NO881638L - DOPAMINE-BETA-hydroxylase inhibitors. - Google Patents

Description

FIELD OF THE INVENTION

This invention relates to inhibitors of dopamine ε-hydroxylase.

BACKGROUND OF THE INVENTION

In the catecholamine biosynthesis pathway, tyrosine is converted in three steps to norepinephrine (NE). Intermediate products are dihydroxyphenylalanine (DOPA) and dopamine (DA). The latter is hydroxylated to norepinephrine by dopamine P-hydroxylase (DBH) in the presence of oxygen and ascorbic acid.

Inhibition of catecholamine activity has been found to reduce hypertension. See, for example, Matta et al., Clin, Pharm. Ther. 14, 541 (1973) and Teresawa et al., Japan Circ. J. 35, 339

(1971). Weinshilboum provides in Mayo Clin. Pro. 55, 39 (1980) an overview of compounds that inhibit catecholamine activity by interfering with adrenergic receptors. Alternatively, the catecholamine biosynthesis pathway may be suppressed at any of the three steps, resulting in decreased NE levels. In addition to reducing hypertension, inhibitors of NE synthesis are active as diuretics, natriuretics, cardiotonics and vasodilators. Inhibition of DBH activity may have the additional benefit of increasing DA levels, which as described by Ehrreich et al., in "New Antihypertensive Drugs", Spectrum Publishing, 1976, pp. 409-432, have been found to have selective vasodilator- activity in certain concentrations.

It is also shown by Hidaka et al., "Catecholamine and Stress", ed. by Usdin et al., Permagon Press, Oxford, 1976, pp. 159-165 and by Osumi et al., Japan. J. Pharmacol. 23, 904 (1973), that DBH inhibitors reduce or prevent the formation of gastric ulcers in rats.

A number of DBH inhibitors are known. These are usually shared

into two classes, namely metal-chelating agents, which bind to copper in the enzyme, and phenethylamine-analogue compounds. Rosenberg et al., "Essays in Neurochemistry and Neuropharmacology, Vol. 4", eds. by Youdim et al., John Wiley & Sons, 1980, pp. 179-192 and Goldstein, Pharmacol. Fox. 18 (1), 77 (1966) gives an overview of DBH inhibitors. The former describes that many of the potent DBH inhibitors have a hydrophobic side chain with a size comparable to the aromatic ring of DA,

leading the authors to suggest that incorporation of a terminal hydroxyl group on a 4-6 carbon side chain of a phenethylamine analog compound may provide a potent" inhibitor.

Known inhibitors include:

5-alkylpicolinic acids [See Suda et al., Chem. Pharm. Bull. 17, 2377 (1969); Umezawa et al., Biochem. Pharmacol. 19, 35 (1969); Hidaka et al., Mol. Pharmacol. 9, 172 (1973); Miyano et al., Chem. Pharm. Bull, 26, 2328 (1978); Miyano et al., Heterocycles 14, 755 (1980); Claxton et al., Eur. J. Pharmacol. 37, 179

(1976)] ;

BRL 8242 [See Claxton et al., Eur. J. Pharmacol. 37, 179

(1976)] ; 1-alkyl-2-mercaptoimidazole [See Hanlon et al., Life Sci. 12, 417 (1973); Fuller et al., Adv. Enzyme Regul. 15, 267 (1976)];

substituted thiourea compounds [See Johnson et al., J. Pharmacol. Exp. Ther. 168, 229 (1969)]; and

benzyloxyamine and benzylhydrazine [See Creveling et al., Biochim. Biophys. Acta 64, 125 (1962); Creveling et al., Biochim. Biophys. Res. Commun. 8, 215 (1962); van der Schoot et al., J. Pharmacol. Exp. Ther. 141, 74 (1963). Bloom, Ann. NEW. Acad. Pollock. 107, 878 (1963)].

The inhibitory effect of all the above-mentioned compounds except benzyloxyamine and benzylhydrazine is clearly due to metal-chelating properties. Alkyl derivatives of 2-mercaptoimidazole are more potent, probably due to non-specific interactions between the alkyl substituent and the enzyme. Benzyloxyamine and benzylhydrazine are phenethylamine derivatives that apparently act as competitive inhibitors.

In addition to the above-mentioned compounds, Runti et al. in II Farmaco Ed. Sc. 36, 260 (1980) that other fusaric acid derivatives and analogous compounds inhibit DBH. These include phenylpicolinic acid, which is described as having twice the inhibitory activity of fusaric acid, and 5-(4-chlorobutyl)picolinic acid, and others such as substituted amides of fusaric acid and acids and amides of 5-butyroylpicolinic acid, 5-aminopicolinic acid and 5- hydrazinepicolinic acid, and derivatives thereof.

