DK168094B1 - Analogifremgangsmaade til fremstilling af imidazodiazepin-derivater eller syreadditionssalte deraf samt mellemprodukter til anvendelse ved fremgangsmaaden - Google Patents
Analogifremgangsmaade til fremstilling af imidazodiazepin-derivater eller syreadditionssalte deraf samt mellemprodukter til anvendelse ved fremgangsmaaden Download PDFInfo
- Publication number
- DK168094B1 DK168094B1 DK391280A DK391280A DK168094B1 DK 168094 B1 DK168094 B1 DK 168094B1 DK 391280 A DK391280 A DK 391280A DK 391280 A DK391280 A DK 391280A DK 168094 B1 DK168094 B1 DK 168094B1
- Authority
- DK
- Denmark
- Prior art keywords
- general formula
- methyl
- ethyl
- group
- benzodiazepine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 48
- 239000002253 acid Substances 0.000 title claims description 17
- 239000000543 intermediate Substances 0.000 title claims description 11
- BMGXAZCDDYTVFV-UHFFFAOYSA-N imidazo[4,5-c]diazepine Chemical class C1=CN=NC2=NC=NC2=C1 BMGXAZCDDYTVFV-UHFFFAOYSA-N 0.000 title claims 2
- 150000001875 compounds Chemical class 0.000 claims description 155
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 67
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- -1 isocyanoacetic acid ester Chemical class 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
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- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
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- 229910052736 halogen Inorganic materials 0.000 claims description 8
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- MZHUTGQZAZLFKW-UHFFFAOYSA-N 1H-1,2-benzodiazepine-3-carboxylic acid Chemical compound C1=CC(C(=O)O)=NNC2=CC=CC=C21 MZHUTGQZAZLFKW-UHFFFAOYSA-N 0.000 claims description 5
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- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
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- 238000003756 stirring Methods 0.000 description 31
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- 239000011591 potassium Substances 0.000 description 28
- 229910052700 potassium Inorganic materials 0.000 description 28
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- 238000010992 reflux Methods 0.000 description 25
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- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 21
- FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- HZABUXCSZMLBHU-UHFFFAOYSA-N 1H-1,4-benzodiazepine-3-carboxylic acid Chemical compound C1=NC(C(=O)O)=CNC2=CC=CC=C21 HZABUXCSZMLBHU-UHFFFAOYSA-N 0.000 description 20
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
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- 230000036407 pain Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
- 235000021395 porridge Nutrition 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
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- 239000003755 preservative agent Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- AFAGUKXLJLMNSO-UHFFFAOYSA-N propan-2-yl 5-methyl-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N(C)C(=O)C2=CC=CC=C2N2C=NC(C(=O)OC(C)C)=C21 AFAGUKXLJLMNSO-UHFFFAOYSA-N 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940018038 sodium carbonate decahydrate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
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- 230000009870 specific binding Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- 239000012258 stirred mixture Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
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- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
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- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- GKTQKQTXHNUFSP-UHFFFAOYSA-N thieno[3,4-c]pyrrole-4,6-dione Chemical compound S1C=C2C(=O)NC(=O)C2=C1 GKTQKQTXHNUFSP-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003571 thiolactams Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
