CA2361437A1 - Pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor and their use for treating tobacco withdrawal symptoms - Google Patents
Pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor and their use for treating tobacco withdrawal symptoms Download PDFInfo
- Publication number
- CA2361437A1 CA2361437A1 CA002361437A CA2361437A CA2361437A1 CA 2361437 A1 CA2361437 A1 CA 2361437A1 CA 002361437 A CA002361437 A CA 002361437A CA 2361437 A CA2361437 A CA 2361437A CA 2361437 A1 CA2361437 A1 CA 2361437A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- nicotine
- pyridyl
- azabicyclo
- pharmaceutical composition
- Prior art date
- 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
Links
- 229960002715 nicotine Drugs 0.000 title claims abstract description 72
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 title claims abstract description 72
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 title claims abstract description 48
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- 239000003446 ligand Substances 0.000 title claims abstract description 23
- 239000003112 inhibitor Substances 0.000 title abstract description 4
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 title abstract 2
- 206010059612 Tobacco withdrawal symptoms Diseases 0.000 title abstract 2
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 claims description 30
- 239000002899 monoamine oxidase inhibitor Substances 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 23
- 241000208125 Nicotiana Species 0.000 claims description 20
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims description 20
- IALVDLPLCLFBCF-CHWSQXEVSA-N befloxatone Chemical compound O=C1O[C@@H](COC)CN1C1=CC=C(OCC[C@@H](O)C(F)(F)F)C=C1 IALVDLPLCLFBCF-CHWSQXEVSA-N 0.000 claims description 17
- 229950000017 befloxatone Drugs 0.000 claims description 17
- -1 rasageline Chemical compound 0.000 claims description 16
- 230000002441 reversible effect Effects 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 235000015218 chewing gum Nutrition 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229960004644 moclobemide Drugs 0.000 claims description 8
- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229940112822 chewing gum Drugs 0.000 claims description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- SQMNCLANJWZZOG-NSHDSACASA-N (5s)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)-1,2-benzoxazol-3-yl]-1,3-oxazolidin-2-one Chemical compound O=C1O[C@H](COC)CN1C1=NOC2=CC(OCCCC(F)(F)F)=CC=C12 SQMNCLANJWZZOG-NSHDSACASA-N 0.000 claims description 4
- JUOSGGQXEBBCJB-UHFFFAOYSA-N Metanicotine Natural products CNCCC=CC1=CC=CN=C1 JUOSGGQXEBBCJB-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
- 229940097496 nasal spray Drugs 0.000 claims description 4
- 239000007922 nasal spray Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- JUOSGGQXEBBCJB-GORDUTHDSA-N rivanicline Chemical compound CNCC\C=C\C1=CC=CN=C1 JUOSGGQXEBBCJB-GORDUTHDSA-N 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- MXYUKLILVYORSK-UHFFFAOYSA-N (+/-)-allo-lobeline Natural products C1CCC(CC(=O)C=2C=CC=CC=2)N(C)C1CC(O)C1=CC=CC=C1 MXYUKLILVYORSK-UHFFFAOYSA-N 0.000 claims description 3
- MXYUKLILVYORSK-HBMCJLEFSA-N (-)-lobeline Chemical compound C1([C@@H](O)C[C@H]2N([C@H](CCC2)CC(=O)C=2C=CC=CC=2)C)=CC=CC=C1 MXYUKLILVYORSK-HBMCJLEFSA-N 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 239000013066 combination product Substances 0.000 claims description 3
- 229940127555 combination product Drugs 0.000 claims description 3
- ANJTVLIZGCUXLD-UHFFFAOYSA-N ent-cytisine Natural products C1NCC2CN3C(=O)C=CC=C3C1C2 ANJTVLIZGCUXLD-UHFFFAOYSA-N 0.000 claims description 3
- 229960002339 lobeline Drugs 0.000 claims description 3
- 229930013610 lobeline Natural products 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims description 3
- 239000012730 sustained-release form Substances 0.000 claims description 3
- ANJTVLIZGCUXLD-BDAKNGLRSA-N (-)-Cytisine Natural products C1NC[C@@H]2CN3C(=O)C=CC=C3[C@H]1C2 ANJTVLIZGCUXLD-BDAKNGLRSA-N 0.000 claims description 2
- VXLBSYHAEKDUSU-JXMROGBWSA-N (2e)-2-(fluoromethylidene)-4-(4-fluorophenyl)butan-1-amine Chemical compound NC\C(=C\F)CCC1=CC=C(F)C=C1 VXLBSYHAEKDUSU-JXMROGBWSA-N 0.000 claims description 2
- SQUNAWUMZGQQJD-UHFFFAOYSA-N 1-(4-ethylphenyl)-2-methyl-3-(piperidin-1-yl)propan-1-one Chemical compound C1=CC(CC)=CC=C1C(=O)C(C)CN1CCCCC1 SQUNAWUMZGQQJD-UHFFFAOYSA-N 0.000 claims description 2
- CLRANNZHQRADST-UHFFFAOYSA-N 1-(5-methoxypyridin-3-yl)-1,4-diazepane Chemical compound COC1=CN=CC(N2CCNCCC2)=C1 CLRANNZHQRADST-UHFFFAOYSA-N 0.000 claims description 2
- SHALYUZFJLUFSL-UHFFFAOYSA-N 1-(5-methoxypyridin-3-yl)-1,5-diazocane Chemical compound COC1=CN=CC(N2CCCNCCC2)=C1 SHALYUZFJLUFSL-UHFFFAOYSA-N 0.000 claims description 2
- LWFPJCHDKSLKOQ-UHFFFAOYSA-N 1-(5-propoxypyridin-3-yl)-1,4-diazepane Chemical compound CCCOC1=CN=CC(N2CCNCCC2)=C1 LWFPJCHDKSLKOQ-UHFFFAOYSA-N 0.000 claims description 2
- JRNYLCIPPWHNEJ-UHFFFAOYSA-N 1-(6-bromopyridin-3-yl)-1,4-diazepane Chemical compound C1=NC(Br)=CC=C1N1CCNCCC1 JRNYLCIPPWHNEJ-UHFFFAOYSA-N 0.000 claims description 2
- GAGCCMIPRTXYNT-UHFFFAOYSA-N 1-(6-chloro-5-methoxypyridin-3-yl)-1,4-diazepane Chemical compound N1=C(Cl)C(OC)=CC(N2CCNCCC2)=C1 GAGCCMIPRTXYNT-UHFFFAOYSA-N 0.000 claims description 2
- GJNNXIYZWIZFRH-UHFFFAOYSA-N 2-(pentylamino)acetamide Chemical compound CCCCCNCC(N)=O GJNNXIYZWIZFRH-UHFFFAOYSA-N 0.000 claims description 2
- PBSFXIHNVFMPNN-UHFFFAOYSA-N 2-pyrrolidin-2-yl-2,3-dihydrofuro[3,2-b]pyridine Chemical compound C1CCNC1C1OC2=CC=CN=C2C1 PBSFXIHNVFMPNN-UHFFFAOYSA-N 0.000 claims description 2
- ITPXKRKCDRCWLZ-UHFFFAOYSA-N 3-(1,4-diazepan-1-yl)quinoline Chemical compound C1CCNCCN1C1=CN=C(C=CC=C2)C2=C1 ITPXKRKCDRCWLZ-UHFFFAOYSA-N 0.000 claims description 2
- QYFWZGSVWFHUKX-UHFFFAOYSA-N 3-(2-methoxyethyl)-5-[4-(4,4,4-trifluorobutoxy)phenyl]-1,3,4-oxadiazol-2-one Chemical compound O1C(=O)N(CCOC)N=C1C1=CC=C(OCCCC(F)(F)F)C=C1 QYFWZGSVWFHUKX-UHFFFAOYSA-N 0.000 claims description 2
- SLNLEPCJCLXEDT-UHFFFAOYSA-N 3-(5-bromopyridin-3-yl)-5-azabicyclo[2.2.2]oct-2-ene Chemical compound BrC1=CN=CC(C=2C3CCC(CN3)C=2)=C1 SLNLEPCJCLXEDT-UHFFFAOYSA-N 0.000 claims description 2
- USXYDBGSWSSTGE-UHFFFAOYSA-N 3-(6-chloropyridazin-3-yl)-3,8-diazabicyclo[3.2.1]octane Chemical compound N1=NC(Cl)=CC=C1N1CC(N2)CCC2C1 USXYDBGSWSSTGE-UHFFFAOYSA-N 0.000 claims description 2
- DWDCLEHDNICBMI-UHFFFAOYSA-N 3-bromocytisine Chemical compound C1C2CNCC1CN1C2=CC=C(Br)C1=O DWDCLEHDNICBMI-UHFFFAOYSA-N 0.000 claims description 2
- NUPUDYKEEJNZRG-LBPRGKRZSA-N 3-ethynyl-5-[(2s)-1-methylpyrrolidin-2-yl]pyridine Chemical compound CN1CCC[C@H]1C1=CN=CC(C#C)=C1 NUPUDYKEEJNZRG-LBPRGKRZSA-N 0.000 claims description 2
- WNLCEACHDKGCIF-UHFFFAOYSA-N 3-fluoro-7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-6-one Chemical compound C1NCC2C3=C(F)C=CC(=O)N3CC1C2 WNLCEACHDKGCIF-UHFFFAOYSA-N 0.000 claims description 2
- YKTSVZRWKHWINV-UHFFFAOYSA-N 4-[(7-hydroxy-6,7-dihydro-5h-cyclopenta[d]pyrimidin-4-yl)amino]benzonitrile Chemical compound OC1CCC2=C1N=CN=C2NC1=CC=C(C#N)C=C1 YKTSVZRWKHWINV-UHFFFAOYSA-N 0.000 claims description 2
- BZTKEUQYHVFBHM-UHFFFAOYSA-N 4-chloro-n-(3-morpholin-4-ylpropyl)benzamide;hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1C(=O)NCCCN1CCOCC1 BZTKEUQYHVFBHM-UHFFFAOYSA-N 0.000 claims description 2
- QWXLXVLWDOYVAW-UHFFFAOYSA-N 5-(5-ethynylpyridin-3-yl)-3-azabicyclo[2.2.2]octane Chemical compound C#CC1=CN=CC(C2C3CCC(CN3)C2)=C1 QWXLXVLWDOYVAW-UHFFFAOYSA-N 0.000 claims description 2
- MXUNKHLAEDCYJL-UHFFFAOYSA-N 5-(hydroxymethyl)-3-(3-methylphenyl)-1,3-oxazolidin-2-one Chemical compound CC1=CC=CC(N2C(OC(CO)C2)=O)=C1 MXUNKHLAEDCYJL-UHFFFAOYSA-N 0.000 claims description 2
