HK1160125A - Azabicyclo[3.2.0]hept-3-yl compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

Azabicyclo [3.2.0] hept-3-yl compounds, process for their preparation and pharmaceutical compositions containing them

The present invention relates to novel azabicyclo [3.2.0] hept-3-yl compounds, processes for their preparation and pharmaceutical compositions containing them.

The compounds of the present invention are of significant value from the pharmacological standpoint of their interaction with the central histaminergic system in vivo.

The aging of the population due to the increase in the average life span at birth also has led to a dramatic increase in the incidence of age-related neuropathologies, particularly alzheimer's disease. The main clinical manifestations of brain aging, and in particular of age-related neuropathologies, are the loss of memory and cognitive function, which may lead to dementia.

Neuropharmacological studies have shown that histamine acts as a neurotransmitter or neuromodulator in physiological or pathophysiological states in the central nervous system via the central histaminergic system (Pell and Green, Annu. Rev. Neurosci., 1986, 9, 209-254; Schwartz et al, Physiol. Rev., 1991, 71, 1-51). Thus, histamine has been shown to be associated with a variety of physiological and behavioral processes, such as thermoregulation, neuroendocrine regulation, nociception, circadian rhythm, state of loss, motility, aggression, eating behavior, learning and recitation, and synaptic plasticity (Hass et al, Histaminergic neurons: morphology and function, Boca Raton, FL: CRC Press, 1991, pp. 196-208; Brown et al, prog. neurobiology, 2001,63637-672; smith et al, Neurommunoperation 2007,14page 317-.

Studies in animals have shown that increased endogenous levels of hypersynaptic (extra-synaptic) histamine have enabled them to enhance alertness, learning and memory processes and to modulate food intake (Brown et al, prog. neurobiol., 2000, 63, 637-charge 672; Passani et al, neurosci. Biobehav. Rev., 2000, 24, 107-charge 113). Thus, possible therapeutic indications for compounds capable of increasing total histamine (turn over) or release in the center are the treatment of cognitive deficits associated with brain aging, with acute and chronic neurodegenerative diseases and with schizophrenia, but also mood disorders, tourette's syndrome (Gulhan Ercan-Senciek et al, New England Journal of Medicine, 20.2010, 1901-1908), schizophrenia, sleep disorders, disorders of sleep-wake rhythm and attention deficit hyperactivity syndrome. In addition, studies have shown that histamine injections into the central hypothalamic nucleus involved in the regulation of satiety can reduce feeding in rats. Furthermore, a reduced function of histamine transmission has been demonstrated in genetically obese rats (Machidori et al Brain Research, 1992, 590, 180-. Therefore, disorders of eating behaviors and obesity are also possible therapeutic indications for the compounds of the present invention.

The present invention relates to novel azabicyclo compounds which differ from the compounds described in WO2005/089747 by the presence of a 3-azabicyclo [3.2.0] heptane ring system.

Surprisingly, the structural differences from the compounds of WO2005/089747 are such that the compounds of the present invention not only have significant cognitive (pro-cognitive) improving properties, but also have potent wake-up, anti-sedation, anti-hypnotic and anti-anxiety properties.

At the neurological level, the combination of these activities opens the door not only to new treatments for cognitive disorders associated with brain aging, neurodegenerative diseases or cranial traumas, but also provides new therapeutic approaches for treating psychobehavioral disorders associated with these pathologies (e.g. sleep disorders, apathy and/or depressive states). In addition, the pharmacological profile of the compounds of the invention also makes them useful as new therapies in the psychiatric field, such as tourette's syndrome, schizophrenia, mood disorders or sleep disorders.

More specifically, the present invention relates to compounds of formula (I), the enantiomers and diastereomers thereof, and to the addition salts thereof with a pharmaceutically acceptable acid or base:

wherein:

ALK represents an alkylene chain,

w represents a group

Wherein R and R' independently of one another represent a hydrogen atom or a linear or branched (C)₁-C₆) Alkyl, optionally substituted with one or more groups selected from halogen, hydroxy and alkoxy,

it should be understood that:

the term "alkylene" denotes a linear or branched divalent radical having 2 to 6 carbon atoms,

the term "alkoxy" represents an alkyl-oxy group in which the alkyl chain, which is linear or branched, has from 1 to 6 carbon atoms.

The pharmaceutically acceptable acid may include, but is not limited to, hydrochloric 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, methanesulfonic acid, camphoric acid, and the like.

Such pharmaceutically acceptable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, and the like.

Preferred compounds of formula (I) are those wherein the W group is in the para position.

ALK preferably represents a linear divalent group having 2 to 6 carbon atoms, such as ethylene, propylene or butylene, more preferably propylene.

A particular embodiment of the invention relates to compounds of formula (I) in which W represents the following group:

another particular embodiment of the invention relates to compounds of formula (I) wherein W represents the following group:

preferably, R and R' independently of one another represent a hydrogen atom, a methyl or ethyl group, these groups being optionally substituted by methoxy.

