FI83309C - FOERFARANDE FOER FRAMSTAELLNING AV DOPAMIN- -HYDROXYLAS INHIBERANDE 1-FENYLALKYL-2 -MERKAPTOIMIDAZOLDERIVAT. - Google Patents

Description

1 83309

Process for the preparation of dopamine 8-hydroxylase inhibitors 1-phenylalkyl-2-mercapidazazole derivatives

The invention relates to a process for the preparation of 1-phenylalkyl-2-mercaptoimidazole derivatives which inhibit dopamine-6-hydroxylase. In catecholamine biosynthesis, tyrosine is converted to norepinephrine (NE) in three steps. The intermediates are dihydroxyphenylalanine (DOPA) and dopamine (DA). Dopamine 8-hydroxylase (DBH) hydroxylates the latter to norepinephrine in the presence of oxygen and ascorbic acid.

Blockade of catecholamine has been shown to lower high blood pressure. See. e.g., Matta et al. / Clin.Pharm.Ther. 14, 541 (1973) and Teresawa et al., Japan Circ. J. 3J5, 339 (1971). In Weinshilboum, Mayo Clin. Proc. 5, 5, 39 (1980) summarizes compounds that inhibit the action of catecholamine by interfering with adrenergic receptor function. Alternatively, catecholamine biosynthesis can be suppressed in any of these three steps so that the amount of NE decreases. In addition to their antihypertensive effect, inhibitors of NE synthesis act as diuretics, natriuretics, cardiac drugs, and vasodilators. Inhibition of DBH activity may further have the advantage of increasing DA levels, as DA is described in Ehrreich et al., "New Antihypertensive Drugs", Spectrum Publishing, 1976, p. 409-432 has been found to have a selective vasodilatory effect at certain concentrations.

Inhibitors of DBH have also been found to reduce or prevent the formation of gastric ulcers in rats / see. Hidka et al., "Catecholami ne and Stress", ed. Usdin et al., Pergamon Press, Oxford, 1976, p. 159-165 and Osumi et al., Japan. J. Pharmacol. 2jJ, 904 (1973 ^ 7.

Although there are several known inhibitors of DBH, none of them have found clinical use because they are nonspecific and often toxic. For example, fusaric acid 2 83309 has been found to be toxic to the liver. See. e.g., Teresawa et al., Japan. Cir.J. 3, 5, 339 (1971) and references cited therein. It is likely that the picolinic acid structure affects several metalloproteins and enzymes in a non-specific manner, resulting in the observed side effects.

UK Patent 1,155,580 discloses compounds of the formula gH

l A.

R1 - N N

w 2 '3

R R

2 3 1 wherein R and R may be hydrogen and R may be substituted phenyl. The compounds are said to have analgesic, anti-inflammatory and antipyretic properties. U.S. Patent No. 3,915,980 discloses such compounds in which R 1 may be phenyl or phen (C 1-4) alkyl as intermediates in imidazolyl-2-thioalkanoic acid esters.

Iverson describes in Acta Chem. Scand. 21, 279 (1967)

R

/ CH ~ yA.

Wherein R may be -CO 2 H or -CH 2 NHCl 2 H 2, but no pharmaceutical use is mentioned for the compounds.

The present invention relates to the finding that the effect of DBH can be inhibited by compounds containing a mercaptoimidazole moiety and a phenylethylamine analog moiety. More particularly, the invention relates to a process for the preparation of novel gaseous compounds of formula (I) 3 83309

SH

(ί ^ 5 ^ - <CH2> n χΛ *

N N

X

wherein X is difluoro, dichloro, fluoro or chloro and n is 1-5.

In preferred compounds of the invention, X is 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluoro and n is 1 or 3. The most preferred compound of formula I is that wherein X is 3,5-difluoro and n is 1.

The above formulas are intended to encompass the tautomer of the imidazole moiety, i.e., compounds having the formula:

S

A

-WH

Compounds of formula I are prepared from intermediates of formula - (CH 2 in '·' · ". NHCH 2 CH (OC 1-4 alkyl) 2

X

4 83309 wherein X is difluoro, dichloro, fluoro or chloro and n is 1-5.