- LQZNYEWCPDVKMC-UHFFFAOYSA-N 5-benzyl-7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-6-one Chemical compound C=1C=C2C(C3)CNCC3CN2C(=O)C=1CC1=CC=CC=C1 LQZNYEWCPDVKMC-UHFFFAOYSA-N 0.000 claims description 2
- WOJZFUYQYWDMCH-UHFFFAOYSA-N 5-methylspiro[1,3-benzodioxole-2,3'-1-azabicyclo[2.2.2]octane] Chemical compound C1N(CC2)CCC2C21OC1=CC=C(C)C=C1O2 WOJZFUYQYWDMCH-UHFFFAOYSA-N 0.000 claims description 2
- ZALOZGRZQMHKEQ-UHFFFAOYSA-N 5-tert-butylspiro[1,3-benzodioxole-2,3'-1-azabicyclo[2.2.2]octane] Chemical compound C1N(CC2)CCC2C21OC1=CC=C(C(C)(C)C)C=C1O2 ZALOZGRZQMHKEQ-UHFFFAOYSA-N 0.000 claims description 2
- PSBVHIOWORWMJO-UHFFFAOYSA-N C1NCC2CC1C1=C2C=C(C#C)C(C#N)=C1 Chemical compound C1NCC2CC1C1=C2C=C(C#C)C(C#N)=C1 PSBVHIOWORWMJO-UHFFFAOYSA-N 0.000 claims description 2
- RBOSSLMMOVBNCD-UHFFFAOYSA-N C1NCC2CC1C1=C2C=C(C(F)(F)F)C(C#N)=C1 Chemical compound C1NCC2CC1C1=C2C=C(C(F)(F)F)C(C#N)=C1 RBOSSLMMOVBNCD-UHFFFAOYSA-N 0.000 claims description 2
- CWRAGTJSJNMKCQ-UHFFFAOYSA-N C1NCC2CC1C1=C2C=C(C(F)(F)F)C(Cl)=C1 Chemical compound C1NCC2CC1C1=C2C=C(C(F)(F)F)C(Cl)=C1 CWRAGTJSJNMKCQ-UHFFFAOYSA-N 0.000 claims description 2
- KVFSHZMDUXXIBY-UHFFFAOYSA-N C1NCC2CC1C1=C2C=C2C(=O)NC(=O)C2=C1 Chemical compound C1NCC2CC1C1=C2C=C2C(=O)NC(=O)C2=C1 KVFSHZMDUXXIBY-UHFFFAOYSA-N 0.000 claims description 2
- MGQATKFFMYTJKY-UHFFFAOYSA-N C=1C=C2C(C3)CNCC3CN2C(=O)C=1C1=CC=CC=C1 Chemical compound C=1C=C2C(C3)CNCC3CN2C(=O)C=1C1=CC=CC=C1 MGQATKFFMYTJKY-UHFFFAOYSA-N 0.000 claims description 2
- 101710191405 Conantokin-G Proteins 0.000 claims description 2
- RPYWXZCFYPVCNQ-RVDMUPIBSA-N DMXB-A Chemical compound COC1=CC(OC)=CC=C1\C=C/1C(C=2C=NC=CC=2)=NCCC\1 RPYWXZCFYPVCNQ-RVDMUPIBSA-N 0.000 claims description 2
- NLPRAJRHRHZCQQ-UHFFFAOYSA-N Epibatidine Natural products C1=NC(Cl)=CC=C1C1C(N2)CCC2C1 NLPRAJRHRHZCQQ-UHFFFAOYSA-N 0.000 claims description 2
- IWVRVEIKCBFZNF-UHFFFAOYSA-N LSM-1636 Chemical compound C1CNC2CCCC3=C2N1C1=CC=C(C)C=C13 IWVRVEIKCBFZNF-UHFFFAOYSA-N 0.000 claims description 2
- DPWPWRLQFGFJFI-UHFFFAOYSA-N Pargyline Chemical compound C#CCN(C)CC1=CC=CC=C1 DPWPWRLQFGFJFI-UHFFFAOYSA-N 0.000 claims description 2
- ILLGYRJAYAAAEW-QMMMGPOBSA-N abt-418 Chemical compound CN1CCC[C@H]1C1=CC(C)=NO1 ILLGYRJAYAAAEW-QMMMGPOBSA-N 0.000 claims description 2
- 239000000556 agonist Substances 0.000 claims description 2
- 229950001297 altinicline Drugs 0.000 claims description 2
- HFQMYSHATTXRTC-JTQLQIEISA-N amiflamine Chemical compound C[C@H](N)CC1=CC=C(N(C)C)C=C1C HFQMYSHATTXRTC-JTQLQIEISA-N 0.000 claims description 2
- 229950004939 amiflamine Drugs 0.000 claims description 2
- KRNDIPHOJLIHRI-UHFFFAOYSA-N bazinaprine Chemical compound N#CC1=CC(C=2C=CC=CC=2)=NN=C1NCCN1CCOCC1 KRNDIPHOJLIHRI-UHFFFAOYSA-N 0.000 claims description 2
- 229950005683 bazinaprine Drugs 0.000 claims description 2
- WZXHSWVDAYOFPE-UHFFFAOYSA-N brofaromine Chemical compound C=1C2=CC(OC)=CC(Br)=C2OC=1C1CCNCC1 WZXHSWVDAYOFPE-UHFFFAOYSA-N 0.000 claims description 2
- 229950004068 brofaromine Drugs 0.000 claims description 2
- KYCBWEZLKCTALM-UHFFFAOYSA-N caroxazone Chemical compound C1=CC=C2OC(=O)N(CC(=O)N)CC2=C1 KYCBWEZLKCTALM-UHFFFAOYSA-N 0.000 claims description 2
- 229950006044 caroxazone Drugs 0.000 claims description 2
- HTBKFGWATIYCSF-QGXIKSNHSA-N conantokin g Chemical compound NC(=O)C[C@@H](C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(C(O)=O)C(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C(O)=O)C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C(O)=O)C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C(O)=O)C(O)=O)NC(=O)[C@H](CC(C(O)=O)C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CN HTBKFGWATIYCSF-QGXIKSNHSA-N 0.000 claims description 2
- KMIROODCYQMZLK-UHFFFAOYSA-N ctk0j1809 Chemical compound C1NCC2CC1C1=C2C=C(F)C(F)=C1 KMIROODCYQMZLK-UHFFFAOYSA-N 0.000 claims description 2
- ANJTVLIZGCUXLD-DTWKUNHWSA-N cytisine Chemical compound C1NC[C@H]2CN3C(=O)C=CC=C3[C@@H]1C2 ANJTVLIZGCUXLD-DTWKUNHWSA-N 0.000 claims description 2
- 229940027564 cytisine Drugs 0.000 claims description 2
- 229930017327 cytisine Natural products 0.000 claims description 2
- 229960002565 eperisone Drugs 0.000 claims description 2
- NLPRAJRHRHZCQQ-IVZWLZJFSA-N epibatidine Chemical compound C1=NC(Cl)=CC=C1[C@@H]1[C@H](N2)CC[C@H]2C1 NLPRAJRHRHZCQQ-IVZWLZJFSA-N 0.000 claims description 2
- CHDGAVDQRSPBTA-UHFFFAOYSA-N esuprone Chemical compound CC1=C(C)C(=O)OC2=CC(OS(=O)(=O)CC)=CC=C21 CHDGAVDQRSPBTA-UHFFFAOYSA-N 0.000 claims description 2
- 229950007673 esuprone Drugs 0.000 claims description 2
- 230000007717 exclusion Effects 0.000 claims description 2
- 229960003980 galantamine Drugs 0.000 claims description 2
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims description 2
- SDIFKXLSGXCGEN-WJUBNSBASA-L gantacurium chloride Chemical compound [Cl-].[Cl-].C1([C@H]2C3=CC(OC)=C(OC)C=C3CC[N@+]2(C)CCCOC(=O)/C=C(\Cl)C(=O)OCCC[N@@+]2(CCC=3C=C(C(=CC=3[C@H]2CC=2C=C(OC)C(OC)=C(OC)C=2)OC)OC)C)=CC(OC)=C(OC)C(OC)=C1 SDIFKXLSGXCGEN-WJUBNSBASA-L 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 2
- 229950005862 lazabemide Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229940126601 medicinal product Drugs 0.000 claims description 2
- 229950000928 milacemide Drugs 0.000 claims description 2
- 229950010854 mofegiline Drugs 0.000 claims description 2
- JZXRLKWWVNUZRB-UHFFFAOYSA-N n-(2-aminoethyl)-5-chloropyridine-2-carboxamide Chemical compound NCCNC(=O)C1=CC=C(Cl)C=N1 JZXRLKWWVNUZRB-UHFFFAOYSA-N 0.000 claims description 2
- 229960001779 pargyline Drugs 0.000 claims description 2
- GJSGGHOYGKMUPT-UHFFFAOYSA-N phenoxathiine Chemical compound C1=CC=C2OC3=CC=CC=C3SC2=C1 GJSGGHOYGKMUPT-UHFFFAOYSA-N 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 229950002220 pirlindole Drugs 0.000 claims description 2
- YRVIKLBSVVNSHF-JTQLQIEISA-N pozanicline Chemical compound CC1=NC=CC=C1OC[C@H]1NCCC1 YRVIKLBSVVNSHF-JTQLQIEISA-N 0.000 claims description 2
- 230000002685 pulmonary effect Effects 0.000 claims description 2
- LVQTUXZKLGXYIU-GWSNJHLMSA-M rapacuronium Chemical compound [Br-].N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)CC)[N+]2(CC=C)CCCCC2)CCCCC1 LVQTUXZKLGXYIU-GWSNJHLMSA-M 0.000 claims description 2
- 229960003335 rapacuronium bromide Drugs 0.000 claims description 2
- 239000000018 receptor agonist Substances 0.000 claims description 2
- 229940044601 receptor agonist Drugs 0.000 claims description 2
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical group C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 claims description 2
- FTKTZRKAVSDSRA-UHFFFAOYSA-N sercloremine Chemical compound C1CN(C)CCC1C1=CC2=CC(Cl)=CC=C2O1 FTKTZRKAVSDSRA-UHFFFAOYSA-N 0.000 claims description 2
- 125000003003 spiro group Chemical group 0.000 claims description 2
- XYHQFFUUHZUZLL-UHFFFAOYSA-N spiro[1,3-benzodioxole-2,3'-1-azabicyclo[2.2.2]octane] Chemical compound O1C2=CC=CC=C2OC1(C1)C2CCN1CC2 XYHQFFUUHZUZLL-UHFFFAOYSA-N 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- MKTAGSRKQIGEBH-SSDOTTSWSA-N tebanicline Chemical compound C1=NC(Cl)=CC=C1OC[C@@H]1NCC1 MKTAGSRKQIGEBH-SSDOTTSWSA-N 0.000 claims description 2
- 229960002309 toloxatone Drugs 0.000 claims description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/465—Nicotine; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- 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
- A61P25/34—Tobacco-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Addiction (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention concerns novel pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor designed for treating tobacco withdrawal symptoms.
