EP1212297A1 - Antikonvulsiv und anxiolytisch wirkende 4-amino-1-aryl-1,5-dihydro-pyrrol-2-one und verfahren zu deren darstellung - Google Patents
Antikonvulsiv und anxiolytisch wirkende 4-amino-1-aryl-1,5-dihydro-pyrrol-2-one und verfahren zu deren darstellungInfo
- Publication number
- EP1212297A1 EP1212297A1 EP00960584A EP00960584A EP1212297A1 EP 1212297 A1 EP1212297 A1 EP 1212297A1 EP 00960584 A EP00960584 A EP 00960584A EP 00960584 A EP00960584 A EP 00960584A EP 1212297 A1 EP1212297 A1 EP 1212297A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dihydro
- pyrrol
- morpholin
- chlorophenyl
- compounds
- 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- Withdrawn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
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 230000000949 anxiolytic effect Effects 0.000 title description 14
- 230000002082 anti-convulsion Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 230000036506 anxiety Effects 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 10
- 206010015037 epilepsy Diseases 0.000 claims abstract description 8
- CDCHBOQVXIGZHA-UHFFFAOYSA-N 1,2-dihydropyrrol-5-one Chemical class O=C1NCC=C1 CDCHBOQVXIGZHA-UHFFFAOYSA-N 0.000 claims abstract description 4
- -1 1 - (4-methylphenyl) -4-morpholin-4-yl-1,5-dihydro-pyrrol-2-one 1 - (4-methoxyphenyl) -4-morpholin-4-yl-1,5-dihydro-pyrrol-2-one Chemical compound 0.000 claims description 17
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- HMTBQDHXRQHMHW-UHFFFAOYSA-N N-(trifluoromethoxy)nitramide Chemical compound FC(ON[N+](=O)[O-])(F)F HMTBQDHXRQHMHW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 4
- IBZKBSXREAQDTO-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)ethanamine Chemical compound COCCNCCOC IBZKBSXREAQDTO-UHFFFAOYSA-N 0.000 claims description 4
- JEGMWWXJUXDNJN-UHFFFAOYSA-N 3-methylpiperidine Chemical compound CC1CCCNC1 JEGMWWXJUXDNJN-UHFFFAOYSA-N 0.000 claims description 4
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 150000003335 secondary amines Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- SDQKVAPWVWKYGD-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(4-methylpiperazin-1-yl)-2h-pyrrol-5-one Chemical compound C1CN(C)CCN1C1=CC(=O)N(C=2C=CC(Cl)=CC=2)C1 SDQKVAPWVWKYGD-UHFFFAOYSA-N 0.000 claims description 2
- FXRIPTJCOYTZIB-UHFFFAOYSA-N 3-morpholin-4-yl-1-phenyl-2h-pyrrol-5-one Chemical compound O=C1C=C(N2CCOCC2)CN1C1=CC=CC=C1 FXRIPTJCOYTZIB-UHFFFAOYSA-N 0.000 claims description 2
- NOKIMVBPEJRWFV-UHFFFAOYSA-N CC=1C=C(C=CC1)N1C(C=C(C1)N1CCCCC1)=O.N1(CCOCC1)C1=CC(N(C1)C1=CC(=C(C(=C1)OC)OC)OC)=O Chemical compound CC=1C=C(C=CC1)N1C(C=C(C1)N1CCCCC1)=O.N1(CCOCC1)C1=CC(N(C1)C1=CC(=C(C(=C1)OC)OC)OC)=O NOKIMVBPEJRWFV-UHFFFAOYSA-N 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- NNWUEBIEOFQMSS-UHFFFAOYSA-N 2-Methylpiperidine Chemical compound CC1CCCCN1 NNWUEBIEOFQMSS-UHFFFAOYSA-N 0.000 claims 3
- 239000000969 carrier Substances 0.000 claims 3
- 150000002431 hydrogen Chemical group 0.000 claims 3
- 239000013543 active substance Substances 0.000 claims 2