The invention relates to a process for the preparation of compounds of formula I by reacting a compound of formula II above with an acid thiosvanate.

The compounds of formula I and the compounds used in the process of the invention can be prepared from the corresponding starting phenyl compounds, such as benzaldehydes, which are already known and reported in the literature or can be easily prepared by known methods, e.g. as shown in Scheme I below. In the diagram, n is 1, although it can be 1-5. Scheme I shows the reductive amination of benzaldehydes (I) with aminoacetaldehyde acetal followed by reduction such as catalytic hydrogenation or treatment with a reducing agent such as NaBH 4.

With LiAlH or AlHn to give the intermediate 4 3 substituted benzylamine (II). When intermediate (II) is reacted with an acidic thiocyanate, mercaptoimidazole (III) is obtained. Mercaptoimidazole products can also be prepared from non-benzaldehydes, as shown in Examples 1 and 4 below.

Scheme I

jj ^ J nh2ch2ch (och2ch3) 2 jQjj ^^ cKKCH ^

X

VM

- (. Ύ NHOLCHiOCH-CH)

or NaBH. Il. I

4

X

II

SH

H + / KSCN *

-> I N

H-0 ethanol I \ /

^ W

X

III

II

5 83309

Compounds in which n is 2, 3, 4 or 5 are preferably prepared by the methods described in Examples 13 and 14 below.

When a substituted phenylalkanoic acid as an acid halide, preferably a chloride, is combined with an aminoacetaldehyde acetal and then reduced to give a substituted phenylalkylamine intermediate.

Because the compounds of the invention can be used to inhibit DBH activity, they have therapeutic value as diuretics, natriuretics, antihypertensives and vasodilators, as well as antiulcer and antiparkinsonian drugs.

The compounds of the invention were screened in vitro for their ability to inhibit the effect of DBH using a standard method measuring the conversion of tyramine to octopamine in the presence of DBH. Octopamine was determined by oxidizing with sodium periodate to p-hydroxybenzaldehyde and then measuring the absorbance spectrophotometrically at 330 nm. The results obtained are shown in Table I. The inhibitory effect is expressed as the molar concentration of the compound at which the DBH activity is halved (IC50) · Melting points (mp) are in degrees Celsius. This method gave an IC50 of fusaric acid of about 8 x 10 10.

Table I

n_X_Sp._IC50_ 1 2,6-Cl2 242-243 10 "4 (7% inhibition) 1 2-C1 206-207 10" 4 (14% inhibition) 1 2,5-Cl2 265 (dec.) 9.7 x 10 "| 1 4-Cl 187-189 9.6 x 10-5 1 2,3-Cl2 195-197 5.2 x 10" ;? 1 4-F 167-169 4.7 x 10-5 1 3,4-Cl2 178-181 2.8 x 10-5 1 2,4-Cl2 185-187 1.7 x 10 "5 1 3-Cl 129-131 1.2 x 10-5 1 3,5-Cl2 209-211 2.4 x 10 * ° 1 3-F 113-114 5.6 x 10 "J? 1 3,5-F2 140-141 1.2 x 10 "° 3 3,5-Cl2 98-99 2.0 x 10 '° 3 3,5-F2 131-132 4.7 x 10-6 6 83309

From the above results, it appears that the compounds of the invention have DBH inhibitory activity.

The in vivo activity of the compounds of the invention was screened by the following method. Male Okamoto-Aoki rats weighing 270-340 g and having spontaneously hypertensive rats (SHR) weighing 270-340 g were used in the experiment. Animals were fasted from the afternoon before the experiment and given the first dose of test compound p.o. and 25 ml / kg of normal saline. The animals were then placed in metabolic cages, three animals per cage, and urine was collected for three hours, after which sodium, potassium, and creatinine were analyzed in the urine. Indirect systolic blood pressure and heart rate were measured by the tail ring method, and within 24 hours of the first dose, the animals were given a second equal dose of the test compound. Two hours after the second dose, systolic blood pressure and heart rate were measured again.