Description
w0 00/45846 1 PcT/FR00/00193 PHARMACEUTICAL COMPOSITIONS CONTAINING NICOTINE OR A
LIGAND FOR THE NICOTINE RECEPTORS AND A MONOAMINE
OXIDASE INHIBITOR, AND THEIR USE IN STOPPING TOBACCO
DEPENDENCY
The present invention relates to a novel pharmaceutical composition comprising nicotine or a ligand for the nicotine receptors, which is intended for stopping tobacco dependency.
The consumption of tobacco is considered as a real public health problem, in so far as tobacco is the cause of several serious diseases such as cardiovascular and respiratory diseases and certain types of cancer. The administration of nicotine or of an analogue such as lobeline transdermally or in the form of a chewing gum or a nasal spray, for example, constitutes a treatment to replace the consumption of tobacco and consequently a tool for stopping tobacco dependency. However, the taking of this type of medication is not without its undesirable effects, in particular an increase in arterial pressure and heart rate and gastrointestinal effects. Moreover, the compounds commercially available such as, for example, Nikoban~, Bantron~, CigArrest~ and Nic-Fit~ are often administered with antacids to avoid the undesirable gastrointestinal effects.
LIGAND FOR THE NICOTINE RECEPTORS AND A MONOAMINE
OXIDASE INHIBITOR, AND THEIR USE IN STOPPING TOBACCO
DEPENDENCY
The present invention relates to a novel pharmaceutical composition comprising nicotine or a ligand for the nicotine receptors, which is intended for stopping tobacco dependency.
The consumption of tobacco is considered as a real public health problem, in so far as tobacco is the cause of several serious diseases such as cardiovascular and respiratory diseases and certain types of cancer. The administration of nicotine or of an analogue such as lobeline transdermally or in the form of a chewing gum or a nasal spray, for example, constitutes a treatment to replace the consumption of tobacco and consequently a tool for stopping tobacco dependency. However, the taking of this type of medication is not without its undesirable effects, in particular an increase in arterial pressure and heart rate and gastrointestinal effects. Moreover, the compounds commercially available such as, for example, Nikoban~, Bantron~, CigArrest~ and Nic-Fit~ are often administered with antacids to avoid the undesirable gastrointestinal effects.
Nicotine, like other substances of various origins (alcohol, cocaine, etc.), gives rise to a dependency. These molecules act via different primary mechanisms leading to the activation of a common mechanism responsible for the pleasure induced by their consumption. Among the neurotransmitters of the central nervous system which are involved in the phenomena of dependency, dopamine plays a major role associated with its involvement in hedonistic behaviour.
Monoamine oxidase inhibitors (MAOIs) -monoamine oxidase being a flavoenzyme involved in the catabolism of biogenic amines including dopamine - have been described as being potentially beneficial in treatment for~stopping tobacco dependency (I. Berlin et al., Clin. Pharmacol. Ther (1995), 58 (4), 444-452).
It is also known, for example, that MAOIs of B type are potentially useful in this type of treatment (see Fowler et al., Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAOB) inhibition. J. add. disease (1998), 17, 23-24 and Fowler et al., Nature (1996), 379, 733-736).
Similarly, in patent application WO 95/28934, the use of monoamine oxidase A inhibitors for controlling tobacco consumption, and in particular during states of craving is described. By increasing the amount of dopamine in the pleasure centres located in the limbic system, these compounds might reproduce therein the hedonistic sensation associated with smoking and help stop the tobacco dependency.
US patent 5 803 081 mentions the possibility of producing a chewing gum containing cut tobacco treated with propolis as a reservoir for a sustained release of nicotine, and optionally a monoamine oxidase B inhibitor as found in tobacco smoke. The advantages cited for this chewing gum stem from pretreating the tobacco with propolis, thus avoiding bursts of release of the nicotine while at the same time prolonging the taste of the chewing gum. However, not only is the presence of monoamine oxidase B inhibitor not described therein as being essential for achieving the abovementioned advantages, but also no monoamine oxidase B inhibitor is specifically cited in its structure or even in its possible role in this chewing gum. Moreover, the chewing gum itself is not illustrated by a technical preparation example.
The aim of the present invention is to provide a pharmaceutical composition comprising nicotine or a ligand for the nicotine receptors, which is useful in stopping tobacco dependency and which has fewer cardiovascular side effects.
The Applicant has in fact been able to demonstrate, surprisingly, that the side effects subsequent to the administration of nicotine or a ligand for the nicotine receptors can be reduced considerably by means of the co-administration of a monoamine oxidase inhibitor.
One subject of the invention is thus a pharmaceutical composition comprising nicotine or a ligand for the nicotine receptors and a monoamine oxidase inhibitor, which is useful for stopping tobacco dependency and which has fewer cardiovascular side effects.
In the context of the present invention, the expression °ligand for the nicotine receptors" means in particular nicotine receptor agonists such as cytisine, lobeline, ABT-418 (Abbott), epibatidine, GTS-21, AR-817779 (AstraZeneca), ABT-594 (Abbott), ABT-089 (Abbott) and other ligands for the nicotine receptors, such as:
AN-072 (Flan), eperisone (Eisai), rapacuronium bromide (Akzo Nobel), altinicline (Sibia), conantokin-G
(Cognetix), GW-280430 (Glaxo Wellcome), RJR-2403 (Targacept), galantamine, SIB 1553 A (Sibia), A-85380 (Abbott), metanicotine, RJR-2531 (R. J. Reynolds Tobacco), RJR-2557 (R.J. Reynolds Tobacco), DBO-83 (Universities of Florence and Milan), 9-bromo-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (Pfizer), 11-fluoro-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (Pfizer), 9-phenyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (Pfizer), ' CA 02361437 2001-07-18 9-benzyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido-[1,2-a][1,5]diazocin-8-one (Pfizer), 9-acetyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a)[1,5)diazocin-8-one (Pfizer), 9-(2-pyridyl)-5 1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5)diazocin-8-one (Pfizer), 9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5)diazocin-8-one (Pfizer), 9-(2-thiazolyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a)[1,5)diazocin-8-one (Pfizer), endo-6-(3-pyridyl)-2-azabicyclo[2.2.2]octane (Sumitomo Pharmaceuticals), endo-6-(5-pyrimidinyl)-2-azabicyclo[2.2.2)octane (Sumitomo Pharmaceuticals), 6-(5-bromo-3-pyridyl)-2-azabicyclo[2.2.2]oct-5-ene (Sumitomo Pharmaceuticals), 6-(5-ethynyl-3-pyridyl)-2-azabicyclo[2.2.2]octane (Sumitomo Pharmaceuticals), (~)-8-methyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene (Neurosearch), (~)-8-(benzyl)-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene (Neurosearch), (t)-3-(6-chloro-3-pyridyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Neurosearch), (t)-3-(8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)aniline (Neurosearch), spiro[1,3-benzodioxole-2,3'-quinuclidine] (Neurosearch), 5-methylspiro[1,3-benzodioxole-2,3'-quinuclidine] (Neurosearch), 5-tert-butylspiro[1,3-benzodioxole-2,3'-quinuclidine]
(Neurosearch), (t)-3-(5-methoxy-3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene (Neurosearch), (~)-3-(5-v methoxy-3-pyridyl)-9-methyl-9-azabicyclo[3.3.1]non-2-ene (Neurosearch), (~)-3-(9-methyl-9-azabicyclo[3.3.1]non-2-en-3-yl)phenylamine (Neurosearch), (t)-3-(3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene (Neurosearch), (~)-9-methyl-3-(3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene (Neurosearch), spiro[1-azabicyclo[2.2.2]octane-3-2'(3'H)-furo[2,3-b]pyridine]-7'-oxide (AstraZeneca), 1-(6-chloro-5-methoxy-3-pyridyl)perhydro-1,4-diazepine (Neurosearch), 1-(5-methoxy-3-pyridyl)perhydro-1,4-diazepine (Neurosearch), 1-(5-methoxy-3-pyridyl)perhydro-1,5-diazocine (Neurosearch), 3-(perhydro-1,4-diazepin-1-yl)quinoline (Neurosearch), 1-(6-bromo-3-pyridyl)perhydro-1,4-diazepine (Neurosearch), 1-(5-propoxy-3-pyridyl)perhydro-1,4-diazepine (Neurosearch), 4-(3-pyridyloxy)perhydroazepine (Neurosearch), 2-methyl-1,2,3,5,6,7,8,9-octahydro-5,9-methanopyrrolo[3,4-h]benzazepine-1,3-dione (Pfizer),~1,3-dimethyl-1,2,3,5,6,7,8,9-octahydro-5,9-methanoimidazo[4,5-h][3]benzazepin-2-one (Pfizer), 1,2,3,5,6,7,8,9-octahydro-5,9-methanopyrrolo[3,4-h][3]benzazepine-1,3-dione (Pfizer), 7,8-difluoro-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine (Pfizer), 8-ethynyl-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine-7-carbonitrile (Pfizer), 7-chloro-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine (Pfizer), 8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine-7-carbonitrile (Pfizer), as well as those described:
- in patent application WO 98/42713, i.e. the 2,3-dihydrofuro[3,2-b]pyridine derivatives and more particularly the (R, R), (S, S), (R, S) and (S, R) compounds of 2-pyrrolidin-2-yl-2,3-dihydrofuro[3,2-b]pyridine, and - in patent application WO 99/02517, i.e. the 6,7-dihydro-5H-2-pyrindine derivatives and more particularly the (R, R), (S, S), (R, S) and (S, R) compounds of 6-pyrrolidin-2-yl-6,7-dihydro-5H-2-pyridine, - the compounds described in patent application PCT/FR99/02974 which are useful in the treatment or prevention of disorders associated with a dysfunction of the nicotine receptors, in particular in the central nervous system or the gastrointestinal system (for example cognitive impairment, schizophrenia, depression, pain, etc.), corresponding to the general formula (I) R U
~N ~
Y Ri in which one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula C-R3 and the third represents a nitrogen atom or a group of formula C-R4 , R3 and R4 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or ( C1-C6 ) alkoxy group, R1 and RZ each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or (C1-C6)alkoxy group, or a phenyl group optionally substituted with one or two halogen atoms,~with one or two trifluoromethyl groups, with a cyano group, with a nitro group, with a hydroxyl group, with a (C1-C6)alkyl group, with one or two (C1-C6)alkoxy groups, with a methylenedioxy group, with an acetyl group, with a trifluoromethoxy group or with a methylthio group, R represents a hydrogen atom or a (C1-C6)alkyl group, with the exclusion, however, of the compounds of general formula (I) in which X represents a group of formula CH, Y and Z each represent a nitrogen atom, and R1 or R2 does not represent an optionally substituted phenyl group, - the compounds described in patent application PCT/FR99/02975, which are also useful in the treatment or prevention of disorders associated with a dysfunction of the nicotine receptors, in particular in the central nervous system or the gastrointestinal system, corresponding to the general formula (I) Ri (I) ,Y
in which one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula C-R3 and the third represents a nitrogen atom or a group of formula C-R4 , R3 and R4 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or ( C1-C6 ) alkoxy group, R1 and R2 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl , ( C1-C6 ) alkyl or ( C1-C6 ) alkoxy group, or a phenyl group optionally substituted with a halogen atom, with one or two trifluoromethyl groups, with a cyano group, with a nitro group, with a hydroxyl group, with a (C1-C6)alkyl group, with a (C1-C6)alkoxy group, with an acetyl group, with a methylenedioxy group, with t a trifluoromethoxy group, with a methylthio group or with a phenyl group.
