WO1995000492A1 - Enantiomers of 4-(5-fluoro-2,3-dihydro-1h-inden-2-yl)-1h-imidazole - Google Patents
Enantiomers of 4-(5-fluoro-2,3-dihydro-1h-inden-2-yl)-1h-imidazole Download PDFInfo
- Publication number
- WO1995000492A1 WO1995000492A1 PCT/FI1994/000263 FI9400263W WO9500492A1 WO 1995000492 A1 WO1995000492 A1 WO 1995000492A1 FI 9400263 W FI9400263 W FI 9400263W WO 9500492 A1 WO9500492 A1 WO 9500492A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- imidazole
- inden
- dihydro
- fluoro
- enantiomer
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
Definitions
- the invention provides new optical isomers of 4-(5-fluoro-2,3-dihydro- 1 H-inden-2-yl)-1H-imidazole and pharmaceutically acceptable salts thereof, their use and preparation. Both optical isomers are potent in the treatment of cognitive disorders, although somewhat different pharmacological profiles may be ascribed to them.
- the (-)-enantiomer is the preferred one of the two enantiomers because it has a wider therapeutic window than the (+)- enantiomer. It is a very powerful antagonist of 012-adrenoceptors without any ⁇ -agonism whereas the (+)-enantiomer is a moderate antagonist of ⁇ - adrenoceptors and a full ⁇ -
- Valuable o ⁇ -adrenoceptor antagonist have been disclosed earlier e.g. in the European patent publications No. 183492, 247764 and 372954.
- PCT patent publication No. 91/18886 discloses the use of some indan-imidazole derivatives, especially atipamezole, in the treatment of age-related memory impairment and other cognitive disorders.
- International patent application No. PCT/FI9200349 describes a group of new long-acting 4(5)-substituted indan- imidazole derivatives which are useful in the treatment of cognitive disorders.
- indan-imidazole derivatives is the racemate of 4-(5-fluoro-2,3- dihydro-1 H-inden-2-yl)-1H-imidazole which has an asymmetric carbon atom in the position 2 of the indan ring:
- optically active enantiomers of 4-(5-fluoro-2,3-dihydro-1 H-inden-2- yl)-1H-imidazole may be prepared e.g. by conversion of racemic 4-(5-fluoro-2,3- dihydro-1H-inden-2-yl)-1 H-imidazole into a mixture of diastereoisomers and separating these by fractional crystallization. Since 4-(5-fluoro-2,3-dihydro-1H- inden-2-yl)-1H-imidazole is a base, it may be converted into diastereoisomer salt mixture by reaction with an optically active acid, preferably with L-(+)- or D- (-)-tartaric acid.
- the diastereoisomers may be separated by repeated crystallization e.g. from water. Once the diastereoisomers have been separated the acid addition salts may be converted back to the free bases by making their aqueous solutions alkaline with a base (e.g. sodium hydroxide) and by extracting the liberated base into an appropriate organic solvent.
- a base e.g. sodium hydroxide
- 1 H-imidazole react with organic or inorganic acids to form the corresponding acid addition salts, which have the same therapeutic activities as the bases. They can thus form many pharmaceutically useful acid addition salts such as chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates.
- the racemate of 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole may be prepared e.g. by nitrating 4-(2,3-dihydro-1H-inden-2-yl)-1 H-imidazole hydrochloride with a strong nitrating agent such as ureanitrate in the presence of sulfuric acid and thereafter reducing the nitro compound to the corresponding amino compound e.g by catalytic hydrogenation using Pt ⁇ 2 or Pd/C as catalysts.
- the amino substituted compound is further converted to the corresponding diazonium fluoroborate with sodium nitrite in fluoboric acid at lowered temperature.
- the diazonium fluoroborate is then decomposed thermally to yield the racemate of 4-(5-fluoro-2,3-dihydro-1 H-inden-2-yl)-1 H- imidazole.
- the compounds according to the invention may be administered enterally or parenterally.
- the preferable daily dosage is from 0.1 to 10 mg/kg, especially preferably from 0.2 to 1 mg/kg.
- the acute toxicity (LD50) for both enantiomers is about 100 mg/kg in mice (p.o.) and about 50 mg/kg in rat.
- the pharmaceutical carriers which are typically employed with the compound of the invention may be solid or liquid and are selected with the planned manner of administration in mind. Choosing the auxiliary ingredients for the formulation is routine for those of ordinary skill in the art.
