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Showing content from https://patents.google.com/patent/CA2758367A1/en below:

CA2758367A1 - Derivatives of n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof

CA2758367A1 - Derivatives of n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof - Google PatentsDerivatives of n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof Download PDF Info

Publication number: CA2758367A1
Authority: CA; Canada
Prior art keywords: alkyl; compound; phenyl; methyl; bicyclo
Prior art date: 2009-04-14
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Abandoned

Application number

CA2758367A

Other languages

French (fr)

Inventor

Gihad Dargazanli

Genevieve Estenne-Bouhtou

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Sanofi SA

Original Assignee

Sanofi SA

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2009-04-14

Filing date

2010-04-13

Publication date

2010-10-21

2010-04-13 Application filed by Sanofi SA filed Critical Sanofi SA

2010-10-21 Publication of CA2758367A1 publication Critical patent/CA2758367A1/en

Status Abandoned legal-status Critical Current

Links

-1 7-aza-bicyclo[2.2.1]hept-1-yl Chemical group 0.000 title claims abstract description 46
238000002360 preparation method Methods 0.000 title claims description 12
230000001225 therapeutic effect Effects 0.000 title abstract description 5
150000001875 compounds Chemical class 0.000 claims abstract description 86
239000002253 acid Substances 0.000 claims abstract description 23
150000003839 salts Chemical class 0.000 claims abstract description 22
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 19
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 16
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
125000005843 halogen group Chemical group 0.000 claims abstract description 14
125000001424 substituent group Chemical group 0.000 claims abstract description 13
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 11
239000001257 hydrogen Substances 0.000 claims abstract description 11
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 8
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 6
125000004399 C1-C4 alkenyl group Chemical group 0.000 claims abstract description 3
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 35
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 20
238000000034 method Methods 0.000 claims description 20
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
208000035475 disorder Diseases 0.000 claims description 9
239000003814 drug Substances 0.000 claims description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
239000000460 chlorine Substances 0.000 claims description 6
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
208000020925 Bipolar disease Diseases 0.000 claims description 5
229910052736 halogen Inorganic materials 0.000 claims description 5
125000004429 atom Chemical group 0.000 claims description 4
230000003542 behavioural effect Effects 0.000 claims description 4
229910052801 chlorine Inorganic materials 0.000 claims description 4
208000007848 Alcoholism Diseases 0.000 claims description 3
208000019901 Anxiety disease Diseases 0.000 claims description 3
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
208000030814 Eating disease Diseases 0.000 claims description 3
208000019454 Feeding and Eating disease Diseases 0.000 claims description 3
208000019695 Migraine disease Diseases 0.000 claims description 3
208000002193 Pain Diseases 0.000 claims description 3
206010033664 Panic attack Diseases 0.000 claims description 3
208000028017 Psychotic disease Diseases 0.000 claims description 3
230000001154 acute effect Effects 0.000 claims description 3
206010001584 alcohol abuse Diseases 0.000 claims description 3
208000025746 alcohol use disease Diseases 0.000 claims description 3
230000036506 anxiety Effects 0.000 claims description 3
230000001684 chronic effect Effects 0.000 claims description 3
230000001149 cognitive effect Effects 0.000 claims description 3
235000014632 disordered eating Nutrition 0.000 claims description 3
208000024714 major depressive disease Diseases 0.000 claims description 3
206010027599 migraine Diseases 0.000 claims description 3
208000019906 panic disease Diseases 0.000 claims description 3
239000008194 pharmaceutical composition Substances 0.000 claims description 3
239000000546 pharmaceutical excipient Substances 0.000 claims description 3
208000019899 phobic disease Diseases 0.000 claims description 3
201000000980 schizophrenia Diseases 0.000 claims description 3
206010012289 Dementia Diseases 0.000 claims description 2
208000019022 Mood disease Diseases 0.000 claims description 2
206010038743 Restlessness Diseases 0.000 claims description 2
230000002950 deficient Effects 0.000 claims description 2
201000010099 disease Diseases 0.000 claims description 2
125000001624 naphthyl group Chemical group 0.000 claims description 2
230000000626 neurodegenerative effect Effects 0.000 claims description 2
208000024891 symptom Diseases 0.000 claims description 2
230000009329 sexual behaviour Effects 0.000 claims 2
208000016153 withdrawal disease Diseases 0.000 claims 2
208000027776 Extrapyramidal disease Diseases 0.000 claims 1
230000006735 deficit Effects 0.000 claims 1
229940126601 medicinal product Drugs 0.000 claims 1
230000036651 mood Effects 0.000 claims 1
230000004770 neurodegeneration Effects 0.000 claims 1
208000015122 neurodegenerative disease Diseases 0.000 claims 1
125000000217 alkyl group Chemical group 0.000 abstract description 7
229910052731 fluorine Inorganic materials 0.000 abstract description 2
125000001153 fluoro group Chemical group F* 0.000 abstract 1
238000001308 synthesis method Methods 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
230000002829 reductive effect Effects 0.000 description 14
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 12
239000000203 mixture Substances 0.000 description 12
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
239000000243 solution Substances 0.000 description 10
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
150000001412 amines Chemical class 0.000 description 8
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
239000012074 organic phase Substances 0.000 description 7
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
239000004480 active ingredient Substances 0.000 description 6
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
239000004471 Glycine Substances 0.000 description 5
238000005481 NMR spectroscopy Methods 0.000 description 5
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
210000004027 cell Anatomy 0.000 description 5
229910052938 sodium sulfate Inorganic materials 0.000 description 5
235000011152 sodium sulphate Nutrition 0.000 description 5
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
150000007513 acids Chemical class 0.000 description 4
238000006243 chemical reaction Methods 0.000 description 4
239000003795 chemical substances by application Substances 0.000 description 4
230000000694 effects Effects 0.000 description 4
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
238000004949 mass spectrometry Methods 0.000 description 4
239000002609 medium Substances 0.000 description 4
229910052757 nitrogen Inorganic materials 0.000 description 4
229920000642 polymer Polymers 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
239000002904 solvent Substances 0.000 description 4
239000003826 tablet Substances 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
229910021529 ammonia Inorganic materials 0.000 description 3
239000002775 capsule Substances 0.000 description 3
229910052799 carbon Inorganic materials 0.000 description 3
125000004432 carbon atom Chemical group C* 0.000 description 3
238000004587 chromatography analysis Methods 0.000 description 3
239000002270 dispersing agent Substances 0.000 description 3
239000000499 gel Substances 0.000 description 3
150000002367 halogens Chemical class 0.000 description 3
239000003112 inhibitor Substances 0.000 description 3
150000002825 nitriles Chemical class 0.000 description 3
229920006395 saturated elastomer Polymers 0.000 description 3
239000000741 silica gel Substances 0.000 description 3
229910002027 silica gel Inorganic materials 0.000 description 3
230000007928 solubilization Effects 0.000 description 3
238000005063 solubilization Methods 0.000 description 3
239000000080 wetting agent Substances 0.000 description 3
238000005160 1H NMR spectroscopy Methods 0.000 description 2
VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
239000007995 HEPES buffer Substances 0.000 description 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
125000003545 alkoxy group Chemical group 0.000 description 2
230000029936 alkylation Effects 0.000 description 2
238000005804 alkylation reaction Methods 0.000 description 2
235000019270 ammonium chloride Nutrition 0.000 description 2
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CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
239000011230 binding agent Substances 0.000 description 2
239000000969 carrier Substances 0.000 description 2
239000003054 catalyst Substances 0.000 description 2
125000001309 chloro group Chemical group Cl* 0.000 description 2
238000001816 cooling Methods 0.000 description 2
230000003111 delayed effect Effects 0.000 description 2
150000004985 diamines Chemical class 0.000 description 2
229940079593 drug Drugs 0.000 description 2
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238000000605 extraction Methods 0.000 description 2
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239000008187 granular material Substances 0.000 description 2
238000004128 high performance liquid chromatography Methods 0.000 description 2
239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
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239000007788 liquid Substances 0.000 description 2
235000019359 magnesium stearate Nutrition 0.000 description 2
238000002844 melting Methods 0.000 description 2
230000008018 melting Effects 0.000 description 2
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
229910052763 palladium Inorganic materials 0.000 description 2
239000001267 polyvinylpyrrolidone Substances 0.000 description 2
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125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
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238000010992 reflux Methods 0.000 description 2
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239000012279 sodium borohydride Substances 0.000 description 2
229910000033 sodium borohydride Inorganic materials 0.000 description 2
239000012453 solvate Substances 0.000 description 2
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CXLGEMRISAZZKM-UHFFFAOYSA-N 2-chloro-n-[(7-methyl-7-azabicyclo[2.2.1]heptan-4-yl)-phenylmethyl]-3-(trifluoromethyl)benzamide Chemical compound CN1C(CC2)CCC12C(C=1C=CC=CC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl CXLGEMRISAZZKM-UHFFFAOYSA-N 0.000 description 1
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125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
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OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
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CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
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125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
150000001721 carbon Chemical group 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
150000001793 charged compounds Chemical class 0.000 description 1
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RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
229910000071 diazene Inorganic materials 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
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150000002118 epoxides Chemical class 0.000 description 1
MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
239000003889 eye drop Substances 0.000 description 1
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239000011737 fluorine Substances 0.000 description 1
235000019253 formic acid Nutrition 0.000 description 1
238000009472 formulation Methods 0.000 description 1
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238000005469 granulation Methods 0.000 description 1
230000003179 granulation Effects 0.000 description 1
239000001963 growth medium Substances 0.000 description 1
150000004820 halides Chemical class 0.000 description 1
125000004438 haloalkoxy group Chemical group 0.000 description 1
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
239000012943 hotmelt Substances 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
238000007327 hydrogenolysis reaction Methods 0.000 description 1
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
150000002466 imines Chemical class 0.000 description 1
238000011534 incubation Methods 0.000 description 1
238000002329 infrared spectrum Methods 0.000 description 1
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238000007918 intramuscular administration Methods 0.000 description 1
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HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
238000002955 isolation Methods 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
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IHFZUIBTENSHSH-UHFFFAOYSA-N n,n-dimethoxy-1-phenylmethanamine Chemical compound CON(OC)CC1=CC=CC=C1 IHFZUIBTENSHSH-UHFFFAOYSA-N 0.000 description 1
MUAUTSZXEFBEPW-UHFFFAOYSA-N n-methyl-n-phenyl-7-azabicyclo[2.2.1]heptan-4-amine Chemical compound C1CC(N2)CCC12N(C)C1=CC=CC=C1 MUAUTSZXEFBEPW-UHFFFAOYSA-N 0.000 description 1
210000000461 neuroepithelial cell Anatomy 0.000 description 1
229910000069 nitrogen hydride Inorganic materials 0.000 description 1
UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
239000002674 ointment Substances 0.000 description 1
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238000007254 oxidation reaction Methods 0.000 description 1
235000019629 palatability Nutrition 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
230000007170 pathology Effects 0.000 description 1
125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
239000003208 petroleum Substances 0.000 description 1
239000000825 pharmaceutical preparation Substances 0.000 description 1
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230000000144 pharmacologic effect Effects 0.000 description 1
NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
230000000704 physical effect Effects 0.000 description 1
229920001223 polyethylene glycol Polymers 0.000 description 1
238000011533 pre-incubation Methods 0.000 description 1
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230000004044 response Effects 0.000 description 1
HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger Î±-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
238000000926 separation method Methods 0.000 description 1
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239000002356 single layer Substances 0.000 description 1
239000011734 sodium Substances 0.000 description 1
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229940045902 sodium stearyl fumarate Drugs 0.000 description 1
239000007787 solid Substances 0.000 description 1
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125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
239000003643 water by type Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical

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Abstract Translated from French

ComposÃ©s de formule (I) : dans laquelle : - R reprÃ©sente un atome d'hydrogÃ¨ne ou un groupe choisi parmi les groupes (C1d- C6)alkyle, (C3-C7)-cycloalkyle, Ã©ventuellement substituÃ© par un ou plusieurs groupes choisis indÃ©pendamment l'un de l'autre parmi l'atome de fluor, les groupes (C3-C7)- cycloalkyle, (C2-C4)alcÃ©nyle, phÃ©nyle, (C1-C6)alcoxy, hydroxy; le groupe phÃ©nyle est Ã©ventuellement substituÃ© par un ou plusieurs groupes (C1-C6)alcoxy; - R1 reprÃ©sente un groupe phÃ©nyle Ã©ventuellement substituÃ© par un ou plusieurs substituants choisis indÃ©pendamment l'un de l'autre parmi les atomes d'halogÃ¨ne, les groupes (C1-C6)alkyle, (C1-C6)alcoxy, halo-(C1C6)alkyle, hydroxy, halo-(C1- C6)alcoxy, (C1C6)alkyle-thio, (C1-C6)alkyle-SO2, - R2 reprÃ©sente un ou plusieurs substituants choisis parmi l'atome d'hydrogÃ¨ne, les atomes d'halogÃ¨ne, les groupes halo-(C1C6)alkyle, (C1-C6)alkyle, (C3-C7)cycloalkyle, (C3-C7)-cycloalkyl-(C1-C3)alkyle, (C1C6)alcoxy, (C1C6)alkyl-thio, (C1C6)alkyle-SO2; Ã l'Ã©tat de base ou de sel d'addition Ã un acide. Utilisation en thÃ©rapeutique et procÃ©dÃ© de synthÃ¨se.Compounds of formula (I): in which: R represents a hydrogen atom or a group chosen from (C1d-C6) alkyl, (C3-C7) -cycloalkyl groups, optionally substituted with one or more groups chosen independently; one of the other from fluorine atom, (C3-C7) -cycloalkyl, (C2-C4) alkenyl, phenyl, (C1-C6) alkoxy, hydroxy; the phenyl group is optionally substituted by one or more (C1-C6) alkoxy groups; R 1 represents a phenyl group optionally substituted by one or more substituents chosen independently of one another from halogen atoms, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy and halo (C 1 -C 6) groups; alkyl, hydroxy, halo- (C1-C6) alkoxy, (C1C6) alkyl-thio, (C1-C6) alkyl-SO2, - R2 represents one or more substituents selected from hydrogen, halogen atoms , halo (C1C6) alkyl, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C7) -cycloalkyl- (C1-C3) alkyl, (C1C6) alkoxy, (C1C6) alkyl-thio (C1C6) alkyl-SO2; in the form of a base or an acid addition salt. Therapeutic use and synthesis method.