Hidaka et al. describes in Molecular Pharmacology, 9, 172-177 (1973) that 5-(3,4-dibromo)butylpicolinic acid and 5-(dimethyldithiocarbamoyl)methylpicolinic acid are DBH inhibitors.

Bupicomide, 5-(n-butyl)picolinamide, is by Ehrreich et al. in "New Antihypertensive Drugs", Spectrum Publications, 1976, pp. 409-432, described to be a DBH inhibitor and to have antihypertensive activity.

Friedman et al. describes in Psychosomatic Med. 40, 107

(1978) that patients treated with alpha-methyl-DOPA, guanethidine and reserpine, but not propanolol and diuretics, have reduced DBH levels, although the significance of the observation is uncertain.

Although there are many known inhibitors for DBH, the majority of these agents have not found clinical use due to non-specific, often toxic properties that they possess. Fusaric acid, for example, is hepatotoxic. See, for example, Teresawa et al., Japan. Cir. J. 35, 339 (1971) and references cited therein. Presumably, there is a mutual influence between the picolinic acid structure and a number of metalloproteins and enzymes in a non-specific way so that you get the observed side effects.

In British patent 1 555 580 compounds are described

with the formula:

where R<2> and R<3> can be H and R<1> can be substituted phenyl. The compounds are said to have analgesic, anti-inflammatory and antipyretic properties. Gebert et al. describes in US patent 3,915,980 such compounds where R<1> can be phenyl or f an (C;1_3 ) alkyl, as intermediates for imidazolyl-2-thioalkanoic acid esters.

Iverson describes in Acta Chem. Scand. 21, 279 (1967) a compound of the formula:

where R may be -CO 2 H or -CH 2 NCH 6 H 5 , but does not describe any pharmaceutical use for the compound.

In European patent application No. 125,033 (published 14 November 1984) a series of 1-phenyl and 1-phenylalkylimidazole compounds with a mercapto or alkylthio group in the 2-position is described. These compounds are described to have DBH inhibitory activity.

US Patent No. 4,532,331 describes various 1-benzyl-2-aminomethylimidazole derivatives that inhibit DBH activity and includes pharmaceutical preparations containing these derivatives and methods for using these derivatives to inhibit DBH activity.

SUMMARY OF THE INVENTION

The invention relates to the discovery that DBH is inhibited by a compound with a mercaptoimidazole part and a phenethylamine analog part. More particularly, the invention is selected new compounds of the formula:

where:

X is -H, -OH, halogen, C1_4<->alkyl, -CN, -NO2, -SO2NH2, -CO2H, -CONH2, -CHO, -CH2OH, -C<F>3,<C>1_4-Alkoxy , -S02<C>1_4-alkyl, -S<0>2<C>1_4-fluoroalkyl, -C<0>2<C>1_4-alkyl or any available combination thereof up to four substituents, Y is - H, -OH, C1-4-Alkoxy, Halogen, C1-4-Alkyl, -CN, -NO2 , -SO2NH2, -CO2H, -CONH2, -CHO, -CH2OH, -CF3, -SO2C1-4-Alkyl,

-S<0>2<C>1-4-fluoroalkyl or -C02C1-4-alkyl,

R is -H or C1-4 alkyl and

n is 0-4,

or a hydrate or, when R is C 1-4 alkyl, a pharmaceutically acceptable acid addition salt thereof, provided that when n is 0,

is Y -OH and when n is 1-3, at least one of Y and X is not -H. As used herein, "available combination thereof" means any other stable combination of substituents available by chemical synthesis.

In preferred compounds of the invention, Y is -OH or -OCH3, R is -H, n is 1 or 3 and X is -H, -OH or halogen (especially 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluoro) or Y is -H, R is -H, n is 1 or 3 and X is halogen (especially 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluoro). In the most preferred compound of the invention, Y is -H, X is 3,5-difluoro, R is -H and n is 1.

The invention is also a method for inhibiting the DBH activity in mammals, which comprises administering internally to an individual an effective amount of a compound with the formula:

where

X is -H, -OH, halogen, C1-4 alkyl, -CN, -NO2, -SO2NH2,

-CO 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , <C>1-4-Alkoxy, -SO 2 <C>1-4-Alkyl, -SO 2 <C>1-4-fluoroalkyl, -CO 2 <C>1-4-Alkyl or which any available combination thereof up to four substituents, Y is -H, -OH, <C>1_4-Alkoxy, halogen, C1_4-alkyl, -CN, -NO2, -SO2NH2, -CO2H, -CONH2, -CHO, - CH2OH, -CF3, -SO2C1_4-alkyl,

-S<0>2<C>1-4-fluoroalkyl or -C02<C>1-4-alkyl,

R is -H or C-L-4-alkyl and

n is 0-4,

or a hydrate or, when R is C-L-4 alkyl, a pharmaceutically acceptable acid addition salt thereof.

