SK157095A3 - (+)-a(-)-enantiomer 4-(5-fluoro-2,3-dihydro-1h-inden-2-yl)-1h-imidazole and process for preparing the same - Google Patents

Abstract

Optical isomers of 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole and pharmaceutically acceptable salts thereof, their use and preparation are described. Both isomers are potent in the treatment of cognitive disorders.

Description

Technical field

The present invention relates to novel optical isomers of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole, their preparation. Both of these optical isomers of cognitive disorders, although pharmacological profiles. The (-) - enantiomer is preferred as it exhibits a wider therapeutic window than the corresponding (+) - enantiomer. The (-) - enantiomer is of strong use and the methods are effective in treating show slightly different? -Adrenoreceptors that show no? -Agonist antagonist.

The (+) - enantiomer is a moderate? ₂ -adrenoreceptor antagonist and a full? 1 -agonist. Both of these enantiomers exhibit good oral bioavailability.

BACKGROUND OF THE INVENTION

Valuable? ₂ -adrenoreceptor antagonists have been previously described, for example, in European Patent Publication Nos. 183,492, 247,764 and 372,954. PCT Patent Publication No. WO 91/18886 discloses the use of certain indanimidazole derivatives, particularly antipamezole, in the treatment of age-related memory impairment. and other cognitive disorders. PCT / FI 92/00349 describes a group of novel 4 (5) -substituted indanimidazole derivatives useful in the treatment of cognitive disorders and showing long-term efficacy. One of these indanimidazole derivatives is the racemate of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -em-imidazole containing an asymmetric carbon atom (indicated by an asterisk) at the 2-position of the indane ring.

SUMMARY OF THE INVENTION

The present invention provides optically active enantiomers of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole. The invention further provides processes for the preparation of these enantiomers. The cptically active enantiomers of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole according to the invention can be obtained, for example, by converting racemic 4- (5-fluoro-2,3-dihydro (1H-inden-2-yl) -1H to a mixture of diastereoisomers and separating this mixture by distillation. Considering that

4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole is a base which can be converted to a mixture of diastereoisomeric salts by reaction with an optically active acid, preferably L - (+) - or D - (-) - tartaric acid. The resulting diastereoisomers may be separated from each other by repeated crystallization, for example from water.

-imidazole fractionated

After separation of the diastereoisomers from each other, the resulting acid addition salts can be converted back to the free bases by alkalinizing their aqueous base solutions (e.g., sodium hydroxide) and extracting the liberated bases into suitable organic solvents.

(-) - and (+) - Enantiomers of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -ΙΗ-imidazole react with organic or inorganic acids to form the corresponding acid addition salts which they have the same therapeutic efficacy as the free bases. Many pharmaceutically acceptable acid addition salts such as chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates can form.

The racemate of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole can be prepared, for example, by nitration of 4- (2,3-dihydro-1H-inden-2-yl) -1H imidazole hydrochloride with a strong nitrating agent such as urea nitrate in the presence of sulfuric acid and subsequent reduction of the resulting nitro compound to the corresponding amino compound, for example, by catalytic hydrogenation using platinum oxide or palladium on carbon catalyst. The resulting amino substituted compound is then converted to the corresponding diazonium fluoroborate by treatment with sodium nitrite in fluoroboric acid at reduced temperature. The diazonium fluoroborate obtained is then thermally decomposed to the racemate of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole.

The compounds of the invention may be administered enterally or parenterally. A preferred daily dose for the treatment of cognitive disorders is in the range of 0.1 to 10 mg / kg, in particular 0.2 to 1 mg / kg.

The acute toxicity (LD) of both enantiomers is about 100

0 mg / kg In mice (p.o.) and about 50 mg / kg in rats.

The pharmaceutical carriers usually used in conjunction with the compounds of the invention may be solid or liquid, and are selected with respect to the intended mode of administration. The choice of excipients of the pharmaceutical compositions according to the invention is a routine work which is within the skill of those skilled in the art.