- NBUDIYRXADSNQC-UHFFFAOYSA-N CC=1C=C(C=CC1)N1C(C=C(C1)N1CCOCC1)=O.ClC1=C(C=CC=C1)N1C(C=C(C1)N1CCOCC1)=O Chemical compound CC=1C=C(C=CC1)N1C(C=C(C1)N1CCOCC1)=O.ClC1=C(C=CC=C1)N1C(C=C(C1)N1CCOCC1)=O NBUDIYRXADSNQC-UHFFFAOYSA-N 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 230000001037 epileptic effect Effects 0.000 claims 1
- 150000005840 aryl radicals Chemical group 0.000 abstract description 3
- 230000000694 effects Effects 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000001961 anticonvulsive agent Substances 0.000 description 6
- 239000002249 anxiolytic agent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 230000001773 anti-convulsant effect Effects 0.000 description 5
- 229960003529 diazepam Drugs 0.000 description 5
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 5
- 206010010904 Convulsion Diseases 0.000 description 4
- 206010039897 Sedation Diseases 0.000 description 4
- 229960003965 antiepileptics Drugs 0.000 description 4
- 229960003120 clonazepam Drugs 0.000 description 4
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 4
- 230000036280 sedation Effects 0.000 description 4
- ZLPPCUPQEDUKOC-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-morpholin-4-yl-2h-pyrrol-5-one Chemical compound C1=CC(Cl)=CC=C1N1C(=O)C=C(N2CCOCC2)C1 ZLPPCUPQEDUKOC-UHFFFAOYSA-N 0.000 description 3
- YLCXGBZIZBEVPZ-UHFFFAOYSA-N Medazepam Chemical compound C12=CC(Cl)=CC=C2N(C)CCN=C1C1=CC=CC=C1 YLCXGBZIZBEVPZ-UHFFFAOYSA-N 0.000 description 3
- 206010029350 Neurotoxicity Diseases 0.000 description 3
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 3
- 206010041349 Somnolence Diseases 0.000 description 3
- 206010044221 Toxic encephalopathy Diseases 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229960002225 medazepam Drugs 0.000 description 3
- 230000007135 neurotoxicity Effects 0.000 description 3
- 231100000228 neurotoxicity Toxicity 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 230000000049 anti-anxiety effect Effects 0.000 description 2
- 229940005530 anxiolytics Drugs 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 230000000147 hypnotic effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FTVVILFRDAMPAR-UHFFFAOYSA-N 1-(2-chlorophenyl)-3-morpholin-4-yl-2h-pyrrol-5-one Chemical compound ClC1=CC=CC=C1N1C(=O)C=C(N2CCOCC2)C1 FTVVILFRDAMPAR-UHFFFAOYSA-N 0.000 description 1
- ILARYGJCEKCIOV-UHFFFAOYSA-N 1-(3-chloro-4-fluorophenyl)-3-morpholin-4-yl-2h-pyrrol-5-one Chemical compound C1=C(Cl)C(F)=CC=C1N1C(=O)C=C(N2CCOCC2)C1 ILARYGJCEKCIOV-UHFFFAOYSA-N 0.000 description 1
- VYWZATAVUHDGOH-UHFFFAOYSA-N 1-(3-methylphenyl)-3-morpholin-4-yl-2h-pyrrol-5-one Chemical compound CC1=CC=CC(N2C(C=C(C2)N2CCOCC2)=O)=C1 VYWZATAVUHDGOH-UHFFFAOYSA-N 0.000 description 1
- TYVZJWFQOCUCAM-UHFFFAOYSA-N 1-(4-bromophenyl)-3-morpholin-4-yl-2h-pyrrol-5-one Chemical compound C1=CC(Br)=CC=C1N1C(=O)C=C(N2CCOCC2)C1 TYVZJWFQOCUCAM-UHFFFAOYSA-N 0.000 description 1
- HJPYJROZESUUDH-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(2-methylpiperidin-1-yl)-2h-pyrrol-5-one Chemical compound CC1CCCCN1C1=CC(=O)N(C=2C=CC(Cl)=CC=2)C1 HJPYJROZESUUDH-UHFFFAOYSA-N 0.000 description 1