Compounds which have been found to be particularly potent and therefore preferred in the method according to the invention are those where Y is -OH or 0CH3, R is -H, n is 1 or 3 and X is -H, -OH or halogen (especially 3, 5-dichloro, 3,5-difluoro, 3-chloro or 3-fluoro) or Y is -H, R is -H, n is 1 or 3 and X is halogen (especially 3,5-dichloro, 3,5- difluoro, 3-chloro or 3-fluoro). In the most preferred method according to the invention, Y is -H, X is 3,5-difluoro, R is -H and n is 1.

It is intended that the above formulas include the tautomer of the compounds where R is -H, i.e. the compounds with the above formulas where the imidazole part has the formula:

The above formulas also include hydrates of the compounds and pharmaceutically acceptable acid addition salts of the compounds wherein R is C 1-4 alkyl. The invention also includes pharmaceutical preparations comprising the compounds of the above formulas, provided that when n is 0, Y is -OH, and pharmaceutical carriers.

The invention is also intermediate products for the compound according to the invention, the intermediate products having the formula: where Y<1>andX<1>are the same as Y and X but are not -OH and n is 0-4 and

where X<1> is the same as X but is not -OH, Y<1> is C₁₋₄-Alkoxy, preferably -OCH3 and n is 0.

The invention is also a method for producing the compound according to the invention, which comprises bringing compound II above into contact with acidic thiocyanate and reacting it with this and such a method comprising bringing compound II A above into contact with an acid and reacting the with this during cyclization of the compound. In both methods, the protective group is optionally removed from Y and/or X when Y<1> and/or X<1> is C1-4-Alkoxy, to produce the compound where Y and/or X is -OH.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention contain weak metal-chelating functional groups derived from N-methyl-2-mercaptoimidazole which is known to be a weak DBH inhibitor. The compounds according to the invention also contain phenyl moieties such as phenethylamine analogue inhibitors such as benzyloxyamine, benzylhydrazine, tryptamine and serotonin.

The compounds according to the invention and the compounds used in the method according to the invention can be prepared from corresponding starting benzyl or phenyl compounds such as benzaldehydes, which are known and described in published references or are readily available, by known techniques as illustrated in Scheme I below, where X< 1> and Y<1> are X and Y respectively, except that when Y is -OH, Y<1> is C1-4-Alkoxy, preferably

-OCH 3 , and when X is -OH, X<1>C 1-4 -Alkoxy, preferably -OCH 3 . As illustrated, n is 1, although n can be 0-4. Scheme I illustrates reductive amination of benzaldehydes (I) with an aminoacetaldehyde acetal followed by reduction by, for example, catalytic hydrogenation or treatment with a reducing agent such as NaBH 4 , LiAlH 4 or AIH 3 , providing substituted benzylamine intermediates (II). When reacted with acidic thiocyanate, the intermediates (II) give mercaptoimidazole products (III). The mercaptoimidazole products can be prepared from compounds other than benzaldehydes, as illustrated in Examples 1 and 4 below.

The 1-phenyl-substituted 2-mercaptoimidazoles (n is 0) are preferably prepared by reacting an appropriately substituted phenyl isothiocyanate with an aminoacetaldehyde acetal followed by cyclization catalyzed by a strong acid, as illustrated in Example 1 below.

The compounds where n is 2, 3 or 4 are preferably prepared as illustrated in Example 4 and in Examples 23 and 24 below. Coupling of substituted phenylalkanoic acids as acid halides, preferably chlorides, with aminoacetaldehyde acetals and subsequent reduction provides such substituted phenylalkylamine intermediates.

Y<1> in Scheme I is the same as Y, except that when Y is -OH, Y<1> is C1_4- alkoxy, preferably -OCH3, providing for the optional removal of the protecting 4-alkoxy group with, for example, BBr3 or HBr, or nucleophilic aromatic substitution with dilute hydroxide, the phenol (Y is -OH). X<1> may be one or more substituents at the 2-, 3-, 5- or 6-positions, provided that the combination of substituents is available, ie does not result in significant instability due to steric hindrance. When X<1> is C1_4 alkoxy, preferably -OCH3, the protecting group can be removed as described above for Y<1>.

The compounds where R is C-1-4-alkyl are preferably prepared by allowing the protecting group to be removed with, for example, BBr3 and an alkanol while continuing to form an alkyl bromide which alkylates the mercapto group as illustrated in Example 6 below. Alternatively, a solution or suspension of a suitably substituted mercaptoimidazole in an inert solvent, for example methanol, tetrahydrofuran or aqueous dimethylformamide, can be reacted with an alkylating agent, for example alkyl iodide, bromide or tosylate. Methyl iodide is preferred in this alternative method.