More particularly, W represents the group-CO-NH-CH₃、-CO-N(CH₃)₂、-CO-NH₂、-CO-N(CH₂CH₃)₂、-NH-CO-CH₃、-N(CH₃)-CO-CH₃or-NH-CO-CH₂-OCH₃。

More particularly preferred are compounds of the meso (meso) configuration.

Even more preferably, the present invention relates to the following compounds of formula (I) and their addition salts with pharmaceutically acceptable acids or bases:

4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } benzamide,

n- (4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } phenyl) acetamide,

4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } -N, N-dimethylbenzamide,

n- (4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } phenyl) -N-methylacetamide.

The addition salts with pharmaceutically acceptable acids are particularly preferably the hydrochloride, oxalate and citrate salts.

The invention also relates to a process for the preparation of compounds of formula (I), which process is characterized in that a compound of formula (II) is used as starting material:

wherein W is as defined for formula (I),

condensing a compound of formula (II) with a compound of formula (III) in a basic medium:

Br——ALK——Cl (III)，

wherein ALK is as defined for formula (I),

obtaining a compound of formula (IV):

wherein W and ALK are as defined above,

condensing it with a compound of formula (V):

obtaining a compound of formula (I) as defined above:

it can be purified according to conventional separation techniques, converted into an addition salt thereof with a pharmaceutically acceptable acid or base if necessary, and separated into its optical isomers according to conventional separation techniques if appropriate.

The compounds of formulae (II), (III) and (V) may be obtained commercially or may be prepared by one skilled in the art using conventional chemistry described in the literature.

Alternatively, by coupling with an amine of formula NHRR '(wherein R and R' are as defined for formula (I)), a compound of formula (VI):

wherein the ALK group is as defined above,

can be used as synthesis intermediates for compounds of formula (I/a) (special case of compounds of formula (I) wherein W represents a-CONRR' group).

Also, by coupling with an amine of formula NHRR '(wherein R and R' are as defined for formula (I)), a compound of formula (VII):

wherein the ALK group is as defined above,

can be used as synthesis intermediates for compounds of formula (I/a) (special case of compounds of formula (I) wherein W represents a-CONRR' group).

Alternatively, the compounds of formula (I/a) (a special case of compounds of formula (I) in which W represents a-CONRR ' group) may also be obtained by coupling amines NHRR ' (in which R and R ' are as defined for formula (I)), using compounds of formula (VIII):

wherein the ALK group is as defined above and R' represents a linear or branched (C)₁-C₆) An alkyl group or a benzyl group, or a substituted or unsubstituted alkyl group,

the compounds of formula (VIII) can be prepared from the corresponding carboxylic acids (VI) or acid chlorides (VII) as indicated above.

Finally, it is also possible to obtain the compounds of formula (I/a) by hydrolysis of the compounds of formula (IX):

wherein the ALK group is as defined above.

Pharmacological studies with compounds of formula (I) have shown that they have cognitive improving properties by promoting memory and learning processes, and also have arousal, anti-sedative, anti-hypnotic (anti-hypnocic) and anxiolytic properties.

At the neurological level, the compounds of the invention may be used for the treatment of cognitive diseases associated with brain aging or with neurodegenerative diseases, such as alzheimer's disease, parkinson's disease, pick's disease, dementia with lewy bodies, frontal and subcortical dementia, frontotemporal dementia, vascular dementia, huntington's disease and multiple sclerosis, in new therapies for cognitive disorders associated with cranial traumas, and also for the treatment of psycho-behavioral disorders associated with these pathologies, such as sleep disorders, apathy and anxiety-depressive states. A particular target disease is sleep disorders associated with alzheimer's disease and parkinson's disease (e.g. excessive daytime sleepiness). In addition, dyskinesias associated with Parkinson's disease can also be treated by the compounds of the present invention.

At the psychiatric level, these compounds may be useful in the treatment of mood disorders, more particularly in the treatment of anxiety-depressive states, tourette's syndrome, schizophrenia and cognitive disorders associated therewith, and also in the treatment of sleep disorders, sleep-wake rhythm disorders and attention deficit hyperactivity syndrome (ADHD). Among these sleep disorders, particular mention may be made of hypersomnia and sleep apnea. Sleep disorders such as lethargy and excessive daytime sleepiness that occur in obstructive sleep apnea syndrome or attention deficit hyperactivity syndrome are also target diseases.

The invention also relates to pharmaceutical compositions comprising a compound of formula (I) and one or more pharmaceutically acceptable excipients.

In the pharmaceutical composition of the present invention, the weight ratio of the active ingredient (the ratio of the weight of the active ingredient to the total weight of the composition) is 1 to 50%.

Among the pharmaceutical compositions of the invention, mention may be made more particularly of those suitable for administration by the following routes: oral, parenteral, nasal, transdermal or transdermal, rectal, lingual, ocular or respiratory, in particular tablet or lozenge, sublingual tablet, sachet, encapsulate (paquets), capsule, sublingual or rectal dosage form (glossettes), lozenge, suppository, cream, ointment, dermal gel and drinkable or injectable ampoule.

