EP1109783A2 - Inhibiteurs d'absorption de gaba a structure pyrrolidinique - Google Patents
Inhibiteurs d'absorption de gaba a structure pyrrolidiniqueInfo
- Publication number
- EP1109783A2 EP1109783A2 EP99968664A EP99968664A EP1109783A2 EP 1109783 A2 EP1109783 A2 EP 1109783A2 EP 99968664 A EP99968664 A EP 99968664A EP 99968664 A EP99968664 A EP 99968664A EP 1109783 A2 EP1109783 A2 EP 1109783A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- mmol
- optionally substituted
- alkyl
- groups
- compounds according
- 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.)
- Withdrawn
Links
- 229940091860 GABA uptake inhibitor Drugs 0.000 title abstract description 7
- 239000002843 gaba uptake inhibitor Substances 0.000 title abstract description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 32
- -1 3-methyl-2-thienyl Chemical group 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 6
- 125000001118 alkylidene group Chemical group 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 230000007428 synaptic transmission, GABAergic Effects 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000004962 physiological condition Effects 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 230000002708 enhancing effect Effects 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 206010015037 epilepsy Diseases 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 95
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 93
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 60
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 40
- 239000012230 colorless oil Substances 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 38
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- 238000004440 column chromatography Methods 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000013078 crystal Substances 0.000 description 26
- 238000000746 purification Methods 0.000 description 24
- 150000004702 methyl esters Chemical class 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- 238000007127 saponification reaction Methods 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 description 20
- 230000035484 reaction time Effects 0.000 description 20
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 19
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 18
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 18
- 230000004044 response Effects 0.000 description 17
- 238000007126 N-alkylation reaction Methods 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- 238000000354 decomposition reaction Methods 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910052731 fluorine Inorganic materials 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007983 Tris buffer Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 7
- GWCPTZNOWFHMER-UHFFFAOYSA-N (4-bromo-1-phenylbut-1-enyl)benzene Chemical compound C=1C=CC=CC=1C(=CCCBr)C1=CC=CC=C1 GWCPTZNOWFHMER-UHFFFAOYSA-N 0.000 description 6
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 6
- 210000003169 central nervous system Anatomy 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- 229940017219 methyl propionate Drugs 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- 102100035254 Sodium- and chloride-dependent GABA transporter 3 Human genes 0.000 description 5
- 101710104417 Sodium- and chloride-dependent GABA transporter 3 Proteins 0.000 description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 5
- 239000001961 anticonvulsive agent Substances 0.000 description 5
- XNYIZVPSGNHISO-CYBMUJFWSA-N benzyl (2r)-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate Chemical compound COC(=O)C[C@H]1CCCN1C(=O)OCC1=CC=CC=C1 XNYIZVPSGNHISO-CYBMUJFWSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- KRXSGXVUQKRSCK-UHFFFAOYSA-N 2-[4-bromo-1-(3-methylthiophen-2-yl)but-1-enyl]-3-methylthiophene Chemical compound C1=CSC(C(=CCCBr)C2=C(C=CS2)C)=C1C KRXSGXVUQKRSCK-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical class [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical group COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
- HGINADPHJQTSKN-UHFFFAOYSA-N Monoethyl malonic acid Chemical compound CCOC(=O)CC(O)=O HGINADPHJQTSKN-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 101710104414 Sodium- and chloride-dependent GABA transporter 1 Proteins 0.000 description 4
- 102100033927 Sodium- and chloride-dependent GABA transporter 1 Human genes 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 230000003556 anti-epileptic effect Effects 0.000 description 4
