AU2002300094B2 - New octahydro-2H-pyrido[1,2-alpha]pyrazine compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents
New octahydro-2H-pyrido[1,2-alpha]pyrazine compounds, a process for their preparation and pharmaceutical compositions containing them Download PDFInfo
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- AU2002300094B2 AU2002300094B2 AU2002300094A AU2002300094A AU2002300094B2 AU 2002300094 B2 AU2002300094 B2 AU 2002300094B2 AU 2002300094 A AU2002300094 A AU 2002300094A AU 2002300094 A AU2002300094 A AU 2002300094A AU 2002300094 B2 AU2002300094 B2 AU 2002300094B2
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- Prior art keywords
- formula
- compounds
- octahydro
- pyrido
- linear
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- 238000000034 method Methods 0.000 title claims description 97
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 10
- 230000008569 process Effects 0.000 title claims description 8
- 150000003216 pyrazines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 289
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 111
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 56
- -1 cyano, hydroxy Chemical group 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 25
- ONHPOXROAPYCGT-UHFFFAOYSA-N 2,3,4,6,7,8,9,9a-octahydro-1h-pyrido[1,2-a]pyrazine Chemical compound C1CNCC2CCCCN21 ONHPOXROAPYCGT-UHFFFAOYSA-N 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 17
- 230000003287 optical effect Effects 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 230000002490 cerebral effect Effects 0.000 claims description 14
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 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 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 230000032683 aging Effects 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 102000000543 Histamine Receptors Human genes 0.000 claims description 7
- 108010002059 Histamine Receptors Proteins 0.000 claims description 7
- 230000009471 action Effects 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 230000007812 deficiency Effects 0.000 claims description 7
- DWKQACOYZLPYLK-UHFFFAOYSA-N 2-[4-(3,4,5-trimethoxyphenoxy)butyl]-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine Chemical compound COC1=C(OC)C(OC)=CC(OCCCCN2CC3CCCCN3CC2)=C1 DWKQACOYZLPYLK-UHFFFAOYSA-N 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
- 208000019022 Mood disease Diseases 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
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- 230000002920 convulsive effect Effects 0.000 claims description 6
- 230000006735 deficit Effects 0.000 claims description 6
- 208000013403 hyperactivity Diseases 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 208000011580 syndromic disease Diseases 0.000 claims description 6
- WHUUNDBNAOLWHH-UHFFFAOYSA-N 4-[4-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)butoxy]benzonitrile Chemical compound C1=CC(C#N)=CC=C1OCCCCN1CC2CCCCN2CC1 WHUUNDBNAOLWHH-UHFFFAOYSA-N 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
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- 235000020824 obesity Nutrition 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 206010012289 Dementia Diseases 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- PXWLUICTRPHECG-UHFFFAOYSA-N azane;trihydrochloride Chemical compound N.Cl.Cl.Cl PXWLUICTRPHECG-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- OVOCXFPHKYKILZ-UHFFFAOYSA-N 2-[4-(2,3-dihydroindol-1-yl)butyl]-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine Chemical compound C1CC2=CC=CC=C2N1CCCCN1CC2CCCCN2CC1 OVOCXFPHKYKILZ-UHFFFAOYSA-N 0.000 claims description 3
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 3
- 208000006264 Korsakoff syndrome Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- HVESBEMFMIGKRO-UHFFFAOYSA-N n-[4-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)butyl]-3,4,5-trimethoxyaniline Chemical compound COC1=C(OC)C(OC)=CC(NCCCCN2CC3CCCCN3CC2)=C1 HVESBEMFMIGKRO-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 230000002739 subcortical effect Effects 0.000 claims description 3
