NO167735B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 4 (5) -SUBSTITUTED IMIDAZOLE DERIVATIVES. - Google Patents

Description

This invention relates to methods for the preparation of new 4(5)-substituted imidazole derivatives and their non-toxic salts.

The imidazole derivatives produced according to the invention are potent and selective α2-receptor antagonists and have the general formula:

where

is lower alkyl, OH-substituted lower alkyl or lower alkenyl.

Production of the non-toxic pharmaceutically acceptable acid addition salts of these compounds is also covered by the invention. The compounds of formula I form acid addition salts with both organic and inorganic acids. They can thus form many pharmaceutically usable acid addition salts, for example chlorides, bromides, sulphates, nitrates, phosphates, sulphonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

Pharmaceutical preparations may comprise at least one compound

of formula (I) or a non-toxic, pharmaceutically acceptable salt thereof, and a compatible pharmaceutically acceptable carrier.

Adrenergic receptors denote physiologically active binding sites that are specific for norepinephrine and adrenaline and located on the surface of the cell membrane. Adrenoceptors of the sympathetic nervous system have been classified into two different types, alpha- (a) and beta- (P) receptors, both of which can be further divided into two subgroups, i.e. and a2 as well as P^ and P2. Of these receptor types, P^, P2 and cx^ are mainly located postsynaptically on the surface of e.g. smooth muscle and thus controls e.g. contraction or relaxation of smooth muscle, while cx2 receptors are mainly located pre-synaptically on noradrenergic nerve endings. If a2 receptors are stimulated by noradrenaline under physiological conditions, the noradrenaline release is blocked, i.e. this is a negative feedback ("feedback") phenomenon.

Apart from norepinephrine, this negative feedback phenomenon can be induced by certain synthetic α2 agonists such as detomidine (compound A) and some of its closely related derivatives. The primary pharmacodynamic effects of detomidine, e.g. sedative effects, have also been determined to be due to its ability to stimulate α2 receptors (Virtanen et al., Progress in Neuro-Psychopharmacology and Biological Psychiatry, suppl. 1983, p. 308).

A need for a selective cx2 antagonist can be expected, e.g. in certain diseases which are believed to be related to reduced norepinephrine availability in the postsynaptic adrenoceptors in the central and/or peripheral nervous system. These diseases include e.g. endogenous depressions and asthma.

Glucose and lipid metabolism is regulated by an inhibition mechanism involving ot2 receptors. a2-antagonists can therefore be important in the treatment of metabolic disorders such as diabetes and obesity.

Presynaptic α-receptors also participate in platelet aggregation. Cx2 agonists have been shown to activate and antagonists to inhibit human platelet aggregation (Grant & Schutter, Nature, 1979, 277, 659). cx2 antagonists may therefore be clinically applicable in pathogenic conditions that involve increased aggregation, e.g. migraine. The acute effects of ergotamine, a classic anti-migraine compound, are thought to be due to its α-agonist action. Compounds with both antagonistic effects on cx2 receptors and agonist effects on postsynaptic α2 receptors can thus have great advantages in the acute and preventive treatment of migraine.

According to the invention, the compounds of the general formula (I) are prepared by the methods specified in claim 1. These methods can be illustrated in more detail as follows: a) An alkali metal salt, e.g. sodium salt, of aceto acetic acid ethyl ester having the formula is reacted with a,a'-dibromo-ortho-xylene having the formula to give 2-acetyl-2,3-dihydro-1H-indene-2-carboxylic acid ethyl ester having the formula

Alternatively, other lower alkyl esters, e.g. the methyl ester of acetoacetic acid, is used.

Compound (IV) is further brominated, e.g. with bromine, in a solvent such as methylene chloride or methanol. The reaction temperature can vary from room temperature to +60°C. The brominated intermediate of the formula is further reacted with formamide with the addition of an excess of formamide at 170-180°C to give 4(5)-(2,3-dihydro-2-ethyl-oxy-carbonyl-1H-inden- 2-yl)imidazole having the formula

