Specification
FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See Section 10; Rule 13)
TITLE
DERIVATIVES OF N-[(7-AZA-BICYCLO[2.2.1]HEPT-l-YL)-ARYL-METHYL]-BENZAMIDE, PREPARATION THEREOF, AND THERAPEUTIC USE THEREOF
APPLICANT
SANOFI
NATIONALITY : FRANCE
OF 174 AVENUE DE FRANCE, F-75013 PARIS
FRANCE
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.
DERIVATIVES OF /V-[(7-AZABICYCL0[2.2.1]HEPT-1-YL)-ARYL-METHYL]BENZAMIDE, PREPARATION THEREOF AND THERAPEUTIC USE
THEREOF
The present invention relates to N-[(7-azabicyclo[2.2.1]hept-1-yl)-aryl-methyl]benzamide derivatives, to the preparation thereof and to the therapeutic use thereof in the treatment or prevention of diseases involving Glyt1 glycine transporters.
The compounds of the invention correspond to general formula (I)
in which:
- R represents a hydrogen atom or a group chosen from the groups (C1-C6)alkyl and (C3-C7)cycloalkyl, optionally substituted with one or more groups chosen, independently of one another, from halogen atoms and (C3-C7)cycloalkyl, (C2-C4)alkenyl, phenyl, (C1-C6)alkoxy and hydroxy! groups; the phenyl group being optionally substituted with one or more (C1-C6)alkoxy groups;
- R1 represents a phenyl or naphthyl group, optionally substituted with one or more substituents chosen, independently of one another, from halogen atoms and (C1-C6)alkyl, (C1-C6)alkoxy, halo-(C1-C6)alkyl, hydroxyl, halo-(C1-C6)alkoxy, (C1-C6)alkyl-thio, (d-C6)alkyl-SO and (C1-C6)alkyl-S02 groups;
- R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms and halo-(C1-C6)alkyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl3-CF3 HCI (1:1) racemic
9 Bn Ph 2-CI,3-CF3 HCI
(1:1) racemic
10 H Ph 2-CI,3-C2H5 HCI (1:1) racemic
TABLE 2
No. Mp°C [OD] 20'C ° LCMS MH+
1 62-63 N.A 389
2 210-211 N.A 443
3 185-186 -50.73 (MeOH, c=0.466 g/100 ml) 443
4 146.5-147.5 N.A 409
5 189.5-191.5 N.A 437
6 181.5-182.5 +34.41 (MeOH, c=0.732g/100 ml) 443
7 244-246 N.A 423
8 153-154 N.A 479
9 159.5-160.5 N.A 499
10 234.2-235.2 N.A 369
The compounds of the invention were subjected to a series of pharmacological tests which demonstrated their advantage as substances having therapeutic activities.
Study of glycine transport in SK-N-MC cells expressing the native human transporter glvt1
[14C]glycine uptake is studied in SK-N-MC cells (human neuroepithelial cells) expressing the native human transporter glytl, by measuring the radioactivity incorporated in the presence or absence of the test compound. The cells are cultured in a monolayer for 48 h in plates pretreated with 0.02% fibronectin. On the day of the experiment, the culture medium is removed and the cells are washed with a Krebs-HEPES ([4-{2-hydroxyethyl)piperazine]-1-ethanesulphonic acid) buffer at pH 7.4. After preincubation for 10 min at 37°C in the presence either of buffer (control batch), or of test compound at various concentrations, or of 10mM glycine (determination of nonspecific uptake), 10 uM [14C]glycine (specific activity 112mCi/mmol) is then added. The incubation is continued for 10 min at 37°C, and the reaction is stopped by means of 2 washes with a Krebs-HEPES buffer at pH 7.4. The radioactivity incorporated by the cells is then estimated after adding 100 ul of liquid scintillant and
stirring for 1 h. The counting is performed on a Microbeta Tri-lux™ counter. The effectiveness of the compound is determined by means of the IC50, which is the concentration of the compound which reduces by 50% the specific uptake of glycine, defined by the difference in radioactivity incorporated by the control batch and the batch which received the glycine at 10 mM.