Description Translated from French

WO 2010/11922 WO 2010/11922

2 PCT/FR2010/050711 DERIVES DE N-[(7-AZA-BICYCLO[2.2.1]HEPT-1-YL)-ARYL-METHYL]-BENZAMIDE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE La prÃ©sente invention se rapporte Ã des dÃ©rivÃ©s de N-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-mÃ©thyl]-benzamide, Ã leur prÃ©paration et leur application en thÃ©rapeutique, dans le traitement ou la prÃ©vention de maladies impliquant les transporteurs de la glycine Glyt1.

Les composÃ©s de l'invention rÃ©pondent Ã la formule gÃ©nÃ©rale (I) R- N Ri O (I) HN

dans laquelle :

- R reprÃ©sente un atome d'hydrogÃ¨ne ou un groupe choisi parmi les groupes (C,-C6)alkyle, (C3-C7)-cycloalkyle, Ã©ventuellement substituÃ© par un ou plusieurs groupes choisis indÃ©pendamment l'un de l'autre parmi les atomes d'halogÃ¨ne, les groupes (C3-C7)-cycloalkyle, (C2-C4)alcÃ©nyle, phÃ©nyle, (C1-C6)alcoxy, hydroxy ; le groupe phÃ©nyle Ã©tant Ã©ventuellement substituÃ© par un ou plusieurs groupes (C,-C6)alcoxy ;
- R, reprÃ©sente un groupe phÃ©nyle ou naphtyle, Ã©ventuellement substituÃ© par un ou plusieurs substituants choisis indÃ©pendamment l'un de l'autre parmi les atomes d'halogÃ¨ne, les groupes (C,-C6)alkyle, (C,-C6)alcoxy, halo-(C,-C6)alkyle, hydroxy, halo-(C,-C6)alcoxy, (C,-C6)alkyle-thio, (C,-C6)alkyle-SO, (C,-C6)alkyle-S02, - R2 reprÃ©sente un ou plusieurs substituants choisis parmi l'atome d'hydrogÃ¨ne, les atomes d'halogÃ¨ne, les groupes halo-(C,-C6)alkyle, (C,-C6)alkyle, (C3-C7)cycloalkyle, (C3-C7)-cycloalkyl-(C1-C3)alkyle, (C1-C6)alcoxy, (C1-C6)alkyl-thio, (C1-C6)alkyle-SO
(C,-C6)alkyle-SO2 ;
Ã l'Ã©tat de base ou de sel d'addition Ã un acide.
Les composÃ©s de formule (I) comportent un atome de carbone asymÃ©trique. Ils peuvent donc exister sous forme d'Ã©nantiomÃ¨res. Ces Ã©nantiomÃ¨res y compris les mÃ©langes racÃ©miques, font partie de l'invention.

Les composÃ©s de formule (I) peuvent exister Ã l'Ã©tat de bases ou de sels d'addition Ã

des acides. De tels sels d'addition font partie de l'invention.
Ces sels sont avantageusement prÃ©parÃ©s avec des acides pharmaceutiquement acceptables, mais les sels d'autres acides utiles, par exemple, pour la purification ou l'isolement des composÃ©s de formule (I), font Ã©galement partie de l'invention.

Dans le cadre de l'invention, on entend par :

- Ct_CZ oÃ¹ t et z peuvent prendre les valeurs de 1 Ã 6, une chaÃ®ne carbonÃ©e pouvant avoir de t Ã z atomes de carbone, par exemple Ci-C6 une chaÃ®ne carbonÃ©e qui peut avoir de 1 Ã 6 atomes de carbone ;
- alkyle, un groupe aliphatique saturÃ©, linÃ©aire ou ramifiÃ© ; par exemple un groupe C,_C6-alkyle reprÃ©sente une chaÃ®ne carbonÃ©e de 1 Ã 6 atomes de carbone, linÃ©aire ou ramifiÃ©e, par exemple un mÃ©thyle, Ã©thyle, propyle, isopropyle, butyle, isobutyle, tert-butyle, pentyle, hexyle ;
- alkylÃ¨ne, un groupe alkyle divalent saturÃ©, linÃ©aire ou ramifiÃ©, par exemple un groupe C,_6-alkylÃ¨ne reprÃ©sente une chaÃ®ne carbonÃ©e divalente de 1 Ã 6 atomes de carbone, linÃ©aire ou ramifiÃ©e, par exemple un mÃ©thylÃ¨ne, Ã©thylÃ¨ne, 1-mÃ©thylÃ©thylÃ¨ne, propylÃ¨ne, - alcoxy, un groupe -0-alkyle, - hydroxy, un groupe -OH, - alkyle-thio, un atome de soufre substituÃ© par un groupe alkyle ;
- atome d'halogÃ¨ne, un fluor, un chlore, un brome ou un iode, - halo-alkyle, un groupe alkyle dont un ou plusieurs atomes d'hydrogÃ¨ne ont Ã©tÃ©
substituÃ©s par un halogÃ¨ne. A titre d'exemple, on peut citer les groupes trifluoromÃ©thyle, trifluoroÃ©thyle ou pentafluoroÃ©thyle ;
- halo-alcoxy, un groupe alcoxy dont un ou plusieurs atomes d'hydrogÃ¨ne ont Ã©tÃ©
substituÃ©s par un halogÃ¨ne.

Parmi les composÃ©s de formule gÃ©nÃ©rale (I) objets de l'invention, un premier groupe de composÃ©s est constituÃ© par les composÃ©s pour lesquels:

- R reprÃ©sente un atome d'hydrogÃ¨ne, un groupe (C,-C6)alkyle ou benzyle ;
- R, et R2 Ã©tant tels que dÃ©finis ci-dessus Parmi les composÃ©s de formule gÃ©nÃ©rale (I) objets de l'invention, un second groupe de composÃ©s est constituÃ© par les composÃ©s pour lesquels: 2 PCT / FR2010 / 050711 N - [(7-AZA-BICYCLO [2.2.1] HEPT-1-YL) -LAYL-METHYL DERIVATIVES -BENZAMIDE, THEIR PREPARATION AND THEIR APPLICATION
THERAPEUTIC
The present invention relates to derivatives of N - [(7-aza-bicyclo [2.2.1] hept-1-yl) -aryl-methyl-benzamide, their preparation and their application in therapeutic, in the treatment or prevention of diseases involving carriers of the wistaria Glyt1.

The compounds of the invention correspond to the general formula (I) R- N Ri O (I) HN

in which :

- R represents a hydrogen atom or a group selected from groups (C, -C6) alkyl, (C3-C7) -cycloalkyl, optionally substituted with one or more groups independently of one another selected from halogen atoms, groups (C3-C7) -cycloalkyl, (C2-C4) alkenyl, phenyl, (C1-C6) alkoxy, hydroxy; the group phenyl being optionally substituted by one or more groups (C, -C6) alkoxy;
- R, represents a phenyl or naphthyl group, optionally substituted by a or several substituents chosen independently of each other from among the atoms halogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halo- (C 1 -C 6) alkyl, hydroxy, halo- (C 1 -C 6) alkoxy, (C 1 -C 6) alkyl-thio, (C 1 -C 6) alkyl-SO, (C 1 -C 6) alkyl-SO 2, R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, halo- (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, (C 3 -C
C7) cycloalkyl, (C3-C7) -cycloalkyl- (C1-C3) alkyl, (C1-C6) alkoxy, (C1-C6) alkyl-thio, (C1-C6) alkyl-SO
(C 1 -C 6) alkyl-SO 2;
in the form of a base or an acid addition salt.
The compounds of formula (I) have an asymmetric carbon atom. They can therefore exist as enantiomers. These enantiomers including racemic mixtures are part of the invention.

The compounds of formula (I) may exist in the form of bases or salts of addition to acids. Such addition salts are part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids acceptable but the salts of other useful acids, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.

In the context of the invention, the following terms mean:

- Ct_CZ where t and z can take the values from 1 to 6, a carbon chain may have from t to z carbon atoms, for example Ci-C6 a chain carbon which may have from 1 to 6 carbon atoms;
alkyl, a saturated, linear or branched aliphatic group; for example a group C 1 -C 6 -alkyl represents a carbon chain of 1 to 6 carbon atoms, linear or branched, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl;
alkylene, a saturated divalent alkyl group, linear or branched, for example a group C, _6-alkylene represents a divalent carbon chain of 1 to 6 atoms linear or branched carbon, for example methylene, ethylene, methylethylene, propylene, - alkoxy, a -O-alkyl group, hydroxy, an -OH group, alkyl-thio, a sulfur atom substituted with an alkyl group;
halogen atom, fluorine, chlorine, bromine or iodine, halo-alkyl, an alkyl group of which one or more hydrogen atoms summer substituted by a halogen. By way of example, mention may be made of groups trifluoromethyl, trifluoroethyl or pentafluoroethyl;
haloalkoxy, an alkoxy group of which one or more hydrogen atoms summer substituted by a halogen.

Among the compounds of general formula (I) which are the subject of the invention, a first group of compounds is constituted by compounds for which:

R represents a hydrogen atom, a (C 1 -C 6) alkyl or benzyl group;
- R, and R2 being as defined above Among the compounds of general formula (I) which are the subject of the invention, a second group of compounds is constituted by compounds for which:

3 - R1 reprÃ©sente un groupe phÃ©nyle ; - R et R2 Ã©tant tels que dÃ©finis ci-dessus.

Parmi les composÃ©s de formule gÃ©nÃ©rale (I) objets de l'invention, un troisiÃ¨me groupe de composÃ©s est constituÃ© par les composÃ©s pour lesquels:

- R2 reprÃ©sente un ou plusieurs substituants choisis parmi l'atome d'hydrogÃ¨ne, les atomes d'halogÃ¨ne, les groupes halo-(C,-C6)alkyle ou (C,-C6)alkyle, - R et R1 Ã©tant tels que dÃ©finis ci-dessus.

Parmi les composÃ©s de formule gÃ©nÃ©rale (I) objets de l'invention, un quatriÃ¨me groupe de composÃ©s est constituÃ© par les composÃ©s pour lesquels:

- R reprÃ©sente un atome d'hydrogÃ¨ne, un groupe (C,-C6)alkyle ou benzyle ;
- R, reprÃ©sente un groupe phÃ©nyle, - R2 reprÃ©sente un ou plusieurs substituants choisis parmi l'atome d'hydrogÃ¨ne, les atomes d'halogÃ¨ne, les groupes halo-(C,-C6)alkyle ou (C,-C6)alkyle, Parmi les composÃ©s de formule gÃ©nÃ©rale (I) objets de l'invention, un cinquiÃ¨me groupe de composÃ©s est constituÃ© par les composÃ©s pour lesquels:
- R reprÃ©sente un atome d'hydrogÃ¨ne ou un groupe mÃ©thyle, Ã©thyle ou benzyle ;
- R, reprÃ©sente un groupe phÃ©nyle, - R2 reprÃ©sente un ou plusieurs substituants choisis parmi l'atome d'hydrogÃ¨ne, l'atome de chlore, les groupes mÃ©thyle, Ã©thyle ou trifluoromÃ©thyle, Ã l'Ã©tat de base ou de sel d'addition Ã un acide.

Les combinaisons des groupes un Ã cinq tels que dÃ©finis ci-dessus font Ã©galement partie de l'invention.

Parmi les composÃ©s de formule gÃ©nÃ©rale (I) objets de l'invention, on peut notamment citer les composÃ©s suivants :

=N-[(7-Aza-bicyclo[2.2.1 ]hept-1 -yl)-phÃ©nyl-mÃ©thyl]-(2-mÃ©thyl-3-trifluoromÃ©thyl)-benzamide;
=N-[(7-Aza-bicyclo[2.2.1 ]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(2,6-dichloro-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ;
=(-)-N-[(7-Aza-bicyclo[2.2.1 ]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(2,6-dichloro-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; 3 - R1 represents a phenyl group;
R and R2 being as defined above.

Among the compounds of general formula (I) which are the subject of the invention, a third group of compounds consists of compounds for which:

R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, halo (C 1 -C 6) alkyl or (C 1 -C 6) alkyl groups, - R and R1 being as defined above.

Among the compounds of general formula (I) that are the subject of the invention, a fourth group of compounds consists of compounds for which:

R represents a hydrogen atom, a (C 1 -C 6) alkyl or benzyl group;
- R, represents a phenyl group, R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, halo- (C 1 -C 6) alkyl or (C 1 -C 6) alkyl groups, Among the compounds of general formula (I) which are the subject of the invention, a fifth group of compounds consists of compounds for which:
R represents a hydrogen atom or a methyl, ethyl or benzyl group;
- R, represents a phenyl group, R2 represents one or more substituents chosen from the atom hydrogen, the chlorine atom, the methyl, ethyl or trifluoromethyl groups, in the basic or addition salt to an acid.