The compounds (I) are prepared according to the invention by hydrolysis of (VI) to the corresponding acid (VII) which has the formula

which is further reduced to the corresponding aldehyde (VIII) Reaction of the aldehyde (VIII) in a Grignard reaction with an alkylmagnesium halide of formula where R5 is a lower alkyl group, and dehydration of the intermediate product (IX), for example by heating with potassium hydrogen sulfate, gives compounds with formula (I) where the 2-substituent is an alkenyl group. The alkenyl group can further be hydrogenated to an alkyl group. b) From the intermediate product (VI) it is likewise possible, according to the invention, with a Grignard reaction followed by dehydration to directly synthesize 2-alkenyl derivatives. These can further be hydrogenated to 2-alkyl derivatives. In this way compound (VI) is reacted with an alkylmagnesium halide at 20-50°C in a suitable ether such as tetrahydrofuran to give compound (X) which is dehydrated, e.g. by heating in the presence of potassium hydrogen sulfate. From the thus obtained compound (XI) of formula

where Rg is H or lower alkyl, compounds of formula (I) where Ri is lower alkyl can further be obtained by hydrogenation.

c) Compounds with formula (I) can further be prepared analogously to Method a by starting from acetoacetonitrile (XII) and

a,a'-dibromo-o-xylene (III)

In this way, the first step results in 2-acetyl-2,3-dihydro-1H-indene-2-carbonitrile having the formula which is brominated, e.g. with bromine in methanol to 2-bromoacetyl-2,3-dihydro-1H-indene-2-carbonitrile having the formula which is then condensed to an imidazole derivative (XV) by heating in formamide at 160-180°C. According to the invention, the nitrile derivative (XV) is converted to compounds of formula (I) by reaction with alkylmagnesium bromide, R5MgBr, in tetrahydrofuran to a 2-acyl derivative (XVI)

Reduction of the acyl derivative (XVI) with sodium borohydride in ethanol gives compounds of formula (IX), from which compounds of formula (I) can. is produced by dehydration and possibly subsequent hydrogenation as described above (Method a).

d) According to this method, an alkali metal salt is reacted, e.g. sodium salt, of 1-alkenyl-2-propanone having the formula

where R 2 is hydrogen or lower alkyl, with an α,α'-dibromo-ortho-xylene of formula to the compound 1-[2,3-dihydro-2-(1-alkenyl)-1H-inden-2-yl]ethanone which has the formula

The compound (XIX) is further brominated, e.g. with bromine in a solvent such as methylene chloride. The reaction temperature can then, for example, be room temperature.

The brominated intermediate having the formula

is further reacted with an excess of formamide at 160-180°C to give compound (Ia), a 4(5)[2,3-dihydro-2-(1-alkenyl)-1H-inden-2-yl]- imidazole derivative where the alkenyl group can optionally be hydrogenated further catalytically to the alkyl group e) According to this method, a 3-alkenoate where R2 is hydrogen or lower alkyl is reacted with an a,a'-dibromo-o-xylene (III) to give ethyl 2,3-dihydro-2-(1-alkenyl)-1H-indene-2-carboxylate having the formula This ester is hydrolyzed to the corresponding acid and then converted to the acyl chloride. Reaction of the acyl chloride with ethoxymagnesium malonic acid ethyl ester, e.g. in dibutyl ether and decarboxylation of the intermediate obtained (XXIII)

under heating in a relatively concentrated acid solution, gives compounds of formula (XIX) which can be converted into compounds of formula (I) as in Method d above.

The intermediates of formula VI, VII, VIII, XV and XVI are new and represent part of the present invention. They can be summarized in the formula stated in claim 2.

For example, the following compounds are particularly important as α2 antagonists:

Compound I 2-[2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-yl]-2-propanol Compound II 4(5)-(2,3-dihydro- 2-isopropenyl-1H-inden-2-yl)imidazole Compound III 4(5)-(2,3-dihydro-2-isopropyl-1H-inden-2-yl)imidazole Compound IV 4(5)-(2, 3-Dihydro-2-vinyl-1H-inden-2-yl)imidazole o<2-antagonism was determined in vitro using isolated, electrically stimulated mouse vas deferens preparations (Marshall et al., Br. J. Pharmac. 62 , 147, 151, 1978). In this model, the α2 agonist (Detomidine) blocks electrically stimulated muscle contractions, and the effect of the α2 antagonist is seen by administering it before the agonist and by determining its pA2 value. Results:

The clinical dosage ranges for the new compounds have been determined to be 0.1-10 mg/kg per day both by oral and IV administration.