- 230000002792 vascular Effects 0.000 claims description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- IPQKDRLTFCPQJI-UHFFFAOYSA-N 3-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)propyl 3,4,5-trimethoxybenzoate Chemical compound COC1=C(OC)C(OC)=CC(C(=O)OCCCN2CC3CCCCN3CC2)=C1 IPQKDRLTFCPQJI-UHFFFAOYSA-N 0.000 claims description 2
- GIYOENKARHSWRZ-UHFFFAOYSA-N 4-[2-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)ethoxy]benzonitrile Chemical compound C1=CC(C#N)=CC=C1OCCN1CC2CCCCN2CC1 GIYOENKARHSWRZ-UHFFFAOYSA-N 0.000 claims description 2
- JRHCWUYZXMHBBQ-UHFFFAOYSA-N 4-[4-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)butoxy]-3-methoxybenzonitrile Chemical compound COC1=CC(C#N)=CC=C1OCCCCN1CC2CCCCN2CC1 JRHCWUYZXMHBBQ-UHFFFAOYSA-N 0.000 claims description 2
- OSTBNQVECLKQAX-UHFFFAOYSA-N 4-[4-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)butylamino]benzonitrile Chemical compound C1=CC(C#N)=CC=C1NCCCCN1CC2CCCCN2CC1 OSTBNQVECLKQAX-UHFFFAOYSA-N 0.000 claims description 2
- 229910014033 C-OH Inorganic materials 0.000 claims description 2
- HPJFIXKIBXIOGX-UHFFFAOYSA-N COC1=C(OC)C(OC)=CC(C(=O)OCCN2CC3CCCCN3CC2)=C1 Chemical compound COC1=C(OC)C(OC)=CC(C(=O)OCCN2CC3CCCCN3CC2)=C1 HPJFIXKIBXIOGX-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910014570 C—OH Inorganic materials 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- PSPSGMYTHVVLNG-UHFFFAOYSA-N n-[4-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)butyl]-2-chloroaniline Chemical compound ClC1=CC=CC=C1NCCCCN1CC2CCCCN2CC1 PSPSGMYTHVVLNG-UHFFFAOYSA-N 0.000 claims description 2
- YYMRTZFPHPHTAG-UHFFFAOYSA-N n-[4-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)butyl]-3,4-dichloroaniline Chemical compound C1=C(Cl)C(Cl)=CC=C1NCCCCN1CC2CCCCN2CC1 YYMRTZFPHPHTAG-UHFFFAOYSA-N 0.000 claims description 2
- IQLXCQAGYULJNH-UHFFFAOYSA-N n-[4-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)butyl]-3,5-dichloroaniline Chemical compound ClC1=CC(Cl)=CC(NCCCCN2CC3CCCCN3CC2)=C1 IQLXCQAGYULJNH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 4
- 239000003814 drug Substances 0.000 claims 3
- 125000006557 (C2-C5) alkylene group Chemical group 0.000 claims 1
- HVEYINFKIWUYJR-UHFFFAOYSA-N 2-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)-1-phenylethanol Chemical compound C1CN2CCCCC2CN1CC(O)C1=CC=CC=C1 HVEYINFKIWUYJR-UHFFFAOYSA-N 0.000 claims 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 238000004452 microanalysis Methods 0.000 description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 76
- 239000000758 substrate Substances 0.000 description 67
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- 238000002844 melting Methods 0.000 description 51
- 230000008018 melting Effects 0.000 description 51
- 239000000243 solution Substances 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 31
- 239000000203 mixture Substances 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- 150000001412 amines Chemical class 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 238000003821 enantio-separation Methods 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 229960001340 histamine Drugs 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 5
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical class C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 5
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 description 5
- 239000011707 mineral Substances 0.000 description 5
- 235000010755 mineral Nutrition 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
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- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 3
- GXWNSJYVSIJRLS-UHFFFAOYSA-N 6-bromo-8-methylimidazo[1,2-a]pyrazine Chemical compound CC1=NC(Br)=CN2C=CN=C12 GXWNSJYVSIJRLS-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
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- 230000002378 acidificating effect Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000007171 neuropathology Effects 0.000 description 3