- C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/42—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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 with nitro or nitroso radicals directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Toxicology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH897279 | 1979-10-04 | ||
| CH897179 | 1979-10-04 | ||
| CH897179 | 1979-10-04 | ||
| CH897279 | 1979-10-04 | ||
| CH1066579 | 1979-11-30 | ||
| CH1066579 | 1979-11-30 | ||
| CH1066479 | 1979-11-30 | ||
| CH1066479 | 1979-11-30 | ||
| CH571680 | 1980-07-25 | ||
| CH571680 | 1980-07-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK391280A DK391280A (da) | 1981-04-05 |
| DK168094B1 true DK168094B1 (da) | 1994-02-07 |
Family
ID=27509256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK391280A DK168094B1 (da) | 1979-10-04 | 1980-09-15 | Analogifremgangsmaade til fremstilling af imidazodiazepin-derivater eller syreadditionssalte deraf samt mellemprodukter til anvendelse ved fremgangsmaaden |
Country Status (23)
| Country | Link |
|---|---|
| US (10) | US4316839A (enExample) |
| EP (1) | EP0027214B1 (enExample) |
| JP (1) | JPH01156968A (enExample) |
| AR (1) | AR227293A1 (enExample) |
| AU (1) | AU533641B2 (enExample) |
| BR (1) | BR8006404A (enExample) |
| CA (1) | CA1143728A (enExample) |
| DE (1) | DE3067868D1 (enExample) |
| DK (1) | DK168094B1 (enExample) |
| FI (1) | FI73683C (enExample) |
| GB (1) | GB2060632B (enExample) |
| GR (1) | GR70772B (enExample) |
| HU (1) | HU182675B (enExample) |
| IE (1) | IE50318B1 (enExample) |
| IL (1) | IL61160A (enExample) |
| LU (1) | LU88298I2 (enExample) |
| MC (1) | MC1355A1 (enExample) |
| NL (1) | NL930056I2 (enExample) |
| NO (1) | NO155774C (enExample) |
| NZ (1) | NZ195071A (enExample) |
| PH (1) | PH16607A (enExample) |
| PT (1) | PT71874B (enExample) |
| ZW (1) | ZW21580A1 (enExample) |
Families Citing this family (55)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1143728A (en) * | 1979-10-04 | 1983-03-29 | Max Gerecke | Imidazodiazepine derivatives |
| CA1174673A (en) * | 1981-02-27 | 1984-09-18 | Walter Hunkeler | Imidazodiazepines |
| CA1184175A (en) * | 1981-02-27 | 1985-03-19 | Walter Hunkeler | Imidazodiazepines |
| US4352817A (en) * | 1981-02-27 | 1982-10-05 | Hoffmann-La Roche Inc. | Imidazo-diazepines and their use |
| CA1173441A (en) * | 1981-02-27 | 1984-08-28 | Hoffmann-La Roche Limited | Imidazodiazepines |
| CA1185602A (en) * | 1981-02-27 | 1985-04-16 | Emilio Kyburz | Imidazodiazepines |
| MC1528A1 (fr) * | 1982-07-21 | 1984-04-13 | Hoffmann La Roche | Imidazobenzodiazepines |
| DK151808C (da) * | 1982-11-16 | 1988-06-20 | Ferrosan As | Analogifremgangsmaade til fremstilling af oxadiazolylimidazo-oe1,4aa-benzodiazepinderivater |
| US4723003A (en) * | 1983-05-18 | 1988-02-02 | Hoechst-Roussel Pharmaceuticals Inc. | Benzopyrrolobenzodiazepines and quinobenzodiazepines |
| CS249146B2 (en) * | 1984-01-19 | 1987-03-12 | Hoffmann La Roche | Method of new imidazodiazepine's derivatives production |
| AU587802B2 (en) * | 1985-03-08 | 1989-08-31 | Ferrosan A/S | Novel oxadiazolyl imidazobenzodiazepine derivatives and methods of preparing such compounds |
| US4622321A (en) * | 1985-05-17 | 1986-11-11 | As Ferrosan | Oxadiazolylimidazobenzodiazepine, compositions, and method |
| US4745112A (en) * | 1985-05-17 | 1988-05-17 | A/S Ferrosan | Oxadiazolylimidazobenzodiazepine, compositions, and method III |
| DK174086D0 (da) * | 1986-04-16 | 1986-04-16 | Ferrosan As | Nye benzodiazepinderivater samt fremgangsmaade til fremstilling af samme |
| FI880814A7 (fi) * | 1987-03-10 | 1988-09-11 | Hoffmann La Roche | Imidazodiazepin-derivat. |
| GB8720414D0 (en) * | 1987-08-28 | 1987-10-07 | Roussel Lab Ltd | Chemical compounds |