Example 1

a) Ethyl 2-acetyl-2,3-dihydro-1H-indene-2-carboxylate

Tetrabutylammonium bromide (3.1 g) and 48% NaOH (90 ml) were added

first added to a flask. The flask was then charged with α,α'-dibromo-o-xylene (50 g) in toluene (250 mL) and ethyl acetoacetate (24.6 g) in toluene (50 mL) added dropwise. During this, the temperature of the reaction mixture rose to 40°C and stirring was continued for 2.5 hours. Water was added and the product was extracted into toluene. The toluene layers were washed with water and evaporated in a rotary evaporator. Yield 49.2 g.

b) Ethyl 2-bromoacetyl-2,3-dihydro-1H-indene-2-carboxylate

Ethyl 2-acetyl-2,3-dihydro-1H-indene-2-carboxylate (43.0 g)

was dissolved in methylene chloride (750 ml) and 29.8 g of bromine in methylene chloride (320 ml) was added dropwise to the solution. After the bromine color had disappeared, the reaction mixture became

washed first with dilute NaHCO 3 solution and then with water.

The organic layer was dried over Na 2 SO 4 and evaporated to dryness. Yield 52.9 g.

c) Ethyl 2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-carboxylate

Ethyl 2-bromoacetyl-2,3-dihydro-1H-indene-2-carboxylate

(44.6 g) and formamide (220 ml) were heated for 8 hours at 160°C. The reaction mixture was then poured into water (200 mL). The solution was acidified with dilute hydrochloric acid, washed with methylene chloride and made alkaline with ammonium hydroxide. The product was extracted into ethyl acetate, washed with water, dried over MgSO 4 and evaporated to dryness. The yield of the crude product was 14.6 g. M.p. 147-149°C (from ethyl acetate).

d) 2-[2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-yl]-2-propanol

A Grignard reagent was prepared from magnesium turnings (0.47 g) and methyl bromide in dry tetrahydrofuran. Ethyl 2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-carboxylate (1.0 g) was dissolved in dry tetrahydrofuran and the Grignard reagent was added dropwise to the solution at 50-60°C. After the addition, the mixture was refluxed for 2 hours. The reaction mixture was poured into acidic ice water and the tetrahydrofuran was evaporated. The aqueous solution was made alkaline with concentrated ammonium hydroxide and the product was extracted into ethyl acetate. The ethyl acetate was dried over MgSO 4 and evaporated to dryness. The product (0.84 g) was converted to the hydrochloride in ethyl acetate. Temp. 148-152°C (from isopropanol). e) 4(5)-(2,3-dihydro-2-isopropenyl-1H-inden-2-yl)imidazole 2-[2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-yl]-2-propanol hydrochloride (0.50 g) and potassium hydrogen sulfate (2.5 g) was mixed. The mixture was heated in an oil bath at 120-140°C for 4 hours with occasional stirring with a glass rod.

Then the cooled reaction mixture was suspended in hot methanol. The salt was filtered off and washed several times with hot ethanol. The combined ethanol solutions were evaporated and the residue dissolved in water. The aqueous solution was made alkaline with dilute NaOH, and the product was extracted into methylene chloride. The methylene chloride solution was dried and evaporated. The evaporation residue was 0.32 g. The product was converted to its HCl salt in a mixture of isopropanol and ethyl acetate. Yield 0.20 g. M.p. 203-207°C. f) 4(5)-(2,3-dihydro-2-isopropyl-1H-inden-2-yl)imidazole 4(5)-(2,3-dihydro-2-isopropenyl-1H-inden-2-yl)imidazole hydrochloride (0.15 g) was hydrogenated in an aqueous ethanol solution in the presence of 10% Pd/C. The charcoal was filtered off and the ethanol evaporated. The residue was dissolved in ethyl acetate and the solution was allowed to stand for several days during which the product precipitated as hydrochloride. Yield 0.12 g. M.p. 227-234°C.

