AU634556B2 - 4(5)-substituted imidazole derivatives, and intermediates and processes for their preparation - Google Patents

Description

634556 COMMONWEALTH OF AUSTRALIA PATENT ACT 1952 COMPLETE SPECIFICATION FOR OFFICE USE CLASS INT. CLASS Application Number: Lodged: Complete Specification Lodged Accepted Published: Priority: Related Art: NAME OF APPLICANT FARMOS-YHTY 4

OY

ADDRESS OF APPLICANT PO;-cBox 425; SF-20101 Turku, r, Finland NAME(S) OF INVENTOR(S) Arja Leena KARJALAINENand Arto Johannes KARJALAINEN ADDRESS FOR SERVICE: DAVIES COLLISON, Patent Attorneys 1 Little Collins Street, Melbourne. Vic. 3000.

COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: IMIDAZOLE DERIVATIVES, AND INTERMEDIATES AND PROCESSES FOR THEIR PREPARATION" The following statement is a full description of this invention, including the best method of performing it known to us: -1 2 This invention relates to imidazole derivatives, methods for their preparation,and intermediates for use therein.

The imidazole derivatives of this invention may be represented by the general formula

R

3

RI

4

H

I4 in which R 1 is isopropyl, vinyl or isopropenyl and R 3 and R4 are each hydrogen, methyl, ethyl, methoxy, or halogen.

(The word "lower" as used herein in the terms lower alkyl, lower alkenyl, lower alkenylidene and lower (hydroxy alkyl) means that the radical in question contains not more than carbon atoms.) This formula includes both intermediates and final products. The compounds in which R 1 is lower alkyl or lower alkenyl are potent and selective a 2 -receptor antagonists.

The salts of the compounds of the invention and especially the non-toxic pharmaceutically acceptable acid salts of the compounds of formula I, are within the scope of the invention. The compounds of the invention form acid salts with both organic and inorganic acids. They can thus form many pharmaceutically usable acid addition salts, as, for instance, chlorides, bromides, sulfates, nitrates, phosphates, sulphonates, formates, tartrates, 3 maleates, citrates, benzoates, salicylates, ascorbates and the like.

The invention includes within its scope pharmaceutical compositions comprising at least one of the compounds of formula or a non-toxic, pharmaceutically acceptable salt thereof, and a compatible pharmaceutically acceptable carrier therefor.

Adrenergic receptors are physiologically active binding sites which are specific to noradrenaline and °o"o 10 adrenaline and are located on the surface of the cell 0 0 1 o fmembrane. The adrenoceptors of the sympathetic nervous system have been classified into two different subtypes, alpha- and beta- receptors, which can both be So° further divided.into two subgroups, i.e. a, and a2 and 13 and 3 Of these receptor types, 0 and a, are mainly located postsynaptically on the surface of, smooth o muscle and thus mediate, smooth muscle contraction or u000 relaxation, whereas a receptors are mainly located So0 presynaptically on the terminals of noradrenergic nerves.

a, 'receptors are stimulated by noradrenaline under physiological conditions, noradrenaline release is blocked, i.e. there is a negative feedback phenomenon.

In addition to the effect caused by noradrenaline, this negative feed-back phenomenon may be induced by certain a 2 -agonists, e.g. detomidine and some of its near i i. I 4 analogues. The primary pharmacodynamic effects of detomidine, e.g. sedation, have also been proved to be due to its ability to stimulate a 2 -receptors (Virtanen et al., Progress in Neuro-Psychopharmacology and Biological Psychiatry, suppl. 1983, p. 308).

A selective a 2 -antagonist may therefore be predicted to be of use in, diseases which are believed to be connected with deficiency of noradrenalin available in the postsynaptic adrenoceptors of the central and/or peripheral nervous system. These diseases include e.g.

endogenous depression and asthma.

Glucose and lipid metabolism are regulated by an inhibitory mechanism involving p 2 -receptors. Thus cr 2 -antagonists may also be useful in the treatment of metabolic diseases like diabetes and obesity.

.o Presynaptic a 2 -receptors also take part in platelet aggregation. It has been shown that a 2 -agonists activate, and a 2 -antagonists inhibit, human platelet o aggregation (Grant Schutter, Nature 1979, 277, 659). Thus c 2 -antagonists may be useful clinically in pathogenic states .i o 'involving increased platelet aggregation, e.g. migraine.