- PJCXZMSGDVIJCF-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(3-methylpiperidin-1-yl)-2h-pyrrol-5-one Chemical compound C1C(C)CCCN1C1=CC(=O)N(C=2C=CC(Cl)=CC=2)C1 PJCXZMSGDVIJCF-UHFFFAOYSA-N 0.000 description 1
- POCLLOIZQYRHBA-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(diethylamino)-2h-pyrrol-5-one Chemical compound C1C(N(CC)CC)=CC(=O)N1C1=CC=C(Cl)C=C1 POCLLOIZQYRHBA-UHFFFAOYSA-N 0.000 description 1
- LWDCLBDXJCPUNW-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-piperidin-1-yl-2h-pyrrol-5-one Chemical compound C1=CC(Cl)=CC=C1N1C(=O)C=C(N2CCCCC2)C1 LWDCLBDXJCPUNW-UHFFFAOYSA-N 0.000 description 1
- VQQWCAINZIGPJI-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-pyrrolidin-1-yl-2h-pyrrol-5-one Chemical compound C1=CC(Cl)=CC=C1N1C(=O)C=C(N2CCCC2)C1 VQQWCAINZIGPJI-UHFFFAOYSA-N 0.000 description 1
- HRCSHSWVTUBRKM-UHFFFAOYSA-N 1-(4-fluorophenyl)-3-morpholin-4-yl-2h-pyrrol-5-one Chemical compound C1=CC(F)=CC=C1N1C(=O)C=C(N2CCOCC2)C1 HRCSHSWVTUBRKM-UHFFFAOYSA-N 0.000 description 1
- VIGOIAXIOFDLKJ-UHFFFAOYSA-N 1-(4-fluorophenyl)-3-piperidin-1-yl-2h-pyrrol-5-one Chemical compound C1=CC(F)=CC=C1N1C(=O)C=C(N2CCCCC2)C1 VIGOIAXIOFDLKJ-UHFFFAOYSA-N 0.000 description 1
- DCRDGADGYHKWLG-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-morpholin-4-yl-2h-pyrrol-5-one Chemical compound C1=CC(OC)=CC=C1N1C(=O)C=C(N2CCOCC2)C1 DCRDGADGYHKWLG-UHFFFAOYSA-N 0.000 description 1
- LSZNUSGRHIZUKK-UHFFFAOYSA-N 1-(4-methylphenyl)-3-morpholin-4-yl-2h-pyrrol-5-one Chemical compound C1=CC(C)=CC=C1N1C(=O)C=C(N2CCOCC2)C1 LSZNUSGRHIZUKK-UHFFFAOYSA-N 0.000 description 1
- FVRMTEYTZBSKAH-UHFFFAOYSA-N 1-(4-methylphenyl)-3-piperidin-1-yl-2h-pyrrol-5-one Chemical compound C1=CC(C)=CC=C1N1C(=O)C=C(N2CCCCC2)C1 FVRMTEYTZBSKAH-UHFFFAOYSA-N 0.000 description 1
- PWMWNFMRSKOCEY-UHFFFAOYSA-N 1-Phenyl-1,2-ethanediol Chemical class OCC(O)C1=CC=CC=C1 PWMWNFMRSKOCEY-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- NISOBBBVBWJEAQ-UHFFFAOYSA-N 3-[bis(2-methoxyethyl)amino]-1-(4-chlorophenyl)-2h-pyrrol-5-one Chemical compound C1C(N(CCOC)CCOC)=CC(=O)N1C1=CC=C(Cl)C=C1 NISOBBBVBWJEAQ-UHFFFAOYSA-N 0.000 description 1
- WTYYLYOKLMVCDC-UHFFFAOYSA-N 3-ethoxy-1-phenyl-2h-pyrrol-5-one Chemical class C1C(OCC)=CC(=O)N1C1=CC=CC=C1 WTYYLYOKLMVCDC-UHFFFAOYSA-N 0.000 description 1
- ZGLMVAFYAPQAPL-UHFFFAOYSA-N 3-morpholin-4-yl-1-[4-(trifluoromethoxy)phenyl]-2h-pyrrol-5-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C=C(N2CCOCC2)C1 ZGLMVAFYAPQAPL-UHFFFAOYSA-N 0.000 description 1
- JVQKOXLDZKEKCO-UHFFFAOYSA-N 3-morpholin-4-yl-1-[4-(trifluoromethyl)phenyl]-2h-pyrrol-5-one Chemical compound C1=CC(C(F)(F)F)=CC=C1N1C(=O)C=C(N2CCOCC2)C1 JVQKOXLDZKEKCO-UHFFFAOYSA-N 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 206010019133 Hangover Diseases 0.000 description 1
- 208000029808 Psychomotor disease Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
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- 210000004556 brain Anatomy 0.000 description 1
- 230000001914 calming effect Effects 0.000 description 1
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- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