Example 2

a) 2-acetyl-2,3-dihydro-1H-indene-2-carbonitrile

Sodium (13.2 g) was dissolved in dry ethanol (220 ml). Dry

ether (270 mL) was added. To the prepared solution were simultaneously added α,α'-dibromo-o-xylene (85.2 g), dry ether (250 ml) and acetonitrile (45.6 g) in dry ether (160 ml) during 1 hour. Acetoacetonitrile was previously prepared according to the description in US patent 4152336. After the addition, the mixture was stirred for 1 hour at room temperature and then refluxed for 2 hours. The cooled reaction mixture was poured into water. The ether layer was separated and the aqueous layer extracted once more with ether. The combined ether solutions were washed with water, dried (MgSO 4 ) and evaporated. Yield of crude product 73.8 g.

b) 2-bromoacetyl-2,3-dihydro-1H-indene-2-carbonitrile 2-acetyl-2,3-dihydro-1H-indene-2-carbonitrile (32.9 g) was

dissolved in ether (33 ml) and aluminum chloride (0.17 g) was added. Bromine (28.4 g) was added dropwise at room temperature and the loss of the bromine color was observed. The ether solution was washed with a Na 2 CO 3 solution and water, dried over MgSO 4 and evaporated. 35.7 g of crude product was obtained.

c) 2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-carbonitrile 2-bromoacetyl-2,3-dihydro-1H-inden-2-carbonitrile (27.8 g )

and formamide (150 mL) was heated at 180°C for 8 hours. The cooled reaction mixture was then poured into dilute hydrochloric acid. The acidic solution was washed with methylene chloride and made alkaline with ammonium hydroxide. The product was extracted

into ethyl acetate and the ethyl acetate solution was washed with water, dried and evaporated. The hydrochloride of the product was prepared in ethyl acetate. Temp. 228-235°C.

d) 1-[2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-yl]ethanone

Mg turnings (1.2 g) and dry tetrahydrofuran were added

to a flask. Methyl bromide was passed through the mixture until the Mg chips had disappeared. The mixture was heated as needed. 2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-carbonitrile (2.1 g) as a base was dissolved in dry tetrahydrofuran and added dropwise to a previously prepared Grignard reagent at 40-50°C. After the addition, the mixture was refluxed for 3 hours. The reaction mixture was cooled to 0°C and a 6M HCl solution was carefully added dropwise, after which the reaction mixture was evaporated to remove THF. Water was added and the acidic solution was washed with methylene chloride. The aqueous phase was made alkaline with ammonium hydroxide and the product was extracted into methylene chloride. The HCl salt was prepared in a mixture of isopropanol and ethyl acetate. Temp. 181-184°C.

e) 1-[2,3-dihydro-2-[imidazol-4(5)-yl]-1H-.inden-2-yl] ethanol 1-[2,3-dihydro-2-[imidazol-4( 5)-yl]-1H-inden-2-yl]ethanone

(0.11 g) was dissolved in dry ethanol (10 ml) and NaBH4 (0.009 g) was added in small portions at room temperature, after which the mixture was stirred at 40°C for 4 hours. Some ethanol was evaporated and the mixture was poured into acidic water. The water was made alkaline and the product was extracted with methylene chloride. The methylene chloride solution was dried and evaporated. Yield 0.06 g.

f) 4(5)-(2,3-dihydro-2-vinyl-1H-inden-2-yl)imidazole

1.5 g of potassium hydrogen sulfate was mixed with 1-[2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-yl]ethanol hydrochloride (0.03 g) and the mixture was stirred with a glass rod to a homogeneous mixture. The mixture was heated to 120-140°C for 3 hours. The cooled reaction mixture was suspended in ethanol under heating. The salts were filtered off and washed several times with hot ethanol. The combined ethanol portions were evaporated to dryness, water was added, the solution made alkaline, and the product extracted into ethyl acetate. The ethyl acetate solution was dried and evaporated to dryness.

Example 3

a) 1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)ethanone

Tetrabutylammonium bromide (1.9 g) and 55 ml of a 48% NaOH solution were mixed in a flask and α,α'-dibromo-o-xylene (30.0 g) in toluene (185 ml) was added. Then, 4-penten-2-one (9.8 g) dissolved in toluene (20 ml) was added dropwise to the mixture. After the addition, the reaction mixture was stirred at 100°C until the gas chromatogram showed that the starting material had disappeared.

The reaction mixture was cooled and water was added. The product was extracted into toluene, and the toluene layers were washed with water and evaporated under reduced pressure. Yield 20.4 g.

MS: 186 (2, M+); 143 (82); 142 (27); 141 (28); 129 (22); 128

(100); 127 (14); 115 (52); 91 (10); 43 (35).