The acute effects of ergotamine, a classical therapeutic agent against migraine, are regarded as being due to its i -agonist effect. Thus compounds with both antagonist effects on a 2 -receptors and agonist effects on postsynaptic a,-receptors may have great advantages in the acute and preventive treatment of migraine.

Mo 5 According to the invention, the new compounds of the formula: R3 4

H

in which R, is isopropyl, vinyl or isopropenyl and R 3 and R4 are each hydrogen, methyl, ethyl, methoxy, or halogen are made by a process which comprises reacting an indene derivative of formula: oa a o R COCH 2

B

4 in which R, is isopropyl, vinyl, isopropenyl, -CN, COOH, COO(lower alkyl), CHO, CO(lower alkyl) or hydroxyalkyl, R3 and R 4 are as hereinbefore defined, with formamide, and if necessary converting the radical R, in thi product obtained into a radical which is isopropyl, vinyl or isopropenyl.

This process may be operated in a variety of ways depending on the starting materials and desired end products. Preferred methods are as follows: I 7 -1 6 Method A A starting material for this method is made by reacting an alkali metal salt, e.g. the sodium salt, of acetoacetic acid ethyl ester, which has the formula 0 0 II I I CH -C-CH-C-OCH CH 3

(V)

NaP with at a'-dibromo-ortho-xylene of the formula

R

3

CH

2 Br 1 p (vi) 4 1 SR4

CH

2 Br o to give 2-acetyl-2,3-dihydro-lH-indene-2-carboxylic acid ethyl ester, which has the formula ,t R -0-CH 2

CH

3 10 -CH3 1

-CH

3 (VII) R4 Alternatively other alkyl esters, e.g. the methyl ester, of acetoacetic acid can be used.

The compound of formula (VII) is then brominated, e.g. with bromine in a solvent which, for example, can be methylene chloride or methanol. The reaction temperature can vary from room temperature to +60°C. The brominated intermediate, which has the formula -7 0

R

3 1LO0CH 2

CH

3 Rj~'Ci H 2 Br

(VIII)

U Ii 1

U

is then reacted with formamide in excess at l70-180 0 C to give 4(5)-(2,3-dihydro-2-ethyloxy-carbonyl-1H-inden-2-yl)imidazole, which has the formula: 0

(IX)

Compounds of the invention can be prepared from the compounds of formula (IX) in various ways. The compound can, for example, be hydrolysed to the corresponding acid of the formula: 0 R?

L-

Cr,) (X) which is then reduced to the aldehyde of formula: 8

R

3

N

Reacting the aldehyde of formula (XI) with an alkyl magnesium halide of the formula

R

5 MgHal 5 where R 5 is a methyl group, and dehydrating the c4 r intermediate of formula: 9 04 9R CHR 11) R14 for example by heating with potassium hydrogen sulfate, gives a compound of formula where the 2-substituent R 1 is a vinyl group. This constitutes an especially 1 a convenient route to compounds of formula I ii! which R 1 is alkenyl.

From the intermediate of formula (IX) it is also possible to synthesize 2-alkenyl derivatives according to the invention by reacting the compound of formula (IX) with an alkyl magnesium halide at 20-50*C in an appropriate ether such as tetrahydrofuran to give a compound of formula:

~L

r I 9 I U N (XIII) which is then dehydrated, e.g. by heating in the presence of potassium hydrogen sulfate, to give an alkenyl compound of the formula:

CH'

rs o R 3 (x-v) V 0 eH which can optionally be hydrogenated to give a corresponding alkyl compound. The hydrogenation may be carried out e.g. with hydrogen in the presence of a hydrogenation catalyst such as palladium on charcoal. The 0 10 reaction may be effected at ambient temperature and pressure.

So Method B The starting materials for this method can be obtained by reaction of acetoacetonitrile of formula 0 CH,-C-CHCN (XV) and an a, a'-dibromo-o-xylene of formula This reaction gives a 2-acetyl-2,3-dihydro-lH-indene-2carbonitrile of the formula: 10

(XVI)

c (xvl) which is then brominated, e.g. with bromine in methanol, to give a 2-bromoacetyl-2,3-dihydro-lH-indene-2-carbonitrile of the for,-ula:

R

3

CN

C-CE

2 Br O s (xvIz) 0 O 2o which is then condensed with formamide preferably at 160-180*C to give an imidazole derivative of formula:

R

3

(XVIII)

O 4 04 0 This nitrile may be converted into a compound of formula (I) by reacting it with an alkyl magnesium bromide of formula RsMgHal in tetrahydrofuran to give a 2-acyl derivative of formula: o

(XIX)

11 Reacting this compound further with an alkyl magnesium halide of formula RMgHal gives a compound of formula V 7

C-R

5 @p (xx) where R 5 and R 7 are each methyl groups. As before the product can be dehydrated and optionally subsequently hydrogenated to give compounds of formula Reduction of the acyl derivative of formula (XIX), e.g. with sodium borohydride in ethanol, gives compounds of formula (XII) from which compounds of formula can be prepared as before (using method A).

Method C In this method an alkali metal salt, e.g. sodium salt, of a l-alkenyl-2-propanone of the formula CH COCH-CH-CH-R' (XXI) where R' is hydrogen or methyl, is reacted with an ns. r a 12 a,a'-dibromo-orthoxylene of the formula R CH 2 Br to give a 1-12,3-dihydro-2-(1-alkenyl)-1H-inden-2-yl]ethanone of the formula R CHCH-R' R4 K COCH 3 where R, and R are as above.

e o The compound of formula (XXII) is then brominated, aone o e.g. with bromine in a solvent which may be, for example, methylene chloride. The reaction temperature may be, for o o Soo0 10 example, room temperature.

The brominated intermediate, which has the formula ooo 3

*CH-R'

oo o 4 OCH2Br is then reacted with formamide in excess formamide, preferably at 160-180 0 C, to give a 4(5)-12,3-dihydro-2-(lalkenyl)-1H-inden-2-yl]-imidazole of formula: (Ia) 13 Method-D In this method, a 3-alkenoate ester of formula R'-CH-CH-CH 2

(XXIV)

where is CH 3 or C 2H 5and R' is hydrogen or lower alkyl, is reacted with an ct-dibromo-o-xylene of formula (VI) to give a 2,3-dihydro-2-(l-alkenyl)-lH-indene-2-carboxylate of the formula

=CIA

R COOR" This ester can then be hydrolysed to the corresponding acid which may be converted into the acyl chloride, e.g. with thionyl chloride. Reacting the acyl chloride with ethoxy magnesium nialonic acid ethyl ester of formula: C 3CH20 CCHMgDCH 2 CH 3

(XXVI)

CH 3

CH

2 00C in dibutylether, and decarboxylating the intermediate obtained of formula: MoCCH 2 C H 3

(XXVII)

\COOCH

2

CK

3 14 by heating in a relatively concentrated acid, e.g. sulphuric acid, solution gives a compound of the formula (XXII) which can be converted into a compound of formula as in method C above.

These methods are described in more detail in the Examples below.

The following compounds of this invention have been found to be especially active a 2-antagonists: 4 0 4 Compound I 2, 3 -dihydro2isoprenyl....Hinden2.yl imidazole CH-

*H

Compound II 4 2 3 -dihydro-2-isopropyl-lH-nden2.yl)imidazole yCl~n~~l .~iU*Y41IJ--.* -I;Y~-U;i~Fnrr*NII~.Cn-II il-.-I I 15 Compound III 4(5)-(2,3-dihydro-2-vinyl-lH-inden-2-yl)imidazole The a -antagonism of these compounds was determined in vitro using the isolated, electrically stimulated mouse vas deferens preparation (Marshall et al., Br. J. Pharmac. 62, 147, 151, 1978). In this model, an aagonist (detomidine) blocks electrically stimulated muscular e° contractions and the effect of the a -antagonist is seen by administering it prior to the agonist and by determining its 10pA 2 value.

o o The following results were obtained Compound c -antagonism (pA 2 vs detomidine) mouse vas deferens 0 4 15 I 00 II 6.4 III 7.6 The clinical dosage range for the compounds of the invention may be 0.1-10 mg/kg per day for oral or administration.

The following Examples illustrate the invention.

J

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

Tetrabutylammonium bromide (3.1 g) and 48% NaOH ml) were placed in a flask. am'-dibromo-o-xylene (50 g) in toluene (250 ml) was added to the flask, followed by ethyl acetoacetate (24.6 g) in toluene (50 ml) added dropwise. During the addition the temperature of the reaction mixture rose to 40°C. After the addition, stirring was continued for 2.5 hours. Water was added and the o 0 o 10 product was extracted into toluene. The toluene extracts o were washed with water and evaporated in a rotary evaporator. 49.2 g of the product were obtained.

o' b) Ethyl 2-bromoacetyl-2,3-dihydro-lH-indene-2-carboxylate.