The dose used depends on the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication and any associated therapy, and ranges from 0.05mg to 500mg per 24 hours for therapies administered 1-3 times per day.

The administration of a combination of a compound of formula (I) with L-dopa, in particular 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } benzamide, or an addition salt thereof with a pharmaceutically acceptable acid or base, in combination with L-dopa also forms an integral part of the invention. This type of combination product can be used for the treatment of cognitive and motor disorders of parkinson's disease.

The following examples are intended to illustrate the invention without limiting it in any way. The structures of the compounds described in the examples can be determined according to conventional spectrophotometric techniques (infrared, NMR, mass spectrometry, etc.).

As information, all of the following compounds have meso-type stereochemistry.

Example 1, scheme a:4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzamide hydrochloride

Step 1: 4- (3-Chloropropoxy) benzamide

A mixture containing 0.004mol of 4-hydroxybenzamide, 0.004mol of 1-bromo-3-chloropropane and 0.006mol of cesium carbonate in 10ml of acetonitrile was heated under reflux for 5 hours.

Step 2: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzamide

To the reaction mixture of step 1 were added 0.004mol of (1R, 5S) -3-azabicyclo [3.2.0] heptane (the synthesis of which is described in the publication J.Med.chem.1967, 10, 621-623) and 0.002mol of sodium iodide at room temperature. Then, heating was resumed under reflux for 16 hours. The precipitate was filtered and washed with acetonitrile. The filtrate was concentrated to dryness. The residue was dissolved in dichloromethane. The solution obtained is extracted with sodium hydroxide solution and then with water, then dried over magnesium sulfate and concentrated to dryness. The residue was purified by preparative chromatography on the Lichroprep RP-18 phase.

Mass spectrum:[M+H]⁺theoretical value m/z 275.1760; the experimental value m/z is 275.1773

Step 3: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzamide hydrochloride

The product obtained in step 2 was dissolved in 10ml of ethanol, to which 2ml of 2N ethereal HCl was added. The product thus obtained is filtered, washed with ethanol and dried in vacuo.

Elemental microanalysis:

％C ％H ％N ％Cl^-

calculated value 61.837.469.0111.41

Found value 61.337.378.8511.50

Example 1, route B:4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzamide hydrochloride

Step 1: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzonitrile

The experimental procedure was the same as for example 1, scheme A, steps 1 and 2, but 4-hydroxybenzonitrile was used instead of 4-hydroxybenzamide in step 1.

Step 2: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzamide hydrochloride

The compound (2.2g) obtained in the above step was dissolved in 90ml of ethanol and heated under reflux in the presence of 5.1g of KOH for 18 hours. The mixture was poured into 90ml of water and then concentrated in vacuo to half volume. The solid obtained was filtered, washed with isopropyl ether and then dried. The hydrochloride salt was prepared according to the procedure of scheme a, step 3, example 1.

Elemental microanalysis：

％C ％H ％N ％Cl^-

Calculated value 61.837.469.0111.41

Found value 61.697.398.7711.47

Example 1, route C:4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzamide hydrochloride

Step 1: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzoic acid methyl ester

The experimental procedure was the same as for example 1, scheme A, steps 1 and 2, but using methyl 4-hydroxybenzoate instead of 4-hydroxybenzamide in step 1.

Step 2:4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzoic acid

A mixture of 3.5g of the compound of step 1, 12.7ml of 2N sodium hydroxide solution and 8ml of methanol was heated under reflux for 1 hour. To the reaction mixture cooled in an ice bath was added 12.7ml of 2N HCl. The precipitate was washed with water and dried in vacuo.

Elemental microanalysis:

％C ％H ％N

calculated value 69.797.695.09

Found value 69.677.735.44

Step 3: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzoyl chloride hydrochloride

A mixture of 1.8g of the product described in step 2 and 20ml of thionyl chloride was heated under reflux for 2 hours. The reaction mixture was concentrated in vacuo and co-evaporated twice with toluene. The solid residue was homogenized with diethyl ether, filtered and dried in vacuo.

Step 4: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzamide hydrochloride

To a solution of 1g of the product described in step 3 in dichloromethane was added 4ml of 2N ammonia dropwise at 0 ℃ to prepare methanol. The mixture was then stirred at room temperature for 1 hour, washed with 2N sodium hydroxide solution and then with water. The organic phase was dried over magnesium sulfate and concentrated. The residual oil was dissolved in 10ml of ethanol, and 2ml of 2N ethereal HCl was added thereto. The product thus obtained is filtered, washed with ethanol and dried in vacuo.

Elemental microanalysis:

％C ％H ％N ％Cl^-

calculated value 61.837.469.0111.41

Found value 61.577.408.7111.53

Example 2: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzamide experimental procedure the procedure of example 1, scheme a, steps 1 and 2, was repeated.

Elemental microanalysis:

％C ％H ％N

calculated value 70.048.0810.21

Found value 69.247.589.76

Example 3: 4- {2- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Ethoxy benzamide

The experimental procedure is the same as for example 1, scheme A, steps 1 and 2, but 1-bromo-2-chloroethane is used instead of 1-bromo-3-chloropropane in step 1.