The pharmaceutically satisfactory acid addition salts of the compounds where R is C1-4-alkyl are formed with strong or moderately strong organic or inorganic acids by methods known in the field. For example, the base is reacted with an inorganic or organic acid in a water-miscible solvent such as ethanol with isolation of the salt by removal of the solvent or in a solvent that is not miscible with water when the acid is soluble in it, such as ethyl ether or chloroform, as desired salt is excreted directly or isolated by removal of the solvent. Examples of the salts included in this invention are maleate, fumarate, lactate, oxalate, methanesulfonate, ethanesulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate, phosphate and nitrate salts.

The compounds according to the invention have, because they can be used for inhibiting DBH activity, therapeutic value as diuretic, natriuretic, cardiotonic, antihypertensive and vasodilator agents, as well as antiulcerogenic and anti-Parkinson's disease agents.

Compounds of the invention and other compounds suitable for the method of the invention were tested for DBH inhibition in vitro by a standard procedure for testing the conversion of tyramine to octopamine in the presence of DBH. Octopamine was tested after sodium periodate oxidation to p-hydroxybenzaldehyde by measuring spectrophotometric absorbance at 330 nm. The results are listed in Table I below. The inhibition is given in molar concentration of the compound at which the DBH activity was halved (IC50)• Melting points (m.p.) are given in °C. By this method, fusaric acid was found to have an IC50 of approx. 8 x 10~<7>. The above results illustrate that compounds according to the invention and other compounds which are suitable for the method according to the invention inhibit the DBH activity.

The following procedure was used for the investigation of compounds according to the invention with regard to activity in vivo. Spontaneously hypertensive male rats of the Okamoto-Aoki strain (SHR), 270-340 g, age 16-20 weeks, were used for testing. The afternoon before the trial, the animals were fasted, and the following morning the first dose of the test compound was administered p.o. together with 2 5 ml per kg normal saline solution. The animals were then placed in metabolism cages, three per cage, and urine was collected for 3 hours and then analyzed for sodium, potassium and creatinine. Indirect systolic blood pressure and cardiac activity were measured via a tail-cuff method, and within 24 hours of the first dose, the animals received an identical second dose of the test compound. Two hours after the second dose, the systolic blood pressure and cardiac activity were again determined. The drugs were administered intraperitoneally as a solution or suspension in 0.9% NaCl with 0.02% ascorbic acid. The dose volume was 5 ml.

The average of the results of the in vivo studies is given in Table II. In all the compounds tested, R is -H and Y is -OH. Except where otherwise indicated, the concentration was 50 mg/kg. The average of the results with control animals is given in parentheses below the results for treated animals.

It appears from Table II that the tested compounds have significant diuretic and/or cardiotonic activity. The compounds where X is 3,5-dichloro showed significant nodiuretic activity as well as diuretic, antihypertensive and cardiotonic activity. Compounds with diuretic activity are known to be suitable as antihypertensive agents.

In further experiments carried out mainly by the above procedure, the compound where X is 3,5-F2, Y is -H, R is

-H and n is 1 (50 mg/kg) found to have a particularly pronounced effect on urinary excretion, as the urine volume was increased approximately fourfold compared to the controls. Cardiac activity was generally reduced by administration of the compound. Various compounds according to the invention, as well as various known DBH inhibitors, were tested for their effect on peripheral dopamine and norepinephrine levels mainly by the method of DaPrada and Ziircher, Life Sci. 19, 1161 (1976). Spontaneously hypertensive rats were dosed twice, the second dose being approx. 18 hours after the first, and was euthanized approx. 2 hours after the second dose. The average of the results, expressed in micrograms of DA per grams of tissue, are listed in Table III and in Table III A, as follows. In Table III, R = -H, Y = -OH and n = 1; in Table III A, R = -H, Y = -H and n = 1; in Table III B, R = -H, Y = -0CH3 and n = 1.

The above results illustrate that the compounds according to the invention inhibit the DBH activity in mammals when they are administered internally in effective amounts. The compounds according to the invention where X is -H, Y is -OH, R is -H and n is 3 were also tested in one rat. The results did not show any significant inhibition of DBH activity. Nevertheless, the compound is believed to be suitable for inhibiting the DBH activity in mammals, because only a single trial was run, because other compounds according to the invention show such activity and because the compound has a low IC50 in vitro (see Table I).

The compounds where Y is -H and X is halogen, especially difluorine and dichloro, show high activity in vivo, as shown in Table HIA. The compound where X is 3,5-difluoro, Y is -H, R is -H and n is 1 (IC50= 1.2 x IO"<6>) showed a particularly pronounced effect on the DA/NE ratio in vivo. Moreover, although compounds where Y is -OCH 3 , n is 1 and X is 3-F or 3,5-F 2 are relatively weak DBH inhibitors in vitro, as shown by the data in Table UIB, they proved to be very potent DBH inhibitors in vivo.