Ethyl 2 -acetyl-2,3-dihydro-lH-indene-2-carboxylate 15(43.0 g) was dissolved in methylene chloride (750 ml) and 29.8 g of bromine in methylene chloride (320 ml) was then added dropwise to the solution.

When the bromine colour had disappeared the reaction nixture was washed first with a dilute NaHCO 3 and then with water. The organic layer was dried over Na 2

SO

4 and evaporated to dryness. 52.9 g of the product were obtained.

c) Ethyl 2,3-dihydro-2-[imidazol-4(5)-yl]-lH-indene-2carboxylate.

Ethyl 2-bromoacetyl-2,3-dihydro-lH-indene-2carboxylate (44.6 g) and formamide (220 ml) were heated for 8 hours at 160 0 C. The reaction mixture was then poured into water (200 ml). The solution was acidified with dilute 17 hydrochloric acid, washed with methylene chloride, and made alkaline with ammonia. The product was extracted into ethyl acetate, and the extract was 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) 2-12,3-Dihydro-2-[imidazol-4(5)-yl]-lH-inden-2-yl]-2propanol hydrochloride.

A Grignard reagent was prepared from magnesium turnings (0.47 g) and methyl bromide in dry tetrahydrofuran.

Ethyl 2,3-dihydro-2-[im'dazol-4(5)-yl]-1H-indene-2carboxylate (1.0 g) was dissolved in dry tetrahydrofuran, and the Grignard reagent was added dropwise at 50-60 0 C to this solution. After the addition the mixture was refluxed for 2 hours. The reaction mixture was poured into acidic icewater and the tetrahydrofuran was evaporated. The aqueous solution was made alkaline with concentrated ammonia and the product was extracted in ethyl acetate. The ethyl acetate extract was dried over MgSO 4 and evaporated to dryness. The product (0.84 g) was converted into the hydrochloride in ethyl acetate. M.p. 148-152°C (from isopropanol).

e) 4(5)-(2,3-Dihydro-2-isopropenyl-1H-inden-2-yl)imidazole hydrochloride.

2-[2,3-Dihydro-2-[imidazol-4(5)-yl]-1H-inden-2yl]-2-propanol hydrochloride (0.50 g) and potassium hydrogen sulfate (2.5 g) were mixed. The mixture was heated in an 18 oil bath at 120-140 0 C for 4 hours and stirred from time to time with a glass stick. The cooled reaction mixture was suspended in warm ethanol. The insoluble salt was filtered off and washed several times with hot ethanol. The combined ethanol solutions were evaporated and the residue was dissolved in water. The aqueous solution was made alkaline with dilute NaOH and the product was extracted with methylene chloride. The methylene chloride so!.tion was dried and evaporated. The evaporation residue was 0.32 g.

The product was converted into its HC1 salt in a mixture of isopropanol and ethyl acetate. 0.20 g of the product, m.p.

203-207 0 C, was obtained.

f) 4(5)-(2,3-Dihydro-2-isopropyl-lH-inden-2-yl)imidazole hydrochloride.

4(5)-(2,3-Dihydro-2-isopropenyl-lH-inden-2-yl)imidazole hydrochloride (0.15 g) was hydrogenated in aqueous ethanol solution in the presence of 10% Pd/C. The charcoal was filtered off and the ethanol was evaporated. The residue was dissolved in ethyl acetate and the solution was to stand for several days. The product precipitated as the hydrochloride in a yield of 0.12 g, m.p. 227-234C.

Example 2 a) 2-Acetyl-2,3-dihydro-lH-indene-2-carbonitrile.

Sodium (13.2 g) was dissolved in dry ethanol (220 Dry diethyl ether (270 ml) was added. To the solution were simultaneously added a,a'-dibromo-o-xylene (85.2 g), 19 dry ether (250 ml) and acetoacetonitrile (45.6 g) in dry ether (160 ml) over a period of one hour.

(Acetoacetonitrile had been prepared by the method described in U.S. Patent No. 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 water layer was extracted once more with ether. The combined ether solutions were washed with water, dried 10 (MgSO and evaporated. The yield of crude product was S 73.8 g.

b) 2-Bromoacetyl-2,3-dihydro-lH-indene-2-carbonitrile.