Elemental microanalysis:

％C ％H ％N

calculated value 69.217.7410.76

Found value 69.007.7210.58

Example 4: 4- {4- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Butoxy benzamide experimental formulaThe procedure is the same as for steps 1 and 2 of scheme A of example 1, except that 1-bromo-4-chlorobutane is used instead of 1-bromo-3-chloropropane in step 1.

Elemental microanalysis:

％C ％H ％N

calculated value 70.808.399.71

Found value 69.188.289.37

Example 5: n- (4- {3- [ (1R, 5S) -3-azabicyclo [ 3.2.0)]Hept-3-yl]Propoxy } phenyl) acetamide

The experimental procedure was the same as for example 1, scheme A, steps 1 and 2, but in step 1N- (4-hydroxyphenyl) acetamide was used instead of 4-hydroxybenzamide.

Elemental microanalysis:

％C ％H ％N

calculated value 70.808.399.71

Found value 70.548.3510.22

Example 6: n- (4- {2- [ (1R, 5S) -3-azabicyclo [ 3.2.0)]Hept-3-yl]Ethoxy } phenyl) acetamide

The experimental procedure was the same as in example 3, but using N- (4-hydroxyphenyl) acetamide instead of 4-hydroxybenzamide.

Elemental microanalysis:

％C ％H ％N

calculated value 70.048.0810.21

Found value 69.447.969.96

Example 7: n- (4- {4- [ (1R, 5S) -3-azabicyclo [ 3.2.0)]Hept-3-yl]Butoxy } phenyl) acetamide

The experimental procedure was the same as in example 4, but using N- (4-hydroxyphenyl) acetamide instead of 4-hydroxybenzamide.

Elemental microanalysis:

％C ％H ％N

calculated value 71.498.679.26

Found value 71.028.588.93

Example 8: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy } -N, N-dimethylbenzamide hydrochloride

The experimental procedure was the same as for the synthesis of scheme A of example 1, but 4-hydroxy-N, N-dimethylbenzamide was used instead of 4-hydroxybenzamide in step 1.

Elemental microanalysis:

％C ％H ％N ％Cl^-

calculated value 63.808.038.2710.46

Found value 63.297.958.1910.50

Example 9: 4- {2- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-2-yl]Ethoxy } -N, N-dimethylbenzamide hydrochloride

The experimental procedure was the same as in example 3, but 4-hydroxy-N, N-dimethylbenzamide was used instead of 4-hydroxybenzamide. The compound thus obtained is converted into a salt according to the procedure of scheme a, step 3 of example 1.

Elemental microanalysis:

％C ％H ％N ％Cl ％Cl^-

calculated value 62.867.768.6210.9110.91

Found value 62.547.668.4010.6610.67

Example 10: 4- {4- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Butoxy } -N, N-dimethylbenzamide hydrochloride

The experimental procedure was the same as in example 4, but 4-hydroxy-N, N-dimethylbenzamide was used instead of 4-hydroxybenzamide. Then 2ml of 2N hydrochloric acid was added to a 10ml ethanol solution of the compound thus obtained. The product obtained is filtered, washed with diethyl ether and dried in vacuo.

Elemental microanalysis:

％C ％H ％N ％Cl^-

calculated value 64.678.287.9410.05

Found value 64.397.767.9410.62

Example 11: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy } -N, N-diethylbenzamide hydrochloride

The experimental procedure was the same as for the synthesis of scheme A of example 1, but 4-hydroxy-N, N-diethylbenzamide was used instead of 4-hydroxybenzamide in step 1.

Elemental microanalysis:

％C ％H ％N ％Cl ％Cl^-

calculated value 65.478.527.639.669.66

Found value 64.668.257.5910.5610.13

Example 12: 4- {2- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Ethoxy } -N, N-diethylbenzamide hydrochloride

The experimental procedure was the same as in example 3, but 4-hydroxy-N, N-diethylbenzamide was used instead of 4-hydroxybenzamide. The compound thus obtained is converted into a salt according to the procedure of scheme a, step 3 of example 1.

Elemental microanalysis:

％C ％H ％N ％Cl^-

calculated value 64.678.287.9410.05

Found value 64.577.918.039.65

Example 13: 4- {4- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Butoxy } -N, N-diethylbenzamide hydrochloride

The experimental procedure was the same as in example 4, but 4-hydroxy-N, N-diethylbenzamide was used instead of 4-hydroxybenzamide. Then 2ml of 2N hydrochloric acid was added to a 10ml ethanol solution of the compound thus obtained. The product obtained is filtered, washed with diethyl ether and dried in vacuo.

Elemental microanalysis:

％C ％H ％N ％Cl^-

calculated value 66.218.737.359.31

Found value 67.418.347.6712.01

Example 14: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy } -N-methylbenzamide hydrochloride

The experimental procedure was the same as for the synthesis of scheme A of example 1, but 4-hydroxy-N-methylbenzamide was used instead of 4-hydroxybenzamide in step 1.