FIG. in the drawings

In FIG. 1, 2 and 3 show the effects of the (-) enantiomer on teaching and memory.

DETAILED DESCRIPTION OF THE INVENTION

The following is a description of pharmacological tests performed using the compounds of the invention.

1) In vitro selectivity to β-adrenorecpt β _{2 -} Antagonism is determined on a preparation consisting of an isolated electrically stimulated prostate portion of rat deferens vases (Virtanen et al., Ar. Int. Pharmadocyn. Et Ther., 297, 192-204, 1989) ). In this model, the κ ₂ -agonist (detomidine) blocks electrically stimulated muscle contractions. The? ₂ -antagonist action is evaluated by administering this agent in front of the agonist and determining the pA _s value. The known? ₂ -antagonist, atipamezole, is used as reference.

To determine the selectivity of the antagonist with respect to _{α 2} receptors, the ability of the antagonist to stimulate β 1 -receptors is investigated using the isolated epididymal portion of rat deferent ligaments. For? -Antagonism determination, muscle contraction is induced by phenylephrine and the pA _{2 of the} test compound is determined as described above. The? -Agonist effect is expressed as a pD ₂ value (negative logarithm of the compound concentration giving 50% of the maximum contraction). The results are shown in Table 1.

Table 1

Selectivity of racemic 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole and its enantiomers as compared to antipamezole

Compound & ₂ -Antagonism -Antagonism to β -Agonism (pA vs detomidine) (pA vs phenylephrine) (pD)

2 2

(-) - enantiomer 8.7 6.7 no effect (+) - enantiomer 7.9 untried 6.0 full agonist racemate 8.0 untried 5.5 part. agonist atipamezole 8.0 5.0 no effect

2) Effects on memory

The effect of the (-) - enantiomer on learning and memory in a linear maze is studied in rats. A linear maze is a modified version of a radial maze that is generally used in rat memory tests. The (-) - enantiomer hydrochloride (0.1 mg / kg s.c.) was dissolved in distilled water. Water is also used as a control medium. All injections have a volume of 1 ml / kg.

Equipment: The maze consists of a wooden board that has the shape of two consecutive crosses. The feed arm is 90 cm long and 12 cm wide. Five additional arms (target arms) are 50 cm long and 12 cm wide. The four target arms are located perpendicular to the feed arm and to the fifth arm, which is opposite the feed arm. There are 2.8 cm high edges on both sides of the feed arm and target arms. At the end of each target arm there is a hole 1 cm deep and 3 cm diameter serving as a food tray. The platform (20 x 20 cm board) is separated from the feed arm by a trap door. The door is 12 cm high and 7 cm wide. The door frame is 20 cm high and 20 cm wide. The maze is raised to a height of 31 cm above the floor and is housed in a poorly lit room that contains other items in addition to the test equipment. A bait consisting of 3 pallets of food as a reward (45 mg pallets, Bio Serve Inc.) is placed in the holes at the end of the target arms.

Procedures: 2 days prior to training, the animals are switched to a food denial regimen to reduce their body weight to 90% of the initial weight. During these days, rats are allowed to habituate (3 times a day), test room, and food to serve as a reward. The next day they are also allowed to get used to the maze without the bait: 3 to 5 animals from the same cage are put into the maze at the same time for 10 minutes. On the third day, the bait is placed in the target arms and only one rat is taught. The rat receives drug or distilled water and is placed on the platform after 60 minutes. After 10 seconds the door is opened and the rat is allowed to explore the maze until all the baits are found. New entrances to the arms that the rat has previously visited during this experiment are considered a mistake. The time it takes for the rat to find all the baits and the number of correct choices until the first mistake occurs. At this time (teaching), each rat is allowed to remain in the maze for at least 5 minutes. The next day, a full memory and teaching session will begin, with a total of 4 days (trial day 1-4). Eight trials were performed with each rat (2 per day). The interval between tests is 50 minutes. Drug or distilled water is administered 30 minutes before the first test on the relevant day. Otherwise, the trials are the same as the trials. There are 20 animals in both groups.