In a study of the effect on blood pressure in spontaneously hypertensive rats with daily doses of compounds according to the invention (50 mg/kg, i.p.) the compound where X is 3,5-dichloro, Y is -H, R is -H and n is 1 a cumulative effect, i.e. blood pressure continued to decrease every day during the 4-day study period.

Another study was conducted to compare the effects on blood pressure of compounds where Y is -OH, X is 3-5 or 3,5-F2 and n is 1 in relation to the analogous compounds where Y is -OCH3. The maximum observed reduction in blood pressure after administration of the hydroxy compound where X is 3-5 was 18%, while half the dose of its methoxy analogue produced a blood pressure reduction of 35%. Furthermore, equivalent doses of the compound where Y is -OH, X is 3,5-F2 and n is 1 and its analogous compound where Y is -OCH3 produced blood pressure reductions of 20 and 35%, respectively.

The compounds can be incorporated into suitable dosage unit forms such as capsules, tablets or injectable preparations. Pharmaceutical carriers that can be used can be solid or liquid. Solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Liquid carriers include syrup, peanut oil, olive oil and water. Similarly, the carrier or diluent may include any sustained-release material, such as glyceryl monostearate or glyceryl distearate, alone or together with a wax. The amount of solid carrier will vary widely, but will preferably be from approx. 25 mg to approx. 1 g per dosage unit. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule or an aqueous or non-aqueous liquid suspension.

The pharmaceutical preparations are prepared by conventional techniques used by a pharmaceutical chemist including mixing, granulating and compacting, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to achieve the desired oral or parenteral end products.

Doses of the present compounds in a pharmaceutical dosage unit will be an effective amount, that is, a non-toxic amount selected from the range of 0.1-1,000 mg of active compound per kg, preferably 10-100 mg/kg. The selected dose is administered to a patient who needs treatment 1-5 times a day, orally, rectally, by injection or by infusion. Parenteral administration, where a low dose is used, is preferred. However, oral administration, at a higher dose, can also be used when it is safe and convenient for the patient. Use of the lowest effective doses is recommended because toxicity has been associated with sulfur-containing compounds.

The following examples are illustrative of the preparation of compounds according to the invention or intermediates thereof. The starting compounds are commercially available or prepared by known techniques. The examples are not intended to limit the scope of the invention as described above and as claimed below. The compounds listed in Tables I, II and III above were prepared essentially by the methods illustrated. All temperatures and melting points (m.p.) are in degrees Celsius (°C).

EXAMPLE 1

1-(4-Methoxyphenyl)-2-mercaptoimidazole

A solution of 10 g (0.06 mol) of p-methoxyphenyl isothiocyanate in 100 ml of CHCl 3 was treated with 6.3 g (0.06 mol) of aminoacetaldehyde dimethyl acetal. The solvent was evaporated and the residue was recrystallized from ethanol to give N-(p-methoxyphenyl)-N'-(3,e-dimethoxyethyl)thiourea, 9.2 g (57%). A suspension of this thiourea in a solution of 5 ml concentrated H 2 SO 4 and 20 ml H 2 O was refluxed for 3 hours. The mixture was cooled and a solid was filtered off, washed with H 2 O and dried. Recrystallization from ethanol gave 1-(4-methoxyphenyl)-2-mercaptoimidazole, 4.9 g (70%), mp 215-217°C. For example, protecting groups can be removed from the compound as illustrated in Examples 5 and 6 below, during the preparation of the phenol, Y is

-OH.

EXAMPLE 2

1-(4-Methoxybenzyl)-2-mercaptoimidazole

A mixture of 13.6 g (0.1 mol) anisaldehyde, 13.3 g (0.1 mol) aminoacetaldehyde diethyl acetal and 1 ml CH 3 OH was heated at 95°C for 10 minutes. A residue was dissolved in 150 ml of ethanol and hydrogenated over 10% Pd on carbon at 0.34 MPa until H2 uptake was complete. The catalyst was filtered off and the filtrate was treated with 10.4 g (0.107 mol) KSCN, 40 mL 3N HCl and 40 mL H 2 O. The mixture was boiled under reflux, the solvent being allowed to evaporate until the volume of the reaction mixture was 100 ml. After 45 min the mixture was cooled and a solid was filtered off, washed with H 2 O and dried. Recrystallization from ethanol gave 1-(4-methoxybenzyl)-2-mercaptoimidazole, 15.0 g (68%), m.p. 140-142°C.