Among the ligands for the nicotine receptors, agonists are preferred.
5 By virtue of the composition according to the present invention, the increase in arterial pressure and in heart rate is minimized. The composition ensures greater safety and better tolerance and thus better adherence to the treatment by the patient.
Monoamine oxidase inhibitors (MAOIs) -monoamine oxidase being a flavoenzyme involved in the catabolism of biogenic amines including dopamine - have been described as being potentially beneficial in treatment for~stopping tobacco dependency (I. Berlin et al., Clin. Pharmacol. Ther (1995), 58 (4), 444-452).
It is also known, for example, that MAOIs of B type are potentially useful in this type of treatment (see Fowler et al., Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAOB) inhibition. J. add. disease (1998), 17, 23-24 and Fowler et al., Nature (1996), 379, 733-736).
Similarly, in patent application WO 95/28934, the use of monoamine oxidase A inhibitors for controlling tobacco consumption, and in particular during states of craving is described. By increasing the amount of dopamine in the pleasure centres located in the limbic system, these compounds might reproduce therein the hedonistic sensation associated with smoking and help stop the tobacco dependency.
US patent 5 803 081 mentions the possibility of producing a chewing gum containing cut tobacco treated with propolis as a reservoir for a sustained release of nicotine, and optionally a monoamine oxidase B inhibitor as found in tobacco smoke. The advantages cited for this chewing gum stem from pretreating the tobacco with propolis, thus avoiding bursts of release of the nicotine while at the same time prolonging the taste of the chewing gum. However, not only is the presence of monoamine oxidase B inhibitor not described therein as being essential for achieving the abovementioned advantages, but also no monoamine oxidase B inhibitor is specifically cited in its structure or even in its possible role in this chewing gum. Moreover, the chewing gum itself is not illustrated by a technical preparation example.
The aim of the present invention is to provide a pharmaceutical composition comprising nicotine or a ligand for the nicotine receptors, which is useful in stopping tobacco dependency and which has fewer cardiovascular side effects.
The Applicant has in fact been able to demonstrate, surprisingly, that the side effects subsequent to the administration of nicotine or a ligand for the nicotine receptors can be reduced considerably by means of the co-administration of a monoamine oxidase inhibitor.
One subject of the invention is thus a pharmaceutical composition comprising nicotine or a ligand for the nicotine receptors and a monoamine oxidase inhibitor, which is useful for stopping tobacco dependency and which has fewer cardiovascular side effects.
In the context of the present invention, the expression °ligand for the nicotine receptors" means in particular nicotine receptor agonists such as cytisine, lobeline, ABT-418 (Abbott), epibatidine, GTS-21, AR-817779 (AstraZeneca), ABT-594 (Abbott), ABT-089 (Abbott) and other ligands for the nicotine receptors, such as:
AN-072 (Flan), eperisone (Eisai), rapacuronium bromide (Akzo Nobel), altinicline (Sibia), conantokin-G
(Cognetix), GW-280430 (Glaxo Wellcome), RJR-2403 (Targacept), galantamine, SIB 1553 A (Sibia), A-85380 (Abbott), metanicotine, RJR-2531 (R. J. Reynolds Tobacco), RJR-2557 (R.J. Reynolds Tobacco), DBO-83 (Universities of Florence and Milan), 9-bromo-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (Pfizer), 11-fluoro-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (Pfizer), 9-phenyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (Pfizer), ' CA 02361437 2001-07-18 9-benzyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido-[1,2-a][1,5]diazocin-8-one (Pfizer), 9-acetyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a)[1,5)diazocin-8-one (Pfizer), 9-(2-pyridyl)-5 1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5)diazocin-8-one (Pfizer), 9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5)diazocin-8-one (Pfizer), 9-(2-thiazolyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a)[1,5)diazocin-8-one (Pfizer), endo-6-(3-pyridyl)-2-azabicyclo[2.2.2]octane (Sumitomo Pharmaceuticals), endo-6-(5-pyrimidinyl)-2-azabicyclo[2.2.2)octane (Sumitomo Pharmaceuticals), 6-(5-bromo-3-pyridyl)-2-azabicyclo[2.2.2]oct-5-ene (Sumitomo Pharmaceuticals), 6-(5-ethynyl-3-pyridyl)-2-azabicyclo[2.2.2]octane (Sumitomo Pharmaceuticals), (~)-8-methyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene (Neurosearch), (~)-8-(benzyl)-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene (Neurosearch), (t)-3-(6-chloro-3-pyridyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (Neurosearch), (t)-3-(8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)aniline (Neurosearch), spiro[1,3-benzodioxole-2,3'-quinuclidine] (Neurosearch), 5-methylspiro[1,3-benzodioxole-2,3'-quinuclidine] (Neurosearch), 5-tert-butylspiro[1,3-benzodioxole-2,3'-quinuclidine]
(Neurosearch), (t)-3-(5-methoxy-3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene (Neurosearch), (~)-3-(5-v methoxy-3-pyridyl)-9-methyl-9-azabicyclo[3.3.1]non-2-ene (Neurosearch), (~)-3-(9-methyl-9-azabicyclo[3.3.1]non-2-en-3-yl)phenylamine (Neurosearch), (t)-3-(3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene (Neurosearch), (~)-9-methyl-3-(3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene (Neurosearch), spiro[1-azabicyclo[2.2.2]octane-3-2'(3'H)-furo[2,3-b]pyridine]-7'-oxide (AstraZeneca), 1-(6-chloro-5-methoxy-3-pyridyl)perhydro-1,4-diazepine (Neurosearch), 1-(5-methoxy-3-pyridyl)perhydro-1,4-diazepine (Neurosearch), 1-(5-methoxy-3-pyridyl)perhydro-1,5-diazocine (Neurosearch), 3-(perhydro-1,4-diazepin-1-yl)quinoline (Neurosearch), 1-(6-bromo-3-pyridyl)perhydro-1,4-diazepine (Neurosearch), 1-(5-propoxy-3-pyridyl)perhydro-1,4-diazepine (Neurosearch), 4-(3-pyridyloxy)perhydroazepine (Neurosearch), 2-methyl-1,2,3,5,6,7,8,9-octahydro-5,9-methanopyrrolo[3,4-h]benzazepine-1,3-dione (Pfizer),~1,3-dimethyl-1,2,3,5,6,7,8,9-octahydro-5,9-methanoimidazo[4,5-h][3]benzazepin-2-one (Pfizer), 1,2,3,5,6,7,8,9-octahydro-5,9-methanopyrrolo[3,4-h][3]benzazepine-1,3-dione (Pfizer), 7,8-difluoro-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine (Pfizer), 8-ethynyl-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine-7-carbonitrile (Pfizer), 7-chloro-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine (Pfizer), 8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine-7-carbonitrile (Pfizer), as well as those described:
- in patent application WO 98/42713, i.e. the 2,3-dihydrofuro[3,2-b]pyridine derivatives and more particularly the (R, R), (S, S), (R, S) and (S, R) compounds of 2-pyrrolidin-2-yl-2,3-dihydrofuro[3,2-b]pyridine, and - in patent application WO 99/02517, i.e. the 6,7-dihydro-5H-2-pyrindine derivatives and more particularly the (R, R), (S, S), (R, S) and (S, R) compounds of 6-pyrrolidin-2-yl-6,7-dihydro-5H-2-pyridine, - the compounds described in patent application PCT/FR99/02974 which are useful in the treatment or prevention of disorders associated with a dysfunction of the nicotine receptors, in particular in the central nervous system or the gastrointestinal system (for example cognitive impairment, schizophrenia, depression, pain, etc.), corresponding to the general formula (I) R U
~N ~
Y Ri in which one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula C-R3 and the third represents a nitrogen atom or a group of formula C-R4 , R3 and R4 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or ( C1-C6 ) alkoxy group, R1 and RZ each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or (C1-C6)alkoxy group, or a phenyl group optionally substituted with one or two halogen atoms,~with one or two trifluoromethyl groups, with a cyano group, with a nitro group, with a hydroxyl group, with a (C1-C6)alkyl group, with one or two (C1-C6)alkoxy groups, with a methylenedioxy group, with an acetyl group, with a trifluoromethoxy group or with a methylthio group, R represents a hydrogen atom or a (C1-C6)alkyl group, with the exclusion, however, of the compounds of general formula (I) in which X represents a group of formula CH, Y and Z each represent a nitrogen atom, and R1 or R2 does not represent an optionally substituted phenyl group, - the compounds described in patent application PCT/FR99/02975, which are also useful in the treatment or prevention of disorders associated with a dysfunction of the nicotine receptors, in particular in the central nervous system or the gastrointestinal system, corresponding to the general formula (I) Ri (I) ,Y
in which one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula C-R3 and the third represents a nitrogen atom or a group of formula C-R4 , R3 and R4 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or ( C1-C6 ) alkoxy group, R1 and R2 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl , ( C1-C6 ) alkyl or ( C1-C6 ) alkoxy group, or a phenyl group optionally substituted with a halogen atom, with one or two trifluoromethyl groups, with a cyano group, with a nitro group, with a hydroxyl group, with a (C1-C6)alkyl group, with a (C1-C6)alkoxy group, with an acetyl group, with a methylenedioxy group, with t a trifluoromethoxy group, with a methylthio group or with a phenyl group.