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- RBWRWAUAVRMBAC-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=[C-]C=C1 RBWRWAUAVRMBAC-UHFFFAOYSA-M 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- JXGVXCZADZNAMJ-LLVKDONJSA-N (2r)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCCN1C(=O)OCC1=CC=CC=C1 JXGVXCZADZNAMJ-LLVKDONJSA-N 0.000 description 3
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108010078791 Carrier Proteins Proteins 0.000 description 3
- 102000014914 Carrier Proteins Human genes 0.000 description 3
- 101150065749 Churc1 gene Proteins 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- 102100038239 Protein Churchill Human genes 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229960003965 antiepileptics Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 150000002081 enamines Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- FECAUVOXGVMVNH-RGMNGODLSA-N methyl 2-[(2s)-pyrrolidin-2-yl]acetate;hydrochloride Chemical compound Cl.COC(=O)C[C@@H]1CCCN1 FECAUVOXGVMVNH-RGMNGODLSA-N 0.000 description 3
- SIGOIUCRXKUEIG-UHFFFAOYSA-N methyl 2-dimethoxyphosphorylacetate Chemical compound COC(=O)CP(=O)(OC)OC SIGOIUCRXKUEIG-UHFFFAOYSA-N 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- BLQYEDXWEDWCNJ-GFCCVEGCSA-N 1-o-benzyl 2-o-methyl (2r)-pyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@H]1CCCN1C(=O)OCC1=CC=CC=C1 BLQYEDXWEDWCNJ-GFCCVEGCSA-N 0.000 description 2
- BLQYEDXWEDWCNJ-LBPRGKRZSA-N 1-o-benzyl 2-o-methyl (2s)-pyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1CCCN1C(=O)OCC1=CC=CC=C1 BLQYEDXWEDWCNJ-LBPRGKRZSA-N 0.000 description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical class OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QCMYYKRYFNMIEC-UHFFFAOYSA-N COP(O)=O Chemical compound COP(O)=O QCMYYKRYFNMIEC-UHFFFAOYSA-N 0.000 description 2
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 2
- 102000005665 Neurotransmitter Transport Proteins Human genes 0.000 description 2
- 108010084810 Neurotransmitter Transport Proteins Proteins 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 102100035242 Sodium- and chloride-dependent GABA transporter 2 Human genes 0.000 description 2
- 101710104420 Sodium- and chloride-dependent GABA transporter 2 Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 238000005830 amidoalkylation reaction Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- ADSALMJPJUKESW-UHFFFAOYSA-N beta-Homoproline Chemical compound OC(=O)CC1CCCN1 ADSALMJPJUKESW-UHFFFAOYSA-N 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 150000003983 crown ethers Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 238000010931 ester hydrolysis Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 150000001469 hydantoins Chemical class 0.000 description 2
- 150000007976 iminium ions Chemical class 0.000 description 2
- HQEIPVHJHZTMDP-NUBCRITNSA-N methyl (2r)-pyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@H]1CCCN1 HQEIPVHJHZTMDP-NUBCRITNSA-N 0.000 description 2
- HQEIPVHJHZTMDP-JEDNCBNOSA-N methyl (2s)-pyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@@H]1CCCN1 HQEIPVHJHZTMDP-JEDNCBNOSA-N 0.000 description 2
- LNLRYSLOKHYXMT-AUEATDLBSA-N methyl (e)-3-[(2r)-1-[2-[tris(4-methoxyphenyl)methoxy]ethyl]pyrrolidin-2-yl]prop-2-enoate Chemical compound COC(=O)\C=C\[C@H]1CCCN1CCOC(C=1C=CC(OC)=CC=1)(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 LNLRYSLOKHYXMT-AUEATDLBSA-N 0.000 description 2
- LNLRYSLOKHYXMT-LVISATDHSA-N methyl (z)-3-[(2r)-1-[2-[tris(4-methoxyphenyl)methoxy]ethyl]pyrrolidin-2-yl]prop-2-enoate Chemical compound COC(=O)\C=C/[C@H]1CCCN1CCOC(C=1C=CC(OC)=CC=1)(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 LNLRYSLOKHYXMT-LVISATDHSA-N 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229960002695 phenobarbital Drugs 0.000 description 2
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 2
- ZSKGQVFRTSEPJT-UHFFFAOYSA-N pyrrole-2-carboxaldehyde Chemical compound O=CC1=CC=CN1 ZSKGQVFRTSEPJT-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
Definitions
- the present invention relates to GABA uptake inhibitors with a pyrrolidine structure.
- the present invention further relates to pharmaceutical compositions containing such compounds and the use of these compounds for the treatment of diseases of the central nervous system (CNS) in which GABA uptake inhibitors play a role, for example epilepsy and Huntington's chorea.