The compounds of the invention, in this test, have an IC50 of the order of 0.001 to 10 uM.
Table 3 indicates some examples of IC50 results for compounds according to the invention.
TABLE 3
Compound 1C50 (uM)
1 0.038
2 0.003
3 0.023
4 0.027
6 0.0016
The results of the tests carried out on the chiral compounds of the invention and the racemates thereof in general formula (I) show that they are inhibitors of the glytl glycine transporter present in the brain.
These results suggest that the compounds of the invention can be used for the treatment of cognitive and/or behavioural disorders associated with neurodegenerative diseases, with dementia; for the treatment of psychoses, in particular of schizophrenia (deficient form and productive form), acute or chronic extrapyramidal symptoms induced by neuroleptics; for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders; for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or to alcohol withdrawal, sexual behaviour disorders, eating disorders, migraine; pain; sleep disorders.
The compounds according to the invention can therefore be used for the preparation
of medicaments, in particular medicaments which inhibit the glyt1 glycine transporter.
Thus, according to another of the aspects of the invention, a subject thereof is medicaments which comprise a compound of formula (I), or an addition salt of the latter with a pharmaceutically acceptable acid or else a hydrate or a solvate of the compound of formula (I).
A subject of the present invention is also pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the form of a pharmaceutically acceptable base, salt or solvate, and as a mixture, where appropriate, with suitable excipients.
Said excipients are chosen according to the pharmaceutical form and the method of administration desired.
The pharmaceutical compositions according to the invention may thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration.
The unit administration forms may be, for example, tablets, gel capsules, granules, powders, oral or injectable solutions or suspensions, patches or suppositories. For topical administration, ointments, lotions and collyria can be envisaged. Said unit forms contain doses so as to allow a daily administration of 0.01 to 20 mg of active ingredient per kg of body weight, according to the galenical form.
In order to prepare tablets, a pharmaceutical carrier which may be composed of
diluents, for example lactose, microcrystaJJine cellulose or starch, and formulation
additives such as binders (polyvinylpyrrolidone, hydroxypropylmethylcelluiose, etc.),
flow agents such as silica, and lubricants such as magnesium stearate, stearic acid,
glyceryl tribehenate or sodium stearylfumarate, are added to the active ingredient,
which may or may not be micronized. Wetting agents or surfactants such as sodium
iauryl sulphate can also be added.
The preparation techniques may be direct compression, dry granulation, wet
granulation or the hot-melt process.
The tablets may be uncoated, sugar-coated, for example with sucrose, or coated with
various polymers or other suitable materials. They can be designed so as to allow rapid, delayed or sustained release of the active ingredient by virtue of polymer matrices or of specific polymers used in the coating.
In order to prepare gel capsules, the active ingredient is mixed with dry pharmaceutical carriers (simple mixing, dry or wet granulation, or the hot-melt process), or liquid or semi-solid pharmaceutical carriers.
The gel capsules may be hard or soft, and optionally film-coated, so as to have a rapid, sustained or delayed activity (for example, for an enteric form).
A composition in the form of a syrup or an elixir or for administration in the form of drops can contain the active ingredient together with a sweetener, preferably a calorie-free sweetener, methylparaben or propylparaben as antiseptic, a flavour enhancer and a colorant.
The water-dispersible powders and granules can contain the active ingredient as a mixture with dispersing agents or wetting agents, or dispersing agents, such as polyvinylpyrrolidone, as well as with sweeteners and flavour-correcting agents.
For rectal administration, recourse is had to suppositories prepared with binders which melt at the rectal temperature, for example cocoa butter or polyethylene glycols.
For parenteral administration, use is made of aqueous suspensions, isotonic saline solutions or injectable sterile solutions comprising pharmacologically compatible dispersing agents and/or wetting agents, for example propylene glycol or butylene
glycol.