- ⁇ 2-Antagonism was determined by means of isolated, electrically stimulated prostatic portion of rat vas deferens preparation (Virtanen et al, Arch. Int. Pharmacodyn et Ther., 297, 190-204, 1989). In this model, o ⁇ -agonist
- detomidine blocks electrically stimulated muscular contractions and the effect of the ⁇ 2-antagonist is seen by administering it prior to the agonist and by determining its pA2 value.
- the known ⁇ 2-antagonist atipamezole was used as a reference substance.
- 012-receptors its ability to inhibit or stimulate ⁇ - -receptors was determined by means of isolated epididymal portion of rat vas deferens.
- ⁇ - j - antagonism muscular contraction was induced by phenylephrine and the pA2 value of the studied compound was determined as above, ⁇ - j -Agonist effect is presented as the pD2 value (negative logarithm of the molar concentration of the compound producing 50 percent of maximal contraction). The results are given in Table 1.
- the effect of the (-)-enantiomer on learning and memory in linear arm maze task in rats was studied.
- the linear arm maze is a modified version of radial arm maze, which is a generally used memory test in rats.
- the (-)- enantiomer hydrochloride (0.1 mg/kg s.c.) was dissolved in distilled water. Water was also used as control. All injections were made in a volume of 1 ml/kg.
- the maze was a wooden platform in a shape of two crosses one after another.
- the stem (starting arm) was 90 cm long and 12 cm wide.
- the five other arms (goal arms) were 50 cm long and 12 cm wide.
- Four goal arms were situated perpendicularly to the stem and to the fifth arm which located opposite to the stem. On either side of the stem and the arms were edges, 2.0 cm high.
- At the end of each goal arm a hole 1 cm deep and 3 cm in diameter, served as a food cup.
- the starting platform (20 x 20 cm) was separated from the stem by a guillotine door.
- the door was 12 cm high and 7 cm wide.
- the door frame was 20 cm high and 20 cm wide.
- the maze was elevated 31 cm above the floor, in a low-lighted test room which contained other objects as well as the test apparatus.
- the holes at the end of the goal arms were baited with three pellets of prize food (45 mg pellets Bio Serve Inc.).
- the thermal decomposition was carried out in a flask which was heated with an electric heating mantle. When the generation of white fumes of boron trifluoride ceased the heating was stopped.
- the crude product was dissolved in methanol, the solution was filtered and evaporated to dryness.
- the yield of the crude 4-(5-fluoro-2,3-dihydro-1H- inden-2-yl)-1 H-imidazole was 9.51 g, 99 %.
- the product was purified by flash chromatography (the eluent methylene chloride - methanol 9.5:0.5).
- D-(-)-Tartaric acid (0.44 g, 0.00293 mol) was dissolved in 2.5 ml of water at 60 °C.
- the racemate of 4-(5-fluoro-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazole (1, 1.03 g, 0.00509 mol) and 178 ⁇ l of concentrated hydrochloric acid were added at 60 °C.
- the mixture was stirred at 60 °C until it became a clear solution.
- the solution was allowed to cool slowly.
- the precipitates were collected and recrystallized five times from water to give the D-(-)-tartaric acid salt of the (-)- enantiomer: mp 186-187 °C.
- the D-(-)-tartaric acid adduct of the (-)-enantiomer was dissolved in water at 60 °C and ethyl acetate was added.
- the solution was made alkaline (pH 10) with diluted sodium hydroxide.
- the ethyl acetate phase was separated and the water phase was extracted twice with ethyl acetate.
- the combined organic phases were washed with water.
- Ethyl acetate was evaporated to dryness and the residue was crystallized from ethyl acetate.
- the (-)-enantiomer base was dissolved in ethyl acetate and filtered by
- (+)-enantiomer was resolved in the same way as the (-)-isomer using L- (+)-tartaric acid as a resolving agent to give the L-(+)-tartaric acid adduct of the (+)-enantiomer: mp 187-189 °C.
- the base and hydrochloride salt mp 187-189 °C.