| US5096695A (en) * | 1988-08-05 | 1992-03-17 | Hoffmann-Laroche Inc. | Radioiodine benzodiazepines as brain imaging agents |
| CA1318668C (en) * | 1988-08-05 | 1993-06-01 | Heinz Carmann | Radioiodine benzodiazepine derivatives |
| CA1327572C (en) * | 1988-08-31 | 1994-03-08 | F. Hoffmann-La Roche Ag | Imidazodiazepine derivatives |
| GB8909700D0 (en) * | 1989-04-27 | 1989-06-14 | Roussel Lab Ltd | Chemical compounds |
| CA2015336A1 (en) * | 1989-05-19 | 1990-11-19 | F. Hoffmann-La Roche Ag | Imidazodiazepines for the treatment of neurological symptoms |
| FR2660310B1 (fr) * | 1990-03-27 | 1992-06-05 | Adir | Nouveaux derives de la 4h-pyrrolo[1,2a] thieno[2,3-f] diazepine[1,4], leur procede de preparation et les compositions pharmaceutiques les renfermant. |
| US5276028A (en) * | 1990-06-22 | 1994-01-04 | Nordisk A/S | Imidazoquinoxaline compounds |
| US5371080A (en) * | 1990-06-22 | 1994-12-06 | Novo Nordisk A/S | Imidazoquinazoline compounds and their use |
| TW201311B (enExample) * | 1991-06-17 | 1993-03-01 | Hoffmann La Roche | |
| US5565449A (en) * | 1991-10-18 | 1996-10-15 | Genentech, Inc. | Nonpeptidyl integrin inhibitors having specificity for the GPIIb IIIa receptor |
| US5250679A (en) * | 1991-10-18 | 1993-10-05 | Genentech, Inc. | Nonpeptidyl platelet aggregation inhibitors having specificity for the GPIIb III.sub. receptor |
| US5438035A (en) * | 1994-06-24 | 1995-08-01 | American Cyanamid Company | Methods for controlling undesirable plant species with benzodiazepine compounds |
| TW349100B (en) * | 1994-11-11 | 1999-01-01 | Hoffmann La Roche | Oxazolyl- and thiazolylimidazo-benzo- and thienodiazepines |
| US5670640A (en) | 1996-02-02 | 1997-09-23 | Hoffmann-La Roche Inc. | Process for the manufacture of imidazodiazepine derivatives |
| GB2328940B (en) * | 1997-09-05 | 1999-12-08 | Dong Kook Pharm Co Ltd | A process for preparing benzodiazepine derivatives |
| PT1691811E (pt) | 2003-12-11 | 2014-10-30 | Sunovion Pharmaceuticals Inc | Combinação de um sedativo e de um modulador de neurotransmissores e métodos para melhorar a qualidade do sono e tratamento da depressão |
| ATE402707T1 (de) | 2004-10-12 | 2008-08-15 | Hoffmann La Roche | Imidazoä1,5aütriazoloä1,5dübenzodiazepin- derivative zur behandlung kognitiver störungen |
| RU2007114763A (ru) | 2004-10-20 | 2008-11-27 | Ф.Хоффманн-Ля Рош Аг (Ch) | Галогенозамещенные производные бензодиазепинов |
| NZ554439A (en) | 2004-10-20 | 2009-09-25 | Hoffmann La Roche | Imidazo-benzodiazepine derivatives |
| WO2006063708A1 (en) | 2004-12-14 | 2006-06-22 | F.Hoffmann-La Roche Ag | Tetracyclic imidazo-benzodiazepines as gaba receptors modulators |
| US7595395B2 (en) * | 2005-05-16 | 2009-09-29 | Wisys Technology Foundation | Gabaergic agents to treat memory deficits |
| EP2258357A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
| EP2275096A3 (en) | 2005-08-26 | 2011-07-13 | Braincells, Inc. | Neurogenesis via modulation of the muscarinic receptors |
| WO2007047978A2 (en) | 2005-10-21 | 2007-04-26 | Braincells, Inc. | Modulation of neurogenesis by pde inhibition |
| EP2314289A1 (en) | 2005-10-31 | 2011-04-27 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
| US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| CA2643199A1 (en) * | 2006-03-08 | 2007-09-13 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| US7678808B2 (en) | 2006-05-09 | 2010-03-16 | Braincells, Inc. | 5 HT receptor mediated neurogenesis |
| US20100009983A1 (en) * | 2006-05-09 | 2010-01-14 | Braincells, Inc. | 5 ht receptor mediated neurogenesis |
| EP2021000A2 (en) | 2006-05-09 | 2009-02-11 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
| WO2008030651A1 (en) * | 2006-09-08 | 2008-03-13 | Braincells, Inc. | Combinations containing a 4-acylaminopyridine derivative |
| EP2066355A2 (en) * | 2006-09-19 | 2009-06-10 | Braincells, Inc. | Combination comprising a peroxisome proliferator activated receptor agent and a second neurogenic agent for treating a nervous system disorder, increasing neurodifferentiation and increasing neurogenesis |