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- 208000028329 epileptic seizure Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 125000003630 glycyl group Chemical class [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
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- 238000005192 partition Methods 0.000 description 1
- 229960005152 pentetrazol Drugs 0.000 description 1
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- 230000002035 prolonged effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
Definitions
- the invention relates to 1,5-dihydro-pyrrol-2-ones which contain a secondary amine radical in the 4-position and an aryl radical in the 1-position, processes for their preparation and their use as medicaments, especially for the treatment of Epilepsy of various forms and for the treatment of anxiety and tension
- Epilepsy is behavioral changes in the form of convulsions. The reason is short-term, extremely strong neuronal discharges of the brain. Overall, about 5% of all people experience an epileptic seizure in their life, 1% suffer from epilepsy
- the invention is therefore based on the object of providing compounds with favorable pharmacological properties which can be used as medicaments, in particular for the treatment of epilepsy.
- Sedation can negatively influence mental processes. In some cases, ataxia and coordination disorders can be observed, which affect performance.
- diazepam The most important representatives of the anxiolytics launched on the market are the active ingredients diazepam, clonazepam and medazepam.
- plasma concentrations 300 to 400 mg / ml are necessary.
- the side effects mentioned such as sedation and psychomotor disorders, also occur, which manifest themselves in day sedation, sleepiness, as well as limited attention and responsiveness.
- Due to the high half-life of diazepam and clonazepam there are strong "hang-over" effects, which are also associated with drowsiness, deterioration in intellectual and motor performance and longer reaction times.
- the anxiolytic effect of clonazepam is dependent on the sedative or hypnotic effect High doses of medazepam are also associated with hypnotic, muscle-relaxing effects.
- a further object of the present invention is therefore to provide medicaments for the treatment of different anxiety and tension states which have a wide therapeutic range.
- X hydrogen, halogen, -CC 4 alkyl, dC alkoxy, trifluoromethyl or trifluoromethoxy, nitro, amine;
- Y secondary amine, e.g. B. morpholine, piperidine, 2-
- Methylpiperidine, 3-methylpiperidine, 4-methylpiperidine, pyrrolidine, 4-methylpiperazine, azepam, diethylamino, bis (methoxyethyl) amine and; m 1 to 3 mean.
- Trifluoromethoxy, nitro, amine; m 1 to 3 mean.
- compounds of general formula 3 can be condensed with the corresponding amines.
- Trifluoromethoxy, nitro, amine; m 1 to 3 mean.
- the compounds according to the invention are suitable for the production of pharmaceutical compositions.
- the pharmaceutical compositions contain at least one of the compounds of the general formula 1.