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL94312194A PL312194A1 (en) | 1993-06-18 | 1994-06-16 | Enantiomers of 4-(5-fluoro-2,3-dihydro-1h-inden-2-yl)-1h-imidazole |
EP94918395A EP0703903A1 (en) | 1993-06-18 | 1994-06-16 | Enantiomers of 4-(5-fluoro-2,3-dihydro-1h-inden-2-yl)-1h-imidazole |
JP7502468A JPH08511554A (en) | 1993-06-18 | 1994-06-16 | New optical isomer |
AU69725/94A AU6972594A (en) | 1993-06-18 | 1994-06-16 | Enantiomers of 4-(5-fluoro-2,3-dihydro-1h-inden-2-yl)-1h-imidazole |
SK1570-95A SK157095A3 (en) | 1993-06-18 | 1994-06-16 | (+)-a(-)-enantiomer 4-(5-fluoro-2,3-dihydro-1h-inden-2-yl)-1h-imidazole and process for preparing the same |
BG100218A BG100218A (en) | 1993-06-18 | 1995-12-13 | Enantiomers of 4-(5- fluoro-2,3-dihydro-1h-inden-2-yl)-1h-imidazole |
NO955056A NO955056D0 (en) | 1993-06-18 | 1995-12-13 | Enantiomers of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole |
FI956040A FI956040A (en) | 1993-06-18 | 1995-12-15 | Enantiomers of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole |
LVP-95-376A LV11462B (en) | 1993-06-18 | 1995-12-19 | Enantiomers of 4- (5- fluoro- 2,3- dihydro- 1h- inden- 2- yl)- 1h- imidazole |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9312669.6 | 1993-06-18 | ||
GB939312669A GB9312669D0 (en) | 1993-06-18 | 1993-06-18 | New opticla isomers |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995000492A1 true WO1995000492A1 (en) | 1995-01-05 |
Family
ID=10737432
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FI1994/000263 WO1995000492A1 (en) | 1993-06-18 | 1994-06-16 | Enantiomers of 4-(5-fluoro-2,3-dihydro-1h-inden-2-yl)-1h-imidazole |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP0703903A1 (en) |
JP (1) | JPH08511554A (en) |
CN (1) | CN1125439A (en) |
AU (1) | AU6972594A (en) |
BG (1) | BG100218A (en) |
CA (1) | CA2165459A1 (en) |
CZ (1) | CZ332195A3 (en) |
EE (1) | EE9400010A (en) |
GB (1) | GB9312669D0 (en) |
HU (1) | HU211271A9 (en) |
IL (1) | IL109984A0 (en) |
LT (1) | LT3468B (en) |
LV (1) | LV11462B (en) |
NO (1) | NO955056D0 (en) |
NZ (1) | NZ267427A (en) |
PL (1) | PL312194A1 (en) |
SK (1) | SK157095A3 (en) |
WO (1) | WO1995000492A1 (en) |
ZA (1) | ZA944346B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1581192A1 (en) * | 2002-11-08 | 2005-10-05 | R.P. Scherer Technologies, Inc. | Improved formulations containing substituted imidazole derivatives |
EP1958935A2 (en) | 2000-11-08 | 2008-08-20 | AMR Technology, Inc. | Process for the production of piperidine derivatives with microorganisms |
JP4749710B2 (en) * | 2002-05-16 | 2011-08-17 | ピエール、ファーブル、メディカマン | Imidazole compounds and their use as alpha-2-adrenergic receptors |
US8188126B2 (en) | 2002-05-16 | 2012-05-29 | Pierre Fabre Medicament | Imidazolic compounds and use thereof as alpha-2 adrenergic receptors |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0310745A2 (en) * | 1984-11-23 | 1989-04-12 | Orion-Yhtymä Oy | Substituted imidazole derivatives and their preparation and use |
WO1993013074A1 (en) * | 1991-12-20 | 1993-07-08 | Orion-Yhtymä Oy | Substituted imidazole derivatives and their preparation and use |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI81092C (en) | 1986-05-15 | 1990-09-10 | Farmos Oy | Process for the preparation of therapeutically active 4 (5) - (2,3-dihydro-1H-inden-2-yl) imidazole derivatives |
GB2225782A (en) | 1988-12-09 | 1990-06-13 | Farmos Group Limited | Imidazole derivatives useful for treatment of diabetes |
GB2244431A (en) | 1990-05-31 | 1991-12-04 | Farmos Oy | Treatment of age related memory impairment and other cognitive disorders |
-
1993
- 1993-06-18 GB GB939312669A patent/GB9312669D0/en active Pending