- CNS central nervous system
- epilepsy is still one of the most common diseases of the brain. Due to the wide variety of seizure types and a still lacking aetiological understanding, the therapeutic approaches are still limited to controlling symptoms, such as that Suppression of seizures.
- the list of anti-epileptics was expanded to include the benzodiazepine group. Examples include diazepam and clonazepam.
- GABA A receptor is an ion channel protein that is composed of different subunits.
- GABA transport protein A high-affinity GABA transport system was discovered in rat cortex sections in 1968, which ensures the uptake of neurotransmitters released into the synaptic cleft and thus the termination of the neurotransmitter signal. Such a GABA transport protein was first isolated in 1978.
- GABA uptake proteins with 0.1% of the membrane proteins occur relatively frequently in the nervous system.
- four different representatives of neurotransmitter transport proteins have been detected by cloning and heterologous expression.
- GAT-1 The first member of this family to clone from cDNA was designated GAT-1. This protein is also the first neurotransmitter transporter that has been successfully cloned and expressed. A short time later, human GAT-1 was cloned.
- GAT-2 transport proteins
- GAT-3 transport proteins
- BGT-1 transport system for betaine and GABA
- nipecotinic acid and guvacin As early as 1975, the inhibitory effect of nipecotinic acid and guvacin on the reuptake of GABA was discovered in studies with nipecotinic acid, guvacin and arecaidin, active ingredients from Bethelnut (Areca catechu). With the knowledge of the relationships in GABAergic neurotransmission, new strategies in the treatment of epilepsy emerged. For example, it is possible to increase the neuronal GABA transmission by direct GABA mimetics. GABA itself is not suitable for this because it cannot cross the blood-brain barrier. One problem with direct GABA mimetics is that tolerance can develop through them.
- GABAergic neurotransmission in a non-specific way in general in the GABAergic synapses and not only where signals arrive.
- Those mechanisms of action represent a particularly useful therapeutic approach that only increase GABAergic neurotransmission when the transmitter is released. This can be achieved on the one hand by inhibiting the degradation of the transmitter and on the other hand by inhibiting its resumption.
- the development of appropriate inhibitors for GABA reuptake began with the compounds nipecotinic acid and guvacin mentioned above. However, like GABA, these cannot or only very barely cross the blood-brain barrier.
- the object of the present invention was to provide new GABA uptake inhibitors and in particular to provide GABA uptake inhibitors with high selectivity for GAT-3 (or at least high affinity for GAT-1).
- the above object is achieved according to the invention by the compounds of the general formula (I)
- a 2 stands for (-CR 10 R 11 -) m , where R 10 and R 11 are independently selected from H, i.e. 2-alkyl and halogen; where for im> 2 the groups R 10 and R 11 can be different in each grouping, there can be a grouping - O- or -S- between two neighboring groups and two groups of R 10 and R 11 each on adjacent C atoms can be replaced by a CC bond; and wherein one of R 10 and R 11 may be combined with one of R 1 to R 9 to form a 5- to 7-membered ring structure; and m is 1, 2, 3 or 4;
- the present invention also relates to pharmaceutical compositions which contain at least one pharmaceutically acceptable carrier or excipient and at least one compound of the general formula (I).
- the present invention is also directed to the use of the compounds of general formula (I) for the manufacture of a medicament for the treatment of diseases in which the enhancement of GABAergic neurotransmission is beneficial, particularly epilepsy, Huntington's disease and related disorders of the CNS.
- the compounds according to the invention can also be used successfully as anticonvulsants, sedatives, anxiolytics and antidepressants.
- the present invention is explained in more detail below on the basis of preferred embodiments thereof.
- -6- alkyl, C 2-6 alkenyl and C 2-6 alkynyl is intended to represent groups which are unsubstituted or (preferably one or two) substituents which are in particular selected from OH, halogen (in particular F, Cl, Br and particularly preferably F), CN, NO 2 and OR 12 .
- the substituents can also (and additionally) be (optionally substituted) aryl or heteroaryl radicals (as defined in more detail below).
- Methyl, ethyl, propyl, CF 3 , CH 2 OCH 3 , CH 2 OH, benzyl and phenethyl can be mentioned as concrete examples of the radicals R 1 to R 7 just discussed.