EXAMPLE 3

1-(3-Bromo-4-methoxybenzyl)-2-mercaptoimidazole

A solution of 10.75 g (0.05 mol) of 3-bromo-4-methoxybenzaldehyde and 6.65 g (0.05 mol) of aminoacetaldehyde diethyl acetal in 25 ml of ethanol was refluxed for 30 minutes. The solvent was evaporated and the residue was dissolved in CH 2 Cl 2 . The CH 2 Cl 2 solution of the Schiff base was washed with saturated aqueous NaCl, dried (K 2 CO 3 ) and filtered, and the solvent was evaporated. Residual-Schiff base was dissolved in 100 ml of methanol, cooled to 5° and treated with 5.0 g of NaBH 4 . The reaction mixture was allowed to warm to 22°, and after 4 hours the solvent was evaporated. The residue was taken up in diethyl ether, washed with H 2 O, dried (MgSO 4 ) and filtered, and the solvent was evaporated. A solution of the residue in CHCl3 on treatment with ethereal HCl after standing gave crystals of N-(3-bromo-4-methoxybenzyl)aminoacetaldehyde diethylacetal hydrochloride, 10.75 g (58%), m.p. 112-120°.

A solution of 10.74 g (0.029 mol) N-(3-bromo-4-methoxy-benzyl)aminoacetaldehyde-diethylacetal hydrochloride and 3.37 g (0.35 mol) KSCN in 50 mL H 2 O, 50 mL ethanol and 5 mL 3N HCl was refluxed for 4.5 hours. 100 mL of H 2 O was added and the mixture was cooled. A solid was filtered off, washed with H 2 O and dried. Recrystallization from ethanol gave 1-(3-bromo-4-methoxybenzyl)-2-mercaptoimidazole, 6.3 g (72%), m.p. 188°.

EXAMPLE 4

1-f 3-(4-Methoxyphenyl)-propyl]-2-mercaptoimidazole

A solution of 12.5 g (0.07 mol) of p-methoxyphenylpropionic acid in 100 ml of CH 2 Cl 2 and one drop of pyridine was treated with 9.8 g (0.077 mol) of oxalyl chloride. After 2.5 hours, the solvents were thoroughly evaporated, giving the acid chloride as an oil. A solution of the acid chloride in 100 mL CH 2 Cl 2 was slowly added to a cold (0°) solution of 14.7 g (0.14 mol) of aminoacetal hydrdimethylacetal in 300 mL CH 2 Cl 2 at a rate such that the temperature remained below 20°. After 1 hour the reaction mixture was poured into H 2 O and the CH 2 Cl 2 layer was separated and washed with aqueous Na 2 CO 3 , 0.5 N HCl and H 2 O. After drying and evaporation of the solvent, N-(P,P-dimethoxyethyl)-p-methoxyphenylpropionamide was obtained as a solid, 10.3 g (55%). A solution of this amide in 300 ml diethyl ether was slowly added to a slurry of 4.0 g LiAlH 4 in 400 ml diethyl ether and 350 ml tetrahydrofuran (THF). After 3.5 hours at 22°, excess LiAlH 4 was carefully discarded, the reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in 100 ml of 0.15 N HCl, washed with diethyl ether, basified with NaHCO 3 and extracted with diethyl ether. The extracts were dried (MgSO 4 ) and the solvent was evaporated to give N-[3-(4-methoxyphenyl)propyl]aminoacetaldehyde dimethyl acetal, 4.6 g (52%), as an unstable oil.

A solution of 3.62 g (0.014 mol) N-[3-(4-methoxyphenyl)-propyl]aminoacetaldehyde dimethyl acetal and 1.4 g (0.0144 mol) KSCN in 20 mL ethanol, 5 mL H 2 O and 2 mL concentrated HCl was refluxed for 5 h. 50 ml H 2 O was added, the mixture was cooled and a solid was filtered off, washed with H 2 O and dried. Recrystallization from ethanol gave 1-[3-(4-methoxyphenyl)-propyl]-2-mercaptoimidazole, 2.4 g (69%), m.p. 108-109°.

EXAMPLE 5

1-(3-Fluoro-4-methoxybenzyl)-2- mercaptoimidazole 3-Fluoro-4-methoxybenzaldehyde (5.0 g, 0.0324 mol) was added to aminoacetaldehyde dimethyl acetal (3.53 mL, 0.0324 mol) and the mixture was heated at 100°C for 2 hours. The reaction mixture was cooled in ice, diluted with ethyl alcohol (50 mL), and sodium borohydride (1.23 g, 0.0324 mol) was added and the mixture was stirred overnight at 25°C. The solvent was removed under

reduced pressure, and the residue was dissolved in ethyl acetate and the solution was washed with water and brine and then dried with sodium sulfate. The mixture was filtered and the solvent removed under reduced pressure to give N-(3-fluoro-4-methoxybenzyl)-aminoacetaldehyde dimethyl acetal as an oil (6.68 g, 85%).