- 239000002858 neurotransmitter agent Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- QPHLRCUCFDXGLY-UHFFFAOYSA-N (3,4,5-trimethoxyphenyl)methanol Chemical compound COC1=CC(CO)=CC(OC)=C1OC QPHLRCUCFDXGLY-UHFFFAOYSA-N 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
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- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
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- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
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- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
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- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 1
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- 238000001990 intravenous administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
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- 239000008101 lactose Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- NDPOGQHCFNMYTR-UHFFFAOYSA-N n,n,2-trimethoxyaniline Chemical compound CON(OC)C1=CC=CC=C1OC NDPOGQHCFNMYTR-UHFFFAOYSA-N 0.000 description 1
- BLIJXOOIHRSQRB-PXYINDEMSA-N n-[(2s)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-5-(1-hydroxyethyl)-1h-pyrazole-3-carboxamide Chemical compound C([C@H](C)NC(=O)C=1NN=C(C=1)C(C)O)N(N=1)C=CC=1C1=CC=C(C#N)C(Cl)=C1 BLIJXOOIHRSQRB-PXYINDEMSA-N 0.000 description 1
- DYFBOXDZEABSPQ-UHFFFAOYSA-N n-[3-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)propyl]-3,4,5-trimethoxybenzamide;dihydrochloride Chemical compound Cl.Cl.COC1=C(OC)C(OC)=CC(C(=O)NCCCN2CC3CCCCN3CC2)=C1 DYFBOXDZEABSPQ-UHFFFAOYSA-N 0.000 description 1
- GBQANZUTADFYSK-UHFFFAOYSA-N n-[4-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)butyl]-3,4,5-trimethoxy-n-methylaniline;trihydrochloride Chemical compound Cl.Cl.Cl.COC1=C(OC)C(OC)=CC(N(C)CCCCN2CC3CCCCN3CC2)=C1 GBQANZUTADFYSK-UHFFFAOYSA-N 0.000 description 1
- NCVYOUUGLJQWTH-UHFFFAOYSA-N n-[4-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)butyl]-3,4,5-trimethoxyaniline;trihydrochloride Chemical compound Cl.Cl.Cl.COC1=C(OC)C(OC)=CC(NCCCCN2CC3CCCCN3CC2)=C1 NCVYOUUGLJQWTH-UHFFFAOYSA-N 0.000 description 1
- JKQIIFGOGZOQAI-UHFFFAOYSA-N n-[4-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl)butyl]-n-(3,4,5-trimethoxyphenyl)acetamide;dihydrochloride Chemical compound Cl.Cl.COC1=C(OC)C(OC)=CC(N(CCCCN2CC3CCCCN3CC2)C(C)=O)=C1 JKQIIFGOGZOQAI-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 230000001962 neuropharmacologic effect Effects 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 101150103670 ple2 gene Proteins 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- RDCFVGPXAHCPPY-UHFFFAOYSA-N pyrazine;dihydrochloride Chemical compound Cl.Cl.C1=CN=CC=N1 RDCFVGPXAHCPPY-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
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- 239000008174 sterile solution Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000028016 temperature homeostasis Effects 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- XWKHFFLZJISKNH-UHFFFAOYSA-N tri(propan-2-yl)-(3,4,5-trimethoxyphenyl)sulfanylsilane Chemical compound COC1=CC(S[Si](C(C)C)(C(C)C)C(C)C)=CC(OC)=C1OC XWKHFFLZJISKNH-UHFFFAOYSA-N 0.000 description 1
- CPKHFNMJTBLKLK-UHFFFAOYSA-N tri(propan-2-yl)-sulfanylsilane Chemical compound CC(C)[Si](S)(C(C)C)C(C)C CPKHFNMJTBLKLK-UHFFFAOYSA-N 0.000 description 1
- REDSKZBUUUQMSK-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC REDSKZBUUUQMSK-UHFFFAOYSA-N 0.000 description 1
- 125000001680 trimethoxyphenyl group Chemical group 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Child & Adolescent Psychology (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0109260A FR2827288B1 (fr) | 2001-07-12 | 2001-07-12 | Nouveaux derives d'octahydro-2h-pyrido[1,2-a]pyrazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR01.09260 | 2001-07-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2002300094A1 AU2002300094A1 (en) | 2003-06-12 |
| AU2002300094B2 true AU2002300094B2 (en) | 2007-06-14 |
Family
ID=8865405