<13>C NMR: (20MHz, CDCl3): S 26.13 (OFR q), 40.47 (2 d), 63.69 (s) , 115.49 (t) , 124 .30 (2 d) , 126.60 (2d) , 140.13 (d) , 140.59 (2s), 208.00 (s).

<1->H NMR (80MHz, CDCl3: 2.19 (3H, s, Me); 3.05 and 3.46 (4H, AB q, J 15.6Hz, methylene protons from the indan ring (H-1 and H-3 ));

5.16 (1H, dd, J(gem) 0.7Hz J(trans) 17.6Hz, a terminal methylene proton); 5.16 (1H, dd, J(gem) 0.7Hz, J(cis) 10.3Hz, the second terminal methylene proton); 6.02 (1H, dd, J(Cis) 10.3Hz, J(trans) 17.6Hz, methine proton; 6.95-7.38 (4H, m, aromatic).

b) 2-bromo-1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)ethanone

The starting material 1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)ethanone (5.0 g) was dissolved in methylene chloride (50 ml) and added to the solution. Bromine (4.3 g) in methylene chloride (45 ml) was added dropwise at room temperature. After the gas chromatogram showed that the starting material had been reacted, the methylene chloride solution was washed first with a dilute NaHCO 3 solution and then with water. The organic layer was dried with Na 2 SO 4 and the solvent was evaporated under reduced pressure.

MS: 266 and 264 (1 and 1, M+); 185 (12); 171 (15); 167 (13); 143

(100) ; 142 (33) ; 141 (48) ; 129 (13) ; 128 (39) ; 127 (12) ; 115 (44) .

c) 4(5)-(2,3-dihydro-2-vinyl-1H-inden-2-yl)imidazole The starting material, 2-bromo-1-(2,3-dihydro-2-vinyl-1H-inden-

2-yl)ethanone (15.0 g) and formamide (100 ml) were heated for 7 hours at 160°C.

The reaction mixture was cooled and poured into water. The water was acidified with dilute hydrochloric acid and washed with toluene. The aqueous phase was made alkaline with ammonium hydroxide, and the product was extracted into methylene chloride. The organic phase was washed with water and dried and the solvent evaporated. The crude product was purified by column chromatography. The hydrochloride of the product was prepared in a mixture of ethyl acetate-isopropanol. Temp. 193-197°C (HCl salt). MS: 210 (100, M+); 209 (55); 195 (50); 183 (41); 182 (22); 181 (17); 168 (13); 167 (17); 166 (12); 141 (13); 129 (15); 128 (15); 127 (10); 115 (23);' 104 (14); 91 (12); 81 (14). HCl salt, <13>C NMR (20MHZ, MeOH-d4): δ 45.11 (OFR 2h); 50.37 (s); 115.49 (h); 117.06(d); 125.42 (2d); 127.99 (2d); 135.47 (d); 140.04 (s); 141.68 (2s); 142.83 (d).

<X>H NMR (HCl salt) (80MHz, MeOH-d4) : S 3.37 (4H, s, methylene protons from the indane ring (H-1 and H-3)); 4.99 (1H, dd, J(gem) 0.5Hz, J(trans) 17.4Hz, a terminal methylene proton); 5.17 (1H, dd, J(gem) 0.5Hz, J(cis) 10.6Hz, the second terminal methylene proton, 6.19 (1H, dd, J(cis) 10.6Hz, J(trans) 17 ,4Hz, methine proton); 7.07-7.32 (4H, m, aromatic); 7.40 (1H, d, <4>J 1.3Hz, im-5(4)); 8.83 (1H , d, <4>J 1.3Hz, im-2).

Example 4

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

4(5)-(2,3-dihydro-2-vinyl-1H-inden-2-yl)imidazole (1.0 g) was hydrogenated in the presence of 10% Pd/C in ethanol (10 mL). After the hydrogen uptake had stopped, the reaction mixture was filtered. The product, 4(5)-(2,3-dihydro-2-ethyl-1H-inden-2-yl)imidazole, was obtained after evaporation.