Elemental microanalysis:

％C ％H ％N ％Cl ％Cl^-

calculated value 62.867.768.6210.9110.91

Found value 62.577.688.6111.1010.99

Example 15: 4- {2- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-2-yl]Ethoxy } -N-methylbenzamide

The experimental procedure was the same as in example 3, but 4-hydroxy-N-methylbenzamide was used instead of 4-hydroxybenzamide.

Elemental microanalysis:

％C ％H ％N

calculated value 70.048.0810.21

Found value 69.667.9810.12

Example 16: 4- {4- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Butoxy } -N-methylbenzamide

The experimental procedure was the same as in example 4, but 4-hydroxy-N-methylbenzamide was used instead of 4-hydroxybenzamide.

Elemental microanalysis:

％C ％H ％N

calculated value 71.498.679.26

Found value 70.998.478.40

Example 17: n- (4- {3- [ (1R, 5S) -3-azabicyclo [ 3.2.0)]Hept-3-yl]Propoxy } phenyl) -N-methylacetamide hydrochloride

The experimental procedure was the same as for the synthesis of scheme A of example 1, but using N- (4-hydroxyphenyl) -N-methylacetamide instead of 4-hydroxybenzamide in step 1.

Elemental microanalysis:

％C ％H ％N ％Cl ％Cl^-

calculated value 63.808.038.2710.4610.46

Found value 64.077.977.8810.1610.30

Example 18: n- (4- {2- [ (1R, 5S) -3-azabicyclo [ 3.2.0)]Hept-2-yl]Ethoxy } phenyl) -N-methylacetoacetateAmine hydrochloride

The experimental procedure was the same as in example 3, but using N- (4-hydroxyphenyl) -N-methylacetamide instead of 4-hydroxybenzamide. The compound thus obtained is converted into a salt according to the procedure of scheme a, step 3 of example 1.

Elemental microanalysis:

％C ％H ％N ％Cl ％Cl^-

calculated value 62.867.768.6210.9110.91

Found value 62.147.868.0611.3210.73

Example 19: n- (4- {4- [ (1R, 5S) -3-azabicyclo [ 3.2.0)]Hept-3-yl]Butoxy } phenyl) -N-methylacetamide hydrochloride

The experimental procedure was the same as in example 13, but using N- (4-hydroxyphenyl) -N-methylacetamide instead of 4-hydroxy-N, N-diethylbenzamide.

Elemental microanalysis:

％C ％H ％N ％Cl ％Cl^-

calculated value 64.678.287.9410.0510.05

Found value 64.257.797.8910.4710.14

Example 20: n- (4- {3- [ (1R, 5S) -3-azabicyclo [ 3.2.0)]Hept-3-yl]Propoxy } phenyl) -2-methoxyacetamide

The experimental procedure was the same as for example 1, scheme A, steps 1 and 2, but in step 1N- (4-hydroxyphenyl) -2-methoxyacetamide was used instead of 4-hydroxybenzamide.

Elemental microanalysis:

％C ％H ％N

calculated value 67.908.238.80

Found value 67.888.228.97

Example 21: n- (4- {2- [ (1R, 5S) -3-azabicyclo [ 3.2.0)]Hept-3-yl]Ethoxy } phenyl) -2-methoxyacetamide hydrochloride

The experimental procedure was the same as in example 3, but using N- (4-hydroxyphenyl) -2-methoxyacetamide instead of 4-hydroxybenzamide. Then 2ml of 2N hydrochloric acid was added to a 10ml ethanol solution of the compound thus obtained. The product obtained is filtered, washed with diethyl ether and dried in vacuo.

Elemental microanalysis:

％C ％H ％N ％Cl ％Cl^-

calculated value 59.917.398.2210.4010.40

Found value 59.767.448.1210.6610.36

Example 22: n- (4- {4- [ (1R, 5S) -3-azabicyclo [ 3.2.0)]Hept-3-yl]Butoxy } phenyl) -2-methoxyacetamide hydrochloride

The experimental procedure was the same as in example 13, but using N- (4-hydroxyphenyl) -2-methoxyacetamide instead of 4-hydroxy-N, N-diethylbenzamide.

Elemental microanalysis:

％C ％H ％N ％Cl ％Cl^-

calculated value 61.867.927.599.619.61

Found value 61.617.837.429.809.41

Example 23: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzamide oxalate

Experimental methods the procedure of example 1, scheme a, steps 1 and 2 was repeated. Then 0.32g of oxalic acid was added to a solution of 0.38g of the compound thus obtained in 6ml of ethanol. The product obtained is filtered, washed with diethyl ether and dried in vacuo.

Elemental microanalysis:

％C ％H ％N

calculated value 59.336.647.69

Found value 58.996.617.49

Example 24: 4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0]Hept-3-yl]Propoxy benzamide citrate salt

The desired product is obtained by dissolving 1 equivalent of the compound of scheme a, step 2 of example 1 in water in the presence of 1.2 equivalents of citric acid monohydrate.