-
1994
- 1994-06-10 IL IL10998494A patent/IL109984A0/en unknown
- 1994-06-15 EE EE9400010A patent/EE9400010A/en unknown
- 1994-06-16 NZ NZ267427A patent/NZ267427A/en unknown
- 1994-06-16 WO PCT/FI1994/000263 patent/WO1995000492A1/en not_active Application Discontinuation
- 1994-06-16 SK SK1570-95A patent/SK157095A3/en unknown
- 1994-06-16 PL PL94312194A patent/PL312194A1/en unknown
- 1994-06-16 EP EP94918395A patent/EP0703903A1/en not_active Withdrawn
- 1994-06-16 CZ CZ953321A patent/CZ332195A3/en unknown
- 1994-06-16 JP JP7502468A patent/JPH08511554A/en active Pending
- 1994-06-16 CN CN94192476A patent/CN1125439A/en active Pending
- 1994-06-16 AU AU69725/94A patent/AU6972594A/en not_active Abandoned
- 1994-06-16 CA CA002165459A patent/CA2165459A1/en not_active Abandoned
- 1994-06-17 LT LTIP1959A patent/LT3468B/en not_active IP Right Cessation
- 1994-06-17 ZA ZA944346A patent/ZA944346B/en unknown
-
1995
- 1995-06-23 HU HU95P/P00421P patent/HU211271A9/en unknown
- 1995-12-13 NO NO955056A patent/NO955056D0/en unknown
- 1995-12-13 BG BG100218A patent/BG100218A/en unknown
- 1995-12-19 LV LVP-95-376A patent/LV11462B/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0310745A2 (en) * | 1984-11-23 | 1989-04-12 | Orion-Yhtymä Oy | Substituted imidazole derivatives and their preparation and use |
WO1993013074A1 (en) * | 1991-12-20 | 1993-07-08 | Orion-Yhtymä Oy | Substituted imidazole derivatives and their preparation and use |
Non-Patent Citations (2)
Title |
---|
J. BIEDERMANN ET AL.: "Two Stereoisomeric Imidazoline Derivatives: Synthesis and Optical and alpha2-Adrenoceptor Activities", J. MED. CHEM., vol. 29, no. 7, 1986, pages 1183 - 1188 * |
J. F. DEBERNARDIS ET AL.: "Conformationally Defined Adrenergic Agents. 5. Resolution, Absolute Configuration, and Pharmacological Characterization of the Enantiomers of 2-(5,6-Dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline: A Potent Agonist at alpha-Adrenoceptors", J. MED. CHEM., vol. 30, no. 6, 1987, pages 1011 - 1017 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1958935A2 (en) | 2000-11-08 | 2008-08-20 | AMR Technology, Inc. | Process for the production of piperidine derivatives with microorganisms |
JP4749710B2 (en) * | 2002-05-16 | 2011-08-17 | ピエール、ファーブル、メディカマン | Imidazole compounds and their use as alpha-2-adrenergic receptors |
US8188126B2 (en) | 2002-05-16 | 2012-05-29 | Pierre Fabre Medicament | Imidazolic compounds and use thereof as alpha-2 adrenergic receptors |
EP1581192A1 (en) * | 2002-11-08 | 2005-10-05 | R.P. Scherer Technologies, Inc. | Improved formulations containing substituted imidazole derivatives |
EP1581192A4 (en) * | 2002-11-08 | 2009-12-02 | Scherer Technologies Inc R P | Improved formulations containing substituted imidazole derivatives |
US9717681B2 (en) | 2002-11-08 | 2017-08-01 | R.P. Scherer Technologies, Llc | Formulations containing substituted imidazole derivatives |
Also Published As
Publication number | Publication date |
---|---|
HU211271A9 (en) | 1995-11-28 |
AU6972594A (en) | 1995-01-17 |
IL109984A0 (en) | 1994-12-29 |
LV11462B (en) | 1996-12-20 |
CA2165459A1 (en) | 1995-01-05 |
NO955056L (en) | 1995-12-13 |
NO955056D0 (en) | 1995-12-13 |
NZ267427A (en) | 1996-10-28 |
SK157095A3 (en) | 1996-06-05 |
EP0703903A1 (en) | 1996-04-03 |
LT3468B (en) | 1995-10-25 |
BG100218A (en) | 1996-06-28 |
EE9400010A (en) | 1995-12-15 |
LTIP1959A (en) | 1995-01-31 |
ZA944346B (en) | 1995-02-15 |
PL312194A1 (en) | 1996-04-01 |
CZ332195A3 (en) | 1996-05-15 |
CN1125439A (en) | 1996-06-26 |
LV11462A (en) | 1996-08-20 |
GB9312669D0 (en) | 1993-08-04 |
JPH08511554A (en) | 1996-12-03 |
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