To a solution of 1-(3-fluoro-4-methoxybenzyl)aminoacetaldehyde-dimethyl acetal (6.68 g, 0.0275 mol) in ethyl alcohol (40 mL) was added potassium thiocyanate (2.94 g, 0.0302' mol ) in water

(65 mL) followed by 12 N hydrochloric acid (6 mL), and the reaction mixture was heated under reflux for 3 h. The solvent was partially removed under reduced pressure and the mixture was cooled in ice and the product filtered. The product was recrystallized from ethyl alcohol to give 1-(3-fluoro-4-methoxybenzyl)-2-mercaptoimidazole as a solid melting at 156-157° (3.98 g, 61%).

EXAMPLE 6

1-( 3. 5- Difluoro- 4- methoxybenzyl)- 2- mercaptoimidazole

A mixture of 3,5-difluoro-4-methoxybenzonitrole (3.50 g, 0.0207 mol) and Raney catalyst powder (3.5 g) in 90% formic acid (35 mL) was stirred and heated under reflux for 2, 5 hours, and the catalyst was filtered off and washed with hot water and hexane. The hexane layer was separated and the aqueous solution was extracted three more times with hexane. The combined hexane extracts were washed with water and brine, dried, and the solvent removed to give 3,5-difluoro-4-methoxy-benzaldehyde as an oil (3.38 g, 95%).

3,5-Difluoro-4-methoxybenzaldehyde (3.38 g, 0.0196 mol) was added to aminoacetaldehyde dimethyl acetal (2.14 mL, 0.0196 mol) and the mixture was heated at 100°C for 2 hours. The reaction mixture was cooled in ice, diluted with ethyl alcohol (35 mL), and sodium borohydride (0.743 g, 0.0196 mol) was added and the mixture was stirred overnight at 25°C. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed with water and saline and then dried with sodium sulfate. The mixture was filtered and the solvent removed under reduced pressure to give N-(3,5-difluoro-4-methoxybenzyl)aminoacetaldehyde dimethyl acetal as an oil (4.94 g, 96%).

To a solution of N-(3,5-difluoro-4-methoxybenzyl)aminoacetaldehyde dimethyl acetal (4.94 g, 0.0189 mol) in ethyl alcohol (30 mL) was added potassium thiocyanate (2.10 g, 0.0216 mol) in water (48 mL) followed by 12 N hydrochloric acid (4 mL), and the reaction mixture was heated under reflux for 3.5 hours. The solvent was partially removed under reduced pressure, the mixture was cooled in ice and the product was filtered. The product was recrystallized from ethyl alcohol-hexane to give 1-(3,5-difluoro-4-methoxy-benzyl)-2-mercaptoimidazole as a solid melting at 160-161° (2.22 g, 46%) .

EXAMPLE 7

1-f 3-(4-Hydroxyphenyl)propyl]-2-mercaptoimidazole

In a solution of 1.75 g (0.007 mol) 1-[3-(4-methoxyphenyl)propyl]-2-mercaptoimidazole in 60 ml CH 2 Cl 2 was protective

groups removed by treatment with a solution of 7.0 g (0.028 mol) BBr 3 in 10 ml CH 2 Cl 2 . After 1.5 hours, the reaction mixture was cooled to 0° and methanol was added carefully. After a vigorous reaction had subsided, the solvents were evaporated.

The residue was recrystallized from ethanol to give 1-[3-(4-hydroxyphenyl)propyl]-2-mercaptoimidazole, 1.02 g (67%), m.p. 185°.

EXAMPLE 8

1- r 3- f4- Hydroxyphenyl) propyl]- 2- thiomethylimidazole

A solution of 1.2 g (0.0046 mol) 1-[3-(4-methoxyphenyl)-propyl]-2-mercaptoimidazole in 40 ml CH 2 Cl 2 was treated with a solution of 3.5 g (0.014 mol) BBr 3 in 10 ml CH 2 Cl 2 . After 4 h, methanol was carefully added, the mixture was stirred for a further 18 h and the solvents were evaporated. The residue was dissolved in H 2 O, washed with ethyl acetate, neutralized with NaHCO 3 and extracted with ethyl acetate. The extracts were dried (MgSO 4 ) and filtered and the solvent was evaporated. The residue was dissolved in 5 ml of ethanol and treated with ethereal HCl. A crystalline product was filtered off and recrystallized from ethanol to give 1-[3-(4-hydroxyphenyl)propyl]-2-thiomethylimidazole hydrochloride, 0.61 g (45%), m.p. 140-142°.

EXAMPLE 9

1-( 3- Nitro- 4- hydroxybenzyl)- 2- mercaptoimidazole

A solution of 1-(3'-nitro-4'-methoxybenzyl)-2-mercaptoimidazole (1.59 g, 6.0 mol) in 10% aqueous NaOH (200 mL) was refluxed for 2 h, cooled, acidified with concentrated HCl, cooled and filtered. The crystalline product was washed with water. Recrystallization from ethanol gave 1.25 g (80%) of the product as yellow prisms, mp 225-227° (dec.).