The active ingredient can also be formulated in the form of microcapsules, optionally with one or more supports or additives, or else with a polymer matrix or with a cyclodextrin (patches, sustained-release forms).
The topical compositions according to the invention comprise a medium compatible with the skin. They can be provided in particular in the form of aqueous, alcoholic or aqueous-alcoholic solutions, of gels, of water-in-oil or oil-in-water emulsions having the appearance of a cream or of a gel, of microemulsions or of aerosols, or else in the
form of vesicular dispersions containing ionic and/or nonionic lipids. These galenical forms are prepared according to the usual methods in the fields under consideration.
By way of example, a unit administration form for a compound according to the invention in tablet form can comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscarmellose 6.0 mg
Maize starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
When given orally, the dose of active ingredient administered per day can reach 0.1 to
20 mg/kg, in one or more intakes.
There may be particular cases where higher or lower dosages are appropriate; such
dosages do not depart from the context of the invention. Depending on the usual
practice, the dosage appropriate for each patient is determined by the physician
according to the method of administration and the weight and response of said
patient.
According to another of its aspects, the present invention also relates to a method for treating the pathologies indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof.
CLAIMS 1. Compound of general formula (I)
in which:
- R represents a hydrogen atom or a group chosen from the groups (C1-C6)alkyl and (C3-C7)cycloalkyl, optionally substituted with one or more groups chosen, independently of one another, from halogen atoms and (C3-C7)cyc[oaikyl, (C2-C4)alkenyl, phenyl, (C1-C6)alkoxy and hydroxyl groups; the phenyl group being optionally substituted with one or more (C1-C6)alkoxy groups;
- R1 represents a phenyl or naphthy] group, optionally substituted with one or more substituents chosen, independently of one another, from halogen atoms and (C1-C6)alkyl, (C1-C6)alkoxy, halo-(C1-C6)alkyl, hydroxyl, halo-fd-(C1-C6)alkoxy, (C1-C6)alkyl-thio, (C1-C6)alkyl-SO and (C1-C6)alkyl-S02 groups;
- R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms and ha!o-(d-C6)alkyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(Cr C3)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-thio, (CrC6)alkyl-SO and (C1-C6)alkyl-S02 groups;
in the form of a base or of an addition salt with an acid.
2. Compound of general formula (I) according to Claim 1, characterized in that
R represents a hydrogen atom or a (C1-C6)alkyl or benzyl group;
R1 and R2 being as defined in Claim 1, in the form of a base or of an addition salt with an acid.
3. Compound of general formula (I) according to Claim 1, characterized in that
R, represents a phenyl group;
R and R2 being as defined in Claim 1, in the form of a base or of an addition salt with
an acid.
4. Compound of general formula (I) according to Claim 1, characterized in that
R2 represents one or more substituents chosen from a hydrogen atom, halogen atoms and halo-(C1-C6)alkyl or (C1-C6)alkyl groups;
R and R being as defined in Claim 1, in the form of a base or of an addition salt with an acid.
5. Compound of general formula (I) according to Claim 1, characterized in that
R represents a hydrogen atom or a (C1-C6)alkyl or benzyl group;
R, represents a phenyl group;
R2 represents one or more substituents chosen from a hydrogen atom, halogen
atoms and halo-(C1-C6)alkyl or (C1-C6)alkyl groups,
in the form of a base or of an addition salt with an acid.
6. R represents a hydrogen atom or a methyl, ethyl or benzyl group;
R1 represents a phenyl group;
R2 represents one or more substituents chosen from a hydrogen atom, a chlorine atom and methyl, ethyl or trifluoromethyi groups, in the form of a base or of an addition salt with an acid.