2-Acetyl-2,3-dihydro-lH-indene-2-carbonitrile (32.9 g) was dissolved in diethyl ether (33 ml). Aluminium chloride (0.17 g) was added. Bromine (28.4 g) was added dropwise at room temperature and the disappearance of the bromine colour was observed. The ether solution was washed with a Na 2

CO

3 -solution and with water, dried over MgS04, and evaporated. 35.7 g of crude product was obtained.

c) 2,3-Dihydro-2-[imidazol-4(5)-yl]-lH-indene-2carbonitrile hydrochloride.

2-Bromoacetyl-2,3-dihydro-lH-indene-2-carbonitrile (27.8 g) and formamide (150 ml) were 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 ammonia. The product was extracted into ethyl acetate. The ethyl acetate El-wsMmi 20 extract was washed with water, dried and evaporated. The hydrochloride of the product was made in ethyl acetate.

M.p. 228-235°C.

d) 1-[2,3-Dihydro-2-[imidazol-4(5)-yll-1H-inden-2-yl]ethanone hydrochloride.

Mg turnings (1.2 g) and dry tetrahydrofuran were placed in a flask. Methyl bromide was passed into the mixture until the Mg turnings had disappeared. The mixture was heated when necessary. 2,3-dihydro-2-[imidazol-4(5)- 10 yl]-1H-indene-2-carbonitrile (2.1 g) as the base dissolved Sin dry tetrahydrofuran was added dropwise to the Grignard reagent at 40-50 0 C. After the addition, the mixture was o oo refluxed for 3 hours. the reaction mixture was cooled to 0 C and a 6M HC1 solution was carefully added dropwise. The 15 reaction mixture was then evaporated to remove the 000 .oo. tetrahydrofuran. Water was added and the acidic solution was washed with methylene chloride. The aqueous phase was made alkaline with ammonia and the product was extracted into methylene chloride. The HC1 salt was prepared in a S 20mixture of isopropanol and ethyl acetate, m.p. 181-184 0

C.

e) 1-1.2,3-Dihydro-2-[imidazol-4(5)-yl]-1H-inden-2-yl)ethanol.

1-12,3-Dihydro-2-imidazol-4(5)-yll-1H-inden-2yl]ethanone (0.11 g) was dissolved in dry ethanol (10 ml) I 25and NaBH 4 (0.009 g) was added in small portions at room temperature. After the addition, the mixture was stirred at 400C for 4 hours. Part of the ethanol was evaporated and 21 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 to give the product in a yield of 0.06 g.

f) 4(5)-(2,3-Dihydro-2-vinyl-lH-inden-2-yl)imidazole.

g of potassium hydrogen sulfate were mixed with 1-[2,3-dihydro-2-[imidazol-4(5)-yl]-lH-inden-2-yl]- S ethanol hydrochloride (0.03 g) and the mixture was stirred with a glass stick to a uniform mixture. Then the mixture was heated at 120-140 0 C for 3 hours. The cooled reaction mixture was suspended in ethanol while heating. The insoluble salts were filtered off and washed several times with hot ethanol. The combined ethanol solutions were evaporated to dryness. Water was added, the solution was alkaline, and the product was extracted with ethyl acetate. The ethyl acetate solution was dried and evaporated to dryness to give the product.

Example 3 a) l-(2,3-Dihydro-2-vinyl-lH-inden-2-yl)ethanone.

Tetrabutylammonium bromide (1.9 g) and 55 ml of a 48% NaOH solution were placed in a flask and a,a'-dibromo-oxylene (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 0 C until a gas chromatogram indicated that the starting material had disappeared.

22 The reaction mixture was cooled and water was added. The product was extracted with toluene. The combined toluene layers were washed with water and evaporated under reduced pressure to give the product in a yield of 20.4 g.