Among the ligands for the nicotine receptors, agonists are preferred.
5 By virtue of the composition according to the present invention, the increase in arterial pressure and in heart rate is minimized. The composition ensures greater safety and better tolerance and thus better adherence to the treatment by the patient.
10 Moreover, the combination of a reversible A
or reversible mixed A,B or reversible or irreversible B
monoamine oxidase inhibitor with nicotine or a ligand for the nicotine receptors can have an amplifying effect on the beneficial effects of nicotine, for example the pleasure sensation, the mood enhancement and the enhancement of the psychomotor and cognitive performance while at the same time reducing the side effects, in particular the cardiovascular effects.
In the context of the present invention, compositions comprising nicotine or a ligand for the nicotine receptors and a reversible monoamine oxidase inhibitor are preferred.
In the context of the present invention, the monoamine oxidase inhibitor can be a reversible monoamine oxidase A inhibitor, a reversible or irreversible monoamine oxidase B inhibitor or a reversible mixed monoamine oxidase A,B inhibitor.
or reversible mixed A,B or reversible or irreversible B
monoamine oxidase inhibitor with nicotine or a ligand for the nicotine receptors can have an amplifying effect on the beneficial effects of nicotine, for example the pleasure sensation, the mood enhancement and the enhancement of the psychomotor and cognitive performance while at the same time reducing the side effects, in particular the cardiovascular effects.
In the context of the present invention, compositions comprising nicotine or a ligand for the nicotine receptors and a reversible monoamine oxidase inhibitor are preferred.
In the context of the present invention, the monoamine oxidase inhibitor can be a reversible monoamine oxidase A inhibitor, a reversible or irreversible monoamine oxidase B inhibitor or a reversible mixed monoamine oxidase A,B inhibitor.
More particularly, reversible MAOIs A which may be mentioned are: befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, RS 8359 (Sankyo), T794 (Tanabe), KP 9 (Krenitsky, USA), E 2011 (Eisai), toloxatone, pirlindole, amiflamine, sercloremine, bazinaprine.
Reversible MAOIs B which may be mentioned are: lazabemide, milacemide, caroxazone, IFO.
Irreversible MAOIs B which may be mentioned are: L-deprenyl, mofegiline, rasageline, pargyline.
MAOIs which may also be mentioned are the compounds described:
- in patent application WO 96/38444, i.e. oxazolidin-2-one derivatives and, for example, (S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-1,2-benzisoxazol-3-yl]oxazolidin-2-one, - in patent application EP 0 699 680, i.e. 3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one derivatives and, for example, [3(S),3a(S)]-3-methoxymethyl-7-(4,4,4-trifluoro-3(R)-hydroxybutoxy)-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one and [3(S),3a(S)]-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one, - in patent application WO 97/13768, i.e. oxazolidin-2-one derivatives and, for example, (R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzo-3-furyl]oxazolidin-2-one and (R)-5-methoxymethyl-3-(6-cyclopropylmethoxybenzo-3-furyl)oxazolidin-2-one, - in patent application WO 97/17347, i.e. compounds derived from oxazolidin-2-one and, for example, (-)3-[2-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-1-benzo-6-pyranyl]-5(R)-methoxymethyloxazolidin-2-one and 3-[2-(3,3,3-trifluoropropyl)-2,3-dihydrobenzo-5-furyl]-5(R)-methoxymethyloxazolidin-2-one, - in patent application WO 97/17346, i.e. compounds derived from 3-(benzo-5-furyl)oxazolidin-2-one and, for example, 3-[2-(3,3,3-trifluoropropyl)benzo-5-furyl]-5(S)-methoxymethyloxazolidin-2-one, 3-(2-propylbenzo-5-furyl)-5(R)-methoxymethyloxazolidin-2-one and 3-(2-phenylbenzo-5-furyl)-5(S)-methoxymethyloxazolidin-2-one, - in patent application EP 0 655 445, i.e. 1,3,4-oxadiazol-2(3H)-one derivatives and, for example, 5-[4-(4,4,4-trifluorobutoxy)phenyl]-3-(2-methoxyethyl)-1,3,4-oxadiazol-2(3H)-one.
Befloxatone and moclobemide are most particularly preferred as reversible monoamine oxidase A inhibitors, as is (-)3-[2-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-1-benzo-6-pyranyl]-5(R)-methoxymethyloxazolidin-2-one.
(S)-5-Methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-1,2-benzisoxazol-3-yl]oxazolidin-2-one is most particularly preferred as a reversible monoamine oxidase B inhibitor.
[3(S),3a(S)]-3-Methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one is most particularly preferred as a reversible mixed monoamine oxidase A,B inhibitor, as are (R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)-benzo-3-furyl]oxazolidin-2-one and (R)-5-methoxymethyl-3-(6-cyclopropylmethoxybenzo-3-furyl)oxazolidin-2-one.
20 Among the various classes of MAOI cited, for the compositions according to the present invention, the reversible A and mixed A,B MAOIs will be preferred.
Another subject of the present invention consists of a pharmaceutical composition comprising nicotine or a ligand for the nicotine receptors and a monoamine oxidase inhibitor, as a combination product for simultaneous or separate use or for use staggered over time, intended for stopping tobacco dependency.
The expression "simultaneous use" means the administration of the compounds of the composition according to the invention included in a single pharmaceutical form.
The expression "separate use" means the administration, at the same time, of the two compounds of the composition according to the invention, each included in a separate pharmaceutical form.
Reversible MAOIs B which may be mentioned are: lazabemide, milacemide, caroxazone, IFO.
Irreversible MAOIs B which may be mentioned are: L-deprenyl, mofegiline, rasageline, pargyline.
MAOIs which may also be mentioned are the compounds described:
- in patent application WO 96/38444, i.e. oxazolidin-2-one derivatives and, for example, (S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-1,2-benzisoxazol-3-yl]oxazolidin-2-one, - in patent application EP 0 699 680, i.e. 3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one derivatives and, for example, [3(S),3a(S)]-3-methoxymethyl-7-(4,4,4-trifluoro-3(R)-hydroxybutoxy)-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one and [3(S),3a(S)]-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one, - in patent application WO 97/13768, i.e. oxazolidin-2-one derivatives and, for example, (R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzo-3-furyl]oxazolidin-2-one and (R)-5-methoxymethyl-3-(6-cyclopropylmethoxybenzo-3-furyl)oxazolidin-2-one, - in patent application WO 97/17347, i.e. compounds derived from oxazolidin-2-one and, for example, (-)3-[2-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-1-benzo-6-pyranyl]-5(R)-methoxymethyloxazolidin-2-one and 3-[2-(3,3,3-trifluoropropyl)-2,3-dihydrobenzo-5-furyl]-5(R)-methoxymethyloxazolidin-2-one, - in patent application WO 97/17346, i.e. compounds derived from 3-(benzo-5-furyl)oxazolidin-2-one and, for example, 3-[2-(3,3,3-trifluoropropyl)benzo-5-furyl]-5(S)-methoxymethyloxazolidin-2-one, 3-(2-propylbenzo-5-furyl)-5(R)-methoxymethyloxazolidin-2-one and 3-(2-phenylbenzo-5-furyl)-5(S)-methoxymethyloxazolidin-2-one, - in patent application EP 0 655 445, i.e. 1,3,4-oxadiazol-2(3H)-one derivatives and, for example, 5-[4-(4,4,4-trifluorobutoxy)phenyl]-3-(2-methoxyethyl)-1,3,4-oxadiazol-2(3H)-one.
Befloxatone and moclobemide are most particularly preferred as reversible monoamine oxidase A inhibitors, as is (-)3-[2-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-1-benzo-6-pyranyl]-5(R)-methoxymethyloxazolidin-2-one.
(S)-5-Methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-1,2-benzisoxazol-3-yl]oxazolidin-2-one is most particularly preferred as a reversible monoamine oxidase B inhibitor.
[3(S),3a(S)]-3-Methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one is most particularly preferred as a reversible mixed monoamine oxidase A,B inhibitor, as are (R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)-benzo-3-furyl]oxazolidin-2-one and (R)-5-methoxymethyl-3-(6-cyclopropylmethoxybenzo-3-furyl)oxazolidin-2-one.
20 Among the various classes of MAOI cited, for the compositions according to the present invention, the reversible A and mixed A,B MAOIs will be preferred.
Another subject of the present invention consists of a pharmaceutical composition comprising nicotine or a ligand for the nicotine receptors and a monoamine oxidase inhibitor, as a combination product for simultaneous or separate use or for use staggered over time, intended for stopping tobacco dependency.
The expression "simultaneous use" means the administration of the compounds of the composition according to the invention included in a single pharmaceutical form.
The expression "separate use" means the administration, at the same time, of the two compounds of the composition according to the invention, each included in a separate pharmaceutical form.
The expression "use staggered over time"
means the successive administration of the first compound of the composition according to the invention, included in one pharmaceutical form, and then of the second compound of the composition according to the invention, included in a separate pharmaceutical form.
In the case of this "use staggered over time"
the time interval between administration of the first compound of the composition according to the invention and administration of the second compound of the same composition according to the invention generally does not exceed 24 hours.
The pharmaceutical forms, comprising either only one of the compounds constituting the composition according to the invention or a combination of the two compounds, which can be used in the various types of use described above may be suitable, for example, for oral, nasal, parenteral or transdermal administration.
Thus, in the case of a "separate use" and of a "use staggered over time", the two separate pharmaceutical forms may be intended for the same route of administration or for a different route of administration (oral and transdermal or oral and nasal or parenteral and transdermal, etc.).
All these pharmaceutical forms also form part of the invention.
Among the pharmaceutical forms which are suitable for oral administration, mention may be made of tablets, gel capsules, pills and chewing gums with immediate or sustained release.
5 For parenteral administration, presentation forms such as injectable solutions or suspensions are suitable.
The composition according to the invention can thus be administered in a single daily dose or in 10 fractional daily doses. In the latter case, the composition can be administered 2 to 3 times a day.
Transdermal patches are suitable, for example, for transdermal administration. Gels or emulsions are also suitable for local administration.
means the successive administration of the first compound of the composition according to the invention, included in one pharmaceutical form, and then of the second compound of the composition according to the invention, included in a separate pharmaceutical form.