- the medicaments can, for example, be administered parenterally (for example intravenously, intramuscularly subcutaneously) or orally.
- the application forms can be prepared by methods which are generally known and customary in pharmaceutical practice, customary pharmaceutical carriers and auxiliaries being used.
- the compounds according to the invention have strong pharmacological effects.
- the compounds of the invention were in vivo after i.p. -Application to mice or rats (po application) according to the international standard (Pharmac.Weekblad, Sc.Ed. 14, 132 (1992) and Antiepileptic Drugs, Third. Ed., Raven Press, New York 1989) on their anticonvulsant Effect tested (Table 1).
- the ED 5 o (po) was 19 mg / kg in the rat in maximum electroshock , in the pentetrazole cramp model the ED 5 o (po) at 11 mg / kg and for the neurotoxicity the NT 50 > 500 mg / kg.
- the aim of the investigations with compounds of the general formula 1 is to estimate the possible influence in models for examining the effect against anxiety states.
- the animals were exposed to different conflict situations and an influence, for example by the compound 1 - (4-chlorophenyl) -4-morpholin-4-yl-1, 5-dihydro-pyrrol-2-one (example 4), was measured.
- Avoidance reactions occur which can be suppressed by substances with an anxiolytic effect.
- the number of tolerated current surges of the animals treated with the substance compared to the vehicle-treated control group is assessed as a measure of the anxiolytic effect.
- Equieffective doses of diazepam and clonazepam are 1 to 3 mg / kg po.o. and 1 mg / kg p.o.
- mice are placed in an elevated gait system with open and closed arms (Pellow, S., Chopin, P., File SE, Briley, M .: Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in rats. J. of Neuroscience Methods 14: 149-167, 1985; Hogg, S .: A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacology Biochemistry and Behavior: 21- 30, 1996). Untreated animals are increasingly striving towards the closed corridors. Anxiety inhibition is measured by the length of stay in the open arms as a percentage of the total length of stay. Treatments with the compounds of the general formula 1 increase the length of stay in the open arms as a percentage, as can be seen from Table 3.
- Formula 1 has a significantly wider therapeutic range.
- the therapeutic index for compound 4 is> 50.
- the therapeutic index of diazepam in bird conflict test 13 serves to further illustrate the invention without restricting it.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19944332 | 1999-09-16 | ||
| DE19944332A DE19944332A1 (de) | 1999-09-16 | 1999-09-16 | Antikonvulsiv und anxiolytisch wirkende 4-Amino-1-aryl-1,5-dihydro-pyrrol-2-one und Verfahren zu deren Herstellung |
| PCT/EP2000/008572 WO2001019793A1 (de) | 1999-09-16 | 2000-09-02 | Antikonvulsiv und anxiolytisch wirkende 4-amino-1-aryl-1,5-dihydro-pyrrol-2-one und verfahren zu deren darstellung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1212297A1 true EP1212297A1 (de) | 2002-06-12 |
Family
ID=7922190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00960584A Withdrawn EP1212297A1 (de) | 1999-09-16 | 2000-09-02 | Antikonvulsiv und anxiolytisch wirkende 4-amino-1-aryl-1,5-dihydro-pyrrol-2-one und verfahren zu deren darstellung |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US6500821B1 (pt) |