The drugs were administered intraperitoneally as a solution or suspension in 0.9% sodium chloride with 0.02% ascorbic acid. The dose volume was 5 ml.

The averages of the in vivo screening results for the compounds of this invention are shown in Table II. The dose concentration was 50 mg / kg. Mean results for control animals are shown in parentheses below the results for drug-treated animals.

CO 7 o

C

G ~ ~ (O O O o o wc · en * 83309> ι · Η <N - '- a) ε £ I \

• rl 3 (0 W

C P -rl o

<D -rl p C

ε p c c - ~ «ICO (0 oo oo

Ό: 0> 1 (N (N VO O

> i> i H · CO Γ0 H '-

W

- 0

05 C

X C ro - ~ to in vo rH es rH CO ^ 00

'w *' · »H H H

<NJ w W

c a> Q) c

C -H W

H (0 0

Ή Oi C

O C C E "^ -

PO) <0 M1 σ 'σν (N

w Vh ^ fv in o

(U · rH rH rH

(Λ> rH - · - + 'ΟΊ1 voin χ Φ · η <vo σ> vo \ Ό σν (N in vo + £ - «· - -to o nr · hh 2 w - - <o I p (0 p rH om • rl lH r ^ P \ rH OH CO ro rH '-r' c ε (0 - wpw M 3 • H 3>> ~ ~ vf h oh in ro rH ro oh

4_> V V V V

• ri + ro o m1 o- P ^ v *; in <N in o- P> i (0 - -

0)> iP

0) H p - -

C O O VO vO O

> i JH M O VO VO

P P \ S '' V

p x o> ro vo vo oo

rldJCd + OM · 00 (N

Vh H a (0 -H rH rH

ω o) w 2 - ^: (0 C Vh CD: <0 P: (0 - C ε ro ro ro ro • H 3 - - '

X

rH 3 ω h h C ro ro

B

0

X d) CM OH

X P rH H

3 w O U

-H -rl II

3 Ό m in (0 Λ - E- ·> <X ro ro β 83309

From the results in Table II, it can be seen that the compounds of the invention have a significant diuretic and / or heart rate lowering effect. The compounds in which X is 3,5-dichloro had an unusually strong natriuretic effect and a diuretic, antihypertensive and heart rate lowering effect. Compounds with diuretic activity are known to be useful antihypertensive drugs.

In further experiments performed with a compound where X is 3,5-F2 and n is 1, using essentially the method described above (50 mg / kg), this compound was found to increase the volume of excreted urine approximately 4-fold compared to controls. Heart rate generally decreased with the administration of this compound.

The various compounds of this invention and some other compounds were tested for their effects on peripheral dopamine and norepinephrine levels, essentially using the methods described in DaPrada and Zurcher, Life Sci.

19, 1161 (1976). Rats with spontaneous hypertension were given two doses, of which the second dose was given approximately 18 hours after the first and the rats were sacrificed 2 hours after the second dose. Table III shows the averages of the results in micrograms of DA per gram of tissue (n = 1).

Table III

Compound DA DA / NE _ number of animals (pg / g) _ ratio

Control (H 2 O) 11 0.260 0.019 0.040 0.002

Fusaric acid 11 0.520 0.053 ^ 1) 0.100 0.007 ^ 1)

Comparison 3 0.219 0.044 0.035 0.002

Hydralazine (25 mg / kg) 3 0.417 0.026 <2) 0.078 0.015 <2) (50 mg / kg) 1 0.835 0.127 0.098 0.018 P <0.001 (2) P <0.05 9 83309

Table IIIA

Compound DA DA / NE _ number of animals (ug / g) _ ratio

Control 4 0.319 ± 0.104 0.042 ± 0.012

Fusaric acid δ 0.642 ± 0.114 0.1240 ± 0.0140 (1) X = 3-F 5 1.096 ± 0.080 0.1946 ± 0.0122 (1) (50 mg / kg) X = 3,5-F2 5 2.109 ± 0.123 0.4485 ± 0.0532 (1) (50 mg / kg)