- Optionally substituted aryl or heteroaryl includes aryl groups preferably having 6 to 12 carbon atoms and heteroaryl radicals having 5 to 12 ring members, of which up to three can be heteroatoms (generally selected from N, O and S). These aryl or heteroaryl radicals can be unsubstituted or (preferably with one to three substituents). Preferred examples of such substituents are C -3 alkyl, C 2- alkenyl, OH, halogen (in particular F, Cl, Br), CN, NO 2 , OR 12 and NR 13 R 14 .
- phenyl, thienyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyranyl and corresponding radicals can be mentioned, which have one to three (preferably one) substituent from the group methyl, ethyl, CF 3 , methoxy , Ethoxy, F, Cl, CN, NH 2 , dimethylamino and diethylamino.
- R 1 to R 7 is halogen
- this halogen is preferably fluorine or chlorine, particularly preferably fluorine.
- R 1 , R 2 and R 7 are preferably not halogen, OR 12 , SR 12 and NR 13 R 14 , since in these cases there is the possibility of enamine formation.
- R 12 is preferably C -3 alkyl, in particular methyl and ethyl.
- R 13 and R 14 are preferably identical and are preferably methyl and Ethyl. However, R 13 and R 14 can also form an alkylene group, which would result, for example, in a pyrrolidinyl or piperidinyl radical.
- R 1 to R 6 are independently selected from H, optionally substituted C -3 alkyl, halogen, OH, CN, optionally substituted phenyl and optionally substituted heteroaryi with five to ten ring members and one or two selected from O, N and S heteroatoms, and in particular from hydrogen, C ⁇ -3 alkyl and phenyl.
- R 7 preferably represents H. In general, it is preferred if no more than two and in particular no more than one radical from R 1 to R 7 are different from H. It can be particularly advantageous if R 1 to R 7 are all hydrogen.
- R 1 to R 7 can also be combined to form a 3- to 6-membered ring system (preferably a 5- or 6-membered ring system), which can also contain one or more (preferably one or two) heteroatoms.
- the heteroatoms are preferably O, N or S.
- oxo O
- the substituents which are optionally present on the alkylidene group are preferably those which have been given above as examples of substituents on alkyl, alkenyl and alkynyl radicals R 1 to R 7 .
- R 1 to R 7 which are located on adjacent C atoms, can also be replaced by a CC bond. This leads to the presence of double or triple bonds in the ring system. In this context, a double bond between the 3 and 4 positions of the pyrrolidine skeleton is preferred.
- a pyrrole structure is also worth mentioning in this context.
- a 1 is a combination of (-CR 8 R 9 -) n and (optionally substituted) C 3-6 - cycloalkylene, this should mean that A 1 in particular alkylene-cycloalkylene, cycloalkylene-alkylene and alkylene-cycloalkylene-alkylene can represent.
- a 1 is preferably (-CR 8 R 9 -) n .
- Particularly preferred meanings of R 8 and R 9 are H and C -3 alkyl, especially methyl.
- N has in particular the value 0.1 or 2, 1 or 2 being preferred.
- a 1 represents or includes optionally substituted C 3-6 cycloalkylene
- preferred examples of the cycloalkylene group are cyclopropylene, cyclopentylene and cyclohexylene. Any substituents present are preferably selected from C -3 alkyl, halogen (eg F or Cl) and OH. However, the cycloalkylene radical preferably does not have any substituents.
- a 1 stands for (-CR 8 R 9 -) n or comprises this, for n> 2 R 8 and R 9 both CR 8 R 9 and each group can be different.
- two groups of R 8 and R 9 on adjacent C atoms can also be replaced by a CC bond (which can lead, for example, to a derivative of acrylic acid) and there can be CR 8 between two adjacent groups R 9 is a -O- or -CO- group, although this is not preferred.
- one of R 8 and R 9 (preferably located on a carbon atom directly attached to the ring) can be combined with one of R 1 to R 7 (preferably R 5 , R 6 or R 7 ) to form a 5- to 7-membered ring structure be combined.
- This ring structure can be saturated or unsaturated and also contain one or more heteroatoms, preferably selected from O, N and S.
- X stands for COOM or a group which can be converted into COOM under physiological conditions.