Mass spectrogram 186 143 142 141 129 128 (100), 127 115 91 43 "C NMR: (20 MHz, CDC13): S26.13 (OFR 40.47 (2d) 63.69 115.49 124.30 126.60 140.13 140.59 208.00 (s) 4t t -H NMR (80 MHz, CDCl): $2.19 (3H, s, Me), 3.05 and 3.46 (4H, AB q, J 15.6 Hz, methylene protons of the indane ring tL.' (H-i and 5.16 (1H, dd, J(gem) 0.7 Hz, J(trans) 17.6 Hz, one terminal methylene proton), 5.16 (1H, dd, J(gem) 0.7 Hz, J(cis) 10.3 Hz, the other terminal methylene proton), 6'.02 (IH, dd, J(cis) 10.3 Hz, J(trans) 17.6 Hz, methine proton, 6.95-7.38 (4H, m, arom.) b) 2-Bromo-l-(2,3-dihydro-2-vinyl-lH-inden-2-yl)ethanone.

l-(2,3-Dihydro-2-vinyl-iH-inden-2-yl)-.thanone g) was dissolved in methylene chloride (50 ml) and to the solution bromine (4.3 g) in methylene chloride (45 ml) was added dropwise at room temperature. When a gas chromatogram indicated that the starting material had reacted, the methylene chloride solution was washed 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 23 at reduced pressure to give the desired product.

Mass spectrogram: 266 and 264 (1 and 1, M 4 185 171 167 143 (100), 142 141 129 128 127 115 (44) o c) 4(5)-(2,3-Dihydro-2-vinyl-1H-inden-2-yl)imidazole f a hydrochloride.

2-Bromo-l-(2,3-dihydro-2-vinyl-lH-inden-2-yl)ethanone (15.0 g) and formamide (100 ml) were heated for 7 hours at 160°C. The reaction mixture was then cooled and poured into water. The water was acidified with dilute hydrochloric acid and washed with toluene. The aqueous phase was made alkaline with ammonia. The product was extracted into methylene chloride. The organic phase was washed with water, dried and the solvent was evaporated.

The crude product was purified by column chromotography.

The hydrochloride of the product was made in a mixture of ethyl acetate-isopropanol. M.p. 193-197°C (HC1-salt).

Mass spectrogram: 210 (100, 209 195 183 182 181 168 167 166 141 129 128 127 115 104 91 81 (14) 24 C NMR (EC1-salt) (80 M1Hz, ?leOH-d 4 %,3.37 (4H, s, methylene protons of the indane ring (H-1 and 4.99 (1H, dd, J(gem) 0.5 Ez, J(trans) 17.4 Hz, one terminal methylene proton), 5.17 (1H, dd, 3(gem) 0.5 Hz, J(cis) 10.6 Ez, the other terminal methylene proton, 6.19 (1H, dd, 3(cis) 10.6 Hz, 3(trans) 17.4 Hz, methine proton), 7.07-7.32 mi, arom.), 7.40 (1H, d, 13 1.3 Hz, 8.83 (1H, d, 1~ 1.3 Hz, im-2).

Example 4 a) Ethyl 2,3-dihydro-2-vinyl-lH-indene-2-carboxylate.

4 Tetrabutylammonium bromide (0.31 g) and 48% N&OH solution (9 ml) were added to a flask. a,cc'-dibromo-oxylene (5.0 g) in toluene (15 ml) was then added to the flask. 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 raised to +60 0 C. The mixture was stirred at this 4. temperature for 3.5,hours and then cooled. The toluene layer was separated, washed with water and evaporated at reduced pressure to give the desired product.

Mlass spectrogram: 216 (17, M+1'1, 143 (100), 142 141 128 115 (38) b) 2,3-Dihydro-2-vinyl-lH-indene-2-carboxylic acid hydrochloride Sodium hydroxide (7.99 g) was dissolved in water ml) and to the solution was added dropwise ethyl 2,3dihydro-2-vinyl-lH-indene-2-carboxylate (7.99 g) dissolved in ethanol (110 ml). After the addition, the reaction mixturei was refluxed for three hours. Excess of the 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 ipto methylene chloride, and the extract was washed with water, dried and evaporated to give the product as hydrochloride salt.