Elemental microanalysis:

％C ％H ％N

calculated value 56.656.486.01

Found value 56.496.605.99

Pharmacological study

Example A: n in NMRI mice^τIntracerebral levels of-methyl histamine

The study was carried out according to the method of Taylor et al (biochem. pharm., 1992,441261-1267) for the purpose of evaluation as H₃Type central histamine receptor antagonists the ex vivo activity of the compounds of the present invention. After administration of the test compound by the oral route, by measuring N^τCentral levels of methyl histamine (which is the major metabolite of histamine) reveal the activity. N is a radical of^τAn increase in the intracerebral concentration of-MethylHistamine is indicated by blocking H₃Central histamine receptor type leads to an increase in the turn-over metabolism (turn-over) of histamine.

NMRI mice (18-20g) were treated by the oral route using the present invention or its vehicle (20 ml/kg). After 1 hour of pharmacological treatment, animals were sacrificed, brains removed, frozen in liquid nitrogen, weighed and frozen at 0.1N HClO at 4 ℃₄And (4) medium homogenizing. The homogenized product was centrifuged (15000g, 17 min, 4 ℃). The supernatant was recovered and divided into equal portions. Aliquots were frozen in liquid nitrogen and stored at-80 ℃ until they were analyzed.

N^τDetermination of the brain levels of histamine-methyl can be carried out by capillary electrophoresis. N is a radical of^τTissue levels of methyl histamine were expressed in μ g/g fresh brain tissue. N between animals treated with vehicle (control) and animals treated with the compounds of the invention^τComparison of the intracerebral levels of methyl histamine can be carried out by one-way analysis of variance and, if desired, by complementation analysis (Dunnett's experiment).

The results show that the compounds of the invention are capable of significantly increasing endogenous N at a dose of 3mg/kg PO^τ-intracerebral concentration of methyl-histamine. Thus, the compounds of examples 1, 5, 8 and 17 are such that N is^τ-the intracerebral concentration of methyl-histamine is increased by more than 100%.

Example B:electroencephalographic recording of conscious Wistar rats

Electrodes were slowly implanted on the surface of the frontal and parietal cortex of adult male Wistar rats. Rats were placed in cages in a sound isolation chamber and cortical electroencephalograms (EEG) were recorded. Compounds and vehicle were administered randomly through the peritoneal cavity at 10 o' clock on the same day, with a minimum of 3 days between each administration, and rats were self-controlled each time. The absolute intensity (1-4Hz) of slow delta activity (slow delta activities) that dominates slow wave sleep and disappears in wakefulness and out of phase sleep averages over a continuous period of 30 minutes. Above 30 minutes, high and low values of the intensity of slow delta activity are indicative of wakefulness and sleep, respectively.

The results show that the compounds of the invention are able to increase cortical arousal (reduction of the triangle wave) in rats.

For example, the compound of example 1 is capable of causing a significant reduction in the intensity of the slow delta wave for 120 minutes when administered at a dose of 3mg/kg IP, which is indicative of cortical activity and arousal.

Example C:interaction with barbiturate in Wistar rats

The purpose of this experiment was to determine the anti-sedative, arousal and/or anti-hypnotic properties of the compounds of the invention. Rats were placed in individual cages and injected with barbiturate (170mg/kg IP). The 4 hour sleep time after barbiturate injection was determined from the absence of righting reflex (loss of the righting reflex). The compound of the present invention or its vehicle is administered orally 30 minutes before barbiturate administration. The results show that the compounds of the present invention have potent anti-sedative, arousal and/or anti-hypnotic activity.

For example, the compound of example 1 is able to reduce barbiturate-induced sleep time by 81% when the dose is 10mg/kg PO.

Example D:object recognition ability of Sprague-Dawley rats

Object recognition experiments in Sprague-Dawley rats (behav. brain res, 1988,3147-59) are based on spontaneous exploratory activity in animals, characteristic of human memory of the scene. This memory test is performed on age (eur.j. pharmacol, 1997,325173-180) and cholinergic neurological dysfunction (pharm. biochem. behav.1996,53(2) 277-283) was performed based on the difference in the exploration of 2 substantially similar shaped objects (one familiar and the other new). Before the experiment was performed, the animals were habituated to the environment (closed space with no objects inside). During the first phase of the experiment, rats were placed in an enclosed space (3 minutes) with 2 identical objects in the enclosed space. The exploration time for each object is measured. During the second phase of the experiment (3 min), after 24 hours, 1 of the 2 objects was replaced by 1 new object. The exploration time for each object is measured. The evaluation criterion is the difference Delta (in seconds) between the time of exploration for the new object and the familiar object during the second phase. Control animals (pre-treated with vehicle given orally 60 minutes before the start of each phase) were probed for familiar and new objects in the same way, indicating that they had forgotten about the previously introduced object. Animals treated with compounds that promote memory cognition preferentially explore new objects, indicating that the animal has previously introduced objects in memory.