The combinations of groups one to five as defined above make also part of the invention.

Among the compounds of general formula (I) which are the subject of the invention, it is possible to include the following compounds:

= N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-methyl-3-yl) trifluoromethyl) -benzamide;
= N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-) trifluoromethyl) -benzamide, and its hydrochloride;
= (-) - N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-) trifluoromethyl) -benzamide, and its hydrochloride;

4 =N-[(7-Aza-bicyclo[2.2.1 ]hept-1 -yl)-phÃ©nyl-mÃ©thyl]-(2-chloro-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; =2-Chloro-N-[(7-Ã©thyl-7-aza-bicyclo[2.2.1 ]hept-1 -yl)-phÃ©nyl-mÃ©thyl]-(3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; =(+)-N-[(7-Aza-bicyclo[2.2.1 ]hept-1 -yl)-phÃ©nyl-mÃ©thyl]-(2,6-dichloro-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; =2-Chloro-N-[(7-mÃ©thyl-7-aza-bicyclo[2.2.1 ]hept-1 -yl)-phÃ©nyl-mÃ©thyl]-3-trifluoromÃ©thyl-benzamide, et son chlorhydrate ; =N-[(7-Benzyl-7-aza-bicyclo[2.2.1 ]hept-1 -yl)-phÃ©nyl-mÃ©thyl]-(2-mÃ©thyl-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; =N-[(7-Benzyl-7-aza-bicyclo[2.2.1 ]hept-1 -yl)-phÃ©nyl-mÃ©thyl]-(2-chloro-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; =N-[(7-Aza-bicyclo[2.2.1 ]hept-1 -yl)-phÃ©nyl-mÃ©thyl]-(2-ch loro-3-Ã©thyl)-benzam ide, et son chlorhydrate. Les composÃ©s de l'invention prÃ©sentent une activitÃ© particuliÃ¨re comme inhibiteurs des transporteurs de la glycine Glyt1, notamment un profil d'activitÃ© et de sÃ©curitÃ© amÃ©liorÃ©s.

Les composÃ©s de formule gÃ©nÃ©rale (I), peuvent Ãªtre prÃ©parÃ©s par un procÃ©dÃ©

illustrÃ© par le schÃ©ma 1 qui suit :

Y O

R- Nzz- Ri R2 (III) NH2 - (I) (11) On effectue un couplage d'une diamine de formule gÃ©nÃ©rale (11), dans laquelle R et R, sont tels que dÃ©finis ci-dessus, notamment quand R reprÃ©sente un atome d'hydrogÃ¨ne, un groupe phÃ©nylmÃ©thyle, avec un acide activÃ©, par exemple via un anhydride mixte ou un chlorure d'acide de formule gÃ©nÃ©rale (III) dans laquelle Y

reprÃ©sente un groupe partant dÃ©rivÃ© par exemple de benzotriazole, d'acylurÃ©e ou un atome d'halogÃ¨ne et R2 est tel que dÃ©fini ci-dessus, en utilisant les mÃ©thodes connues de l'Homme du mÃ©tier.

Les composÃ©s de formule gÃ©nÃ©rale (I) dans laquelle R reprÃ©sente l'atome

4 = N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-) trifluoromethyl) -benzamide, and its hydrochloride;
= 2-Chloro-N - [(7-ethyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) benzamide, and its hydrochloride;
= (+) - N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-) trifluoromethyl) -benzamide, and its hydrochloride;
= 2-Chloro-N - [(7-methyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] -3-trifluoromethylbenzamide, and its hydrochloride;
= N - [(7-Benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-methyl-3-yl) trifluoromethyl) benzamide, and its hydrochloride;
= N - [(7-Benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-) trifluoromethyl) benzamide, and its hydrochloride;
= N - [(7-Azabicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-ethyl) -benzam ide, and its hydrochloride.
The compounds of the invention exhibit a particular activity as inhibitors carriers of glycine Glyt1, including a profile of activity and security improved.

The compounds of general formula (I) can be prepared by a process illustrated by the following diagram 1:

R- Nzz- Ri R2 (III) NH2 - (I) (11) Coupling of a diamine of general formula (11) in which R and R, are as defined above, especially when R represents an atom hydrogen, a phenylmethyl group, with an activated acid, for example via a mixed anhydride or an acid chloride of the general formula (III) in which Y

represents a leaving group derived for example from benzotriazole, acylurea or one halogen atom and R2 is as defined above, using the methods known to those skilled in the art.

Compounds of the general formula (I) in which R represents the atom

5 d'hydrogÃ¨ne peuvent Ãªtre aussi prÃ©parÃ©s Ã partir de composÃ©s de formule gÃ©nÃ©rale (I) dans laquelle R reprÃ©sente : - soit un groupe phÃ©nylmÃ©thyle en dÃ©protÃ©geant l'azote par hydrogÃ©nolyse, - soit un groupe alcÃ©nyle, de prÃ©fÃ©rence allyle, en dÃ©protÃ©geant l'azote, par exemple par un complexe du palladium zÃ©ro selon les mÃ©thodes connues de l'Homme du mÃ©tier, - soit un groupe dimÃ©thoxybenzyle en dÃ©protÃ©geant par les mÃ©thodes d'oxydation connues de l'Homme du mÃ©tier.

Les composÃ©s de formule gÃ©nÃ©rale (I) dans laquelle R est diffÃ©rent de l'atome d'hydrogÃ¨ne, peuvent Ãªtre aussi prÃ©parÃ©s Ã partir de composÃ©s de formule gÃ©nÃ©rale (I) dans laquelle R reprÃ©sente un atome d'hydrogÃ¨ne, soit par alkylation dudit composÃ© de formule gÃ©nÃ©rale (I) avec un halogÃ©nure ou mÃ©sylate du type RX, dans lequel R est tel que dÃ©fini ci-dessus et X est un mÃ©sylate ou halogÃ¨ne, en prÃ©sence d'une base minÃ©rale, par exemple le carbonate de potassium dans l'acÃ©tonitrile ; soit par une rÃ©action de type Eschweiler-Clarke ou une amination rÃ©ductrice avec un aldÃ©hyde ou une cÃ©tone appropriÃ©s selon les mÃ©thodes connues de l'Homme du mÃ©tier ; soit avec un dÃ©rivÃ© Ã©poxyde appropriÃ©, selon les mÃ©thodes connues de l'Homme du mÃ©tier.

La diamine de formule gÃ©nÃ©rale (11) peut Ãªtre prÃ©parÃ©e par le procÃ©dÃ© illustrÃ©

par le schÃ©ma 2 pour l'amine de formule gÃ©nÃ©rale (Ila) et pour l'amine de formule gÃ©nÃ©rale (IIb) qui suit : Hydrogen can also be prepared from compounds of the formula General (I) wherein R represents:
or a phenylmethyl group by deprotecting the nitrogen by hydrogenolysis, - an alkenyl group, preferably allyl, by deprotecting nitrogen, by example by a complex of palladium zero according to the methods known to man of the job, - a dimethoxybenzyl group by deprotecting by oxidation methods known to those skilled in the art.

Compounds of the general formula (I) in which R is different from the atom of hydrogen, can also be prepared from compounds of formula General (I) wherein R represents a hydrogen atom, or by alkylation of said compound of general formula (I) with an RX type halide or mesylate, in which R is as defined above and X is a mesylate or halogen, in presence of a mineral base, for example potassium carbonate in acetonitrile ; is by an Eschweiler-Clarke type reaction or a reductive amination with a aldehyde or a ketone suitable according to the methods known to man of the job ; with an appropriate epoxide derivative, according to the known methods of the skilled person.

The diamine of general formula (11) can be prepared by the process illustrated speak scheme 2 for the amine of general formula (IIa) and for the amine of formula General (IIb) which follows:

6 H N N N R1Li N (VI) C02CH3 CN H2N _ H2N Ri (IV) (V) (Ila) (Ilb) Selon le schÃ©ma 2, l'ester de formule (IV) est transformÃ© en nitrile de formule (V), par chauffage au reflux du xylÃ¨ne en prÃ©sence du complexe de trimÃ©thylaluminium et de chlorure d'ammonium prÃ©alablement formÃ©, selon une mÃ©thode dÃ©crite dans Synthetic Commun., 1982,12 (13), 989-993 et dans Tetrahedron Lett., 1979, (51), 4907-4910. On fait ensuite rÃ©agir le nitrile de formule (V) avec l'aromatique lithiÃ© de formule gÃ©nÃ©rale (VI), dans laquelle R, est tel que dÃ©fini ci-dessus, dans un solvant Ã©thÃ©rÃ© tel que le tÃ©trahydrofurane ou l'Ã©ther, Ã basse tempÃ©rature, par exemple -70 C. On obtient ainsi une imine qui est rÃ©duite avec un rÃ©ducteur tel que le borohydrure de sodium dans un solvant protique tel que le mÃ©thanol, pour donner l'amine de formule gÃ©nÃ©rale (Ila). L'amine (Ila) peut Ãªtre dÃ©benzylÃ©e par hydrogÃ©nation en prÃ©sence de catalyseur au palladium pour fournir l'amine dÃ©protÃ©gÃ©e de formule gÃ©nÃ©rale (Ilb).

Pour les composÃ©s de formule (IV) et (V), on pourrait notamment remplacer le groupe benzyle par un autre groupe protecteur, par exemple par un groupe allyle ou un groupe dimÃ©thoxybenzyle, soit :

- en dÃ©benzylant puis en reprotÃ©geant, par exemple via une rÃ©action d'alkylation avec l'Ã©lectrophile appropriÃ©, par exemple un bromure d'allyle ou un bromure de dimÃ©thoxybenzyle, selon les mÃ©thodes connues de l'Homme du mÃ©tier;
- soit selon la mÃ©thode dÃ©crite dans Tetrahedron : Asymmetry, 2006 (17), 252-258. en remplacant la benzylamine par l'allylamine ou une dimÃ©thoxybenzylamine, notamment la 2,4-dimÃ©thoxybenzylamine. 6 H
NOT
NN R1Li N
(VI) C02CH3 CN H2N _ H2N Ri (IV) (V) (Ila) (Ilb) According to Scheme 2, the ester of formula (IV) is converted into nitrile of formula (V), by refluxing the xylene in the presence of the trimethyl ammonium chloride previously formed, according to a method described in Synthetic Commun., 1982, 12 (13), 989-993 and in Tetrahedron Lett., 1979, (51) 4907-4910. The nitrile of formula (V) is then reacted with the aromatic lithiated general formula (VI), wherein R, is as defined above, in a solvent ether, such as tetrahydrofuran or ether, at low temperature, by example -C. An imine is thus obtained which is reduced with a reducing agent such as sodium borohydride in a protic solvent such as methanol, for give the amine of general formula (IIa). The amine (IIa) can be debenzylated by hydrogenation in the presence of palladium catalyst to provide the amine deprotected of general formula (Ilb).

For the compounds of formula (IV) and (V), it would be possible in particular to replace the benzyl group by another protecting group, for example by a group allyle or a dimethoxybenzyl group, that is:

by debenzylating and then reprotecting, for example via a reaction alkylation with the appropriate electrophile, for example an allyl bromide or a bromide of dimethoxybenzyl, according to the methods known to those skilled in the art;
- according to the method described in Tetrahedron: Asymmetry, 2006 (17), 252-258. by replacing benzylamine with allylamine or dimethoxybenzylamine, especially 2,4-dimethoxybenzylamine.

7 Par ailleurs les composÃ©s chiraux de formule gÃ©nÃ©rale (I) correspondants aux Ã©nantiomÃ¨res S ou R peuvent Ãªtre obtenus par sÃ©paration des composÃ©s racÃ©miques par chromatographie liquide Ã haute performance (CLHP) sur colonne chirale, ou pourraient Ãªtre obtenus par dÃ©doublement de l'amine racÃ©mique de formule gÃ©nÃ©rale (11) par utilisation d'un acide chiral, tel que l'acide dibenzoyl-tartrique ou par la recristallisation fractionnÃ©e et prÃ©fÃ©rentielle d'un sel diastÃ©rÃ©oisomÃ©rique. L'ester de formule (IV) est prÃ©parÃ© selon une mÃ©thode dÃ©crite dans Tetrahedron, 2002 (58), 10167-10171. Le nitrile de formule (V) pourrait Ãªtre Ã©galement prÃ©parÃ© selon une mÃ©thode dÃ©crite dans Tetrahedron : Asymmetry, 2006 (17), 252-258. Les dÃ©rivÃ©s lithiÃ©s de formule gÃ©nÃ©rale (VI) peuvent Ãªtre prÃ©parÃ©s selon des mÃ©thodes connues de l'Homme du mÃ©tier. Les acides et chlorures d'acide de formule gÃ©nÃ©rale (III) sont disponibles dans le commerce ou prÃ©parÃ©s par analogie Ã des mÃ©thodes connues de l'Homme du mÃ©tier.