H NMR (80 MHz, CDCl 3 S3.10 and 3.56 (4H, AB q, 1 15.8 Hz, methylene protons of the indane ring (H-1 and 5.04-5.27 (2H, m, terminal methylene proton 6.12 (1H, dd, J(cis) 10.6 Hz, 3(trans)), 17.3 Hz methine proton), 6.9-7.4 (4H, m, arom.), 9.96 (1H, broad s, -COOH) c) 2 ,3-Dihydro-2-vinyl-lH-indene-2-carboxylic acid chloride A mixture 2,3-dihydro-2-vinyl-lH-indene-2carboxylic acid (5.09 g) and thionyl chloride (25 ml) was refluxed for 10 hours. Excess thionyl chloride was distilled off under reduced pressure. The crude product was used as such for the following reactior.

d) 3-Dihydro-2-vinyl-1H-inden-1-yl)ethanone 1- 3-Dihydro-2-vinyl-1H-inden-2-yl )-ethanone was prepared by treating 2,3-dihydro-2-vinyl-lH-indene-2carboxylic acid chloride with ethoxy magnesium malonic acid ethyl ester in dibutylether and after that with sulfuric acid according to the method of Reynolds, G.A. and Hauser, Org. Synth. 30 (1957) e) 2 -Bromo-1-(2,3-dihydro-2-vinyl-lH-inden-2-yl)ethanone and 4 2 ,3-dihydro-2-vinyl-lm-inden-2-yl)imidazole were then prepared according to the method of Example 3 above.

Claims (12)

1. An imidazole derivative of the formula: R R 3 1 R 4/ 4 N H in which Ri is isopropyl, vinyl or isopropenyl and R 3 and R4 are each hydrogen, methyl, ethyl, methoxy or halogen, and its non-toxic pharmaceutically acceptable acid addition salts.

2. A compound according to claim 1, which is 4(5)-(2,3-dihydro-2-isopropyl-lH-inden-2-yl)imidazole.

3. A compound according to claim 1, which is 4(5)-(2,3-dihydro-2-vinyl-lH-inden-2-yl)imidazole. 15

4. A compound according to claim 1, which is 4(5)-2(2,3-dihydro-2-isopropenyl-1H-inden-2-yl)imidazole.

5. Process for the preparation of an imidazole i derivative as claimed in claim 1, which comprises reacting an indene derivative of formula: RR tL %G COCH 2 Br in which R, is isopropyl, vinyl, isopropenyl, -CN, COOH, COO(lower alkyl), CHO, CO(lower alkyl) or hydroxyalkyl, R 3 and R 4 are as hereinbefore defined, with formamide, and if necessary converting the radical R, in the product obtained into a radical within the definition of R, in claim 1. 27

6. Process according to claim 5 in which, an intermediate product is obtained in which R 1 is -COO(lower alkyl), and this product is hydrolysed to give the corresponding acid of formula: R3 COOH N 4 H which is reduced to the aldehyde of formula: CHO R R 4 H and this aldehyde is reacted with an alkyl magnesium halide of the formula: R 5 MgHal where R 5 is methyl, to give a compound of formula: S0 o OH SR CH-R i 4 44 which is dehydrated to give a compound where R 1 is vinyl.

7. Process according to claim 5 in which, an intermediate product is obtained in which R 1 is -COO(lower alkyl), and this product is reacted with an alkyl magnesium halide of formula: R 5 MgHal where R 5 is methyl, to give a compound of the formula Yj. 28 OH R R 3 C-R 5 N N R I 4 H which is dehydrated to give a compound of the formula: CH 2 R- 3 R H SII 42 which may optionally be hydrogenated to give a compound SO where R 1 is isopropyl.

8. Process according to claim 5 in which, an 2'o intermediate product is obtained in which R 1 is-CN and this product is reacted with an alkyl magnesium halide of S' R 3 C-R R H which is reacted with an alkyl magnesium halide of formula R 7 MgHal, where R 7 is methyl, to give a compound of formula: OH R R3 C-R N R/ H R dehydrating the product to give a compound where R 1 is I, dehdrain the prdc ogv omon hr ^i 29 isopropenyl, which can optionally be hydrogenated to a compound where R 1 is isopropyl.

9. Process according to claim 5 in which, an intermediate product is obtained in which R 1 is -CO(lower alkyl), and this product is reduced with sodium borohydride to give a compound of formula: OH R CH-R R 4 H Swhere R 4 is methyl which is dehydrated to a compound where R 1 is vinyl.

Process for the preparation of an imidazole derivative of the formula given in claim 1 in which R 1 is isopropyl which comprises hydrogenating an imidazole derivative of the formula given in claim 1 in which R 1 is isopropenyl.

11. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 4 in association with a compatible, pharmaceutically acceptable carrier.

12. A compound according to claim 1 or a process for the preparation thereof substantially as hereinbefore described with reference to the examples. Dated this 28th day of November, 1991 ORION-YHTYMA OY, By its Patent Attorneys DAVIES COLLISON CAVE