In the case of this "use staggered over time"
the time interval between administration of the first compound of the composition according to the invention and administration of the second compound of the same composition according to the invention generally does not exceed 24 hours.
The pharmaceutical forms, comprising either only one of the compounds constituting the composition according to the invention or a combination of the two compounds, which can be used in the various types of use described above may be suitable, for example, for oral, nasal, parenteral or transdermal administration.
Thus, in the case of a "separate use" and of a "use staggered over time", the two separate pharmaceutical forms may be intended for the same route of administration or for a different route of administration (oral and transdermal or oral and nasal or parenteral and transdermal, etc.).
All these pharmaceutical forms also form part of the invention.
Among the pharmaceutical forms which are suitable for oral administration, mention may be made of tablets, gel capsules, pills and chewing gums with immediate or sustained release.
5 For parenteral administration, presentation forms such as injectable solutions or suspensions are suitable.
The composition according to the invention can thus be administered in a single daily dose or in 10 fractional daily doses. In the latter case, the composition can be administered 2 to 3 times a day.
Transdermal patches are suitable, for example, for transdermal administration. Gels or emulsions are also suitable for local administration.
15 A transdermal patch which allows slow and uniform administration of at least one of the two compounds of the combination is particularly preferred.
This gives the patient greater autonomy with respect to his or her treatment.
A patch allows a release of composition which can last between 8 and 72 hours.
The pharmaceutical compositions which are suitable for use in a transdermal patch may be in the form of a gel, an ointment, a solution, a cream or an emulsion. They can be prepared according to processes that are conventional for those skilled in the art.
This gives the patient greater autonomy with respect to his or her treatment.
A patch allows a release of composition which can last between 8 and 72 hours.
The pharmaceutical compositions which are suitable for use in a transdermal patch may be in the form of a gel, an ointment, a solution, a cream or an emulsion. They can be prepared according to processes that are conventional for those skilled in the art.
The compositions can also be formulated in the form of a nasal spray, a pulmonary spray or a suppository.
Preferably, at least one of the two components of the combination is administered transdermally, for example via a transdermal patch. For example, the MAOI may be administered orally and the nicotine or the ligand for the nicotine receptors administered by patch or conversely, or alternatively the MAOI and the nicotine or the ligand for the nicotine receptors can both be administered by transdermal patch.
Usually, the pharmaceutical compositions according to the present invention are dosed to allow a daily administration of from 2 to 20 mg of nicotine or of ligand for the nicotine receptors and from 1 to mg of monoamine oxidase inhibitor.
Finally, a subject of the present invention is also the use of nicotine or of a ligand for the 20 nicotine receptors and of a monoamine oxidase inhibitor, for the manufacture of a medicinal product intended for stopping tobacco dependency.
The effect of the combination of a monoamine oxidase inhibitor with nicotine on the mean arterial pressure and on the heart rate was the subject of a study which demonstrated the value of this combination in stopping tobacco dependency.
Preferably, at least one of the two components of the combination is administered transdermally, for example via a transdermal patch. For example, the MAOI may be administered orally and the nicotine or the ligand for the nicotine receptors administered by patch or conversely, or alternatively the MAOI and the nicotine or the ligand for the nicotine receptors can both be administered by transdermal patch.
Usually, the pharmaceutical compositions according to the present invention are dosed to allow a daily administration of from 2 to 20 mg of nicotine or of ligand for the nicotine receptors and from 1 to mg of monoamine oxidase inhibitor.
Finally, a subject of the present invention is also the use of nicotine or of a ligand for the 20 nicotine receptors and of a monoamine oxidase inhibitor, for the manufacture of a medicinal product intended for stopping tobacco dependency.
The effect of the combination of a monoamine oxidase inhibitor with nicotine on the mean arterial pressure and on the heart rate was the subject of a study which demonstrated the value of this combination in stopping tobacco dependency.
MATERIALS AND METHODS
The study was carried out on male rats of the Sprague-Dawley strain weighing from 277 to 345 g on the day of the treatment.
Befloxatone or moclobemide is suspended in a vehicle (0.5~ w/v Tween 80, 0.5~ w/v methyl cellulose in water for injectable preparation). Nicotine is dissolved in water for an injectable preparation.
Experimental scheme Under general anaesthesia by intraperitoneal injection of ketamine (116 mg/kg i.p.), the animals underwent insertion of catheters into the carotid and the jugular vein with exteriorization of the catheters in the dorso-scapular region. On the day after the implantation, the animals were connected up to measuring machines for continuously recording the arterial pressure and the heart rate.
After a stabilization period of about 30 minutes, the animals received the treatment orally, then, 45 minutes later, three increasing doses of nicotine, administered intravenously at intervals of 5 minutes.
The animals were then sacrificed by intracardiac injection of Dolethal.
The study was carried out on male rats of the Sprague-Dawley strain weighing from 277 to 345 g on the day of the treatment.
Befloxatone or moclobemide is suspended in a vehicle (0.5~ w/v Tween 80, 0.5~ w/v methyl cellulose in water for injectable preparation). Nicotine is dissolved in water for an injectable preparation.
Experimental scheme Under general anaesthesia by intraperitoneal injection of ketamine (116 mg/kg i.p.), the animals underwent insertion of catheters into the carotid and the jugular vein with exteriorization of the catheters in the dorso-scapular region. On the day after the implantation, the animals were connected up to measuring machines for continuously recording the arterial pressure and the heart rate.
After a stabilization period of about 30 minutes, the animals received the treatment orally, then, 45 minutes later, three increasing doses of nicotine, administered intravenously at intervals of 5 minutes.
The animals were then sacrificed by intracardiac injection of Dolethal.
mr~~~~~~~
Two groups of animals were established (n = 7/group). One was treated with befloxatone at a dose of 1 mg/kg p.o., i.e. a volume of 5 ml/kg. The other group received an equivalent volume of vehicle under the same conditions. Separately, two other groups of animals were established (n = 6/group). One was treated with moclobemide at a dose of 10 mg/kg p.o., i.e. a volume of 5 ml/kg. The other received an equivalent volume of vehicle under these same conditions.
Each animal received nicotine at doses of 30, 50 and 100 ug/kg, successively, in the form of an intravenous bolus over about 30 seconds.
Parameters measured The mean arterial pressure and the heart rate were measured before treatment and before each administration of nicotine, as well as at the height of the effect of these administrations.
Expressing the results The homogeneity of the base values (for the mean arterial pressure and the heart rate) between the groups before administration (treatment or nicotine) was checked by a 2-factor variance analysis (group x time) with measurements repeated over time.
Two groups of animals were established (n = 7/group). One was treated with befloxatone at a dose of 1 mg/kg p.o., i.e. a volume of 5 ml/kg. The other group received an equivalent volume of vehicle under the same conditions. Separately, two other groups of animals were established (n = 6/group). One was treated with moclobemide at a dose of 10 mg/kg p.o., i.e. a volume of 5 ml/kg. The other received an equivalent volume of vehicle under these same conditions.
Each animal received nicotine at doses of 30, 50 and 100 ug/kg, successively, in the form of an intravenous bolus over about 30 seconds.
Parameters measured The mean arterial pressure and the heart rate were measured before treatment and before each administration of nicotine, as well as at the height of the effect of these administrations.
Expressing the results The homogeneity of the base values (for the mean arterial pressure and the heart rate) between the groups before administration (treatment or nicotine) was checked by a 2-factor variance analysis (group x time) with measurements repeated over time.
The values obtained before treatment, before the first injection of nicotine and at the height of the effect of each dose of nicotine were recorded and presented in the form of means ~ SEM.
The groups treated with befloxatone and moclobemide were compared with the respective control groups by means of a 2-factor variance analysis (group x dose of nicotine) with repeated measurements on the dose of nicotine, followed by a Dunnett test with a fixed level of nicotine dose.
RESULTS AND CONCLUSIONS
Under these experimental conditions, nicotine causes an increase in the mean arterial pressure and a slight increase in the heart rate of the animals.
Befloxatone at 1 mg/kg p.o. and moclobemide at 10 mg/kg p.o. reduce the induced increases in arterial pressure and heart rate, between 45 and 60 min after the treatment, with intravenous administrations of nicotine. (Tables 1 to 4).
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EXAMPLES OF PHARMACEUTICAL COMPOSITIONS
Example 1: Tablet containing befloxatone and transdermal patch containing nicotine Tablets are manufactured containing 10 mg of befloxatone, according to the following composition:
Befloxatone 5.0~
Lactose 150 mesh 66.0$
Microcrystalline cellulose 20.0 Povidone 4.0~
Crospovidone 4.0~
Magnesium stearate 1.0~
The first five components are mixed together, granulated with water, dried and calibrated. The granules are then mixed with the magnesium stearate and tableted to form tablets with a mass of 200 mg, using a rotary press.
A transdermal patch with an area of 20 cm2, capable of releasing 14 mg in 24 hours, is prepared according to the following composition:
Matrix layer:
- S(-)-Nicotine 35 mg - Duro-Tak 387-2353 acrylic polymer - Miglyol 812 triglyceride absorption promoter - Eudragit E100 methacrylic copolymer Support layer:
- Polyester film (Paratex III/40~
Adhesive layer:
- Duro-Tak 387-2353 self-adhesive acrylic polymer - Miglyol 812 triglyceride-absorption promoter Example 2: Two-layer tablet containing befloxatone and nicotine The granules are prepared by wet granulation according to the following compositions:
Befloxatone 5~
Lactose 150 mesh 66~
Microcrystalline cellulose 20~
Povidone 4~
Crospovidone 4~
Magnesium stearate 1$
Nicotine polacrylix qs 5~ nicotine Lactose 150 mesh qs 100 Microcrystalline cellulose 20~
Povidone 4~
Hydroxypropylmethylcellulose 25~
Magnesium stearate 1~
The first five components of each granulate are mixed together, granulated with water and the granules obtained are then dried and calibrated. The magnesium stearate is then added and mixed. Two-layer tablets are prepared by tableting using a Manesty BL
press. Each layer contains 100 mg of granulate, such that each tablet contains 5 mg of befloxatone and 5 mg of nicotine.
Example 3: Capsule containing befloxatone and nasal spray containing nicotine Tablets containing 10 mg of befloxatone are prepared according to the following composition:
Befloxatone 6.25 Lactose 150 mesh 84.15 Povidone 4.00 Crospovidone 5.00 Magnesium stearate 0.50 Colloidal silica 0.10 The first five components of each granulate are mixed together, granulated with water, dried and calibrated. The granules are then mixed with the magnesium stearate and the colloidal silica, and size 2 gelatin capsules are then filled with 160 mg of the granules thus prepared.