Control 5 0.250 ± 0.014 0.037 ± 0.003 X = 3,5-C1 5 0.670 ± 0.065 0.110 ± 0.008 (1) (50 mg / kg)

Control 5 0.308 ± 0.023 0.045 ± 0.004 X = 3.5-C12 5 0.688 ± 0.020 0.103 ± 0.002 (1) (50 mg / kg) (1) P <0.001

From the above results, it appears that the compounds of the invention inhibit DBH activity in mammals when administered in effective amounts internally.

Compounds in which X is 3,5-difluoro, 3,5-dichloro or 3-fluoro have a particularly high in vivo activity compared to compounds in which X is another substituent. The compound where X is 3,5-difluoro and n is 1 (IC50 = 1.2 x 10 ") had a particularly strong effect on the DA / NE ratio in vivo.

When studying the effect on blood pressure in rats with spontaneous hypertension, daily administration of a compound according to the invention (50 mg / kg i.p.) had a cumulative effect, i.e. a decrease in blood pressure, continuously every day during the four-day study period.

10 83309

The compounds may be incorporated into suitable unit dosage forms such as capsules, tablets, or injectables. The pharmaceutical carriers used may be solid or liquid. Solid carriers include e.g. lactose, white kaolin, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Liquid carriers include e.g. syrup, peanut oil, olive oil and water. The carrier or diluent may also contain any delaying agent, such as glyceryl monostearate or glyceryl distearate, either alone or with a wax. The amount of carrier can vary widely, but is usually used from about 25 mg to about 1 g per unit dose. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution such as an ampoule, or aqueous or non-aqueous liquid suspension.

The pharmaceutical preparations can be made by conventional methods in the art, which include mixing, granulating and, if necessary, compressing into a tablet form, or mixing, filling or dissolving the ingredients as necessary to obtain the desired end products for oral or parenteral administration.

The novel compounds are administered in an effective amount in pharmaceutical unit doses in a non-toxic amount in the range of 0.1-1000 mg / kg, preferably 10-100 mg / kg. The selected unit dose is administered to the patient in need of treatment 1-5 times daily orally, rectally or by injection or infusion. It is preferred to use a parenteral route of administration in which the dose is small. However, the preparations may also be administered orally in larger amounts if it is safe and advantageous for the patient. The use of the lowest possible effective dose is recommended due to the toxicity associated with sulfur-containing compounds.

li 11 83309

The preparation of the compounds of formula I and their intermediates is illustrated by the following examples. The starting materials are commercial preparations or can be prepared by known methods. The compounds listed in Tables I, II and III have been prepared essentially by the methods described herein. All temperatures and melting points (mp) are in degrees Celsius (° C).

Example 1 1- [3 ', 5, -Dichlorobenzyl] -2-mercaptoimidazole A mixture of 3,5-dichlorobenzaldehyde (17.5 g, 0.1 mol) and aminoacetaldehyde diethyl acetal (13.3 g, 0.1 mol). , was heated on a steam bath. The resulting solution was stirred at room temperature while sodium borohydride (3 g, 0.08 mol) was added slowly and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of oil, water (100 ml), concentrated hydrochloric acid (22 ml), ethanol (41 ml) and potassium thiocyanate (10.7 g, 0.11 mol) was refluxed for 2 hours.

The mixture was cooled and diluted with water (250 ml) and the crude product was filtered off and dried. Recrystallization twice from acetic acid gave 7.3 g of the title compound (30%) as pale yellow crystals, m.p. 209-211 °.

Example 2 1- [2 ', 6'-Dichlorobenzyl] -2-mercaptoimidazole

When 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol) and diethyl acetal of aminoacetaldehyde (13.3 g, 0.1 mol) were reacted substantially as described above, 5.4 g (21%) of the title compound were obtained. compound as white needles, m.p.

242-243 ° (ethanol / ether).

