LT3468B - New optical isomers and process for preparing thereof - 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

The present invention provides novel optical isomers of 4- (5-fluoro-2,3-dihydrol-H-inden-2-yl) -ΙΗ-imidazole and pharmaceutically acceptable salts thereof, and their use and preparation. Both optical isomers are potent drugs for the treatment of cognitive impairment, although they may be assigned slightly different pharmacological profiles. The (-) - antipode is the more acceptable of the two antipodes because it has a greater therapeutic width than the (+) - antipode. It is a very potent α ₂ adrenoceptor antagonist but has no α 2 agonism, whereas the (+) antipode has moderate α ₂ adrenoreceptor antagonism and is a complete α 2 agonist. Both antipodes have good oral bioavailability.

A valuable α ₂ adrenoreceptor antagonist has been described previously, e.g., in European Patent Publication Nos. 183492, 247764 and 372954. PCT Patent Publication No. 91/18886 describes the use of some indanimidazole derivatives, particularly atipamezole, in the treatment of age-related memory impairment and other cognitive impairment. International Application No. PCT / FI 92/00349 describes a group of novel long acting 4 (5) -changed indanimidazole derivatives useful in the treatment of cognitive impairment. One of the following indanimidazole derivatives is 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole racemate which has an asymmetric carbon at the 2-position of the indane ring:

NH

Optically active 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole antipodes may be prepared, e.g., by converting the racemic 4- (5-fluoro-2,3-dihydro-1H) -inden-2-yl) 1H-imidazole into a mixture of diastereoisomers and separating them by fractional crystallization. Since 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -ΙΗ-imidazole is a base, it can be converted into a mixture of salts of diastereoisomers with optically active acids, more preferably with L - (+) - or D - (-) - tartaric acid. The diastereoisomers can be separated by recrystallization, for example in water.

After separation of the diastereoisomers, the salts obtained by the addition of the acid can be converted back to the free bases by alkaline treatment of their aqueous solutions with bases (e.g., caustic soda) and extraction of the liberated bases with an appropriate organic solvent.

4- (5-Fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole (-) and (+) - antipodes react with organic and inorganic acids to form the corresponding salts having the same therapeutic activity as do the bases. Thus, they can form many pharmaceutically useful salts such as chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, food, citrates, benzoates, salicylates, and ascorbic acid salts.

4- (5-Fluoro-2,3-dihydro-1H-inden-2-yl) -ΙΗ-imidazole racemate may be prepared, for example, by nitration of 4- (2,3-dihydro-1H-inden-2-yl) - ΙΗ-Imidazole hydrochloride with a strong nitrating reagent such as urea nitrate in the presence of sulfuric acid followed by reduction of the nitro compound with the appropriate amino compound, for example by catalytic hydrogenation using PtO ₂ or Pd / C as catalysts. The amine compounds are further converted to the corresponding diazonium fluoroborate at low temperature with sodium nitrite in fluoroboric acid. The diazonium fluoroborate is then thermally decomposed to give 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole racemate.

The compounds of the present invention may be administered by the gastrointestinal tract or parenterally. For cognitive impairment, daily doses of 0.1 to 10 mg / kg, particularly 0.2 to 1 mg / kg, are more acceptable.

The acute toxicity (LD ₅₀ ) for both antipodes is about 100 mg / kg in mice (po) and about 50 mg / kg in rats.

The pharmaceutical carriers commonly used with the compounds of the present invention may be in solid or liquid form and will be selected according to the intended mode of administration. Auxiliary ingredients are usually selected by those of ordinary skill in the art.

1. In vitro a ₂ adrenoreceptor selectivity A ₂ antagonism was determined using an isolated, electrically stimulated prostate portion of a rat effluent preparation (Virtanen et al., 1989, Arch. Int. Pharmacodyn et Ther., 297, 190-204). In this model, a ₂ agonist (detomidine) blocks electrically stimulated muscular contractions oa ₂ antagonistic effect is observed when administered prior to agonist and by determining its pA ₂ value. The known α ₂ antagonist atipamezole was used as a comparator.

In order to obtain information on the antagonist selectivity for α ₁ and α ₂ receptors, the ability of the antagonist to inhibit and excite β ₁ receptors was also determined using an isolated portion of the rat testicular tubule. a, Antagonism was determined by inducing muscle contraction with phenylethrin and assaying for pA _{2 of the} test compound as described above. The agonist effect is reported as pD ₂ (the negative logarithm of the molar concentration of the compound that causes 50 percent of the maximum contraction). The results are shown in Table 1.

table. Selectivity of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole racemate and its antipodes relative to atipamezole

The compound (¾ antagonism (pA ₂ against detomidine) αχ antagonism (pA ₂ against phenylephrine) a ₂ agonism (pD ₂ ) (-) - Antipode 9.1 6.7 there was no effect (+) - Antipode 7.9 not investigated 6.0 a full agonist Racemat 8.0 not investigated 5.5 partial agonist Atypamezole 8.0 5.0 there was no effect

2. Memory effects (-) - The effect of the antipode on rat training and memory was investigated in tasks with the linear path maze. The linear path maze is a modified maze of radial paths that is commonly used in rat memory studies. (-) - Antipode hydrochloride (0.1 mg / kg s.c.) was dissolved in distilled water. Water was also used as a control. All injections were given at 1 ml / kg.

