzoguanamine replacement step 丨 4_ Hydroxybenzamide. Elemental microanalysis:

% C % Η % Ν % Cl % CT δ·27 10.46 10.46 7.99 10.02 10.11 Theoretical value 63.80 8.03 Measured value 63.63 7.94 Example 17. ν·(4-{3·[anti-hexahydrocyclopentane and called 洛洛_1(2Η)yl]dioxyindole phenylmethylacetamide hydrochloride This test procedure is the same as in Example 10, synthetic route A, replacing step i with N_(4) via stupid)_N-methylacetamidine 4: mercaptophthalamide. Elemental microanalysis: Theoretical value measured % c % Η 64.67 8.28 64.10 8.15 % Ν % Cl- 7.94 10.05 7.91 10.01 152491.doc •27· 201144280 Example 18 · N-(4-{3_[trans-hexa-argon cyclopentane And [b] ib-l-(2H)-yl 1 propoxy}phenyl)-2-methoxyacetamide hydrochloride This test procedure is the same as in Example 10, Synthetic Path A, by N (4) Hydroxyphenyl)-2_methoxyacetamide is substituted for the 4-hydroxybenzoguanamine in the step. Elemental microanalysis: % C % Η % Ν % C1' Theoretical value 61.86 7.92 7.59 9.61 Measured value 61.31 7.86 7.56 9.60 Pharmacological study example A · Brain concentration of methyl histamine in NMRI mice This study is based on Taylor et al. The method was carried out (Bi〇chem pharm, 1992, 44, 1261-1267) for the purpose of evaluating the activity of the compound of the present invention as a % type of central histamine receptor antagonist outside the living tissue. The activity of the major metabolite of histamine, NT-methylhistamine, at the central point was measured by measuring the test compound by the oral route. An increase in brain concentration of Ντ•methylhistamine indicates an increase in histamine conversion by blocking the % type of central histamine receptor. NMRI mice (18 to 20 g) were killed by oral administration of the compound of the present invention or its carrier (20 ml/kg) for » hours after treatment; the animals were sacrificed; the brain was removed and frozen in liquid nitrogen. It was weighed and homogenized in (7) 丨N HCIO4. The homogenized product was centrifuged (15 ,, i7 min, 4 ° C), and the supernatant was recovered and divided into aliquots. The aliquots were frozen in liquid nitrogen and stored at _8 Torr. Kneeling until being analyzed. The brain concentration of Ντ_methylhistamine was determined by capillary electrophoresis. ν'Methyl 15249I.doc •28· 201144280 The concentration of histamine in tissues is expressed in pg/g fresh brain. One-way variation analysis, if necessary, followed by a complementary analysis (Dunnett, s) test) to compare the brains of methyl histamine between animals treated with the vector (control) and animals treated with the compounds of the invention concentration. The results show that the compound of the present invention can significantly increase the endogenous brain concentration of N-methylhistamine by more than 14% at a dose of 3 mg/kg p〇. For example, when the compounds of Examples 7, 8 and 9 were administered at 3 mg/kg p〇, the endogenous brain concentrations of NT-methylhistamine increased by 145%, 143% and 190%, respectively. These results demonstrate that the compounds of the invention are potent; antagonists of the type of central histamine receptor. Example B: Affinity of mouse h3 receptors This example aims to measure the affinity of the compounds of the invention against H3 type mouse histamine receptors transfected into CH〇 cells. Different concentrations of these compounds were cultured at room temperature for 24 hours in transfected CHO cells, iodopropoxyphene (i〇d〇pr〇xyfan) (as a radiolabeled ligand, which is specific for the H3 receptor) And the presence of glittering beads. At the end of the culture, the substitution of the test compound for the specifically bound ligand is measured and the affinity constant of these compounds for the mouse H3 receptor is measured. , '. The compound of the present invention has a strong affinity for the H3 type histamine receptor (Ki < 2.1 〇 7 μ) >