12 83309

Example 3 1- [2'-Chlorobenzyl] -2-mercaptoimidazole

When 2-chlorobenzaldehyde (14 g, 0.1 mol) and diethyl acetal of aminoacetaldehyde (13.3 g, 0.1 mol) were reacted substantially as described above, 11.2 g (50 °) of the title compound were obtained as white crystals. mp. 206-207 ° (acetone / ethanol).

Example 4 1- / 2 1,5'-Dichlorobenzyl-2-mercaptoimidazole When 2,5-dichlorobenzaldehyde (10.25 g, 0.059 mol) and diethyl acetal of aminoacetaldehyde (7.79 g, 0.059 mol) were reacted substantially with each other as described above. 5.2 g (34%) of the title compound were obtained as white crystals, m.p. 265 ° (dec.) (Propionic acid).

Example 5 1- [4'-Chlorobenzyl] -2-mercaptoimidazole

When 4-chlorobenzaldehyde (14 g, 0.1 mol) was reacted with diethyl acetal (13.3 g, 0.1 mol) of aminoacetaldehyde essentially as described above, 8.3 g (36%) of the title compound were obtained as white crystals, m.p. . 187-189 ° (acetonitrile).

Example 6 1- [2 ', 3'-Dichlorobenzyl] -2-mercaptoimidazole

When 2,3-dichlorobenzaldehyde (8.7 g, 0.05 mol) and diethyl acetal of aminoacetaldehyde (6.65 g, 0.05 mol) were reacted substantially with the method described above, 3.0 g (23%) of the title compound were obtained. compound as white crystals, m.p. 195-197 ° (ethanol).

Example 7 1- [4-Fluorobenzyl] -7-2-mercaptoimidazole

When 4-fluorobenzaldehyde (12.4 g, 0.1 mol) and diethyl acetal of aminoacetaldehyde (13.3 g, 0.1 mol) were reacted substantially as described above, 13.0 g (62.5%) of ) the title compound as white crystals, m.p. 167-169 ° (ethanol).

Example 8 1- [31,4l-Dichlorobenzyl] -2-mercaptolmidazole

When 3,4-dichlorobenzaldehyde (17.5 g, 0.1 mol) and diethyl acetal of aminoacetaldehyde (13.3 g, 0.1 mol) were reacted substantially as described above, 10 g (39%) of the title compound were obtained. compound as white crystals, m.p. 178-181 ° (ethanol).

Example 9 1- [2 ', 4'-Dichlorobenzyl] -2-mercaptoimidazole

When 2,4-dichlorobenzaldehyde (17.5 g, 0.1 mol) and diethyl acetal of aminoacetaldehyde (13.3 g, 0.1 mol) were reacted substantially as described above, 8.5 g (33% ) the title compound as white crystals, m.p. 185-187 ° (2-propanol).

Example 10 1- [3 1-Chlorobenzyl] -2-mercaptoimidazole

When 3-chlorobenzaldehyde (14 g, 0.1 mol) and diethyl acetal of aminoacetaldehyde (13.3 g, 0.1 mol) were reacted substantially as described above, 14 g (62.5%) of the title compound were obtained as white crystals. mp. 129-131 ° (acetonitrile).

14 83309

Example 11 1- [3-Fluorobenzyl] -2-mercaptoimidazole

When 3-fluorobenzaldehyde (24.8 g, 0.2 mol) and diethyl acetal of aminoacetaldehyde (26.6 g, 0.2 mol) were reacted substantially as described above, 28 g (67%) of the title compound were obtained as white crystals. mp. 112.5-114 ° (2-propanol / water).

Example 12 1- [3 ', 5'-Difluorobenzyl] -2-mercaptoimidazole

When 3,5-difluorobenzaldehyde (14.7 g, 0.104 mol) and aminoacetaldehyde dimethyl acetal (10.8 g, 0.104 mol) were reacted substantially as described above, 10.0 g (43%) of the title compound were obtained as white crystals. mp. 140-141 ° (ethyl acetate / hexane).