Means: The Labyrinth was a wooden platform with two crosses placed one behind the other. The trunk (runway) was 90 cm long and 12 cm wide. Five other trails (target trails) were 50 cm long and 12 cm wide. The four target lanes were perpendicular to the trunk and the fifth lane was opposite the stem. Each side of the trunk and trails had a 2.0 cm high wall. There was a hole 1 cm deep and 3 cm in diameter at the end of each target trail, serving as a food cup. The starting platform (20x20 cm) was separated from the trunk by a guillotine type door. The doors were 12 cm high and 7 cm wide The door frames were 20 cm high and 20 cm wide. The maze was raised 31 cm above the floor in a dimly lit test room containing other objects and test equipment. Three bonus food pieces (45 mg Bio Serve Inc) were placed in the holes in the back of the target paths for massaging.

Procedures: Two days prior to training, the animals were fed without food to reduce their body weight to 90% of their initial weight. During these days, the rats were trained (three times daily) to handle the prize food in the test room. On the second day, they were also challenged to a maze without bait: three to five animals from the same cage at the same time ten minutes each. On the third day, target paths were massaged and training experiments were performed with each rat individually. The rats were given drugs or distilled water and transferred to the starter platform after 60 minutes. After ten seconds, the door opened and the rat could explore the maze until it found all the bait. Re-entering the trail that had already been visited at that test was considered a mistake. The time it took to find all the cozy and the time to make the right choices until the first mistake was recorded. At that time (during training) each rat was allowed to remain in the maze for at least five minutes. The next day, the actual memory and training tests began and continued for four days (1 to 4 test days). Rats were given eight trials, two per day. Gaps between tests 50 minutes. Drugs or distilled water were administered 30 minutes before the first test of the day. In other respects the tests coincided with the training tests. There were 20 animals in each group.

Statistical Analysis: Results were expressed as the mean of errors per trial, the average of correct choices per trial, and the average time per trial (seconds). Disparity analysis with duplicate data (ANOVA) was used to compare drug and test day effects on training and memory.

Results: The effect of (-) - antipode on training and memory is presented in Figs. 1,2 and 3. Drugs have reduced the number of errors, i.e. the number of repeated accesses to the trail that had already been visited during that test (Fig. 1). The (-) - antipode also increased the number of correct choices made to the first error in the trial (Fig. (Fig.2). 2). This should be considered as an effect on working memory and the ability to concentrate on tests, respectively. Medications also tended to reduce task resolution time (Fig. 3). This can be considered as an effect on the timing of decisions, in this case the right choices. Decreases in the number and timing of errors and increases in correct choices were observed with each trial, indicating a proficiency in the control group as well. There was no interaction between group x and repeats, meaning that the (-) - antipode effect was independent of the trials. These results suggest that the (-) - antipode has a stimulating effect on adult rat training and memory.

3. Preparation of optically active isomers

4- (5-Fluoro-2,3-dihydro-1H-inden-2-yl) -ΙΗ-imidazole racemate

Concentrated sulfuric acid (58 ml) was cooled to -10 ° C and 4- (2,3-dihydro-1H-inden-2-yl) -1H-imidazole hydrochloride (Karjalainen, AJ et al.) Was added in small portions to this acid solution. 4,689,339;

13.8 g, 0.0625 mol) and urea nitrate (7.70 g, 0.0625 mol) while maintaining the temperature at -10 ° C. After the reaction, the solution is poured onto ice. The solution is made alkaline and extracted three times with ethyl acetate. The organic extracts are mixed, dried and evaporated to dryness. Yield: 13.0 g, 91% of 4- (2,3-dihydro-5-nitro-1H-inden-2-yl) -1H-imidazole.

Reduction of 4- (2,3-dihydro-5-nitro-1H-inden-2-yl) -1H-imidazole to 4- (5-amino-2,3-dihydro-1H-inden-2-yl) -1H-imidazole was performed 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) -1H-imidazole in 100 ml of ethanol and shaking the mixture under hydrogen atmosphere at room temperature. When the reduction stops, the catalyst is removed. The filtrate was concentrated to give 9.63 g (94%) of 4- (5-amino-2,3-dihydro-1H-inden-2-yl) -1H-imidazole. The resulting product was purified by flash chromatography eluting with methylene chloride-methanol (9.5: 0.5).