Example 5

a) Ethyl 2,3-dihydro-2-vinyl-1H-indene-2-carboxylate Tetrabutylammonium bromide (0.31 g) and 48% NaOH solution

(9 mL) was added to a flask. To the flask was added α,α'-dibromo-o-xylene (5.0 g) in toluene (15 mL). The mixture was stirred and ethyl 3-butenoate (2.16 g) in toluene (15 mL) was added

dropwise at room temperature. After the addition, the temperature was slowly allowed to rise to +60°C. The mixture was stirred at this temperature for 3.5 hours and then cooled. The toluene layer was separated, washed with water and evaporated under reduced pressure.

MS: 216 (17, M+); 143 (100); 142 (62); 141 (42); 128 (50); 115 (38).

b) 2,3-dihydro-2-vinyl-1H-indene-2-carboxylic acid

Sodium hydroxide (7.99 g) was dissolved in water (80 ml) and

to the solution was added dropwise ethyl 2,3-dihydro-2-vinyl-1H-indene-2-carboxylate (7.99 g) dissolved in ethanol (110 ml). After the addition, the reaction mixture was refluxed

for 3 hours. Excess ethanol was evaporated, water was added and the mixture was washed with ether. The aqueous solution was acidified with concentrated hydrochloric acid. The product was extracted into methylene chloride which was washed with water, dried and evaporated to give the product as a hydrochloride salt.

^■H NMR (80MHz, CDCl 3 ): S 3.10 and 3.56 (4H, AB q, J 15.8Hz, methylene protons from the indane ring (H-1 and H-3)); 5.04-5.27 (2H,

m, terminal methylene protons); 6.12 (1H, dd, J(cis) 10.6Hz, J(trans)); 17.3Hz, methine proton); 6.9-7.4 (4H, m, aromatic), 9.96 (1H, broad s, -COOH).

c) 2,3-dihydro-2-vinyl-1H-indene-2-carboxylic acid chloride

A mixture of the starting material, 2,3-dihydro-2-vinyl-1H-indene-2-carboxylic acid (5.09 g) and thionyl chloride (25 ml) was refluxed for 10 hours. Excess thionyl chloride was distilled from under reduced pressure, and the crude product was used as such in the further processing. d) 1-(2,3-dihydro-2-vinyl-1H-inden-1-yl)ethanone 1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)ethanone was prepared by treating 2,3-dihydro-2-vinyl-1H-inden-2-carboxylic acid chloride with ethoxymagnesium malonic acid ethyl ester in dibutyl ether and then with sulfuric acid according to the literature (Reynolds, G. A. and Hauser, C. B., Org. Synth., 30 (1957) 70). e) 2-bromo-1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)-ethanone and 4(5)-(2,3-dihydro-2-vinyl-1H-inden- 2-yl)imidazole was prepared in the same way as in Example 3.

Example 6

1-[2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-yl]ethanol

Preparation of the starting material, ethyl 2,3-dihydro-2-[imidazol-4(5)-yl]-1H-indene-2-carboxylate, is described in example 1c.

a) 2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-carboxylic acid

A mixture consisting of ethyl 2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-carboxylate (10.0 g), ethanol (140 ml), sodium hydroxide (10 g) and water (100 ml) was boiled for 4 hours (the reaction was checked by thin layer chromatography). The ethanol was driven off by evaporation. The aqueous solution was washed with methylene chloride. Then the pH of the water solution was adjusted to 6, and the solution was washed with ethyl acetate. Then the pH was adjusted to 3, and the product was extracted into n-butanol. The solvent was removed by evaporation, after which the product was obtained in base form. The hydrochloride was prepared by adding a 2 M HCl solution and a small amount of acetone to the evaporation residue. The solution was evaporated to dryness. Acetone was added to the evaporation residue while simultaneously heating. The solution was allowed to stand until the hydrochloride had precipitated. The product was filtered and dried. Melting point 240-250°C.

MS: 288 (23,M<+>), 184(45), 183(100), 182(39), 181(16,

156(10), 154(15), 129(14), 128(17), 127(16), 115(26), 91(30), 77(11).

HCl salt, <13>NMR (20 MHZ, MeOH-d4): S 43.65 (OFR 2h) , 53.82 (s) , 117.76 (d), 125.30 (2d), 128.14 (2d), 135.62 (d), 136.95 (s),. 140.92 (2s), 174.44 (s).