| CN101827597B (zh) * | 2007-08-20 | 2013-03-13 | 伊沃泰克国际有限责任公司 | 睡眠障碍的治疗 |
| US20090054412A1 (en) * | 2007-08-20 | 2009-02-26 | John Alan Kemp | Treatment of Sleep Disorders |
| US20090270373A1 (en) * | 2008-04-11 | 2009-10-29 | Cypress Biosciences, Inc. | Treatment of down syndrom with benzodiazepine receptor antagonists |
| US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
| GB0917612D0 (en) * | 2009-10-08 | 2009-11-25 | Ge Healthcare Ltd | In vivo imaging agents |
| AU2012221704B2 (en) | 2011-02-23 | 2013-12-05 | Coeruleus Ltd. | Flumazenil complexes, compositions comprising same and uses thereof |
| CN102267999B (zh) * | 2011-07-15 | 2013-05-29 | 海南美兰史克制药有限公司 | 一种氟马西尼化合物及其制法 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3933794A (en) * | 1971-08-04 | 1976-01-20 | The Upjohn Company | 2-(2-Alkynylamino)-3H-1,4-benzodiazepines |
| US4002610A (en) * | 1975-09-22 | 1977-01-11 | Mcneil Laboratories, Incorporated | 2-Aminobenzodiazepine-5-ones |
| US4031079A (en) * | 1975-09-22 | 1977-06-21 | Mcneil Laboratories, Incorporated | Intermediates for 2-aminobenzodiazepine-5-ones |
| US4118386A (en) * | 1977-04-04 | 1978-10-03 | Hoffmann-La Roche Inc. | Synthesis of imidazo[1,5-a]diazepine-3-carboxylates |
| ZA806016B (en) * | 1979-10-04 | 1981-09-30 | Hoffmann La Roche | Imidazodiazepine derivatives |
| CA1143728A (en) * | 1979-10-04 | 1983-03-29 | Max Gerecke | Imidazodiazepine derivatives |
| JPH089074B2 (ja) * | 1987-07-02 | 1996-01-31 | 株式会社アマダ | タレツトパンチプレス |
-
1980
- 1980-09-10 CA CA000360028A patent/CA1143728A/en not_active Expired
- 1980-09-15 DK DK391280A patent/DK168094B1/da not_active IP Right Cessation
- 1980-09-19 ZW ZW215/80A patent/ZW21580A1/xx unknown
- 1980-09-26 NZ NZ195071A patent/NZ195071A/en unknown
- 1980-09-29 AU AU62782/80A patent/AU533641B2/en not_active Expired
- 1980-09-29 IL IL61160A patent/IL61160A/xx not_active IP Right Cessation
- 1980-09-30 PH PH24651A patent/PH16607A/en unknown
- 1980-10-01 HU HU802390A patent/HU182675B/hu unknown
- 1980-10-02 FI FI803135A patent/FI73683C/fi not_active IP Right Cessation
- 1980-10-02 MC MC801474A patent/MC1355A1/fr unknown
- 1980-10-02 DE DE8080105970T patent/DE3067868D1/de not_active Expired
- 1980-10-02 EP EP80105970A patent/EP0027214B1/de not_active Expired
- 1980-10-02 GR GR63031A patent/GR70772B/el unknown
- 1980-10-03 US US06/193,775 patent/US4316839A/en not_active Expired - Lifetime
- 1980-10-03 GB GB8031902A patent/GB2060632B/en not_active Expired
- 1980-10-03 BR BR8006404A patent/BR8006404A/pt unknown
- 1980-10-03 NO NO802946A patent/NO155774C/no unknown
- 1980-10-03 PT PT71874A patent/PT71874B/pt unknown
- 1980-10-03 AR AR282769A patent/AR227293A1/es active
- 1980-10-03 IE IE2056/80A patent/IE50318B1/en not_active IP Right Cessation
-
1981
- 1981-11-16 US US06/321,492 patent/US4346031A/en not_active Expired - Lifetime
- 1981-11-16 US US06/322,031 patent/US4346035A/en not_active Expired - Lifetime
- 1981-11-16 US US06/321,491 patent/US4346030A/en not_active Expired - Lifetime
- 1981-11-16 US US06/321,941 patent/US4346034A/en not_active Expired - Lifetime
- 1981-11-16 US US06/322,091 patent/US4363762A/en not_active Expired - Lifetime
- 1981-11-16 US US06/322,113 patent/US4346036A/en not_active Expired - Lifetime
- 1981-11-16 US US06/321,942 patent/US4359420A/en not_active Expired - Lifetime
- 1981-11-16 US US06/321,821 patent/US4346033A/en not_active Expired - Lifetime
- 1981-11-16 US US06/321,519 patent/US4346032A/en not_active Expired - Lifetime
-
1988
- 1988-10-25 JP JP63267347A patent/JPH01156968A/ja active Granted
-
1993
- 1993-06-09 LU LU88298C patent/LU88298I2/fr unknown
- 1993-06-11 NL NL930056C patent/NL930056I2/nl unknown
Also Published As
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PUP | Patent expired |