A solution for nasal administration is prepared containing 50 mg of nicotine, 900 mg of sodium chloride, 10 mg of benzalkonium chloride, 100 mg of sodium EDTA and 100 mg of sterilized water. This solution is filtered and distributed in ampules.
The groups treated with befloxatone and moclobemide were compared with the respective control groups by means of a 2-factor variance analysis (group x dose of nicotine) with repeated measurements on the dose of nicotine, followed by a Dunnett test with a fixed level of nicotine dose.
RESULTS AND CONCLUSIONS
Under these experimental conditions, nicotine causes an increase in the mean arterial pressure and a slight increase in the heart rate of the animals.
Befloxatone at 1 mg/kg p.o. and moclobemide at 10 mg/kg p.o. reduce the induced increases in arterial pressure and heart rate, between 45 and 60 min after the treatment, with intravenous administrations of nicotine. (Tables 1 to 4).
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EXAMPLES OF PHARMACEUTICAL COMPOSITIONS
Example 1: Tablet containing befloxatone and transdermal patch containing nicotine Tablets are manufactured containing 10 mg of befloxatone, according to the following composition:
Befloxatone 5.0~
Lactose 150 mesh 66.0$
Microcrystalline cellulose 20.0 Povidone 4.0~
Crospovidone 4.0~
Magnesium stearate 1.0~
The first five components are mixed together, granulated with water, dried and calibrated. The granules are then mixed with the magnesium stearate and tableted to form tablets with a mass of 200 mg, using a rotary press.
A transdermal patch with an area of 20 cm2, capable of releasing 14 mg in 24 hours, is prepared according to the following composition:
Matrix layer:
- S(-)-Nicotine 35 mg - Duro-Tak 387-2353 acrylic polymer - Miglyol 812 triglyceride absorption promoter - Eudragit E100 methacrylic copolymer Support layer:
- Polyester film (Paratex III/40~
Adhesive layer:
- Duro-Tak 387-2353 self-adhesive acrylic polymer - Miglyol 812 triglyceride-absorption promoter Example 2: Two-layer tablet containing befloxatone and nicotine The granules are prepared by wet granulation according to the following compositions:
Befloxatone 5~
Lactose 150 mesh 66~
Microcrystalline cellulose 20~
Povidone 4~
Crospovidone 4~
Magnesium stearate 1$
Nicotine polacrylix qs 5~ nicotine Lactose 150 mesh qs 100 Microcrystalline cellulose 20~
Povidone 4~
Hydroxypropylmethylcellulose 25~
Magnesium stearate 1~
The first five components of each granulate are mixed together, granulated with water and the granules obtained are then dried and calibrated. The magnesium stearate is then added and mixed. Two-layer tablets are prepared by tableting using a Manesty BL
press. Each layer contains 100 mg of granulate, such that each tablet contains 5 mg of befloxatone and 5 mg of nicotine.
Example 3: Capsule containing befloxatone and nasal spray containing nicotine Tablets containing 10 mg of befloxatone are prepared according to the following composition:
Befloxatone 6.25 Lactose 150 mesh 84.15 Povidone 4.00 Crospovidone 5.00 Magnesium stearate 0.50 Colloidal silica 0.10 The first five components of each granulate are mixed together, granulated with water, dried and calibrated. The granules are then mixed with the magnesium stearate and the colloidal silica, and size 2 gelatin capsules are then filled with 160 mg of the granules thus prepared.
A solution for nasal administration is prepared containing 50 mg of nicotine, 900 mg of sodium chloride, 10 mg of benzalkonium chloride, 100 mg of sodium EDTA and 100 mg of sterilized water. This solution is filtered and distributed in ampules.
Claims (16)
1. Pharmaceutical composition comprising nicotine or a ligand for the nicotine receptors and a monoamine oxidase inhibitor, as a combination product for simultaneous or separate use or for use staggered over time, intended for stopping tobacco dependency.
2. Pharmaceutical composition comprising nicotine or a ligand for the nicotine receptors and a reversible A or mixed A,B monoamine oxidase inhibitor, as a combination product for simultaneous or separate use or for use staggered over time, intended for stopping tobacco dependency.
3. Pharmaceutical composition according to either of Claims 1 and 2, characterized in that the monoamine oxidase inhibitor is chosen from the group consisting of:
- among MAOIs of A type: befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, RS 8359 (Sankyo), T794 (Tanabé), KP 9 (Krenitsky, USA), E 2011 (Eisei), toloxatone, pirlindole, amiflamine, sercloremine, bazinaprine, (-)3-[2-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-1-benzo-6-pyranyl]-5(R)-methoxymethyloxazolidin-2-one, 3-(2-propylbenzo-5-furyl)-5(R)-methoxymethyloxazolidin-2-one, and 3-[2-(3,3,3-trifluoropropyl)-2,3-dihydrobenzo-5-furyl]-5(R)-methoxymethyloxazolidin-2-one, - among the MAOIs of B type: lazabemide, milacemide, caroxazone, IFO, L-deprenyl, mofegiline, rasageline, pargyline, (S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-1,2-benzisoxazol-3-yl]oxazolidin-2-one and 5-[4-(4,4,4-trifluorobutoxy)phenyl]-3-(2-methoxyethyl)-1,3,4-oxadiazol-2(3H)-one, - among the MAOIs of mixed A,B type:
[3(S),3a(S)]-3-methoxymethyl-7-(4,4,4-trifluoro-3(R)-hydroxybutoxy)-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one, [3(S),3a(S)]3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one, (R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzo-3-furyl]oxazolidin-2-one, (R)-5-methoxymethyl-3-(6-cyclopropylmethoxybenzo-3-furyl)oxazolidin-2-one, 3-[2-(3,3,3-trifluoropropyl)benzo-5-furyl]-5(S)-methoxymethyloxazolidin-2-one and 3-(2-phenylbenzo-5-furyl)-5(S)-methoxymethyloxazolidin-2-one.
- among MAOIs of A type: befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, RS 8359 (Sankyo), T794 (Tanabé), KP 9 (Krenitsky, USA), E 2011 (Eisei), toloxatone, pirlindole, amiflamine, sercloremine, bazinaprine, (-)3-[2-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-1-benzo-6-pyranyl]-5(R)-methoxymethyloxazolidin-2-one, 3-(2-propylbenzo-5-furyl)-5(R)-methoxymethyloxazolidin-2-one, and 3-[2-(3,3,3-trifluoropropyl)-2,3-dihydrobenzo-5-furyl]-5(R)-methoxymethyloxazolidin-2-one, - among the MAOIs of B type: lazabemide, milacemide, caroxazone, IFO, L-deprenyl, mofegiline, rasageline, pargyline, (S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-1,2-benzisoxazol-3-yl]oxazolidin-2-one and 5-[4-(4,4,4-trifluorobutoxy)phenyl]-3-(2-methoxyethyl)-1,3,4-oxadiazol-2(3H)-one, - among the MAOIs of mixed A,B type:
[3(S),3a(S)]-3-methoxymethyl-7-(4,4,4-trifluoro-3(R)-hydroxybutoxy)-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one, [3(S),3a(S)]3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one, (R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzo-3-furyl]oxazolidin-2-one, (R)-5-methoxymethyl-3-(6-cyclopropylmethoxybenzo-3-furyl)oxazolidin-2-one, 3-[2-(3,3,3-trifluoropropyl)benzo-5-furyl]-5(S)-methoxymethyloxazolidin-2-one and 3-(2-phenylbenzo-5-furyl)-5(S)-methoxymethyloxazolidin-2-one.
4. Pharmaceutical composition according to any one of Claims 1 to 3, characterized in that it is intended for oral, nasal, parenteral, transdermal or mixed administration.
5. Pharmaceutical composition according to Claim 4, characterized in that at least one from among the monoamine oxidase inhibitor, nicotine and a receptor for the nicotine ligands is intended for transdermal administration.
6. Pharmaceutical composition according to Claim 5, characterized in that the transdermal administration is carried out via a transdermal patch.
7. Pharmaceutical composition according to any one of Claims 1 to 6, characterized in that the ligand for the nicotine receptors is chosen from the following nicotine receptor agonists: cytisine, lobeline, ABT-418, epibatidine, GTS-21, AR-R17779, ABT-594, ABT-089, as well as the following nicotine agonists or antagonists:
AN-072, eperisone, rapacuronium bromide, altinicline, conantokin-G, GW-280430, RJR-2403, galantamine, SIB 1553 A, A-85380, metanicotine, RJR-2531, RJR-2557, DBO-83, 9-bromo-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 11-fluoro-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-phenyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-benzyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-acetyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-(2-pyridyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-(2-thiazolyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, endo-6-(3-pyridyl)-2-azabicyclo[2.2.2]octane, endo-6-(5-pyrimidinyl)-2-azabicyclo[2.2.2]octane, 6-(5-bromo-3-pyridyl)-2-azabicyclo[2.2.2]oct-5-ene, 6-(5-ethynyl-3-pyridyl)-2-azabicyclo[2.2.2]octane, (~)-8-methyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene, (~)-8-(benzyl)-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene, (~)-3-(6-chloro-3-pyridyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene, (~)-3-(8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)aniline, spiro[1,3-benzodioxole-2,3'-quinuclidine], 5-methylspiro[1,3-benzodioxole-2,3'-quinuclidine], 5-tert-butylspiro[1,3-benzodioxole-2,3'-quinuclidine], (~)-3-(5-methoxy-3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene, (~)-3-(5-methoxy-3-pyridyl)-9-methyl-9-azabicyclo[3.3.1]non-2-ene, (~)-3-(9-methyl-9-azabicyclo[3.3.1]non-2-en-3-yl)phenylamine, (~)-3-(3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene, (~)-9-methyl-3-(3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene, spiro[1-azabicyclo[2.2.2]octane-3-2'(3'H)-furo[2,3-b]pyridine]-7'-oxide, 1-(6-chloro-5-methoxy-3-pyridyl)perhydro-1,4-diazepine, 1-(5-methoxy-3-pyridyl)perhydro-1,4-diazepine, 1-(5-methoxy-3-pyridyl)perhydro-1,5-diazocine, 3-(perhydro-1,4-diazepin-1-yl)quinoline, 1-(6-bromo-3-pyridyl)perhydro-1,4-diazepine, 1-(5-propoxy-3-pyridyl)perhydro-1,4-diazepine, 4-(3-pyridyloxy)perhydroazepine, 2-methyl-1,2,3,5,6,7,8,9-octahydro-5,9-methanopyrrolo[3,4-h]benzazepine-1,3-dione, 1,3-dimethyl-1,2,3,5,6,7,8,9-octahydro-5,9-methanoimidazo[4,5-h][3]benzazepin-2-one, 1,2,3,5,6,7,8,9-octahydro-5,9-methanopyrrolo[3,4-h][3]benzazepine-1,3-dione, 7,8-difluoro-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine, 8-ethynyl-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine-7-carbonitrile, 7-chloro-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine, 8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine-7-carbonitrile, the (R,R), (S,S), (R,S) and (S, R) compounds of 2-pyrrolidin-2-yl-2,3-dihydrofuro[3,2-b]pyridine and 6-pyrrolidin-2-yl-6,7-dihydro-5H-2-pyrindine, as well as - the compounds corresponding to the general formula in which one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula C-R3 and the third represents a nitrogen atom or a group of formula C-R4, R3 and R4 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or (C1-C6) alkoxy group, R1 and R2 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6) alkyl or (C1-C6) alkoxy group, or a phenyl group optionally substituted with one or two halogen atoms, with one or two trifluoromethyl groups, with a cyano group, with a nitro group, with a hydroxyl group, with a (C1-C6)alkyl group, with one or two (C1-C6)alkoxy groups, with a methylenedioxy group, with an acetyl group, with a trifluoromethoxy group or with a methylthio group, R represents a hydrogen atom or a (C1-C6)alkyl group, with the exclusion, however, of the compounds of general formula (I) in which X represents a group of formula CH, Y and Z each represent a nitrogen atom, and R1 or R2 does not represent an optionally substituted phenyl group, - and the compounds corresponding to the general formula (I) in which one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula C-R3 and the third represents a nitrogen atom or a group of formula C-R4, R3 and R4 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or (C1-C6)alkoxy group, R1 and R2 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or (C1-C6)alkoxy group, or a phenyl group optionally substituted with a halogen atom, with one or two trifluoromethyl groups, with a cyano group, with a nitro group, with a hydroxyl group, with a (C1-C6)alkyl group, with a (C1-C6)alkoxy group, with an acetyl group, with a methylenedioxy group, with a trifluoromethoxy group, with a methylthio group or with a phenyl group.