Les exemples qui vont suivre illustrent la prÃ©paration de quelques composÃ©s de l'invention. Dans ces exemples :

- Les microanalyses Ã©lÃ©mentaires, les spectres I.R. et R.M.N. et la CLHP sur colonne chirale confirment les structures et les puretÃ©s Ã©nantiomÃ©riques des composÃ©s obtenus, - Pour les descriptions RMN, "m" signifie multiplet, "s" singulet, "t"
triplet, "d"
doublet, "q" quadruplet, dxd signifie double doublet, txt signifie triple triplet, dxt double triplet, etc.
- Les numÃ©ros indiquÃ©s entre parenthÃ¨ses dans les titres des exemples correspondent Ã ceux de la lÃ¨re colonne du tableau donnÃ© plus loin, - "dÃ©comp." signifie "dÃ©composition", - La nomenclature employÃ©e est la nomenclature suivant les recommandations IUPAC (International Union of Pure and Applied Chemistry).

Dans les noms des composÃ©s, le tiret "-" fait partie du mot, et le tiret "-"

ne sert que pour la coupure en fin de ligne ; il est Ã supprimer en l'absence de coupure, et ne doit Ãªtre remplacÃ© ni par un tiret normal ni par un espace. 7 Moreover, the chiral compounds of general formula (I) corresponding to S or R enantiomers can be obtained by separation of the compounds racemic by high performance liquid chromatography (HPLC) column chiral, or could be obtained by resolution of the racemic amine general formula (11) using a chiral acid, such as dibenzoyltartaric tartaric or by the fractional and preferential recrystallization of a salt diastereoisomeric.
The ester of formula (IV) is prepared according to a method described in Tetrahedron, 2002 (58), 10167-10171.
The nitrile of formula (V) could also be prepared according to a method described in Tetrahedron: Asymmetry, 2006 (17), 252-258.
The lithiated derivatives of general formula (VI) can be prepared according to methods known to those skilled in the art.
Acids and acid chlorides of general formula (III) are available in the trade or prepared by analogy with methods known to job.

The examples which follow illustrate the preparation of some compounds of the invention. In these examples:

- Elemental microanalyses, IR and NMR spectra and HPLC on chiral column confirm the structures and enantiomeric purities of compounds obtained, - For NMR descriptions, "m" means multiplet, "s" singlet, "t"
triplet, "d"
doublet, "q" quadruplet, dxd means double doublet, txt means triple triplet, dxt double triplet, etc.
- Numbers indicated in parentheses in the titles of the examples correspond to those in the first column of the table given below, - "decomp." means "decomposition", - The nomenclature used is the nomenclature following the recommendations IUPAC (International Union of Pure and Applied Chemistry).

In the compound names, the hyphen "-" is part of the word, and the hyphen "-"

only serves for the cut at the end of the line; it is to be deleted in the absence of a break, and not must be replaced by a standard hyphen or space.

8 Exemple 1 (composÃ© n 4) : Chlorhydrate de N-[(7-aza-bicyclo[2.2.1]hept-l-yl)-phÃ©nyl-mÃ©thyl]-(2-chloro-3-trifluoromÃ©thyl)benzamide (1:1) 1.1. (7-Benzyl-7-aza-bicyclo[2.2.1lheptane)-1-carbonitrile Dans un tricol de 250 ml sous azote, on prÃ©pare le complexe de trimÃ©thylaluminium et de chlorure d'ammonium (environ 0,67M), ci-aprÃ¨s dÃ©nommÃ© complexe A, en plaÃ§ant 1,5 g de chlorure d'ammonium sec (28 mmoles) dans 30 ml de toluÃ¨ne anhydre, auxquels on ajoute aprÃ¨s refroidissement 15 ml d'une solution de trimÃ©thylaluminium 2N dans le toluÃ¨ne (30 mmoles) et que l'on laisse Ã tempÃ©rature ambiante jusqu'Ã la fin du dÃ©gagement gazeux. Dans un tricol de 250 ml sous azote muni d'un rÃ©frigÃ©rant, on place 1,27 g de(7-benzyl-7-aza-bicyclo[2.2.1]heptan)-1-carboxylate de mÃ©thyle (5,18 mmoles) dans ml de xylÃ¨ne anhydre. On ajoute goutte Ã goutte 20 ml du complexe A (13 mmoles) et on chauffe la nuit au reflux. AprÃ¨s refroidissement, le milieu est acidifiÃ© Ã pH 4-5 avec une solution d'acide chlorhydrique 1 N puis est extrait successivement avec de l'acÃ©tate d'Ã©thyle (100 ml) puis du dichloromÃ©thane (100 ml). Les phases organiques sont sÃ©chÃ©es sur sulfate de sodium, filtrÃ©es, rÃ©unies puis Ã©vaporÃ©es sous pression rÃ©duite. Le rÃ©sidu est purifiÃ© par chromatographie sur colonne de gel de silice en Ã©luant avec un mÃ©lange d'Ã©ther de pÃ©trole et d'acÃ©tate d'Ã©thyle. On obtient ainsi 210 mg de (7-benzyl-7-aza-bicyclo[2.2.1]heptane)-1-carbonitrile sous forme d'huile.

RMN 'H (200 MHz,CDCl3) 8 ppm 7,5 (m, 5H), 3,75 (s, 2H), 3,40 (m, 1H), 2,25 (m, 2H), 2,0 (m, 4H), 1,4 (m, 2H).

1.2. (7-Benzyl-7-aza-bicyclo[2.2.1 lhept-1-yl)-phÃ©nyl-mÃ©thylamine Dans un tricol de 50 ml sous argon, on place 0,45 g de (7-benzyl-7-aza-bicyclo[2.2.1]heptane)-1-carbonitrile (2,12 mmoles) Ã -70 C dans 15 ml de tÃ©trahydrofurane anhydre. On additionne goutte Ã goutte 5,65 ml d'une solution 0,75M (cyclohexane/Ã©ther) de phÃ©nyl lithium (4,24 mmoles).

On laisse pendant 2 heures et demie Ã -70 C puis on hydrolyse Ã -20 C avec 10 ml d'eau.
AprÃ¨s extraction Ã l'acÃ©tate d'Ã©thyle, la phase organique est concentrÃ©e sous pression rÃ©duite puis le rÃ©sidu est repris dans 20 ml de mÃ©thanol. 0,40 g de 8 Example 1 (Compound No. 4): N - [(7-Azabicyclo [2.2.1] hept-1-yl) Hydrochloride phenyl-methyl] - (2-chloro-3-trifluoromethyl) benzamide (1: 1) 1.1. (7-Benzyl-7-aza-bicyclo [2.2.1lheptane) -1-carbonitrile In a three-necked 250 ml under nitrogen, the complex of trimethyl and ammonium chloride (about 0.67M), hereinafter referred to as complex A, in placing 1.5 g of dry ammonium chloride (28 mmol) in 30 ml of toluene anhydrous, to which 15 ml of a solution of 2N trimethylaluminium in toluene (30 mmol) and which is left to temperature until the end of the evolution of gas.
In a 250 ml three-necked flask under nitrogen equipped with a condenser, place 1.27 g of (7-methyl benzyl-7-aza-bicyclo [2.2.1] heptan) -1-carboxylate (5.18 mmol) in ml of anhydrous xylene.
20 ml of the complex A (13 mmol) are added dropwise and the night at reflux.
After cooling, the medium is acidified to pH 4-5 with a solution acid 1N hydrochloric acid and is then extracted successively with ethyl acetate (100 ml) then dichloromethane (100 ml).
The organic phases are dried over sodium sulphate, filtered, combined then evaporated under reduced pressure.
The residue is purified by chromatography on a column of silica gel in eluent with a mixture of petroleum ether and ethyl acetate. 210 mg is thus obtained of (7-benzyl-7-aza-bicyclo [2.2.1] heptane) -1-carbonitrile as an oil.

1 H NMR (200 MHz, CDCl 3) Î´ 7.5 ppm (m, 5H), 3.75 (s, 2H), 3.40 (m, 1H), 2.25 (m, 2H), 2.0 (m, 4H), 1.4 (m, 2H).

1.2. (7-Benzyl-7-aza-bicyclo [2.2.1-hept-1-yl] -phenyl-methylamine In a 50 ml three-necked flask under argon, 0.45 g of (7-benzyl-7-aza) bicyclo [2.2.1] heptane) -1-carbonitrile (2.12 mmol) at -70 Â° C in 15 ml of anhydrous tetrahydrofuran. 5.65 ml of a solution are added dropwise 0.75M (cyclohexane / ether) phenyl lithium (4.24 mmol).

It is left for 2 hours and a half at -70 Â° C. and then hydrolyzed at -20 Â° C. with 10 Â° C.
ml of water.
After extraction with ethyl acetate, the organic phase is concentrated under reduced pressure and the residue is taken up in 20 ml of methanol. 0.40 g of

9 borohydrure de sodium (10,6 mmoles) y sont ajoutÃ©s par portions. Le milieu rÃ©actionnel est laissÃ© sous agitation pendant la nuit Ã tempÃ©rature ambiante. AprÃ¨s Ã©vaporation sous pression rÃ©duite, le rÃ©sidu est repris par 25 ml d'Ã©ther et 25 ml d'eau. On acidifie le milieu avec une solution d'acide chlorhydrique 1N puis on extrait. La phase aqueuse est basifiÃ©e avec de l'ammoniaque puis rÃ©extraite 2 fois avec 50 ml de dichloromÃ©thane. Les phases organiques sont rÃ©unies, sÃ©chÃ©es sur sulfate de sodium, filtrÃ©es et Ã©vaporÃ©es sous pression rÃ©duite. Le rÃ©sidu est purifiÃ© par chromatographie sur colonne de gel de silice en Ã©luant avec un mÃ©lange dichloromÃ©thane et de mÃ©thanol ammoniacal. On obtient ainsi 0,5 g de (7-benzyl-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thylamine sous forme d'huile qui cristallise. RMN 'H (400 MHz,CDCl3) 8 ppm 7,56 -7,22 (m, 10H), 4,31 (s, 1H), 3,86 (d, J = 13,3 Hz, 1 H), 3,37 (d, J = 13,3 Hz, 1 H), 3,19 (t, J = 4,5 Hz, 1 H), 2,23 (m, 1 H), 2,00 (m, 1 H), 1,80-1,56 (m, 2H), 1,37 (m, 1 H), 1,22 -1,06 (m, 2H), 0,97 (m, 1 H). PF = 87-88 C 1.3. (7-aza-bicyclo[2.2.llhept-1-yl)-phÃ©nyl-mÃ©thylamine Dans un autoclave, 0,5 g de (7-benzyl-7-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thylamine (1,71 mmole) en solution dans 20 ml d'Ã©thanol et 3,4 ml d'acide chlorhydrique 1 N en prÃ©sence d'une pointe de spatule de palladium sur charbon Ã 9 Sodium borohydride (10.6 mmol) is added in portions. The environment The reaction mixture is left stirring overnight at room temperature. After evaporation under reduced pressure, the residue is taken up in 25 ml of ether and 25 ml of water. The medium is acidified with a hydrochloric acid solution 1N then we extract. The aqueous phase is basified with ammonia and then reextracted 2 times with 50 ml of dichloromethane. The organic phases are combined, dried on sodium sulphate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel eluting with a mixture dichloromethane and ammoniacal methanol. 0.5 g of (7-benzyl) aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methylamine as an oil which crystallizes. 1 H NMR (400 MHz, CDCl 3) Î´ ppm 7.56 -7.22 (m, 10H), 4.31 (s, 1H), 3.86 (d, J = 13.3 Hz, 1H), 3.37 (d, J = 13.3 Hz, 1H), 3.19 (t, J = 4.5 Hz, 1H), 2.23 (m, 1 H), 2.00 (m, 1H), 1.80-1.56 (m, 2H), 1.37 (m, 1H), 1.22-1.06 (m, 2H), 0.97 (m, 1H). PF = 87-88 Â° C 1.3. (7-aza-bicyclo [2.2.llhept-1-yl) -phenyl-methylamine In an autoclave, 0.5 g of (7-benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methylamine (1.71 mmol) in solution in 20 ml of ethanol and 3.4 ml of acid hydrochloric acid 1N in the presence of a spatula tip of palladium on charcoal at

10% sont placÃ©s sous une pression de 7 atmosphÃ¨res d'hydrogÃ¨ne Ã 50 C pendant 6 heures. AprÃ¨s filtration du catalyseur et concentration du filtrat sous pression rÃ©duite, le rÃ©sidu est repris dans 25 ml de dichloromÃ©thane et 25 ml d'eau basifiÃ©e avec de l'ammoniaque. AprÃ¨s extraction, la phase organique est sÃ©chÃ©e sur sulfate de sodium, filtrÃ©e et Ã©vaporÃ©e sous pression rÃ©duite. On obtient ainsi 0,28 g de (7-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thylamine sous forme d'une huile qui se solidifie au froid et que l'on utilise telle quelle dans l'Ã©tape suivante. RMN 'H (400 MHz,CDCl3) 8 ppm 7,36 -7,13 (m, 5H), 4,24 (s, 1H), 3,49 (t, J = 4,8 Hz, 1H), 1,74-1,15 (m, 8H). PF = 62-63 C 1.4. Chlorhydrate de N-[(7-aza-bicyclo[2.2.llhept-1-yl)-phÃ©nyl-mÃ©thyll-(2-chloro-3-trifluoromÃ©thyl)benzam ide (1:1). Dans un ballon de 25 ml, on place 0,26 g d'acide (2-chloro-3-trifluoromÃ©thyl)benzoÃ¯que (1,19 mmole), 0,16 g d'hydroxybenzotriazole (1,19 mmole), 0,23 g de chlorhydrate de 1-[3-(dimÃ©thylamino)propyl]-3-Ã©thylcarbo-diimide (1,19 mmole) en solution dans 5 ml de dichloromÃ©thane et on agite le mÃ©lange Ã tempÃ©rature ambiante pendant 15 minutes. On ajoute 0,2 g (1,0 mmole) de (7-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thylamine en solution dans 2 ml de dichloromÃ©thane et on agite Ã tempÃ©rature ambiante pendant une nuit. Le milieu rÃ©actionnel est ensuite diluÃ© avec 2 ml de dichloromÃ©thane puis lavÃ© successivement Ã l'eau (3 ml), Ã la soude 1 N (3 ml) et avec une solution saturÃ©e de 5 chlorure de sodium (3 ml). La phase organique est sÃ©chÃ©e sur sulfate de sodium, filtrÃ©e et Ã©vaporÃ©e sous pression rÃ©duite. Le rÃ©sidu est purifiÃ© par chromatographie sur colonne de gel de silice en Ã©luant avec un mÃ©lange de dichloromÃ©thane et de mÃ©thanol ammoniacal. On obtient ainsi 260 mg de N-[(7-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(2-10 chloro-3-trifluoromÃ©thyl)benzamide, qui est salifiÃ© sous forme de chlorhydrate par solubilisation de la base dans l'Ã©ther, ajout d'un excÃ¨s d'acide chlorhydrique 1 N dans l'Ã©ther puis concentration sous pression rÃ©duite. RMN 'H (300 MHz,DMSO-d6) 8 ppm 9,52 (d, J = 9 Hz, 1H), 9,32 (m, 1H), 8,92 (m, 1 H), 7,96 (m, 2H), 7,65 (m, 1 H), 7,55-7,30 (m, 5H), 5,69 (d, J = 9,1 Hz, 1 H), 4,07 (m, 1 H), 2,30-0,65 (m, 8H). PF = 146,5-147,5 C.