For example, the results obtained with the compound of example 1 of the invention show that the difference Delta is 8 seconds at a dose of 3mg/kg PO, indicating that the compound of the invention is able to greatly enhance memory even at lower doses.

Example E:social cognition in Wistar rats

Social cognitive testing was initially described in 1982(j.comp. physiol., 1982,961000-,91，363-368；Psychopharmacology，1989，97262-268) for studying the cognitive effects of the new compounds on memory. The experiment is carried out according to the natural expression of olfactory memory of a rat and the natural tendency of the olfactory memory of the rat to be forgotten easily, and the memory is evaluated through the cognition of an adult rat to a young animal of the same kind. Young rats (21 days) were randomly selected and placed in cages of adult rats for 5 minutes. The experimenter observes the social cognitive behavior of the adult rat through a video device and measures the total time of the adult rat. Young rats were then removed from adult rat cages and placed in their own cages until the second introduction. The experimental compound was administered to adult rats by the intraperitoneal route and after 2 hours, it was again placed together with young rats (5 minutes). Social cognitive performance was then observed again and duration was determined. The evaluation criterion was the difference between the cognitive times of 2 encounters (T2-T1), expressed in seconds.

The results obtained with the compound of example 1 show that the difference (T2-T1) is 24 seconds and 36 seconds at doses of 1 and 3mg/kg IP, respectively, which indicates that the compound of the invention is able to greatly enhance memory even at lower doses.

Example F:tail suspension experiments in NMRI mice

Tail suspension experiments in mice (Porsolt et al, arch. int. pharmacodyn, 1987,288and 11) the psychopharmacological properties of the compounds can be determined. NMRI mice were hung with a piece of tape on a hook for 6 minutes: the motionless time is automatically measured using a motion sensor. Animals were treated with the compound of the invention or its vehicle separately by the intraperitoneal route 24 hours and 30 minutes before suspension.

The results show that the compound of example 1 is able to give a 119% increase in immobility time when administered at a dose of 10mg/kg IP. This result demonstrates anxiolytic (anxiolytic) properties of the compounds of the invention.

Example G: intracerebral microdialysis in the striatum of conscious rats

Intracerebral microdialysis in the striatum of awake rats has enabled the evaluation of the effect of compounds on the release of neurotransmitters (e.g., dopamine) into the extracellular space of the cerebellar structure (e.g., the striatum).

The technology is carried out in two steps: a surgical procedure (stereotactic implantation of a guide catheter (canula-guide) in anesthetized animals) and a microdialysis procedure (collection of a sample of extracellular brain fluid) in conscious animals.

Male rats of the Wistar species (280-320g) were anesthetized and placed in a stereotaxic apparatus. The guide catheter is implanted into the striatum of the animal according to the following stereotactic coordinates: anterior-posterior (anti-spatial) -1mm, laterality) +2.8mm, depth-3 mm relative to the pro-halo point, according to the scheme of Paxinos and Watson (1996).

One week after surgery, a microdialysis probe (CMA11, 4mm long, Phymep) was implanted into the guide catheter. Animals were placed in experimental cages and the probe inlet was connected to a pump continuously perfused with artificial cerebrospinal fluid (flow rate 1. mu.l/min). After 2 hours of stabilization, collection of microdialysate was started. Samples were collected under baseline conditions (4 samples) and then administered intraperitoneally (6 post-treatment samples were collected).

The extracellular level of dopamine in each microdialysate was evaluated by liquid chromatography with an electrochemical detector. The measurements relative to the baseline (reference 100%) are expressed as mean ± SEM.

The results show that the compound of example 1 of the invention is able to significantly increase the intracerebral concentration of endogenous dopamine up to + 123% (compared to the basal value) at a dose of 10mg/kg i.p.

Example H: pharmaceutical composition

A formulation for making 1000 tablets, each tablet containing 100mg of active ingredient:

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Claims (27)

1. A compound of formula (I), enantiomers and diastereomers thereof, and addition salts thereof with a pharmaceutically acceptable acid or base:

wherein:

ALK represents an alkylene chain,

w represents a groupOr

Wherein R and R' independently of one another represent a hydrogen atom or a linear or branched (C)₁-C₆) Alkyl, optionally substituted with one or more groups selected from halogen, hydroxy and alkoxy,

it should be understood that:

the term "alkylene" represents a linear or branched divalent radical having from 2 to 6 carbon atoms,

the term "alkoxy" represents an alkyl-oxy group in which the alkyl chain, which is linear or branched, has from 1 to 6 carbon atoms.

2. A compound of formula (I) according to claim 1, wherein the W group is in the para position.

3. A compound of formula (I) according to claim 1, wherein ALK represents a linear divalent group having 2-4 carbon atoms, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.

4. A compound of formula (I) according to claim 1, wherein ALK represents propylene, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.

5. A compound of formula (I) according to claim 1, the enantiomers and diastereomers thereof, and the addition salts thereof with a pharmaceutically acceptable acid or base, wherein W represents the group:

。

6. a compound of formula (I) according to claim 1, the enantiomers and diastereomers thereof, and the addition salts thereof with a pharmaceutically acceptable acid or base, wherein W represents the group:

7. a compound of formula (I) according to claim 1, wherein R and R' independently of each other represent a hydrogen atom, a methyl or ethyl group, optionally substituted by methoxy, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base.