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002300094A Ceased AU2002300094B2 (en) | 2001-07-12 | 2002-07-12 | New octahydro-2H-pyrido[1,2-alpha]pyrazine compounds, a process for their preparation and pharmaceutical compositions containing them |
Country Status (24)
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1611902A4 (en) * | 2003-04-03 | 2006-04-12 | Kyowa Hakko Kogyo Kk | MEANS FOR THE PREVENTION AND / OR TREATMENT OF NEUROPATHIC PAIN |
| MY141255A (en) * | 2003-12-11 | 2010-03-31 | Memory Pharm Corp | Phosphodiesterase 4 inhibitors, including n-substituted diarylamine analogs |
| FR2866647B1 (fr) * | 2004-02-20 | 2006-10-27 | Servier Lab | Nouveaux derives azabicycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| WO2006000914A1 (en) * | 2004-06-22 | 2006-01-05 | Pfizer Products Inc. | Diazabicyclic histamine-3 receptor antagonists |
| EP2233470B1 (en) * | 2005-07-04 | 2011-12-07 | High Point Pharmaceuticals, LLC | Histamine H3 receptor antagonists |
| RU2442775C2 (ru) * | 2005-07-04 | 2012-02-20 | Хай Пойнт Фармасьютикалс, ЛЛС | Антагонисты гистаминовых н3-рецепторов |
| US7795262B2 (en) * | 2006-03-10 | 2010-09-14 | Neurogen Corporation | Piperazinyl oxoalkyl tetrahydroisoquinolines and related analogues |
| KR100871691B1 (ko) | 2006-10-16 | 2008-12-05 | 삼성전자주식회사 | 병렬 비트 테스트 방법 및 그 방법을 사용하는 반도체메모리 장치 |
| JP7015092B2 (ja) | 2016-07-28 | 2022-02-02 | 塩野義製薬株式会社 | ドーパミンｄ３受容体拮抗作用を有する含窒素縮環化合物 |
| CN111801330B (zh) | 2018-01-26 | 2024-04-05 | 盐野义制药株式会社 | 具有多巴胺d3受体拮抗作用的稠环化合物 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3388128A (en) * | 1965-09-03 | 1968-06-11 | Allan R. Day | Substituted 1, 4-diazabicyclo [4. 4. 9] decanes |
| GB8518236D0 (en) * | 1985-07-19 | 1985-08-29 | Beecham Group Plc | Compounds |
| WO1994006794A1 (en) * | 1992-09-24 | 1994-03-31 | National Institutes Of Health | Aralkyl diazabicycloalkane derivatives for cns disorders |
| US6231833B1 (en) * | 1999-08-05 | 2001-05-15 | Pfizer Inc | 2,7-substituted octahydro-1H-pyrido[1,2-A]pyrazine derivatives as ligands for serotonin receptors |
| WO1996010570A1 (en) * | 1994-09-30 | 1996-04-11 | Pfizer Inc. | NEUROLEPTIC 2,7-DISUBSTITUTED PERHYDRO-1H-PYRIDO[1,2-a]PYRAZINES |
| AU773317B2 (en) * | 1999-07-19 | 2004-05-20 | Merck Canada Inc. | Pyrazinones, compositions containing such compounds |
-
2001
- 2001-07-12 FR FR0109260A patent/FR2827288B1/fr not_active Expired - Fee Related
-
2002
- 2002-07-05 MX MXPA02006699A patent/MXPA02006699A/es active IP Right Grant
- 2002-07-10 JP JP2002201793A patent/JP3950018B2/ja not_active Expired - Fee Related
- 2002-07-11 NO NO20023345A patent/NO322966B1/no not_active IP Right Cessation
- 2002-07-11 EP EP02291745A patent/EP1275647B1/fr not_active Expired - Lifetime
- 2002-07-11 DE DE60200089T patent/DE60200089T2/de not_active Expired - Fee Related
- 2002-07-11 NZ NZ520120A patent/NZ520120A/en unknown
- 2002-07-11 ES ES02291745T patent/ES2210219T3/es not_active Expired - Lifetime
- 2002-07-11 SI SI200230005T patent/SI1275647T1/xx unknown
- 2002-07-11 EA EA200200663A patent/EA005160B1/ru not_active IP Right Cessation
- 2002-07-11 BR BR0202681-3A patent/BR0202681A/pt not_active IP Right Cessation
- 2002-07-11 DK DK02291745T patent/DK1275647T3/da active
- 2002-07-11 PT PT02291745T patent/PT1275647E/pt unknown
- 2002-07-11 TR TR2003/02001T patent/TR200302001T4/xx unknown
- 2002-07-11 AT AT02291745T patent/ATE254124T1/de not_active IP Right Cessation
- 2002-07-12 AR ARP020102607A patent/AR036166A1/es unknown
- 2002-07-12 PL PL02355034A patent/PL355034A1/xx not_active Application Discontinuation
- 2002-07-12 CA CA002394027A patent/CA2394027C/fr not_active Expired - Fee Related
- 2002-07-12 CN CNB021241481A patent/CN1197863C/zh not_active Expired - Fee Related
- 2002-07-12 US US10/195,019 patent/US6992085B2/en not_active Expired - Fee Related
- 2002-07-12 AU AU2002300094A patent/AU2002300094B2/en not_active Ceased
- 2002-07-12 KR KR10-2002-0040727A patent/KR100485020B1/ko not_active Expired - Fee Related
- 2002-07-12 ZA ZA200205596A patent/ZA200205596B/xx unknown
- 2002-07-12 HU HU0202282A patent/HUP0202282A3/hu unknown
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