Statistical analysis: Results are reported as the mean of the number of errors per experiment, the mean of the number of correct choices per experiment, and the mean of the time per experiment (seconds). Variance analysis (ANOVA) is used for repeated measurements to compare the effect of drug and test day order on learning and memory.

The results; the effects of the (-) enantiomer on education and memory are shown in FIG. 1, 2 and 3. The drug reduces the number of errors (i.e., new entrances to the arms that have been previously visited during the same experiment (Fig. 1)). The (-) enantiomer also increases the number of correct choices before the first mistake of the assay (FIG.

2). These results illustrate the effect on working memory and on the ability of animals to concentrate in the assay. The test drug also tends to reduce the time it takes to accomplish the task (Fig. 3). This reflects the effect of speeding up the making of the right decision, in this case the right choice. From trial to land, the number of errors and time decreases, and the number of correct choices increases, indicating the learning, even in the control group. There are no group x experiment interactions, which means that the (-) - enantiomer effect is independent of the experiment. These results demonstrate that the (-) enantiomer exhibits stimulatory effects on the learning and memory of adult rats.

3) Preparation of optically active isomers

Racemic 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole

Concentrated sulfuric acid (58 mL) was cooled to -10 ° C and a mixture of 4- (2,3-dihydro-1H-inden-2-yl) -1H-imidazole hydrochloride was added in small portions at -10 ° C. (Karjalainen, AJ et al., US 4,689,339, 13.8 g, 0.0625 mol) and urea nitrate (7.70 g, 0.0625 mol). After completion of the reaction, the resulting solution was poured onto ice, basified and extracted three times with ethyl acetate. The organic extracts were combined, dried and evaporated to dryness. 13.0 g, 91% of 4- (2,3-dihydro-5-nitro-1H-inden-2-yl) -1H-imidazole are obtained.

4- (2,3-Dihydro-5-nitro-1H-inden-2-yl) -ΙΗ-imidazole is reduced to 4- (2,3-dihydro-5-amino-1H-inden-2-yl) - 1H-imidazole by adding 1.0 g of 10% palladium on carbon to 11.7 g (0.0512 mol) of 4- (2,3-dihydro-5-nitro-1H-inden-2-yl) - 1 H-imidazole in 100 ml ethanol and the resulting mixture was shaken under a hydrogen atmosphere at room temperature. When the reduction is stopped (i.e., when hydrogen absorption is complete), the catalyst is separated and the filtrate is concentrated. 9.63 g (94%) of 4- (2,3-dihydro-5-amino-1H-inden-2-yl)-yl-imidazole are obtained. The product obtained is purified by flash chromatography using a mixture of methylene chloride and methanol in a ratio

9.5: 0.5 as eluent. Bank containing acid fluoroboric (weight 48% solution within water, 120 ml) 'a 9,50 g (0.0475 M)

- (2,3-Dihydro-5-amino-1H-inden-2-yl) -ΙΗ-imidazole was placed in a bath of salt and ice and cooled to 0 ° C. A solution of sodium nitrite (3.30 g, 0.0478 mol) in water (10 ml) was slowly added to the mixture while maintaining the temperature at 0 ° C. The mixture was then stirred at 0 ° C for 1 hour and at room temperature for a further hour. Next, the reaction mixture was evaporated to dryness twice with toluene. The thermal decomposition takes place in a flask heated by an electrically heated jacket. Heating stops when white boron trifluoride vapors stop developing. The crude product was dissolved in methanol, the resulting solution was filtered and evaporated to dryness. Crude 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole (9.51 g, 99%) was obtained. The product was purified by flash chromatography using a 9.5: 0.5 mixture of methylene chloride and methanol as eluent.