AN-072, eperisone, rapacuronium bromide, altinicline, conantokin-G, GW-280430, RJR-2403, galantamine, SIB 1553 A, A-85380, metanicotine, RJR-2531, RJR-2557, DBO-83, 9-bromo-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 11-fluoro-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-phenyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-benzyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-acetyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-(2-pyridyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, 9-(2-thiazolyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one, endo-6-(3-pyridyl)-2-azabicyclo[2.2.2]octane, endo-6-(5-pyrimidinyl)-2-azabicyclo[2.2.2]octane, 6-(5-bromo-3-pyridyl)-2-azabicyclo[2.2.2]oct-5-ene, 6-(5-ethynyl-3-pyridyl)-2-azabicyclo[2.2.2]octane, (~)-8-methyl-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene, (~)-8-(benzyl)-3-(3-pyridyl)-8-azabicyclo[3.2.1]oct-2-ene, (~)-3-(6-chloro-3-pyridyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene, (~)-3-(8-methyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)aniline, spiro[1,3-benzodioxole-2,3'-quinuclidine], 5-methylspiro[1,3-benzodioxole-2,3'-quinuclidine], 5-tert-butylspiro[1,3-benzodioxole-2,3'-quinuclidine], (~)-3-(5-methoxy-3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene, (~)-3-(5-methoxy-3-pyridyl)-9-methyl-9-azabicyclo[3.3.1]non-2-ene, (~)-3-(9-methyl-9-azabicyclo[3.3.1]non-2-en-3-yl)phenylamine, (~)-3-(3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene, (~)-9-methyl-3-(3-pyridyl)-9-azabicyclo[3.3.1]non-2-ene, spiro[1-azabicyclo[2.2.2]octane-3-2'(3'H)-furo[2,3-b]pyridine]-7'-oxide, 1-(6-chloro-5-methoxy-3-pyridyl)perhydro-1,4-diazepine, 1-(5-methoxy-3-pyridyl)perhydro-1,4-diazepine, 1-(5-methoxy-3-pyridyl)perhydro-1,5-diazocine, 3-(perhydro-1,4-diazepin-1-yl)quinoline, 1-(6-bromo-3-pyridyl)perhydro-1,4-diazepine, 1-(5-propoxy-3-pyridyl)perhydro-1,4-diazepine, 4-(3-pyridyloxy)perhydroazepine, 2-methyl-1,2,3,5,6,7,8,9-octahydro-5,9-methanopyrrolo[3,4-h]benzazepine-1,3-dione, 1,3-dimethyl-1,2,3,5,6,7,8,9-octahydro-5,9-methanoimidazo[4,5-h][3]benzazepin-2-one, 1,2,3,5,6,7,8,9-octahydro-5,9-methanopyrrolo[3,4-h][3]benzazepine-1,3-dione, 7,8-difluoro-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine, 8-ethynyl-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine-7-carbonitrile, 7-chloro-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine, 8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine-7-carbonitrile, the (R,R), (S,S), (R,S) and (S, R) compounds of 2-pyrrolidin-2-yl-2,3-dihydrofuro[3,2-b]pyridine and 6-pyrrolidin-2-yl-6,7-dihydro-5H-2-pyrindine, as well as - the compounds corresponding to the general formula in which one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula C-R3 and the third represents a nitrogen atom or a group of formula C-R4, R3 and R4 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or (C1-C6) alkoxy group, R1 and R2 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6) alkyl or (C1-C6) alkoxy group, or a phenyl group optionally substituted with one or two halogen atoms, with one or two trifluoromethyl groups, with a cyano group, with a nitro group, with a hydroxyl group, with a (C1-C6)alkyl group, with one or two (C1-C6)alkoxy groups, with a methylenedioxy group, with an acetyl group, with a trifluoromethoxy group or with a methylthio group, R represents a hydrogen atom or a (C1-C6)alkyl group, with the exclusion, however, of the compounds of general formula (I) in which X represents a group of formula CH, Y and Z each represent a nitrogen atom, and R1 or R2 does not represent an optionally substituted phenyl group, - and the compounds corresponding to the general formula (I) in which one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula C-R3 and the third represents a nitrogen atom or a group of formula C-R4, R3 and R4 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or (C1-C6)alkoxy group, R1 and R2 each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl, (C1-C6)alkyl or (C1-C6)alkoxy group, or a phenyl group optionally substituted with a halogen atom, with one or two trifluoromethyl groups, with a cyano group, with a nitro group, with a hydroxyl group, with a (C1-C6)alkyl group, with a (C1-C6)alkoxy group, with an acetyl group, with a methylenedioxy group, with a trifluoromethoxy group, with a methylthio group or with a phenyl group.
8. Pharmaceutical composition according to Claim 4, characterized in that the monoamine oxidase inhibitor is befloxatone.
9. Pharmaceutical composition according to Claim 4, characterized in that the monoamine oxidase inhibitor is moclobemide.
10. Pharmaceutical composition according to Claim 4, characterized in that the monoamine oxidase inhibitor is (S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-1,2-benzisoxazol-3-yl]oxazolidin-2-one.
11. Pharmaceutical composition according to Claim 4, characterized in that the monoamine oxidase inhibitor is [3(S),3a(S)]-3-methoxymethyl-7-[4,4,4-trifluorobutoxy-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one.
12. Pharmaceutical composition according to Claim 4, characterized in that the monoamine oxidase inhibitor is [3(S),3a(S)]-3-methoxymethyl-7-(4,4,4-trifluoro-3(R)-hydroxybutoxy)-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one.
13. Pharmaceutical composition comprising nicotine or a ligand for the nicotine receptors and a monoamine oxidase inhibitor.
14. Pharmaceutical composition according to Claim 13, characterized in that the monoamine oxidase inhibitor is of reversible A or mixed A,B type.
15. Pharmaceutical composition according to any one of Claims 1 to 14, for simultaneous use over time, characterized in that it is in one of the following pharmaceutical forms: tablet, pills, gel capsule, chewing gum with immediate or sustained release, transdermal patch, nasal spray or pulmonary spray, injectable solution or suspension, or suppository.
16. Use of a combination of nicotine or of a ligand for the nicotine receptors and of a monoamine oxidase inhibitor, for the manufacture of a medicinal product intended for stopping tobacco dependency.
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FR99/01144 | 1999-02-02 | ||
FR9901144A FR2788982B1 (en) | 1999-02-02 | 1999-02-02 | PHARMACEUTICAL COMPOSITIONS CONTAINING NICOTINE AND THEIR APPLICATION IN SMOKING WITHDRAWAL |
PCT/FR2000/000193 WO2000045846A1 (en) | 1999-02-02 | 2000-01-28 | Pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor and their use for treating tobacco withdrawal symptoms |
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CA002361437A Abandoned CA2361437A1 (en) | 1999-02-02 | 2000-01-28 | Pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor and their use for treating tobacco withdrawal symptoms |
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EP (1) | EP1150715A1 (en) |
JP (1) | JP2002536342A (en) |
AR (1) | AR028983A1 (en) |
AU (1) | AU2298800A (en) |
CA (1) | CA2361437A1 (en) |
FR (1) | FR2788982B1 (en) |
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US5803081A (en) * | 1996-06-28 | 1998-09-08 | Regent Court Technologies | Tobacco and related products |
-
1999
- 1999-02-02 FR FR9901144A patent/FR2788982B1/en not_active Expired - Fee Related
-
2000
- 2000-01-28 HU HU0201279A patent/HUP0201279A2/en unknown
- 2000-01-28 WO PCT/FR2000/000193 patent/WO2000045846A1/en not_active Application Discontinuation
- 2000-01-28 EP EP00901660A patent/EP1150715A1/en not_active Withdrawn
- 2000-01-28 JP JP2000596965A patent/JP2002536342A/en not_active Withdrawn
- 2000-01-28 AU AU22988/00A patent/AU2298800A/en not_active Abandoned
- 2000-01-28 CA CA002361437A patent/CA2361437A1/en not_active Abandoned
- 2000-01-31 AR ARP000100404A patent/AR028983A1/en not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
---|---|
AU2298800A (en) | 2000-08-25 |
FR2788982B1 (en) | 2002-08-02 |
EP1150715A1 (en) | 2001-11-07 |
JP2002536342A (en) | 2002-10-29 |
WO2000045846A1 (en) | 2000-08-10 |
FR2788982A1 (en) | 2000-08-04 |
HUP0201279A2 (en) | 2002-09-28 |
AR028983A1 (en) | 2003-06-04 |
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