Exemple 2 (composÃ© n 5) : Chlorhydrate de 2-chloro-N-[(7-Ã©thyl-7-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(3-trifluoromÃ©thyl)benzamide (1:1).

Dans un ballon de 25 ml muni d'un rÃ©frigÃ©rant, on place 95 mg de N-[(2-aza-bicyclo[2.1.1 ]hex-1-yl)-phÃ©nyl-mÃ©thyl]-(2-chloro-3-trifluoromÃ©thyl)-benzamide (0,23 mmole) dans 2 ml d'acÃ©tonirile, 64 mg de carbonate de potassium auxquels on ajoute 30 pl d'iodoÃ©thane (0,36 mmole). Le milieu rÃ©actionnel est agitÃ© une nuit Ã
45 C, puis 3 heures Ã 50 C et puis est concentrÃ© sous pression rÃ©duite. Le rÃ©sidu est ensuite diluÃ© avec 10 ml de dichloromÃ©thane puis lavÃ© Ã l'eau (5 ml).
AprÃ¨s extraction, la phase organique est sÃ©chÃ©e sur sulfate de sodium, filtrÃ©e et concentrÃ©e sous pression rÃ©duite. Le rÃ©sidu est purifiÃ© par chromatographie sur colonne de gel de silice en Ã©luant avec un mÃ©lange de dichloromÃ©thane et de mÃ©thanol ammoniacal. On obtient ainsi 90 mg de 2-chloro-N-[(7-Ã©thyl-7-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(3-trifluoromÃ©thyl)-benzamide qui est salifiÃ©
sous forme de chlorhydrate par solubilisation de la base dans le dichloromÃ©thane, ajout d'un excÃ¨s d'acide chlorhydrique 1N dans l'Ã©ther puis concentration sous pression rÃ©duite.
RMN 'H (400 MHz,DMSO-d6) 8 ppm 10,29 (m, 1H), 9,48 (d, J = 9,1 Hz, 1H), 8,12 (m, J = 8 Hz, 1 H), 7,94 (m, J = 7,6 Hz, 1 H), 7,71-7,31 (m, 6H), 5,68 (d, J =
9,3 Hz, 1 H), 4,21 (m, 1 H), 3,41-3,03 (m, 2H), 2,39-1,15 (m, 11 H). 10% are placed under a pressure of 7 atmospheres of hydrogen at 50 C during 6 hours. After filtration of the catalyst and concentration of the filtrate under pressure reduced, the residue is taken up in 25 ml of dichloromethane and 25 ml of water basified with ammonia. After extraction, the organic phase is dried on sulfate sodium, filtered and evaporated under reduced pressure. 0.28 g is thus obtained of (7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methylamine in the form of an oil which is solidifies in the cold and is used as is in the next step.
1 H NMR (400 MHz, CDCl 3) Î´ ppm 7.36 -7.13 (m, 5H), 4.24 (s, 1H), 3.49 (t, J =
4.8 Hz, 1H), 1.74-1.15 (m, 8H).
PF = 62-63 Â° C
1.4. N - [(7-aza-bicyclo [2.2.1-hept-1-yl] -phenyl-methyl-2-hydroxychloridate chloro-3-trifluoromethyl) benzam ide (1: 1).
In a 25 ml flask, 0.26 g of (2-chloro-3-trifluoromethyl) benzoic acid (1.19 mmol), 0.16 g of hydroxybenzotriazole (1.19 g) mmol), 0.23 g of 1- [3- (dimethylamino) propyl] -3-ethylcarbohydrochloride.
diimide (1.19 mmol) in solution in 5 ml of dichloromethane and the mixture is stirred at room temperature for 15 minutes. 0.2 g (1.0 mmol) of (7-aza) bicyclo [2.2.1] hept-1-yl) -phenyl-methylamine dissolved in 2 ml of dichloromethane and stirred at room temperature overnight.
The reaction medium is then diluted with 2 ml of dichloromethane and then washed successively with water (3 ml), with 1N sodium hydroxide (3 ml) and with a solution saturated with Sodium chloride (3 ml).
The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is purified by gel column chromatography of silica eluting with a mixture of dichloromethane and ammonia methanol.
260 mg of N - [(7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl are thus obtained.
(2-Chloro-3-trifluoromethyl) benzamide, which is salified in the form of hydrochloride by solubilization of the base in ether, addition of an excess of hydrochloric acid 1 N in ether and concentration under reduced pressure.
1 H NMR (300 MHz, DMSO-d 6) Î´ ppm 9.52 (d, J = 9 Hz, 1H), 9.32 (m, 1H), 8.92 (m, 1H), 7.96 (m, 2H), 7.65 (m, 1H), 7.55-7.30 (m, 5H), 5.69 (d, J = 9.1 Hz, 1H), H), 4.07 (m, 1H), 2.30-0.65 (m, 8H).
Mp = 146.5-147.5 Â° C.

EXAMPLE 2 (Compound No. 5): 2-Chloro-N - [(7-ethyl-7-azabate) hydrochloride bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) benzamide (1: 1).

In a 25 ml flask equipped with a condenser, 95 mg of N - [(2-aza) bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide (0.23 mmol) in 2 ml of acetonitrile, 64 mg of potassium carbonate to which add 30 Î¼l of iodoethane (0.36 mmol). The reaction medium is stirred night in 45 C, then 3 hours at 50 C and then is concentrated under reduced pressure. The residue is then diluted with 10 ml of dichloromethane and then washed with water (5 ml).
After extracted, the organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography sure silica gel column eluting with a mixture of dichloromethane and ammonia methanol. 90 mg of 2-chloro-N - [(7-ethyl-7-aza) bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide which is salified as hydrochloride by solubilization of the base in the dichloromethane addition of an excess of 1N hydrochloric acid in the ether and concentration under reduced pressure.
1H NMR (400MHz, DMSO-d6) Î´ ppm 10.29 (m, 1H), 9.48 (d, J = 9.1Hz, 1H), 8.12 (m, J = 8Hz, 1H), 7.94 (m, J = 7.6Hz, 1H), 7.71-7.31 (m, 6H), 5.68 (d, J =
9.3 Hz, 1H), 4.21 (m, 1H), 3.41-3.03 (m, 2H), 2.39-1.15 (m, 11H).

11 PF = 189,5-191,5 C.

Exemple 3 (composÃ© n 7) : Chlorhydrate de 2-chloro-N-[(7-mÃ©thyl-7-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(3-trifluoromÃ©thyl)-benzamide (1:1) Dans un ballon de 25 ml muni d'un rÃ©frigÃ©rant, on place 0,09 g de N-[(2-aza-bicyclo[2.1.1 ]hex-1-yl)-phÃ©nyl-mÃ©thyl]-(2-chloro-3-trifluoromÃ©thyl)-benzamide (0,22 mmole) et 2 ml de formaldÃ©hyde dans 2 ml d'acide formique. Le mÃ©lange rÃ©actionnel est chauffÃ© Ã 100 C pendant 72 heures. AprÃ¨s refroidissement, le milieu est hydrolysÃ©, basifiÃ© Ã pH 9 avec de l'ammonique puis extrait avec du dichloromÃ©thane.

La phase organique est sÃ©chÃ©e sur sulfate de sodium, filtrÃ©e et Ã©vaporÃ©e sous pression rÃ©duite. On obtient ainsi 70 mg de 2-chloro-N-[(7-Ã©thyl-7-aza-bicyclo[2.2. 1 ]hept-1 -yl)-phÃ©nyl-mÃ©thyl]-(3-trifluoromÃ©thyl)-benzam ide qui est salifiÃ©
sous forme de chlorhydrate par solubilisation de la base dans le dichloromÃ©thane, ajout d'un excÃ¨s d'acide chlorhydrique 1N dans l'Ã©ther puis concentration sous pression rÃ©duite.

RMN 1H (400 MHz,DMSO-d6) 8 ppm 10,58 (m, 1 H), 9,54 (d, J = 9,6 Hz, 1 H), 8,26 (m, J = 7,4 Hz, 1 H), 7,97 (m, J = 7,6 Hz, 1 H), 7,75-7,33 (m, 7H), 5,71 (d, J =

9,4 Hz, 1 H), 4,05 (m, 1H), 2,87 (m, 3H), 2,44-1,18 (m, 8H).
PF = 244-246 C.

Les autres composÃ©s listÃ©s dans le tableau sont obtenus suivant les mÃ©thodes dÃ©crites dans les exemples 1 Ã 3 Ã partir d'amines de formule gÃ©nÃ©rale (Ila) ou (Ilb), de lithiens de formule gÃ©nÃ©rale (VI), de dÃ©rivÃ©s d'acides carboxyliques de formule gÃ©nÃ©rale (III) ou d'agents alkylants appropriÃ©s.

Le tableau 1 qui suit illustre les structures chimiques de quelques composÃ©s de l'invention.

Dans la colonne Sels , - dÃ©signe un composÃ© Ã l'Ã©tat de base, "HCI", dÃ©signe un chlorhydrate, le chiffre entre parenthÃ¨ses indique le rapport (acide :
base) ;
Dans les colonnes R, R, et R2 :
- CI signifie chlore, - CH3 signifie mÃ©thyle, - Ph signifie phÃ©nyle, - Bn signifie benzyle, - CF3 signifie trifluoromÃ©thyle, 11 Mp = 189.5-191.5 Â° C.

Example 3 (Compound No. 7): 2-Chloro-N - [(7-methyl-7-azabate) hydrochloride bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzamide (1: 1) In a 25 ml flask equipped with a condenser, 0.09 g of N - [(2-aza) bicyclo [2.1.1] hex-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide (0.22 mmol) and 2 ml of formaldehyde in 2 ml of formic acid. The mixture reaction is heated at 100 C for 72 hours. After cooling, the medium is hydrolyzed, basified to pH 9 with ammonia and then extracted with dichloromethane.

The organic phase is dried over sodium sulphate, filtered and evaporated under reduced pressure. In this way 70 mg of 2-chloro-N - [(7-ethyl-7-aza) bicyclo [2.2. 1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) -benzam ide which is salified as hydrochloride by solubilization of the base in the dichloromethane addition of an excess of 1N hydrochloric acid in the ether and concentration under reduced pressure.

1H NMR (400MHz, DMSO-d6) Î´ ppm 10.58 (m, 1H), 9.54 (d, J = 9.6Hz, 1H), 8.26.

(M, J = 7.4 Hz, 1H), 7.97 (m, J = 7.6 Hz, 1H), 7.75-7.33 (m, 7H), 5.71 (d, J =
9.4 Hz, 1H), 4.05 (m, 1H), 2.87 (m, 3H), 2.44-1.18 (m, 8H).
Mp = 244-246C.

The other compounds listed in the table are obtained according to the methods described in Examples 1 to 3 from amines of general formula (IIa) or (Ilb), lithiens of general formula (VI), carboxylic acid derivatives of formula general (III) or suitable alkylating agents.

The following table 1 illustrates the chemical structures of some compounds of the invention.

In the Salts column, - denotes a compound in the basic state, "HCI", means a hydrochloride, the number in parentheses indicates the ratio (acid:
base);
In the columns R, R, and R2:
- CI means chlorine, - CH3 means methyl, Ph denotes phenyl - Bn means benzyl, CF3 means trifluoromethyl,

12 - dans la colonne R2 , le chiffre devant les substituants indique la position dans la formule gÃ©nÃ©rale (I), - Les composÃ©s du tableau se prÃ©sentent sous la forme de chlorhydrate solvatÃ© par une ou plusieurs molÃ©cules d'eau. Les composÃ©s n 3 et 6 du tableau 1 forment un couple d'Ã©nantiomÃ¨res qui sont sÃ©parÃ©s par HPLC prÃ©parative, en utilisant une colonne Chirobiotic T2 5 m et en tant que solvant un mÃ©lange mÃ©thanol/ triÃ©thylamine/acide acÃ©tique 100/0,1/0,05. La stÃ©rÃ©ochimie absolue a Ã©tÃ© dÃ©terminÃ©e par diffraction de rayons X.