Example 13 1- [3- (3,5,5-Difluoro-phenyl) -propyl] -N-mercaptoimidazole A mixture of 3,5-difluorobenzaldehyde (5.5 g, 0.039 mol), malonic acid (6.06 g, 0.058 mol) ), pyridine (2.1 ml) and piperidine (0.105 ml) were heated on a steam bath for 2 hours and then for 1 hour at 155 ° C. The reaction mixture was poured into cold 3N aqueous hydrochloric acid and then filtered. Recrystallization from ethanol gave 4.7 g (66%) of 3,5-difluorocinnamic acid as light needles, m.p. 199-201 °.

3,5-Difluorocinnamic acid (4.6 g, 0.025 mol) was dissolved in tetrahydrofuran (50 ml) and the resulting solution was added to a suspension of 0.75 g of palladium / carbon in ethyl acetate. The mixture was shaken under 0.34 MPa hydrogen pressure for 5 hours and then filtered and concentrated to give 4.5 g (97%) of 3- [3 ', E-difluorophenyl-7-propanoic acid as colorless crystals, m.p. 56 ° (methanol).

A solution of 3- [3 ', 5'-difluorophenyl] -propionic acid (4.4 g, 0.024 mol), Ν, Ν-dimethylformamide (one drop) and is thionyl chloride (15 mL) was heated at 60 ° C for 3 h. :in. Excess thionyl chloride was distilled off under reduced pressure. Distillation (Kugelrohr) under reduced pressure (ca. 0.25 mm (33 Pa)) gave 4.1 g (85%) of 3- [3 ', 5'-difluorophenyl / propionyl chloride as an oil.

A solution of 3- [3 ', 5'-difluorophenyl] propionyl chloride (4 g, 0.0196 mol) in methylene chloride (40 ml) was added to a solution of aminoacetaldehyde dimethyl acetal (4.3 g, 0.0412 mol) in methylene chloride (100 ml), and the addition took place at such a rate that the temperature did not rise above 20 ° C. · The reaction mixture was stirred for 1 hour. It was then poured into water and the layers were separated. The organic layer was washed with 5% aqueous sodium carbonate solution, 0.05% aqueous hydrogen chloride solution and water, and then dried over sodium sulfate and concentrated to give 5.5 g (103%) of 3- [3 ', 5'-difluorophenyl / propanamide. N-acetaldehyde dimethyl acetal as an oil.

A solution of 3- [3 ', 5'-difluorophenyl] -propionamide N-acetal dehyde dimethyl acetal (5.3 g, 0.0194 mol) in diethyl ether (100 mL) was added slowly to a suspension of lithium aluminum hydride. (4.4 g, 0.116 mol) in diethyl ether (200 mL). The reaction mixture was stirred at ambient temperature (20-25 °) for 18 hours. Water (4.5 ml) was then carefully added, followed by 10% aqueous sodium hydroxide solution (7 ml) and water (11 ml). The mixture was filtered and the filtrate was dried over sodium sulfate and concentrated to give 4.4 g (88%) of 3- [31,5'-difluorophenyl] propanamine N-acetaldehyde dimethyl acetal as a colorless oil.

A solution of 3- [3 ', 51-difluorophenyl / propanamine N-acetaldehyde dimethyl acetal (4.3 g, 0.0166 mol), potassium thiocyanate (1.6 g, 0.0166 mol), ethanol (12 ml), water (20 ml) and concentrated hydrochloric acid (4 ml) were refluxed for 1 hour and then cooled and a large amount of water was added. The product was filtered and recrystallized to give 2.2 g (55%) of 1- [3- (3 ', 5'-difluorophenyl) propyl] -2-mercaptoimidazole as white needles, m.p. 131-132 ° (ethanol).

16 83309

Example 14 3- (3 ', 5t-Dichlorophenyl) propyl-2-mercaptoimidazole When 3,5-dichlorobenzaldehyde (26.9 g, 0.154 mol), malonic acid (24.1 g, 0.232 mol), pyridine (8 ml) and piperidine (0.4 ml) was reacted essentially as described above to give 22.9 g (69%) of 3,5-dichlorocinnamic acid as white needles, m.p. 169-170 ° C (ethanol).