- the latter groups include, for example, esters, nitrile and salts.
- M is preferably hydrogen and corresponding cations of sodium, potassium, calcium and magnesium and ammonium. H and Na are even more preferred as meanings for M, with the most preferred meaning for M being hydrogen.
- a 2 in the above general formula (I) stands for (-CR 10 R 11 -) m, where R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
- R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
- R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
- R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
- R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
- R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
- m preferably has the value 2 or 3, 2 being particularly preferred. If m> 2, the groups R 10 and R 11 can be different both from one another and from each group CR 10 R 11
- two adjacent groups CR 10 R 11 can be separated by a group -O- or -S- and two groups of R 10 and R 11 on adjacent C atoms can be replaced by a CC bond, which leads to a double (or triple) bond.
- the C atom adjacent to the N atom should be free of structural elements which (can) result in an enamine or iminium ion structure.
- one of R 10 and R 11 can be combined with one of R 1 to R 9 (preferably one of R 1 , R 2 , R 7 , R 8 and R 9 ) combined to form a 5- to 7-membered ring structure, which ring structure may be saturated or unsaturated and may also contain one or more heteroatoms selected from O, N and S, in addition to the ring nitrogen atom.
- Y are preferably identical. Further preferred meanings for Y are optionally substituted phenyl and optionally substituted thienyl, furanyl and pyrrolyl. Optionally substituted phenyl is particularly preferred. If substituents are present, their number preferably does not exceed 3 and in particular 2, with (only) one substituent being more preferred. Preferred substituents are selected from C 1-3 alkoxy, C -3 alkyl, halogen, OH, NO 2 , CN and NR 13 R 14 . Specific examples of such substituents are methoxy, ethoxy, methyl, ethyl, F, Cl, NH 2 , dimethylamino and diethylamino. A particularly preferred substituent is C -3 alkoxy, especially methoxy. In the case of a phenyl ring, this grouping is preferably in the 2- and / or 4-position, more preferably in the 4-position.
- the two groups Y are also preferably identical. Further preferred meanings for Y in this case are optionally substituted phenyl or optionally substituted heteroaryl with 5 or 6 Ring members and one or two heteroatoms selected from O, N and S. With regard to the substituents which may be present, reference may be made to the above statements regarding groups Y. When Y is phenyl, the phenyl ring preferably has no substituents. If Y is heteroaryl, Y is preferably optionally substituted thienyl, in particular 3-methyl-2-thienyl.
- R 15 is preferably H or methyl, more preferably H.
- R 1 to R 7 hydrogen
- a 2 -CH 2 CH 2 -;
- the present invention also includes the individual isomers (enantiomers, diastereomers, optionally cis / trans isomers) of the compounds of the general formula (I) according to the invention.
- the carbon atom bearing R 7 and A 1 -X is a chiral center, so that the compounds according to the invention are at least present as enantiomers.
- the present invention is intended to include both the individual enantiomers and racemates of these compounds.
- the compounds according to the invention have a remarkably high selectivity towards GAT-3 and / or GAT-1 and can accordingly be used for the treatment of disease states in which these transport proteins play a role. Epilepsy and Huntington's disease should be mentioned in this context.
- the compounds according to the invention and the precursors thereof can be prepared by conventional processes described in the literature or in analogy to such processes. Some of these methods are briefly outlined below. Individual isomers (enantiomers) can be prepared in addition to the usual separation (e.g. by racemate resolution) using processes that use chiral auxiliaries in the preparation. Examples of such methods are also briefly outlined below.
- Compound rac-3 is also accessible by catalytic hydrogenation of 4 with Pt-C as a catalyst according to the following procedure: Clemo, Melrose, J. Chem. Soc, 1942, 424
- the compound rac-9 can be synthesized from pyrrole-2-carbaldehyde 5 using the three-step procedure shown in Scheme 2.
- the condensation product 7 is obtained by reaction of 5 with 6 according to the procedure of Ch. Robinson, L. J. Wiseman, J. Leonhard, C. D. Slater, Tetrahedron, 1989, 45, 4103-4112. Subsequent catalytic hydrogenation, ester hydrolysis and decarboxylation according to the instructions of Clemo et al., J. Chem. Soc, 1950, 1140 leads to rac-9.