Example 1 Compound: Ki = l 50 nM Example 3 Compound: Ki = 86 nM Example 5 Compound: Ki = 64 nM Example 9 Compound: Ki = 47 nM 152491.doc • 29- 201144280 Example c: Pharmaceutical composition for preparation of 1000 tablets Formulation of each lozenge containing 100 mg of active ingredient: Compound of Example 7 ................................... ....................1〇〇g Hydroxypropylcellulose........................ ..................................20 g polyvinylpyrrolidone......... .....................................20 g wheat starch... .................................................. .......150 g lactose ........................................ ...........................900 g magnesium stearate................... .......................................30 g 152491.doc -30-

Claims (1)

201144280 VII. Patent application scope: 1. A compound of formula (I), " its enantiomers and diastereomers, and additionally with pharmaceutically acceptable acid or base addition salts, wherein: ALK represents an alkyl chain, W represents a group - fjl - jj - R or an ijl-R, wherein R and R, each independently R· 〇Ο R· represents a hydrogen atom or, as the case may be, a linear or one or more substituents selected from a group consisting of a hydroxyl group and a hydroxyl group; Branched chain (Ci-CJ alkyl, it should be understood that the term "alkylene" means a straight or branched bond divalent group having 2 to 6 carbon atoms, and the term "alkoxy" means an alkyl-oxy group, wherein The linear or branched alkyl chain contains from 1 to 6 carbon atoms. 2. The compound of the formula (I) of claim 1 wherein the w group is in the para position. 3. The compound of the formula (1) according to claim 1 And its enantiomers and diastereomers, and additionally addition salts with pharmaceutically acceptable acids or bases, wherein ALK is exoethyl or propyl. 4. As in claim 1 (1) a compound 'enantiomer and diastereomer 152491.doc 201144280, and additionally an addition salt with a pharmaceutically acceptable acid or base, wherein ALK Stretch propyl. 5.6. An addition salt of a compound of the formula (I), an enantiomer thereof and a diastereomer of the formula 1 and additionally a pharmaceutically acceptable acid or base, wherein Is a compound of the formula (I), the enantiomers and diastereomers thereof of claim 1 and additionally an addition salt with a pharmaceutically acceptable acid or base, wherein w is a group - N π D 〇!_丁 R' Ο The compound of the formula (I) of claim 1 , its enantiomers and diastereomers ' and additionally an addition salt with a pharmaceutically acceptable acid or base Wherein R and R' each independently represent a hydrogen atom, a methyl group, or an ethyl group, and the groups are optionally substituted with a methoxy group. 8. The compound of the formula (1), the enantiomers and diastereomers thereof of claim 1 and additionally an addition salt with a pharmaceutically acceptable acid or base, wherein w is **®-CO- NH2, -CO-NH-CH3, -CO-N(CH3)2, _c〇·N(CH2CH3)2, -NH-CO-CH3, -N(CH3)-CO-CH3 or -NH-CO-CH2 -OCH3. 9. The compound of formula (I) of claim 1 which is: 4-{3.[cis-hexahydrocyclopenta[b]pyrrole-1(2H)-yl]propoxy}phenylhydrazine Indoleamine, ν_(4-{3·[cis-hexahydrocyclopenta[b]indolepyr-1(2H)-yl]propoxy}phenyl)acetamidamine, 152491.doc 201144280 "[ Shunqi cyclopentane and [b].嘻-1 (2H)-yl]propoxy b N,N-dimethylbenzamide, 4-{3_[cis-hexahydrocyclopenta[b]pyrrole-1(2H)-yl ] propoxybu-N-methyl benzylamine, Ν·(4·{3·[cis-hexahydrocyclopenta[b]n-pyrrol-1(2H)-yl]propoxy}phenyl )-Ν·Methylacetamide, Ν-(4-{3-[cis-hexahydrocyclopenta[b]D-pyrylene-1(211)-yl]propoxy} phenyl)-2 - oxime acetamide, its enantiomers' and additionally addition salts with pharmaceutically acceptable acids or bases. Ίο. A method of preparing a compound according to claim 1, characterized in that a compound of the formula (II) is used as a starting material: Wherein W is a compound of formula (II) condensed with a compound of formula (III) as defined in claim 1 : Br-ALK-Cl (III), wherein ALK is as defined in formula (I) To obtain a compound of formula (IV): Wherein 'W and ALK are as defined