EP0703903A1 - 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

Info

Publication number
EP0703903A1
EP0703903A1 EP94918395A EP94918395A EP0703903A1 EP 0703903 A1 EP0703903 A1 EP 0703903A1 EP 94918395 A EP94918395 A EP 94918395A EP 94918395 A EP94918395 A EP 94918395A EP 0703903 A1 EP0703903 A1 EP 0703903A1
Authority
EP
European Patent Office
Prior art keywords
imidazole
inden
dihydro
fluoro
enantiomer
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Withdrawn
Application number
EP94918395A
Other languages
German (de)
English (en)
French (fr)
Inventor
Arto Johannes Karjalainen
Raimo Einari Virtanen
Arja Leena Karjalainen
Seppo Sulevi Lennart Parhi
Maire Marjatta Eloranta
Antti Sakari Haapalinna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Orion Oyj
Original Assignee
Orion Yhtyma Oy
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Orion Yhtyma Oy filed Critical Orion Yhtyma Oy
Publication of EP0703903A1 publication Critical patent/EP0703903A1/en
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP94918395A 1993-06-18 1994-06-16 Enantiomers of 4-(5-fluoro-2,3-dihydro-1h-inden-2-yl)-1h-imidazole Withdrawn EP0703903A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB939312669A GB9312669D0 (en) 1993-06-18 1993-06-18 New opticla isomers
GB9312669 1993-06-18
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

Publications (1)

Publication Number Publication Date
EP0703903A1 true EP0703903A1 (en) 1996-04-03

Family

ID=10737432

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94918395A Withdrawn EP0703903A1 (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 (lt)
JP (1) JPH08511554A (lt)
CN (1) CN1125439A (lt)
AU (1) AU6972594A (lt)
BG (1) BG100218A (lt)
CA (1) CA2165459A1 (lt)
CZ (1) CZ332195A3 (lt)
EE (1) EE9400010A (lt)
GB (1) GB9312669D0 (lt)
HU (1) HU211271A9 (lt)
IL (1) IL109984A0 (lt)
LT (1) LT3468B (lt)
LV (1) LV11462B (lt)
NO (1) NO955056D0 (lt)
NZ (1) NZ267427A (lt)
PL (1) PL312194A1 (lt)
SK (1) SK157095A3 (lt)
WO (1) WO1995000492A1 (lt)
ZA (1) ZA944346B (lt)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6613907B2 (en) 2000-11-08 2003-09-02 Amr Technology, Inc. Process for the production of piperidine derivatives with microorganisms
US8188126B2 (en) 2002-05-16 2012-05-29 Pierre Fabre Medicament Imidazolic compounds and use thereof as alpha-2 adrenergic receptors
FR2839719B1 (fr) * 2002-05-16 2004-08-06 Pf Medicament Nouveaux composes imidazoliques, leur procede de preparation et leur utilisation a titre de medicaments
GB0226076D0 (en) 2002-11-08 2002-12-18 Rp Scherer Technologies Inc Improved formulations containing substituted imidazole derivatives

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2167408B (en) 1984-11-23 1988-05-25 Farmos Oy Substituted imidazole derivatives and their preparation and use
FI81092C (fi) 1986-05-15 1990-09-10 Farmos Oy Foerfarande foer framstaellning av terapeutiskt aktiva 4(5)-(2,3-dihydro-1h-inden-2-yl)-imidazolderivat.
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
GB9127050D0 (en) * 1991-12-20 1992-02-19 Orion Yhtymae Oy Substituted imidazole derivatives and their preparation and use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9500492A1 *

Also Published As

Publication number Publication date
AU6972594A (en) 1995-01-17
PL312194A1 (en) 1996-04-01
CA2165459A1 (en) 1995-01-05
CZ332195A3 (en) 1996-05-15
IL109984A0 (en) 1994-12-29
LV11462B (en) 1996-12-20
NO955056L (no) 1995-12-13
CN1125439A (zh) 1996-06-26
LTIP1959A (en) 1995-01-31
ZA944346B (en) 1995-02-15
NO955056D0 (no) 1995-12-13
LT3468B (en) 1995-10-25
WO1995000492A1 (en) 1995-01-05
EE9400010A (et) 1995-12-15
SK157095A3 (en) 1996-06-05
NZ267427A (en) 1996-10-28
HU211271A9 (en) 1995-11-28
GB9312669D0 (en) 1993-08-04
JPH08511554A (ja) 1996-12-03
BG100218A (bg) 1996-06-28
LV11462A (lv) 1996-08-20

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