- N-substituted amino acids rac-12 can be synthesized analogously to known processes starting from the amino acid esters rac-10 by alkylation with a suitable electrophile and subsequent ester hydrolysis KE Andersen et al, J Med Chem 1993, 36, 1716-1725 TGM Dhar et al, J Med Chem 1994, 37, 2334-2342
- Melting points Melting point apparatus according to Dr. Tottoli (Büchi company, No. 512). The melting points were not corrected.
- Optical rotations Polarimeter 241 MC (from Perkin Elmer).
- IR spectra FT-IR spectrometer 1600 and Paragon 1000 (from Perkin Elmer). The spectra were recorded as KBr pellets or as a film between NaCl plates.
- NMR spectra JNMR-GX 400 (Jeol, 400 MHz), TMS as internal standard. The coupling constants were specified with an accuracy of 0.5 Hz. The spectra were post-processed with NUTS, 2D version 4.35, Acora NMR, 1994.
- Mass spectra Mass spectra: Mass Spectrometer 5989 A with 59980 B Particle Beam LC / MS Interface (Hewlett Packard).
- Analytical HPLC Chromatography pumps L-6200 Intelligent-Pump and L-6000 (Merck-Hitachi), UV-VIS detectors L-4000 and L-7400 (242 and 254 nm, Merck-Hitachi), integrators D -7500 and D-2500 (Merck-Hitachi), columns: LiChroCart ® cartridge system (Merck):
- LiChrospher ® Si 60 (5 ⁇ m, 250 x 4 mm with guard column 4 x 4 mm)
- LiChrosorb ® Si 60 (5 ⁇ m, 250 x 4 mm with guard column 4 4 mm).
- Reagents and Solvents All reagents were of commercial quality. Dried and distilled solvents were used for the reactions. For Chromatographic purposes were distilled solvents which were additionally degassed for HPLC.
- HCl gas was introduced into anhydrous CH 2 C1 2 (1 ml 0.1 mmol 14) over a period of 20 min. Then, with vigorous stirring, enamide 14, dissolved in CH 2 C1 2 (0.5 ml each 0.1 mmol), was slowly added dropwise. The introduction of gaseous HCl was not interrupted and continued for another 10-20 minutes. Excess HCl gas was then removed in a high vacuum at -78 ° for 1 h. A solution of the respective organometallic reagent was then added dropwise to the reaction mixture obtained. After the specified reaction time, hydrolysis (H 2 O) took place at -78 °. After separation of the Phases, the aqueous phase was extracted four times with CH 2 C1 2 , the organic phases with sat.
- Electrophilic amidoalkylation, general working instructions: 0.158 g (0.6 mmol) 14, 6.6 ml ( 4 eq.)
- the aqueous phase was i. Vak. concentrated and brought to dryness under high vacuum.
- N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters General procedure A: 179 mg (10 mmol) (S) -r> rxOlidin-2-ylacetic acid methyl ester hydrochloride (S-19-HC1, see preparation example 5), 16.6 mg (0.1 mmol) potassium iodide, 276 mg (2.0 mmol ) Potassium carbonate, 327 mg (1.0 mmol) 4,4-bis (3-methyl-2-thienyl) but-3-en-1-yl bromide. Response time: 46 h.
- the reaction mixture was aqueous in a two-phase system consisting of 10 ml dichloromethane, 15 ml water and 3.7 ml Poured potassium hydroxide solution.