| EP (1) | EP1212297A1 (pt) |
| JP (1) | JP2003509407A (pt) |
| KR (1) | KR20020027657A (pt) |
| CN (1) | CN1374948A (pt) |
| AR (1) | AR025700A1 (pt) |
| AU (1) | AU7283000A (pt) |
| BG (1) | BG106437A (pt) |
| BR (1) | BR0013961A (pt) |
| CA (1) | CA2317257A1 (pt) |
| CZ (1) | CZ2002915A3 (pt) |
| DE (1) | DE19944332A1 (pt) |
| EE (1) | EE200200137A (pt) |
| HU (1) | HUP0202607A3 (pt) |
| IL (1) | IL147808A0 (pt) |
| MX (1) | MXPA02001370A (pt) |
| NO (1) | NO20021143L (pt) |
| SK (1) | SK3782002A3 (pt) |
| TR (1) | TR200200678T2 (pt) |
| WO (1) | WO2001019793A1 (pt) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106008304B (zh) * | 2016-05-18 | 2018-07-17 | 湖北科技学院 | 一种1,3-二氢吡咯-2-酮类化合物及其合成方法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH543504A (de) * | 1971-03-25 | 1973-10-31 | Lonza Ag | Verfahren zur Herstellung 1-substituierter 4-Aminopyrrolin-3-one-(2) |
| US4511568A (en) | 1982-05-12 | 1985-04-16 | Ici Americas Inc. | CNS-Depressant pyrazolopyridines |
-
1999
- 1999-09-16 DE DE19944332A patent/DE19944332A1/de not_active Withdrawn
-
2000
- 2000-08-30 CA CA002317257A patent/CA2317257A1/en not_active Abandoned
- 2000-08-31 US US09/652,488 patent/US6500821B1/en not_active Expired - Fee Related
- 2000-09-02 JP JP2001523373A patent/JP2003509407A/ja active Pending
- 2000-09-02 MX MXPA02001370A patent/MXPA02001370A/es unknown
- 2000-09-02 AU AU72830/00A patent/AU7283000A/en not_active Abandoned
- 2000-09-02 HU HU0202607A patent/HUP0202607A3/hu unknown
- 2000-09-02 EP EP00960584A patent/EP1212297A1/de not_active Withdrawn
- 2000-09-02 SK SK378-2002A patent/SK3782002A3/sk unknown
- 2000-09-02 IL IL14780800A patent/IL147808A0/xx unknown
- 2000-09-02 BR BR0013961-0A patent/BR0013961A/pt not_active Application Discontinuation
- 2000-09-02 EE EEP200200137A patent/EE200200137A/xx unknown
- 2000-09-02 CZ CZ2002915A patent/CZ2002915A3/cs unknown
- 2000-09-02 WO PCT/EP2000/008572 patent/WO2001019793A1/de not_active Application Discontinuation
- 2000-09-02 KR KR1020027003491A patent/KR20020027657A/ko not_active Application Discontinuation
- 2000-09-02 CN CN00812985A patent/CN1374948A/zh active Pending
- 2000-09-02 TR TR2002/00678T patent/TR200200678T2/xx unknown
- 2000-09-15 AR ARP000104877A patent/AR025700A1/es unknown
-
2002
- 2002-02-26 BG BG06437A patent/BG106437A/bg unknown
- 2002-03-07 NO NO20021143A patent/NO20021143L/no unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO0119793A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0202607A3 (en) | 2003-05-28 |
| AR025700A1 (es) | 2002-12-11 |
| CA2317257A1 (en) | 2001-03-16 |
| CZ2002915A3 (cs) | 2002-06-12 |
| DE19944332A1 (de) | 2001-03-22 |
| NO20021143D0 (no) | 2002-03-07 |
| US6500821B1 (en) | 2002-12-31 |
| BR0013961A (pt) | 2002-05-21 |
| AU7283000A (en) | 2001-04-17 |
| BG106437A (bg) | 2002-09-30 |
| WO2001019793A1 (de) | 2001-03-22 |
| SK3782002A3 (en) | 2002-07-02 |
| HUP0202607A2 (hu) | 2002-12-28 |
| NO20021143L (no) | 2002-03-07 |
| EE200200137A (et) | 2003-04-15 |
| IL147808A0 (en) | 2002-08-14 |
| TR200200678T2 (tr) | 2002-07-22 |
| JP2003509407A (ja) | 2003-03-11 |
| CN1374948A (zh) | 2002-10-16 |
| KR20020027657A (ko) | 2002-04-13 |
| MXPA02001370A (es) | 2004-09-10 |
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