When 3,5-dichlorocinnamic acid (22.9 g, 0.106 mol) and 3 g of palladium / carbon were reacted as described above, 23 g (99%) of 3- [3 ', 5'-dichlorophenyl / propanoic acid were obtained as an oil.

A 1M solution of borane in tetrahydrofuran (233 mL) was added dropwise to a solution of 3- (3 ', 5'-dichlorophenyl) propanoic acid (23 g, 0.106 mol) in distilled tetrahydrofuran (200 mL) cooled to 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. Methanol was then added and the solution was concentrated to give 21.2 g (98%) of 1- [3- (3 ', 5'-dichlorophenyl] propanol as a clear oil.

A solution of dimethyl sulfoxide (6.75 g, 0.083 mol) in dry methylene chloride (15 mL) was added dropwise at -78 ° C to a solution of oxalyl chloride (6.2 g, 0.049 mol) in dry methylene chloride (15 mL). The reaction mixture was stirred for 2 minutes. A solution of 1- [3- (3 ', 5'-dichlorophenyl) zpropanol (5 g, 0.0245 mol) in dry methylene chloride (20 mL) was then added slowly, keeping the temperature below -60 ° C. 15 minutes at -70 ° C, after which triethylamine (16 g, 0.160 mol) was added dropwise The reaction mixture was stirred for a further 5 minutes at -60 ° C and then warmed to room temperature and diluted with water. 3N aqueous solution followed by saturated brine and dried over sodium sulfate.

Concentration of the solution gave 5.0 g (100%) of 3- (3 ', 5'-dichlorophenyl) propionaldehyde as a yellow oil.

li 17 83309

The amino acid acetaldehyde dimethyl acetal (2.1 g, 0.0197 mol) was added with stirring to a solution of 3- (3,5 '- dichlorophenyl) propionaldehyde (5 g, 0.025 mol) in hexane (10 mL). The mixture was stirred for 1 hour at room temperature and then sodium borohydride (7.3 g, 0.192 mol) in ethanol (25 ml) was added. The reaction mixture was stirred for 18 hours and then diluted with water and concentrated. The residue was stirred in ethyl acetate, washed with water, dried over sodium sulfate and concentrated to give 6.8 g (93%) of 3- (3 ', 5'-dichlorophenyl) propanamide N-acetaldehyde dimethyl acetal as a yellow oil.

A solution of 3- (3 ', 51-dichlorophenyl) propanamide N-acetaldehyde dimethyl acetal, potassium thiocyanate (2.2 g, 0.0223 mol), ethanol (20 ml), water (30 ml) and concentrated hydrochloric acid was returned. 1 hour. The reaction mixture was cooled and diluted with water. After allowing the mixture to stand for 3 hours, the crude product crystallized and was filtered. Chromatography on silica gel using a solution of 0.5-1% methanol in methylene chloride as eluent gave 2.0 g (31%) of 3- (3 ', 5'-dichlorophenyl) propyl-2-mercaptoimidazole as white crystals, m.p. 98-99 ° (ethanol).

Claims (1)

A process for the preparation of 1-phenylalkyl-2-mercaptoimidazole which inhibits dopamine N-hydroxylase of the formula SH - - (CH 2) n NWX wherein X is difluoro, dichloro, fluorine or chlorine and n is 1-5, characterized in that that a compound of the following formula J --- * (CH2) NHCH2CH (OC1-4 alkyl) 2 is reacted with an acid thiocyanate. For the preparation of 1-phenylalkyl-2-mercaptoimidazole with inert dopamine-β-hydroxylase of the formula SH f ^> N ~ -_ (CH2) n NN ^> <W NX 1 vilken formula X is difluoro, dichloro, fluorine or chlorine is 1-5, and the reaction is carried out with the addition of formyl (CH2) n NHCH2CH (OC1-4 alkyl) 2 X is mediated with thiocyanate.