A flask containing fluoroboric acid (48% w / w aqueous solution, 120 mL) and 9.50 g (0.0457 mol) of 4- (5-amino-2,3-dihydro-1H-inden-2-yl) -1H-imidazole was added to the flask. ice-salt bath and cool to 0 ° C. While maintaining at 0 ° C, 3.30 g (0.0478 mol) of sodium nitrate dissolved in 10 ml of water were slowly added. The mixture was stirred for one hour at 0 ° C and then for one hour at room temperature. The reaction mixture was evaporated twice to dryness with toluene. Thermal decomposition was performed in a flask heated with an electric heating cap. The heating was stopped when the white vapor of boron trifluoride stopped. The crude product is dissolved in methanol, filtered and evaporated to dryness. Crude 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole yield 9.51 g, 99%. The product was purified by flash chromatography (methylene chloride-methanol (9.5: 0.5)).

¹ H NMR (300 MHz, CD ₃ OD): δ 2, 96-3.08 (2H, m, one H and one H-3), 3.19-3.27 (2H, m, other H 1 and other H-3), 3.68 (1H, quintet, ³ Jhh θ'3 Hz, H-2), 6, 80-6.86 (1H, m, H-6), 6.83 (1H, s, im-5), 6.92 (1H, dd, ³ J _HF 8.9 Hz, ⁴ Jh 2.4 Hz, H-4), 7.16 (1H, dd, ³ J H H 8.1 Hz, ⁴ J _HF 5.3 Hz, H-7), 7.59 (1H, s, im-4).

Separation of antipodes

D - (-) - tartaric acid (, 44 g, 0.00293 mol) was dissolved in 2.5 mL of water at 60 ° C. 4- (5-Fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole racemate (1.03 g, 0.00509 mol) and 178 μΐ concentrated hydrochloric acid at 60 ° C were added. at temperature. The mixture was stirred at temperature until it became a clear solution. The solution is then allowed to cool slowly. The precipitate is collected and recrystallized five times in water to give the (-) - antipode D - (-) - tartaric acid salt: mp 186-187 ° C.

The adduct of D - (-) - tartaric acid and (-) - antipode was dissolved in water at 60 ° C and ethyl acetate was added. The solution is made alkaline (pH 10) using dilute sodium hydroxide solution. The ethyl acetate phase is separated and the aqueous phase is extracted twice with ethyl acetate. After mixing the organic phases, they are washed with water. The ethyl acetate is evaporated to dryness and the residue is crystallized from ethyl acetate. The crude product was filtered with suction and washed with cold ethyl acetate: mp 139 ° C (DSC), specific rotation at 2O ^J C in methanol solution -3.7 ° C (c = 20 mg / ml).

The (-) - antipode base is dissolved in ethyl acetate and filtered with Millipore. The filtrate is acidified (pH 1) with anhydrous hydrochloric acid-ethyl acetate solution and cooled to -10 ° C. The precipitate is filtered and washed with ethyl acetate. Recrystallization from ethyl aceLT 3468 B gives 4- (5-fluoro-2,3-dihydrol-H-inden-2-yl) -ΙΗ-imidazole salt of hydrochloric acid as a white crystalline solid: mp 191 ° C (DSC); 99.8% chromatographic purity (HPLC); optical purity 99.9% (HPLC); comparative rotation at ambient temperature in aqueous solution -3.5 ° (c = 20 mg / ml).

The (+) - antipode was dissolved in a similar manner to the (-) - isomer using L - (+) - tartaric acid as the solubilizing reagent to give the L - (+) - tartaric acid and (+) - antipode adduct; mp 187-189 ° C. The base and hydrochloric acid salt (melting point 190 ° C) were made as described above. Chromatographic purity of hydrochloric acid salt 98.7% (HPLC); optical purity 99, 6% (HPLC); comparative rotation at ambient temperature in aqueous solution + 3.2 ° (c = 20 mg / ml).

Claims (6)

DEFINITION OF INVENTION A 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole (-) - antipode and pharmaceutically acceptable salts thereof. 2. A process for the preparation of 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole (-) - antipode, which comprises converting 4- (5-fluoro-2,3-dihydro) -1H-inden-2-yl) -1H-imidazole racemate to the diastereoisomeric salt mixture by treatment with optically active acids and then partitioning the diastereoisomeric salt mixture by fractional crystallization to convert the separated 4- (5-fluoro-2,3dihydro-1H-indene) -2-yl) -IH-imidazole salt (-) - antipod to free base. 3. A process according to claim 2, wherein the optically active acid is D - (-) - tartaric acid. 4. 4- (5-Fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole (+) - antipode and pharmaceutically acceptable salts thereof. 5. A method of separating 4- (5-fluoro-2,3-dihydro-1H-inden-2-yl) -1H-imidazole (+) - antipode, which comprises converting 4- (5-fluoro-2,3- dihydro-1H-inden-2-yl) -H-imidazole racemate is converted to the diastereoisomeric salt mixture by treatment with optically active acids and then partitioned between the diastereoisomeric salt mixture by fractional crystallization to convert the separated 4- (5-fluoro-2,3-dihydro-1 H- inden-2-yl) -lH-imidazole salt (+) - antipod to free base. 6. A process according to claim 5, wherein the optically active acid is L - (+) - tartaric acid.