7. Compound according to Claim 1 or 2, characterized in that it is chosen from:
•N-[(7-azabicyclo[2.2.1 ]hept-1 -yl)phenylmethyl](2-methyl-3-
trifluoromethyl)benzamide;
•N-[(7-azabicyc!o[2.2.1 ]hept-1 -yl)phenylmethyl](2,6-dichloro-3-trifluoromethyl)benzamide, and the hydrochloride thereof; •(-HV-[(7-azabicyclo[2.2.1 ]hept-1 -yl)phenylmethyl](2,6~dichloro-3-trifluoromethyl)benzatnide, and the hydrochloride thereof;
•/V-[(7-azabicyclo[2.2.1]hept-1-yl)phenylmethyl](2-chloro-3-trifluoromethyl)benzamide, and the hydrochloride thereof;
•2-chloro-/V-[(7-ethyl-7-azabicyclo[2.2.1]hept-1 -yl)phenyfmethyl](3-trifluoromethyi)benzamide, and the hydrochloride thereof;
•(+)-/\/-[(7-azabicyclo[2.2.1]hept-1-yl)phenylnnethyl](2,6-dichloro-3-trifluoromethyl)benzamide, and the hydrochloride thereof;
•2-chloro-N-[(7-methyl-7-azabicyclo[2.2.1]hept-1-yl)phenylmethyl]-3-trifluoromethyl-benzamide, and the hydrochloride thereof;
•/V-[(7-benzyl-7-azabicyclo[2.2.1]hept-1-yl)phenylmethyi]-(2-methyl-3-trifluoro-methyl)benzamide, and the hydrochloride thereof; •N-[(7-benzyl-7-azabicyclo[2.2.1]hept-1-yl)phenylmethyl](2-chloro-3-trifiuoromethyl)benzamide, and the hydrochloride thereof;
•N-[(7-azabicyclo[2.2.1]hept-1-yl)phenylmethyl](2-chloro-3-ethyl)benzamide, and the hydrochloride thereof.
8. Process for preparing a compound of general formula (I) according to Claim 1, characterized in that a compound of general formula (II)
in which R and R, are as defined according to Claim 1, reacts with a compound of general formula (III)
in which Y represents a leaving group or a halogen atom and R2 is as defined according to Claim 1.
9. Compound of general formula (II)
in which R and R1 are as defined in Claim 1.
10. Medicament, characterized in that it comprises a compound of formula (I)
according to any one of Claims 1 to 7, or an addition salt of this compound with a pharmaceutically acceptable acid.
11. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 7, or a pharmaceutically acceptable salt of this compound, and also at least one pharmaceutically acceptable excipient.
12. Use of a compound of formula (I) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of cognitive and/or behavioural disorders associated with neurodegenerative diseases; with dementia.
13. Use of a compound of formula (I) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of psychoses, of schizophrenia (deficient form and productive form) and of acute or chronic extrapyramidal symptoms induced by neuroleptics.
14. Use of a compound of formula (I) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of various forms of anxiety, panic attacks, phobias and obsessive-compulsive disorders.
15. Use of a compound of formula (I) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or alcohol withdrawal, sexual behaviour disorders, eating disorders, and migraine.
16. Use of a compound of formula (I) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of pain.
17. Use of a compound of formula (I) according to any one of Claims 1 to 7, for the preparation of a medicament for the treatment of sleep disorders.
18. Compound according to any one of Claims 1 to 7, for the treatment of cognitive and/or behavioural disorders associated with neurodegenerative diseases; with dementia.
19. Compound according to any one of Claims 1 to 7, for the treatment of psychoses, of schizophrenia (deficient form and productive form) and of acute or chronic extrapyramidal symptoms induced by neuroleptics.
20. Compound according to any one of Claims 1 to 7, for the treatment of various forms of anxiety, panic attacks, phobias and obsessive-compulsive disorders.
21. Compound according to any one of Claims 1 to 7, for the treatment of various forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or alcohol withdrawal, sexual behaviour disorders, eating disorders, and.migraine.
22. Compound according to any one of Claims 1 to 7, for the treatment of pain.
23. Compound according to any one of Claims 1 to 7, for the treatment of sleep disorders.