8. A compound of formula (I) according to claim 1, wherein W represents the group-CO-NH, its enantiomers and diastereomers and addition salts thereof with a pharmaceutically acceptable acid or base₂、-CO-NH-CH₃、-CO-N(CH₃)₂、-CO-N(CH₂CH₃)₂、-NH-CO-CH₃、-N(CH₃)-CO-CH₃or-NH-CO-CH₂-OCH₃。

9. A compound of formula (I) according to claim 1, which is:

4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } benzamide,

n- (4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } phenyl) acetamide,

4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } -N, N-dimethylbenzamide,

n- (4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } phenyl) -N-methylacetamide.

10. A compound of formula (I) according to claim 1, which is:

4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } benzamide hydrochloride,

4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } benzamide oxalate,

4- {3- [ (1R, 5S) -3-azabicyclo [3.2.0] hept-3-yl ] propoxy } benzamide citrate.

11. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that a compound of formula (II):

wherein W is as defined in claim 1,

condensing a compound of formula (II) with a compound of formula (III) in a basic medium:

Br-ALK——Cl (III)，

wherein ALK is as defined for formula (I),

obtaining a compound of formula (IV):

wherein W and ALK are as defined above,

condensing a compound of formula (IV) with a compound of formula (V):

obtaining a compound of formula (I) as defined above:

it is purified according to conventional separation techniques, converted into an addition salt, if necessary, with a pharmaceutically acceptable acid or base, and, if appropriate, separated into its optical isomers according to conventional separation techniques.

12. A compound of formula (VI):

wherein the ALK group is as defined in claim 1,

useful as synthesis intermediates for compounds of formula (I/a) in the particular form of a compound of formula (I) according to claim 1, wherein W represents the group-CONRR ', with the understanding that W, R and R' are as defined in claim 1.

13. A compound of formula (VII):

wherein the ALK group is as defined in claim 1,

useful as synthesis intermediates for compounds of formula (I/a) in the particular form of a compound of formula (I) according to claim 1, wherein W represents the group-CONRR ', with the understanding that W, R and R' are as defined in claim 1.

14. A compound of formula (VIII):

wherein the ALK group is as defined in claim 1 and R' is a linear or branched chain (C)₁-C₆) An alkyl group or a benzyl group, or a substituted or unsubstituted alkyl group,

useful as synthesis intermediates for compounds of formula (I/a) in the particular form of a compound of formula (I) according to claim 1, wherein W represents the group-CONRR ', with the understanding that W, R and R' are as defined in claim 1.

15. A compound of formula (IX):

wherein the ALK group is as defined in claim 1,

useful as synthesis intermediates for compounds of formula (I/a) in the particular form of a compound of formula (I) according to claim 1, wherein W represents the group-CONRR ', with the understanding that W, R and R' are as defined in claim 1.

16. A pharmaceutical composition comprising as active ingredient a compound of formula (I) according to any one of claims 1 to 10 or an addition salt thereof with a pharmaceutically acceptable acid or base in admixture with one or more pharmaceutically acceptable excipients.

17. The pharmaceutical composition according to claim 16 for the treatment of cognitive and psycho-behavioral disorders associated with brain aging, neurodegenerative disorders or cranial traumas.

18. The pharmaceutical composition according to claim 17 for the treatment of cognitive and psycho-behavioral disorders associated with: alzheimer's disease, Parkinson's disease, pick's disease, dementia with Lewy bodies, frontal and subcortical dementia, vascular dementia, Huntington's disease and multiple sclerosis.

19. The pharmaceutical composition according to claim 17 for use in the treatment of psycho-behavioral disorders.

20. The pharmaceutical composition according to claim 19, wherein the psycho-behavioral disorders are sleep disorders, apathy and anxiety-depressive states.

21. The pharmaceutical composition of claim 19 for the treatment of sleep disorders associated with alzheimer's disease and parkinson's disease.

22. The pharmaceutical composition of claim 16 for the treatment of dyskinesias associated with parkinson's disease.

23. The pharmaceutical composition of claim 16, for treating the following diseases: mood disorders, anxiety-depressive states, tourette's syndrome, schizophrenia and cognitive disorders associated therewith, pain, and also for the treatment of sleep disorders, sleep-wake rhythm disorders and attention deficit hyperactivity syndrome.

24. A pharmaceutical composition according to claim 23 for the treatment of sleep disorders.

25. The pharmaceutical composition according to claim 24, wherein the sleep disorder is hypersomnia, hypersomnia or attention deficit hyperactivity syndrome arising from obstructive sleep apnea syndrome, and excessive daytime sleepiness.

26. A combination of a compound of formula (I) according to any one of claims 1 to 10 and L-dopa.

27. A combination product as claimed in claim 26 for use in the treatment of cognitive and motor disorders of parkinson's disease.