Le tableau 2 donne les propriÃ©tÃ©s physiques, points de fusion et pouvoirs rotatoires des composÃ©s du tableau 1.

Dans le tableau 2 :

- la colonne [ad 20-c renseigne le rÃ©sultat d'analyse du pouvoir rotatoire des composÃ©s du tableau Ã la longueur d'onde de 589 nM et Ã la tempÃ©rature de C. Le solvant indiquÃ© entre parenthÃ¨ses correspond au solvant employÃ© pour rÃ©aliser la mesure du pouvoir rotatoire en degrÃ©s et la lettre c indique la concentration du solvant en g/100 ml. N.A. signifie que la mesure du pouvoir rotatoire n'est pas applicable, 20 - la colonne "m/z" renseigne l'ion molÃ©culaire (M+H+) ou (M+) observÃ© par analyse des produits par spectromÃ©trie de masse, soit par LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) rÃ©alisÃ©e sur un appareil de type Agilent LC-MSD
Trap en mode ESI positif, soit par introduction directe par MS (Mass Spectroscopy) sur un appareil Autospec M (EBE) en utilisant la technique DCI-NH3 ou en utilisant la technique d'impact Ã©lectronique sur un appareil de type Waters GCT. 12 - in column R2, the number in front of the substituents indicates the position in the general formula (I), - The compounds of the table are in the form of solvated hydrochloride by one or more water molecules.
Compounds Nos. 3 and 6 of Table 1 form a pair of enantiomers which are separated by preparative HPLC, using a 5m Chirobiotic T2 column and in as a solvent a methanol / triethylamine / acetic acid mixture 100 / 0.1 / 0.05. The Absolute stereochemistry was determined by X-ray diffraction.

Table 2 gives the physical properties, melting points and powers rotary compounds of Table 1.

In Table 2:

- column [ad 20-c gives the result of the analysis of the rotatory power of compounds of the table at the wavelength of 589 nM and at the temperature of C. The solvent indicated in parentheses corresponds to the solvent used for realize the measure of the rotary power in degrees and the letter c indicates the solvent concentration in g / 100 ml. NA means that measuring the power rotary is not applicable, The column "m / z" informs the molecular ion (M + H +) or (M +) observed by analysis products by mass spectrometry, either by LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) performed on an Agilent LC-MSD device Trap in ESI positive mode, either by direct introduction by MS (Mass Spectroscopy) on an Autospec M (EBE) device using DCI-NH3 or using the electronic impact technique on a type device Waters GCT.

13 Ri 5 ~ (1) N R R, R2 Sels stÃ©rÃ©ochimie 1 H Ph 2-CH3,3-CF3 - racÃ©mique HCI 2 H Ph 2,6-(CI)2,3-CF3 (1 :1) racÃ©mique HCI Chiral 3 H Ph 2,6-(CI)2,3-CF3 (1 :1) lÃ©vogyre R HCI 4 H Ph 2-C1,3-CF3 (1 :1) racÃ©mique HCI 5 C2H5 Ph 2-C1,3-CF3 (1 :1) racÃ©mique HCI Chiral 6 H Ph 2,6-(CI)2,3-CF3 (1 :1) dextrogyre S HCI 7 CH3 Ph 2-C1,3-CF3 (1 :1) racÃ©mique HCI 8 Bn Ph 2-CH3,3-CF3 (1 :1) racÃ©mique HCI 9 Bn Ph 2-C1,3-CF3 (1 :1) racÃ©mique HCI 10 H Ph 2-CI,3-C2H5 (1 :1) racÃ©mique 13 Ri 5 ~ (1) NRR, R2 Stereochemistry salts 1H Ph 2 -CH3,3-CF3 - racemic HCI 2 H Ph 2,6- (Cl) 2,3-CF3 (1: 1) racemic HCI Chiral 3H Ph 2,6- (Cl) 2,3-CF3 (1: 1) levorotatory R HCI 4 H Ph 2-C1,3-CF3 (1: 1) Racemic HCI Racemic C2H5 Ph 2-C1,3-CF3 (1: 1) HCI Chiral 6H Ph 2,6- (Cl) 2,3-CF3 (1: 1) dextrogyre S HCI 7 CH3 Ph 2-C1,3-CF3 (1: 1) Racemic HCI Racemic 8 Bn Ph 2 -CH3,3-CF3 (1: 1) HCI Racemic 9 Bn Ph 2-C1,3-CF3 (1: 1) HCI 10 H Ph 2 -Cl, 3-C2H5 (1: 1) racemic

14 LCMS N PF C [CD] 20 C 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 409 189,5-191,5 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 499 234,2-235,2 N.A 369 5 Les composÃ©s de l'invention ont Ã©tÃ© soumis Ã une sÃ©rie d'essais pharmacologiques qui ont mis en Ã©vidence leur intÃ©rÃªt comme substances Ã activitÃ©s thÃ©rapeutiques. Etude du transport de la glycine dans les cellules SK-N-MC exprimant le transporteur humain glyt1 natif. 10 La capture de [14C]glycine est Ã©tudiÃ©e dans les cellules SK-N-MC (cellules neuro-Ã©pithÃ©liales humaines) exprimant le transporteur humain glyt1 natif par la mesure de la radioactivitÃ© incorporÃ©e en prÃ©sence ou en absence du composÃ© Ã tester. Les cellules sont cultivÃ©es en monocouche pendant 48 h dans des plaques prÃ©traitÃ©es Ã la fibronectine Ã 0,02%. Le jour de l'expÃ©rience, le milieu de culture est Ã©liminÃ© et les cellules sont lavÃ©es par un tampon Krebs-HEPES (acide [4-(2-hydroxyÃ©thyl)pipÃ©razine-1-Ã©thanesulfonique) Ã pH 7,4. AprÃ¨s 10 min de prÃ©incubation Ã 37 C en prÃ©sence soit de tampon (lot tÃ©moin), soit de composÃ© Ã tester Ã diffÃ©rentes concentrations ou de 10 mM de glycine (dÃ©termination de la capture non spÃ©cifique), 10 pM de [14C]glycine (activitÃ© spÃ©cifique 112 mCi/mmole) sont ensuite ajoutÃ©s. L'incubation se poursuit pendant 10 min Ã 37 C, et la rÃ©action est arrÃªtÃ©e par 2 lavages avec un tampon Krebs-HEPES Ã pH 7,4. La radioactivitÃ© incorporÃ©e par les cellules est alors estimÃ©e aprÃ¨s ajout de 100 pl de scintillant liquide et agitation pendant 1 h. Le comptage est rÃ©alisÃ© sur compteur Microbeta Tri-IUXTM L'efficacitÃ© du composÃ© est dÃ©terminÃ©e par la C150, concentration du composÃ© qui diminue de 50% la capture spÃ©cifique de glycine, dÃ©finie par la diffÃ©rence de radioactivitÃ© incorporÃ©e par le lot tÃ©moin et le lot qui a reÃ§u la glycine Ã 10 mM. Les composÃ©s de l'invention, dans ce test, ont une C150 de l'ordre de 0,001 Ã 10 pM.

ComposÃ© C150 (pM) 1 0,038 2 0,003 3 0,023 4 0,027 6 0,0016 Les rÃ©sultats des essais effectuÃ©s sur les composÃ©s chiraux de l'invention et leurs 10 racÃ©mates dans la formule gÃ©nÃ©rale (1) montrent qu'ils sont des inhibiteurs du transporteur de la glycine glyt1 prÃ©sents dans le cerveau.

Ces rÃ©sultats suggÃ¨rent que les composÃ©s de l'invention peuvent Ãªtre utilisÃ©s pour le traitement des troubles cognitifs et/ou comportementaux associÃ©s Ã des maladies

14 LCMS
N PF C [CD] 20 C MH +

3 185-186 -50.73 (MeOH, c = 0.466 g / 100 ml) 443 4 146.5-147.5 NA 409 189.5-191.5 NA 437 6 181.5-182.5 +34.41 (MeOH, c = 0.732g / 100 ml) 443 9 159.5-160.5 NA 499 234.2-235.2 NA 369 The compounds of the invention have been subjected to a series of tests pharmacological who have highlighted their interest as active substances therapeutic.

Study of glycine transport in SK-N-MC cells expressing carrier human glyt1 native.
[14C] glycine uptake is studied in SK-N-MC cells (cells neuro-epithelial cells) expressing the native human transporter glyt1 by the measure of the radioactivity incorporated in the presence or absence of the test compound. The cells are cultured in monolayer for 48 h in plates pre-processed to fibronectin at 0.02%. On the day of the experiment, the culture medium is eliminated and cells are washed with Krebs-HEPES buffer (acid [4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) at pH 7.4. After 10 minutes of preincubation at 37 Â° C. in the presence of either buffer (control group) or compound at test at different concentrations or 10 mM glycine (determination of the nonspecific uptake), 10 Î¼M [14C] glycine (specific activity 112 mCi / mmol) are then added. Incubation is continued for 10 min at 37 Â° C, and the reaction is stopped by 2 washes with Krebs-HEPES buffer pH 7.4. The radioactivity incorporated by the cells is then estimated after adding 100 Î¼l of glittering liquid and stirring for 1 h. Counting is carried out on a Microbeta Tri-IUXTM
The effectiveness of the compound is determined by the C150 concentration of the compound who reduces by 50% the specific uptake of glycine, defined by the difference in radioactivity incorporated by the control group and the lot that received glycine 10 mM.
The compounds of the invention, in this test, have a C150 of the order of 0.001 to 10 Î¼M.

Table 3 gives some examples of C150 results for compounds according to the invention.

C150 compound (pM) 1 0.038 2 0.003 0.023 4 0.027 6 0.0016 The results of the tests carried out on the chiral compounds of the invention and their 10 racemates in the general formula (1) show that they are inhibitors of glycine transporter glyt1 present in the brain.

These results suggest that the compounds of the invention can be used for the treatment of cognitive and / or behavioral disorders associated with diseases

15 neurodÃ©gÃ©nÃ©ratives, Ã la dÃ©mence ; pour le traitement des psychoses, notamment de la schizophrÃ©nie (forme dÃ©ficitaire et forme productive), des symptÃ´mes extrapyramidaux aigus ou chroniques induits par les neuroleptiques ; pour le traitement des diverses formes d'anxiÃ©tÃ©, des attaques de panique, des phobies, des troubles obsessionnels compulsifs ; pour le traitement des diffÃ©rentes formes de dÃ©pression, y compris la dÃ©pression psychotique ; pour le traitement des troubles bipolaires, des troubles maniaques, des troubles de l'humeur ; pour le traitement des troubles dus Ã l'abus ou au sevrage d'alcool, des troubles du comportement sexuel, des troubles de la prise de nourriture, de la migraine ; de la douleur; des troubles du sommeil. Les composÃ©s selon l'invention peuvent donc Ãªtre utilisÃ©s pour la prÃ©paration de mÃ©dicaments, en particulier de mÃ©dicaments inhibiteurs du transporteur de la glycine glyt1.

Neurodegenerative, to dementia; for the treatment of psychoses, including schizophrenia (deficient form and productive form), symptoms acute or chronic extrapyramidal induced by neuroleptics; for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorder; for the treatment of different forms of depression, including psychotic depression; for the treatment of unrest bipolar, manic disorders, mood disorders; for the treatment of disorders due to alcohol abuse or withdrawal, behavioral disorders sexual, eating disorders, migraine; pain; of the disorders of the sleep.
The compounds according to the invention can therefore be used for the preparation of drugs, particularly inhibitor drugs the carrier of the wistaria glyt1.

Thus, according to another of its aspects, the subject of the invention is medicaments who

16 comprennent un composÃ© de formule (I), ou un sel d'addition de ce dernier Ã un acide pharmaceutiquement acceptable ou encore un hydrate ou un solvate du composÃ© de formule (I).

La prÃ©sente invention a Ã©galement pour objet des compositions pharmaceutiques contenant une dose efficace d'au moins un composÃ© selon l'invention, Ã l'Ã©tat de base ou de sel ou de solvat pharmaceutiquement acceptable, et en mÃ©lange, le cas Ã©chÃ©ant, avec des excipients convenables.

l'administration orale, sublinguale, sous-cutanÃ©e, intramusculaire, intraveineuse, topique, intratrachÃ©ale, intranasale, transdermique, rectale, intraocculaire.

Les formes unitaires d'administration peuvent Ãªtre, par exemple, des comprimÃ©s, des gÃ©lules, des granules, des poudres, des solutions ou suspensions orales ou injectables, des timbres transdermiques ("patch"), des suppositoires. Pour l'administration topique, on peut envisager des pommades, lotions et collyres.