^X H NMR (300 MHz CD ₃ 0D): 2.96-3.08 (2H, m, one H) -1 a one H-3), 3.19 - 3,27 (2H, m, another H-1 and another H-3), 3.68 (1 H, quintet, ^3J HH 8.3 Hz, H-2), 6 80 - 6.86 (1 H, m, H-6), 6.83 (1 H, s, im-5), 6.92 (1 H, dd, ^3o 'HF 8 9 Hz, ^4J HH 2.4Hz, H-4), 7.16 (1 H, dd, ^3, RHH 8.1 Hz, ^4J HF, 5.3 Hz, H-7), 7.59 (1 H, s, im-4)

Separation of enantiomers

D - (-) - tartaric acid (0.44 g, 0.00293 mol) was dissolved in 2.5 ml of water at 60 ° C. To the resulting solution was added 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -4-imidazole racemate (I, 1.03 g, 0.00509 mol) and 178 L of concentrated hydrochloric acid. . The mixture was stirred at 60 ° C until a clear solution was formed, which was then allowed to slowly cool.

> The precipitate is collected and recrystallized 5 times from water. The salt of the (-) - enantiomer with D - (-) - tartaric acid is obtained, m.p. 186-187 ° C.

The D - (-) - tartaric acid addition salt of the (-) - enantiomer was dissolved in water at 60 ° C and ethyl acetate was added to the resulting solution. The resulting solution was basified with dilute sodium hydroxide to pH 10. The ethyl acetate phase was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases are washed with water. The ethyl acetate was evaporated and the dry residue was recrystallized from ethyl acetate. The product obtained is filtered off with suction and washed with cold ethyl acetate. Its melting point (DSC) is 139 ° C, its specific rotation at 20 ° C in methanol solution is -3.7 ° (c - 20 mg / ml).

and

The (-) enantiomer base was dissolved in ethyl acetate and the solution was filtered through Millipore. The resulting filtrate was acidified to pH 1 with a dry solution of hydrogen chloride in ethyl acetate and cooled to -10 ° C. The resulting precipitate was filtered off with suction and washed with ethyl acetate. The precipitate is recrystallized from ethyl acetate to give (-) - 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole hydrochloride as a white crystalline solid, m.p. (DSC) 191 ° C, chromatographic purity 99.8% (HPLC), optical purity 99.9% (HPLC) and specific rotation at ambient temperature in aqueous solution - 3.5 ° (c = 20 mg / ml).

The (+) - enantiomer is resolved in the same manner as the (-) - isomer using L - (+) - tartaric acid as the resolving agent. An L - (+) - tartaric acid adduct with the (+) - enantiomer of melting point is obtained.

Mp 187-189 ° C. The corresponding base and hydrochloride (melting point 190 ° C) are also prepared using the above process. The chromatographic purity of the hydrochloride is 98.7% (HPLC), the optical purity is 99.6% (HPLC), and the specific rotation at ambient temperature in the aqueous solution is + 3.2 ° (c = 20 mg / ml).

Claims (6)

PATENT CLAIMS (-) - Enantiomer of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole and pharmaceutically acceptable salts thereof. A process for the preparation of (-) - enantilmer of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -4-imidazole, characterized in that: «. racemic 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole * is converted to a mixture of diastereomeric salts with an optically active acid and the resulting mixture of diastereomeric salts is separated by fractional crystallization, and then the separated (-) - enantiomer of the salt of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -4-imidazole is converted to the free base. Process according to claim 2, characterized in that D - (-) - tartaric acid is used as the optically active acid. 4. (+) - Enantiomer of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole and pharmaceutically acceptable salts thereof. b. 5. A process for the preparation of the (+) - enantiomer of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -ΙΗ-imidazole, characterized in that racemic 4- (5-fluoro-2) is obtained. The 3-dihydro-1H-inden-2-yl) -1H-imidazole is converted to the diastereomeric salt by reaction with an optically active acid, and the resulting mixture of diastereomeric salts is separated by fractional crystallization, and then the separated (+) - enantiomer of the 4- ( 5-Fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole was converted to the free base. Process according to claim 5, characterized in that L - (+) - tartaric acid is used as the optically active acid.