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- Neurosurgery (AREA)
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- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
L'invention concerne des composés de la formule générale (I) dans laquelle R?1 à R7, A1, A2¿, X et Z ont la signification mentionnée dans la description. Ces composés s'utilisent comme inhibiteurs d'absorption de GABA pour traiter des affections telles que par exemple l'épilepsie.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19840611 | 1998-09-05 | ||
DE19840611A DE19840611A1 (de) | 1998-09-05 | 1998-09-05 | GABA-uptake-Inhibitoren mit Pyrrolidinstruktur |
PCT/EP1999/006486 WO2000014064A2 (fr) | 1998-09-05 | 1999-09-03 | Inhibiteurs d'absorption de gaba a structure pyrrolidinique |
Publications (1)
Publication Number | Publication Date |
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EP1109783A2 true EP1109783A2 (fr) | 2001-06-27 |
Family
ID=7879962
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP99968664A Withdrawn EP1109783A2 (fr) | 1998-09-05 | 1999-09-03 | Inhibiteurs d'absorption de gaba a structure pyrrolidinique |
Country Status (6)
Country | Link |
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EP (1) | EP1109783A2 (fr) |
JP (1) | JP2002524443A (fr) |
AU (1) | AU5972699A (fr) |
CA (1) | CA2343531A1 (fr) |
DE (1) | DE19840611A1 (fr) |
WO (1) | WO2000014064A2 (fr) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US7355042B2 (en) | 2001-10-16 | 2008-04-08 | Hypnion, Inc. | Treatment of CNS disorders using CNS target modulators |
JP2005529840A (ja) | 2001-10-16 | 2005-10-06 | ヒプニオン, インコーポレイテッド | Cns標的モジュレータを使用するcns障害の治療 |
US7189757B2 (en) | 2001-10-16 | 2007-03-13 | Hypnion, Inc. | Treatment of sleep disorders using CNS target modulators |
AU2008258599B2 (en) * | 2007-06-05 | 2013-06-13 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Disubstituted phenylpyrrolidines as modulators of cortical catecholaminergic neurotransmission |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4383999A (en) * | 1981-05-26 | 1983-05-17 | Smithkline Beckman Corporation | Inhibition of GABA uptake by N-substituted azaheterocyclic carboxylic acids and their esters |
US4514414A (en) * | 1982-10-25 | 1985-04-30 | Smithkline Beckman Corporation | N-Substituted pyrrolidineacetic acids and their esters |
GB8320704D0 (en) * | 1983-08-01 | 1983-09-01 | Wellcome Found | Chemotherapeutic agents |
US4610995A (en) * | 1984-07-27 | 1986-09-09 | Coker Geoffrey G | Certain 1,1-diaryl-propenyl-3-(1-pyrrolidino-2-carboxylic acids, derivatives thereof and their anti-histaminic properties |
DK704488D0 (da) * | 1988-12-19 | 1988-12-19 | Novo Industri As | Nye n-substituerede azaheterocykliske carboxylsyrer |
DK288385D0 (da) * | 1985-06-26 | 1985-06-26 | Novo Industri As | Aminosyrederivater |
US4910312A (en) * | 1985-11-08 | 1990-03-20 | Warner-Lambert Company | Various N-substituted 3-piperidine carboxylic acids or N-substituted 3-pyridinecarboxylic acids and derivatives thereof |
IL81179A (en) * | 1986-01-07 | 1992-02-16 | Novo Nordisk As | N-phenylbutenyl substituted azaheterocyclic carboxylic acids,their preparation and pharmaceutical compositions comprising them |
SK285854B6 (sk) * | 1996-05-31 | 2007-09-06 | Allelix Neuroscience Inc. | Substituovaný amín, spôsoby jeho prípravy a použitie, farmaceutický prostriedok a jeho použitie |
-
1998
- 1998-09-05 DE DE19840611A patent/DE19840611A1/de not_active Withdrawn
-
1999
- 1999-09-03 WO PCT/EP1999/006486 patent/WO2000014064A2/fr not_active Application Discontinuation
- 1999-09-03 CA CA002343531A patent/CA2343531A1/fr not_active Abandoned
- 1999-09-03 JP JP2000568823A patent/JP2002524443A/ja active Pending
- 1999-09-03 EP EP99968664A patent/EP1109783A2/fr not_active Withdrawn
- 1999-09-03 AU AU59726/99A patent/AU5972699A/en not_active Abandoned
Non-Patent Citations (1)
Title |
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See references of WO0014064A2 * |
Also Published As
Publication number | Publication date |
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AU5972699A (en) | 2000-03-27 |
JP2002524443A (ja) | 2002-08-06 |
DE19840611A1 (de) | 2000-03-09 |
CA2343531A1 (fr) | 2000-03-16 |
WO2000014064A2 (fr) | 2000-03-16 |
WO2000014064A3 (fr) | 2000-07-20 |
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