Lesdites formes unitaires sont dosÃ©es pour permettre une administration journaliÃ¨re de 0,01 Ã 20 mg de principe actif par kg de poids corporel, selon la forme galÃ©nique.
Pour prÃ©parer des comprimÃ©s, on ajoute au principe actif, micronisÃ© ou non, un vÃ©hicule pharmaceutique qui peut Ãªtre composÃ© de diluants, comme par exemple le lactose, la cellulose microcristalline, l'amidon, et des adjuvants de formulation comme des liants, (polyvinylpyrrolidone, hydroxy-propylmÃ©thylcellulose, etc), des agents d'Ã©coulement comme la silice, des lubrifiants comme le stÃ©arate de magnÃ©sium, l'acide stÃ©arique, le tribehenate de glycerol, le stÃ©aryl-fumarate de sodium.
Des agents mouillants ou tensioactifs tels que le laurylsulfate de sodium peuvent aussi Ãªtre ajoutÃ©s.
Les techniques de rÃ©alisation peuvent Ãªtre la compression directe, la granulation sÃ¨che, la granulation humide ou la fusion Ã chaud.
Les comprimÃ©s peuvent Ãªtre nus, dragÃ©ifiÃ©s, par exemple par du saccharose, ou enrobÃ©s avec divers polymÃ¨res ou autres matiÃ¨res appropriÃ©es. Ils peuvent Ãªtre conÃ§us pour permettre une libÃ©ration rapide, retardÃ©e ou prolongÃ©e du principe actif 16 comprise a compound of formula (I), or an addition salt thereof to a acid a pharmaceutically acceptable salt or a hydrate or a solvate of the formula (I).

The present invention also relates to pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the state basic or a pharmaceutically acceptable salt or solvate, and in a mixture, the case with appropriate excipients.

Said excipients are chosen according to the pharmaceutical form and the mode desired administration.

The pharmaceutical compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraocular.

The unitary forms of administration may be, for example, tablets, capsules, granules, powders, oral solutions or suspensions or injectables, transdermal patches, suppositories. For topical administration, it is possible to envisage ointments, lotions and eye drops.

Said unit forms are dosed to allow administration daily from 0.01 to 20 mg of active ingredient per kg of body weight, depending on the form dosage.
To prepare tablets, one adds to the active principle, micronized or not, a pharmaceutical vehicle which may be composed of diluents, for example the lactose, microcrystalline cellulose, starch, and adjuvants of formulation as binders, (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), agents like silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate.
of the wetting agents or surfactants such as sodium lauryl sulphate may as well to be added.
The realization techniques can be direct compression, granulation dry, wet granulation or hot melt.
The tablets may be bare, sugar-coated, for example with sucrose, or coated with various polymers or other suitable materials. They can be designed to allow rapid, delayed or prolonged release of the principle active

Pour prÃ©parer des gÃ©lules, on mÃ©lange le principe actif avec des vÃ©hicules pharmaceutiques secs (simple mÃ©lange, granulation sÃ¨che ou humide, ou fusion Ã

chaud), liquides ou semi-solides.
Les gÃ©lules peuvent Ãªtre dures ou molles, pelliculÃ©es ou non, de maniÃ¨re Ã
avoir une activitÃ© rapide, prolongÃ©e ou retardÃ©e (par exemple pour une forme entÃ©rique).

Une composition sous forme de sirop ou d'Ã©lixir ou pour l'administration sous forme de gouttes peut contenir le principe actif conjointement Ã un Ã©dulcorant, de prÃ©fÃ©rence acalorique, du mÃ©thylparaben ou du propylparaben comme antiseptique, un agent de sapiditÃ© et un colorant.

Les poudres et granules dispersibles dans de l'eau peuvent contenir le principe actif en mÃ©lange avec des agents de dispersion ou des agents mouillants, ou des agents dispersants comme la polyvinylpyrrolidone, de mÃªme qu'avec des Ã©dulcorants et des agents correcteurs de goÃ»t.

Pour l'administration rectale, on recourt Ã des suppositoires prÃ©parÃ©s avec des liants fondant Ã la tempÃ©rature rectale, par exemple du beurre de cacao ou des polyÃ©thylÃ¨neglycols.

Pour une administration parentÃ©rale, on utilise des suspensions aqueuses, des solutions salines isotoniques ou des solutions stÃ©riles injectables contenant des agents de dispersion et/ou des mouillants pharmacologiquement compatibles, par exemple le propylÃ¨neglycol ou le butylÃ¨ne-glycol.

Le principe actif peut Ãªtre formulÃ© Ã©galement sous forme de microcapsules, Ã©ventuellement avec un ou plusieurs supports ou additifs, ou bien avec une matrice polymÃ¨re ou avec une cyclodextrine (timbres transdermiques, formes Ã

Les compositions topiques selon l'invention comprennent un milieu compatible avec la peau. Elles peuvent se prÃ©senter notamment sous forme de solutions aqueuses, alcooliques ou hydroalcooliques, de gels, d'Ã©mulsions eau-dans-huile ou huile-dans-

17 thanks to polymer matrices or specific polymers used in coating.

To prepare capsules, the active ingredient is mixed with vehicles pharmaceutical products (simple mixing, dry or wet granulation, or hot), liquid or semi-solid.

Capsules may be hard or soft, film-coated or not, so that have a rapid, prolonged or delayed activity (eg enteric form).

A composition in the form of syrup or elixir or for administration under form drops may contain the active ingredient together with a sweetener, preference acaloric acid, methylparaben or propylparaben as an antiseptic, an agent of palatability and a dye.

Dispersible powders and granules in water may contain the active ingredient in admixture with dispersants or wetting agents, or agents dispersants such as polyvinylpyrrolidone, as well as with sweeteners and of the taste correcting agents.

For rectal administration, suppositories prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing of the dispersants and / or pharmacologically compatible wetting agents, by for example propylene glycol or butylene glycol.

The active ingredient can be formulated also in the form of microcapsules, possibly with one or more supports or additives, or with a matrix polymer or with a cyclodextrin (transdermal patches, release extended).

The topical compositions according to the invention comprise a compatible medium with the skin. They may be in particular in the form of aqueous solutions, alcoholic or hydroalcoholic, gels, water-in-oil or oil-in-oil emulsions in-

18 eau ayant l'aspect d'une crÃ¨me ou d'un gel, de microÃ©mulsions, d'aÃ©rosols, ou encore sous forme de dispersions vÃ©siculaires contenant des lipides ioniques et/ou non ioniques. Ces formes galÃ©niques sont prÃ©parÃ©es selon les mÃ©thodes usuelles des domaines considÃ©rÃ©s. A titre d'exemple, une forme unitaire d'administration d'un composÃ© selon l'invention sous forme de comprimÃ© peut comprendre les composants suivants :

ComposÃ© selon l'invention 50,0 mg Mannitol 223,75 mg Croscaramellose sodique 6,0 mg Amidon de maÃ¯s 15,0 mg Hydroxypropyl-mÃ©thylcellulose 2,25 mg StÃ©arate de magnÃ©sium 3,0 mg Par voie orale, la dose de principe actif administrÃ©e par jour peut atteindre 0,1 Ã 20 mg/kg, en une ou plusieurs prises.

Il peut y avoir des cas particuliers oÃ¹ des dosages plus Ã©levÃ©s ou plus faibles sont appropriÃ©s ; de tels dosages ne sortent pas du cadre de l'invention. Selon la pratique habituelle, le dosage appropriÃ© Ã chaque patient est dÃ©terminÃ© par le mÃ©decin selon le mode d'administration, le poids et la rÃ©ponse dudit patient.

La prÃ©sente invention, selon un autre de ses aspects, concerne Ã©galement une mÃ©thode de traitement des pathologies ci-dessus indiquÃ©es qui comprend l'administration, Ã un patient, d'une dose efficace d'un composÃ© selon l'invention, ou un de ses sels pharmaceutiquement acceptables.

18 water having the appearance of a cream or a gel, microemulsions, aerosols, or again in the form of vesicular dispersions containing ionic lipids and / or no Ionic. These galenic forms are prepared according to the usual methods of fields considered.
By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg Orally, the dose of active ingredient administered per day can reach 0.1 to 20 mg / kg, in one or more doses.

There may be special cases where higher or higher dosages weak are appropriate; such dosages are not outside the scope of the invention. According to convenient usual, the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the weight and the response of said patient.

The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which includes administration to a patient of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof.