HCl salt, % NMR (80 MHZ, MeOH-d4): S 3.44 and 3.85 (4H, AB q,

J 15.7 Hz, inner ring methyl protons (H-1 and H-3)), 7.17-7.67 (4H, Bl, arom.), 7.49 (1H, d, <4>J 1.5 Hz, im-5(4)), 8.85 (1H, d, 4J 1.5 Hz, im-2).

b) 2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-carbaldehyde

2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-carboxylic acid

(5.0 g calculated as base) was dissolved in dry tetrahydrofuran (30 ml). Borane-methyl sulfide (2.0 M THF solution, 11 mL) was added under a nitrogen atmosphere and room temperature. After the addition, the mixture was boiled for 2 hours. The solvent and dimethyl sulfide were removed by evaporation, and the evaporation residue was dissolved in methylene chloride (10 mL). This methylene chloride solution was added dropwise to a suspension consisting of pyridinium chlorochromate (5.19 g) and methylene chloride (40 ml). After the addition, the mixture was boiled for 2 hours, after which 100 ml of ether was added. The mixture was then filtered through diatomaceous earth, and the solvent was removed by evaporation.

c) 1-[2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-yl]-ethanol

2,3-dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-carbaldehyde

was reacted with a Grignard reagent prepared from magnesium shavings and methyl iodide (cf. example 1d). The HCl salt was prepared in ethyl acetate.

MS: 228 (9, M<+>), 213 (2 M-CH 3 ), 210 (6 M-H 2 O), 209 (7),

184 (39), 183 (100, M-CH(OH)CH3), 182 (15), 128 (10),

115 (16).

HCl salt, <3->H NMR (80 MHz, MeOH-d4) : S 1.04 (3H, d, JH 6.3 Hz, CH3),. 3.22 (2H, s, H-l or H-3 of the inner ring), 3.25 and

3.45 (2H, AB q, J 16.2 Hz, H-1 or H-3 of the inner ring),

4.03 (1H, q, J 6.3 Hz, >CHCH3), 7.04-7.29 (4H, m, arom.),

7.35 (1H, d, <4>J 1.4 HZ, im-5(4)), 8.74 (1H, d, <4>J 1.4 Hz, im-2).

Claims (2)

1. Analogous process for the preparation of therapeutically active 4(5)-substituted imidazoles of formula (I): where Ri is lower alkyl, OH-substituted lower alkyl or lower alkenyl, and their non-toxic acid addition salts, characterized in that a) an ester with the formula: where R is lower alkyl, is hydrolysed to the corresponding acid: which is further reduced to the aldehyde: which is reacted with an alkylmagnesium halide of the formula: R5MgHal where R5 is lower alkyl, to give the compound: which can be dehydrated to a compound of formula (I), where Ri is lower alkenyl, which can optionally be hydrogenated to a compound of formula (I), where R^ is lower alkyl b) an ester of the formula: where R is lower alkyl, is reacted with the alkylmagnesium halide: R5MgHal where R5 is lower alkyl, to give a compound of the formula: which is dehydrated to give the compound: where R6 is hydrogen or lower alkyl, which can optionally be hydrogenated to a compound of formula (I) where R^ is alkyl, c) a nitrile of the formula: is reacted with the alkylmagnesium bromide R5MgBr, where R5 is lower alkyl, to give the ketone: which is reduced with sodium borohydride to the compound: which can be dehydrated to a compound of formula (I), where Ri is lower alkenyl, after which the compound can optionally be hydrogenated to a compound of formula (I), where R^ is lower alkyl d) a compound of the formula: where R2 is hydrogen or lower alkyl, is brominated to the compound: which is further reacted with formamide to the compound: where Ri is -CH=CH-R2, whereupon the compound can optionally be hydrogenated catalytically to the corresponding compound where R x is -CH2-CH2-R<2>, or e) an ester with the formula: where R2 is hydrogen or lower alkyl, is hydrolysed to the corresponding acid which is further converted to the corresponding acid chloride which is then reacted with ethoxymagnesium malonic acid ethyl ester and after decarboxylation of the intermediate gives a ketone: which are further converted into compounds of formula (I) according to the method described in step (d), and optionally the product formed is converted into an acid addition salt. 2. New compound, characterized by the formula: where X is -COOR, where R is lower alkyl; -COOH; -CHO; -CN or where R 5 is lower alkyl.