above, condensed with a compound of formula (V): 152491.doc (IV), 201144280 It can be purified according to conventional separation techniques, if desired, converted to its addition to a pharmaceutically acceptable acid or base, and, where appropriate, separated into its optical isomers according to conventional separation techniques. body. 11. A compound of the following formula (VI), (VI), wherein the ALK basis is as defined in claim 1, in particular as in the case of claim j, it is understood that it is a compound of formula (I) which is a synthetic intermediate of a compound of formula (I/a) Where w is the group _c〇nrr, 12. W, R and R are as defined in the request. a compound of the following formula (VII), (VH), wherein the ALK basis is as claimed in claim 152491.doc 201144280, which is a person of the compound of formula (I/a) «intermediate, special % # > stomach & formula (I) In the compound, w is its face (1), and if pi is the group -conrr, the case of w, R and R' is as defined in claim i. 13. —A compound of the following formula (vm), '4 OR" where the ALK base is as claimed, and R" is a linear or octagonal (CVC6) alkyl or benzyl group, ^ knife (VIII), which is used as the formula (I/a) The compound of the compound ^ is an intermediate, especially as requested! In the compound of formula (I), W Λ箕 〇 喝 1 w D is a group - c viscous, in the case, it should be understood that the trade, ruler and ruler are as defined in claim 1. 14. A compound of the following formula (IX), (K), ALK-〇 Wherein the ALK group is as defined in the claim i, which is a synthetic intermediate of the formula _ compound, in particular, as in the case of the compound of the formula (1), wherein W is a group -CONRR, it should be understood that W, R And R| is as defined in claim i. A pharmaceutical composition 1 comprising the compound of the formula (1) according to any one of claim 19, or an addition salt thereof with a pharmaceutically acceptable acid or base as an active ingredient' and/or a plurality of pharmaceutically acceptable substances Combination of excipients. 152491.doc 201144280 The pharmaceutical composition of claim 15 for use in the treatment of cognitive and psychological behavioral disorders associated with brain aging, neuropathy: disease or intracranial trauma. The pharmaceutical composition of claim 16 is for treating Alzheimer's Parkinson's disease, Pick's disease, Lewy body dementia frontal lobe and subcortical dementia , forehead leaf type dementia, vascular dementia, Dyton's disease and multiple sclerosis related cognitive and psychological behavior disorders. The pharmaceutical composition of claim 16 for use in the treatment of psychological behavioral disorders, such as sleep disorders, sluggishness, and anxiety-depression states. 19. The pharmaceutical composition of claim 18 is provided. Alzheimer's disease and sleep disorders associated with Parkinson's disease. 2. The pharmaceutical composition of claim 15 which has a poetic treatment disorder, anxiety _ inhibition state, Tori's syndrome, schizophrenia and related cognitive disorders, and pain, and is also used for cardiac sleep disorders , sleep arousal rhythm disorders and attention to lack of hyperactivity syndrome. A pharmaceutical composition according to claim 20, which is for use in the treatment of a sleep disorder such as 'sleepiness, apnoea in obstructive sleep apnea syndrome or in attention deficit hyperactivity disorder, and diurnal narcolepsy. / w , 22 - A combination of a compound of the formula (1) according to any one of claims 1 to 9 and a B:cholesterase inhibitor. Risk @曰23. - A combination of a compound of formula (1) according to any one of claims 1 to 9 with d〇nepezil, gaiantamine or les astastigmine . 24. A combination of claim 22 or 23 for use in the treatment of a cognitive disorder with Akan. Maternal disease phase 152491.doc 201144280 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the most A chemical formula that shows the characteristics of the invention: 152491.doc