Claims (23) Translated from French 1. ComposÃ© de formule gÃ©nÃ©rale (I) dans laquelle : - R reprÃ©sente un atome d'hydrogÃ¨ne ou un groupe choisi parmi les groupes (C1-C6)alkyle, (C3-C7)-cycloalkyle, Ã©ventuellement substituÃ© par un ou plusieurs groupes choisis indÃ©pendamment l'un de l'autre parmi les atomes d'halogÃ¨ne, les groupes (C3-C7)-cycloalkyle, (C2-C4)alcÃ©nyle, phÃ©nyle, (C1-C6)alcoxy, hydroxy ; le groupe phÃ©nyle est Ã©ventuellement substituÃ© par un ou plusieurs groupes (C1-C6)alcoxy ; - R1 reprÃ©sente un groupe phÃ©nyle ou naphtyle, Ã©ventuellement substituÃ© par un ou plusieurs substituants choisis indÃ©pendamment l'un de l'autre parmi les atomes d'halogÃ¨ne, les groupes (C1-C6)alkyle, (C1-C6)alcoxy, halo-(C1-C6)alkyle, hydroxy, halo-(C1-C6)alcoxy, (C1-C6)alkyle-thio, (C1-C6)alkyle-SO, (C1-C6)alkyle-SO2, - R2 reprÃ©sente un ou plusieurs substituants choisis parmi l'atome d'hydrogÃ¨ne, les atomes d'halogÃ¨ne, les groupes halo-(C1-C6)alkyle, (C1-C6)alkyle, (C3-C7)cycloalkyle, (C3-C7)-cycloalkyl-(C1-C3)alkyle, (C1-C6)alcoxy, (C1-C6)alkyl-thio, (C1-C6)alkyle-SO (C1-C6)alkyle-SO2 ; Ã l'Ã©tat de base ou de sel d'addition Ã un acide. 1. Compound of general formula (I) in which : R represents a hydrogen atom or a group selected from groups (C1-C6) alkyl, (C3-C7) -cycloalkyl, optionally substituted with one or more groups independently of one another selected from halogen atoms, groups (C3-C7) -cycloalkyl, (C2-C4) alkenyl, phenyl, (C1-C6) alkoxy, hydroxy; the group phenyl is optionally substituted with one or more (C1-C6) alkoxy groups ; R 1 represents a phenyl or naphthyl group, optionally substituted with a or several substituents chosen independently of each other from among the atoms halogen, (C1-C6) alkyl, (C1-C6) alkoxy, halo- (C1-C6) alkyl, hydroxy, halo- (C1-C6) alkoxy, (C1-C6) alkyl-thio, (C1-C6) alkyl-SO, (C1-C6) alkyl-SO2, R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, halo (C1-C6) alkyl, (C1-C6) alkyl groups, (C3-C7) cycloalkyl, (C3-C7) -cycloalkyl- (C1-C3) alkyl, (C1-C6) alkoxy, (C1-C6) alkyl-thio, (C1-C6) alkyl-SO (C1-C6) alkyl-SO2; in the form of a base or an acid addition salt. 2. ComposÃ© de formule gÃ©nÃ©rale (I) selon la revendication 1, caractÃ©risÃ© en ce que R reprÃ©sente un atome d'hydrogÃ¨ne, un groupe (C1-C6)alkyle ou benzyle ; R1 et R2 Ã©tant tels que dÃ©finis dans la revendication 1, Ã l'Ã©tat de base ou de sel d'addition Ã un acide. 2. Compound of general formula (I) according to claim 1, characterized in that than R represents a hydrogen atom, a (C 1 -C 6) alkyl or benzyl group; R1 and R2 being as defined in claim 1, in the basic state or salt addition to an acid. 3. ComposÃ© de formule gÃ©nÃ©rale (I) selon la revendication 1, caractÃ©risÃ© en ce que R1 reprÃ©sente un groupe phÃ©nyle ; R et R2 Ã©tant tels que dÃ©finis dans la revendication 1, Ã l'Ã©tat de base ou de sel d'addition Ã un acide. 3. Compound of general formula (I) according to claim 1, characterized in that than R1 represents a phenyl group; R and R2 being as defined in claim 1, in the basic state or salt addition to an acid. 4. ComposÃ© de formule gÃ©nÃ©rale (I) selon la revendication 1, caractÃ©risÃ© en ce que R2 reprÃ©sente un ou plusieurs substituants choisis parmi l'atome d'hydrogÃ¨ne, les atomes d'halogÃ¨ne, les groupes halo-(C1-C6)alkyle ou (C1-C6)alkyle, R et R1 Ã©tant tels que definis dans la revendication 1, Ã l'Ã©tat de base ou de sel d'addition Ã un acide. 4. Compound of general formula (I) according to claim 1, characterized in that than R2 represents one or more substituents chosen from the hydrogen atom, the halogen atoms, halo (C1-C6) alkyl or (C1-C6) alkyl groups, R and R1 being as defined in claim 1, in the basic state or salt addition to an acid. 5. ComposÃ© de formule gÃ©nÃ©rale (I) selon la revendication 1, caractÃ©risÃ© en ce que - R reprÃ©sente un atome d'hydrogÃ¨ne ou un groupe (C1-C6)alkyle, benzyle ; - R1 reprÃ©sente un groupe phÃ©nyle, - R2 reprÃ©sente un ou plusieurs substituants choisis parmi l'atome d'hydrogÃ¨ne, les atomes d'halogÃ¨ne, les groupes halo-(C1-C6)alkyle ou (C1-C6)alkyle, Ã l'Ã©tat de base ou de sel d'addition Ã un acide. 5. Compound of general formula (I) according to claim 1, characterized in that than R represents a hydrogen atom or a (C 1 -C 6) alkyl or benzyl group; R1 represents a phenyl group, R2 represents one or more substituents chosen from the atom hydrogen, halogen atoms, halo (C1-C6) alkyl or (C1-C6) alkyl groups, in the form of a base or an acid addition salt. 6. R reprÃ©sente un atome d'hydrogÃ¨ne ou un groupe mÃ©thyle, Ã©thyle ou benzyle ; R1 reprÃ©sente un groupe phÃ©nyle, R2 reprÃ©sente un ou plusieurs substituants choisis parmi l'atome d'hydrogÃ¨ne, l'atome de chlore, les groupes mÃ©thyle, Ã©thyle ou trifluoromÃ©thyle, Ã l'Ã©tat de base ou de sel d'addition Ã un acideR represents a hydrogen atom or a methyl, ethyl or benzyl group; R 1 represents a phenyl group, R2 represents one or more substituents chosen from the hydrogen atom, atom chlorine, methyl, ethyl or trifluoromethyl, in the basic state or salt addition to an acid 7. ComposÃ© selon la revendication 1 ou 2, caractÃ©risÃ© en ce qu'il est choisi parmi .cndot.N-[(7-Aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(2-mÃ©thyl-3-trifluoromÃ©thyl)-benzamide ; .cndot.N-[(7-Aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(2,6-dichloro-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; .cndot.(-)-N-[(7-Aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(2,6-dichloro-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; .cndot.N-[(7-Aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(2-chloro-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; .cndot.2-Chloro-N-[(7-Ã©thyl-7-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; .cndot.(+)-N-[(7-Aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(2,6-dichloro-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; .cndot.2-Chloro-N-[(7-mÃ©thyl-7-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-3-trifluoromÃ©thyl-benzamide, et son chlorhydrate ; .cndot.N-[(7-Benzyl-7-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(2-mÃ©thyl-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; .cndot.N-[(7-Benzyl-7-aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(2-chloro-3-trifluoromÃ©thyl)-benzamide, et son chlorhydrate ; .cndot.N-[(7-Aza-bicyclo[2.2.1]hept-1-yl)-phÃ©nyl-mÃ©thyl]-(2-chloro-3-Ã©thyl)-benzamide, et son chlorhydrate. 7. Compound according to claim 1 or 2, characterized in that it is chosen among .cndot.N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-methyl-3-trifluoromethyl) -benzamide; .cndot.N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide, and its hydrochloride; .cndot. (-) - N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide, and its hydrochloride; .cndot.N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) -benzamide, and its hydrochloride; .cndot.2-Chloro-N - [(7-ethyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (3-trifluoromethyl) benzamide, and its hydrochloride; .cndot (+) -. N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2,6-dichloro-3-trifluoromethyl) -benzamide, and its hydrochloride; .cndot.2-Chloro-N - [(7-methyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] -3 trifluoromethylbenzamide, and its hydrochloride; .cndot.N - [(7-Benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-methyl-3-trifluoromethyl) benzamide, and its hydrochloride; .cndot.N - [(7-Benzyl-7-aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-trifluoromethyl) benzamide, and its hydrochloride; .cndot.N - [(7-Aza-bicyclo [2.2.1] hept-1-yl) -phenyl-methyl] - (2-chloro-3-ethyl) -benzamide, and its hydrochloride. 8. ProcÃ©dÃ© de prÃ©paration d'un composÃ© de formule gÃ©nÃ©rale (I) selon la revendication 1, caractÃ©risÃ© en ce qu'un composÃ© de formule gÃ©nÃ©rale (II) dans laquelle R et R1 sont tels que dÃ©finis selon la revendication 1, rÃ©agit avec un composÃ© de formule gÃ©nÃ©rale (III) dans laquelle Y reprÃ©sente un groupe partant ou un atome d'halogÃ¨ne et R2 est tel que dÃ©fini selon la revendication 1. 8. Process for the preparation of a compound of general formula (I) according to Claim 1, characterized in that a compound of the general formula (II) wherein R and R 1 are as defined in claim 1, react with a compound of general formula (III) wherein Y represents a leaving group or a halogen atom and R2 is such as defined in claim 1. 9. ComposÃ© de formule gÃ©nÃ©rale (II) dans laquelle R et R1 sont tels que dÃ©finis dans la revendication 1. 9. Compound of general formula (II) wherein R and R 1 are as defined in claim 1. 10. MÃ©dicament, caractÃ©risÃ© en ce qu'il comprend un composÃ© de formule (I) selon l'une quelconque des revendications 1 Ã 7, ou un sel d'addition de ce composÃ© Ã un acide pharmaceutiquement acceptable. 10. Medicinal product, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 7, or an addition salt thereof has a pharmaceutically acceptable acid. 11. Composition pharmaceutique, caractÃ©risÃ©e en ce qu'elle comprend un composÃ© de formule (I) selon l'une quelconque des revendications 1 Ã 7, ou un sel pharmaceutiquement acceptable, de ce composÃ©, ainsi qu'au moins un excipient pharmaceutiquement acceptable.11. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 7, or a salt pharmaceutically acceptable, of this compound, and at least one excipient pharmaceutically acceptable. 12. Utilisation d'un composÃ© de formule (I) selon l'une quelconque des revendications 1 Ã 7, pour la prÃ©paration d'un mÃ©dicament destinÃ© au traitement des troubles cognitifs et/ou comportementaux associÃ©s Ã des maladies neurodÃ©gÃ©nÃ©ratives ; Ã la dÃ©mence. 12. Use of a compound of formula (I) according to any one of claims 1 to 7, for the preparation of a medicament for treating disorders cognitive and / or behavioral associated with neurodegenerative diseases; at the dementia. 13. Utilisation d'un composÃ© de formule (I) selon l'une quelconque des revendications 1 Ã 7, pour la prÃ©paration d'un mÃ©dicament destinÃ© au traitement des psychoses, de la schizophrÃ©nie (forme dÃ©ficitaire et forme productive), des symptÃ´mes extrapyramidaux aigus ou chroniques induits par les neuroleptiques. 13. Use of a compound of formula (I) according to any one of claims 1-7 for the preparation of a medicament for the treatment of psychoses, of schizophrenia (deficient form and productive form), symptoms acute or chronic extrapyramidal events induced by neuroleptics. 14. Utilisation d'un composÃ© de formule (I) selon l'une quelconque des revendications 1 Ã 7, pour la prÃ©paration d'un mÃ©dicament destinÃ© au traitement pour le traitement des diverses formes d'anxiÃ©tÃ©, des attaques de panique, des phobies, des troubles obsessionnels compulsifs. 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 treatment various forms of anxiety, panic attacks, phobias, unrest obsessive compulsive. 15. Utilisation d'un composÃ© de formule (I) selon l'une quelconque des revendications 1 Ã 7, pour la prÃ©paration d'un mÃ©dicament destinÃ© au traitement des diffÃ©rentes formes de dÃ©pression, y compris la dÃ©pression psychotique ; pour le traitement des troubles bipolaires, des troubles maniaques, des troubles de l'humeur ; pour le traitement des troubles dus Ã l'abus ou au sevrage d'alcool, des troubles du comportement sexuel, des troubles de la prise de nourriture, de la migraine. 15. Use of a compound of formula (I) according to any one of claims 1-7 for the preparation of a medicament for the treatment of different forms of depression, including psychotic depression; for the treatment of the bipolar disorder, manic disorders, mood disorders; for the treatment of alcohol abuse or withdrawal disorders, sexual behavior, eating disorders, migraine. 16. Utilisation d'un composÃ© de formule (I) selon l'une quelconque des revendications 1 Ã 7, pour la prÃ©paration d'un mÃ©dicament destinÃ© au traitement de la douleur. 16. Use of a compound of formula (I) according to any one of claims 1-7 for the preparation of a medicament for the treatment of pain. 17. Utilisation d'un composÃ© de formule (I) selon l'une quelconque des revendications 1 Ã 7, pour la prÃ©paration d'un mÃ©dicament destinÃ© au traitement des troubles du sommeil. 17. Use of a compound of formula (I) according to any one of claims 1 to 7, for the preparation of a medicament for treating disorders of sleep. 18. ComposÃ© selon l'une quelconque des revendications 1 Ã 7, pour le traitement des troubles cognitifs et/ou comportementaux associÃ©s Ã des maladies neurodÃ©gÃ©nÃ©ratives ; Ã la dÃ©mence. 18. A compound according to any one of claims 1 to 7 for the treatment of Cognitive and / or behavioral disorders associated with diseases neurodegenerative; to madness. 19. ComposÃ© selon l'une quelconque des revendications 1 Ã 7, pour le traitement des psychoses, de la schizophrÃ©nie (forme dÃ©ficitaire et forme productive), des symptÃ´mes extrapyramidaux aigus ou chroniques induits par les neuroleptiques. 19. A compound according to any one of claims 1 to 7 for the treatment of psychoses, schizophrenia (a form of deficit and a productive form), acute or chronic extrapyramidal symptoms induced by neuroleptics. 20. ComposÃ© selon l'une quelconque des revendications 1 Ã 7, pour le traitement des diverses formes d'anxiÃ©tÃ©, des attaques de panique, des phobies, des troubles obsessionnels compulsifs. 20. A compound according to any one of claims 1 to 7 for the treatment of various forms of anxiety, panic attacks, phobias, disorders obsessive compulsive. 21. ComposÃ© selon l'une quelconque des revendications 1 Ã 7, pour le traitement des diffÃ©rentes formes de dÃ©pression, y compris la dÃ©pression psychotique ; pour le traitement des troubles bipolaires, des troubles maniaques, des troubles de l'humeur ; pour le traitement des troubles dus Ã l'abus ou au sevrage d'alcool, des troubles du comportement sexuel, des troubles de la prise de nourriture, de la migraine. 21. A compound according to any one of claims 1 to 7, for treatment of different forms of depression, including psychotic depression; for the treatment of bipolar disorders, manic disorders, mood for the treatment of alcohol abuse or withdrawal disorders, disorders of the sexual behavior, eating disorders, migraine. 22. ComposÃ© selon l'une quelconque des revendications 1 Ã 7, pour le traitement de la douleur. 22. A compound according to any one of claims 1 to 7 for the Treatment of pain. 23. ComposÃ© selon l'une quelconque des revendications 1 Ã 7, pour le traitement des troubles du sommeil. 23. A compound according to any of claims 1 to 7 for the treatment of sleeping troubles. CA2758367A 2009-04-14 2010-04-13 Derivatives of n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof Abandoned CA2758367A1 (en) Applications Claiming Priority (3) Application Number Priority Date Filing Date Title FR0901809A FR2944284A1 (en) 2009-04-14 2009-04-14 N- (7-AZA-BICYCLO) 2.2.1! HEPT-1-YL) -LARYL-METHYL DERIVATIVES -BENZAMIDE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION FR09/01809 2009-04-14 PCT/FR2010/050711 WO2010119222A1 (en) 2009-04-14 2010-04-13 Derivatives of n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof Publications (1) Publication Number Publication Date CA2758367A1 true CA2758367A1 (en) 2010-10-21 Family ID=41228015 Family Applications (1) Application Number Title Priority Date Filing Date CA2758367A Abandoned CA2758367A1 (en) 2009-04-14 2010-04-13 Derivatives of n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, preparation thereof, and therapeutic use thereof Country Status (14) Families Citing this family (1) * Cited by examiner, â Cited by third party Publication number Priority date Publication date Assignee Title KR20160045182A (en) 2014-10-16 2016-04-27 íëìëì°¨ì£¼ìíì¬ Gray cast iron for cylinder liner and method for manufacturing cylinder liner using the same Family Cites Families (4) * Cited by examiner, â Cited by third party Publication number Priority date Publication date Assignee Title FR2842804B1 (en) * 2002-07-29 2004-09-03 Sanofi Synthelabo N- [PHENYL (PIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION FR2861076B1 (en) * 2003-10-17 2006-01-06 Sanofi Synthelabo N-HETEROCYCLYMETHYLBENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE WO2008065500A2 (en) * 2006-11-30 2008-06-05 Pfizer Products Inc. Heteroaryl amides as type i glycine transport inhibitors WO2009013535A1 (en) * 2007-07-23 2009-01-29 Astrazeneca Ab 2-azabicyclo(2.2.2)octane derivatives as modulators of the glycine transporter i receptor

2009
- 2009-04-14 FR FR0901809A patent/FR2944284A1/en not_active Withdrawn
2010
- 2010-04-12 AR ARP100101220A patent/AR076276A1/en unknown
- 2010-04-13 CA CA2758367A patent/CA2758367A1/en not_active Abandoned
- 2010-04-13 SG SG2011075017A patent/SG175222A1/en unknown
- 2010-04-13 WO PCT/FR2010/050711 patent/WO2010119222A1/en active Application Filing
- 2010-04-13 EP EP10723665A patent/EP2419431A1/en not_active Withdrawn
- 2010-04-13 AU AU2010238409A patent/AU2010238409A1/en not_active Abandoned
- 2010-04-13 TW TW099111503A patent/TW201041581A/en unknown
- 2010-04-13 BR BRPI1015484A patent/BRPI1015484A2/en not_active Application Discontinuation
- 2010-04-13 JP JP2012505205A patent/JP2012523448A/en not_active Withdrawn
- 2010-04-13 MX MX2011010929A patent/MX2011010929A/en not_active Application Discontinuation
- 2010-04-13 KR KR1020117026894A patent/KR20120013378A/en not_active Withdrawn
- 2010-04-14 UY UY0001032561A patent/UY32561A/en not_active Application Discontinuation
2011
- 2011-10-10 IL IL215673A patent/IL215673A0/en unknown

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