EXAMPLE 10

1-( 2 . 6- Dichloro- 4- hydroxybenzvl)- 2- mercaptoimidazole

A mixture of 1-(2',6'-dichloro-4'-methoxybenzyl)-2-mercaptoimidazole (Ig) in concentrated aqueous hydrobromic acid (50 mL) was heated under reflux under argon for 1.25 hours and then cooled. The product was collected by filtration. Washing with concentrated aqueous hydrobromic acid and water and drying gave 0.64 g (60%) of product as pale yellow crystals, m.p. 235° (dec.).

EXAMPLE 11

1-(3-Trifluoromethyl-4-hydroxybenzyl)-2-mercaptoimidazole

A mixture of 1-(3'-trifluoromethyl-4'-methoxybenzyl)-2-mercaptoimidazole (2.0 g) and pyridine hydrochloride (15 g) was melted at 210° for 30 minutes, cooled, diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were treated with charcoal, dried over sodium sulfate and concentrated to give a thick oil. Addition of THF (3 mL), ether (6 mL) and hexane (15 mL) gave yellow crystals. Recrystallization from ethyl acetate/hexane gave 0.7 g (0.37%) of cream-colored crystals, m.p. 220° (dec.).

EXAMPLE 12

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 during the slow addition of sodium borohydride (3 g, 0.08 mol), and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed sequentially with water and brine and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was heated under reflux with water

(100 mL), concentrated hydrochloric acid (22 mL), ethanol (41 mL), and potassium thiocyanate (10.7 g, 0.11 mol) for 2 hours. The mixture was cooled and diluted with water (250 mL), and the crude product was collected by filtration and dried. Recrystallization twice from acetic acid gave 7.3 g (30%) of the title compound as pale yellow crystals, m.p. 209-211°.

EXAMPLE 13

1-(2',6'-Dichlorobenzyl)-2-mercaptoimidazole

Reaction of 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mol) and aminoacetaldehyde diethyl acetal (13.3 g, 0.1 mol) essentially as above afforded 5.4 g (21%) of the title compound as white needles , m.p. 242-243° (ethanol/ether).

EXAMPLE 14

1-(2'-Chlorobenzyl)-2- mercaptoimidazole

Reaction of 2-chlorobenzaldehyde (14 g, 0.1 mol) and aminoacetaldehyde-diethyl acetal (13.3 g, 0.1 mol) essentially as above gave 11.2 g (50%) of the title compound as white crystals, m.p. 206-207° (acetone/ethanol).

EXAMPLE 15

1-(2'.5'-Dichlorobenzyl)-2- mercaptoimidazole

Reaction of 2,5-dichlorobenzaldehyde (10.25 g, 0.059 mol) and aminoacetaldehyde diethyl acetal (7.79 g, 0.059 mol) essentially as above gave 5.2 g (34%) of the title compound as white crystals, m.p. 265° (dec.) (propionic acid).

EXAMPLE 16

1-(4'-Chlorobenzyl)-2-mercaptoimidazole

Reaction of 4-chlorobenzaldehyde (14 g, 0.1 mol) and aminoacetaldehyde-diethyl acetal (13.3 g, 0.1 mol) essentially as above gave 8.3 g (36%) of the title compound as white crystals, m.p. 187-189° (acetonitrile).

EXAMPLE 17

1-(2'.3'-Dichlorobenzyl)-2- mercaptoimidazole

Reaction of 2,3-dichlorobenzaldehyde (8.7 g, 0.05 mol) and aminoacetaldehyde diethyl acetal (6.65 g, 0.05 mol) essentially as above afforded 3.0 g (23%) of the title compound as white crystals , m.p. 195-197° (ethanol).

EXAMPLE 18

1-(4'-Fluorobenzyl)-2- mercaptoimidazole

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

EXAMPLE 19

1-(3',4'-Dichlorobenzyl)-2-mercaptoimidazole

Reaction of 3,4-dichlorobenzaldehyde (17.5 g, 0.1 mol) and aminoacetaldehyde diethyl acetal (13.3 g, 0.1 mol) essentially as above gave 10 g (39%) of the title compound as white crystals, m.p. . 178-181° (ethanol).

EXAMPLE 2 0

1-(2'^'-Dichlorobenzyl)-2-mercaptoimidazole

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

EXAMPLE 21

1-( 3/- Chlorobenzyl)- 2- mercaptoimidazole

Reaction of 3-chlorobenzaldehyde (14 g, 0.1 mol) and aminoacetaldehyde diethyl acetal (13.3 g, 0.1 mol) essentially as above gave 14 g (62.5%) of the title compound as white crystals, mp 129 -131° (acetonitrile).

EXAMPLE 2 2

1-( 2/. 4' , 6'- Trichlorobenzyl)- 2- mercaptoimidazole Reaction of 2,4,6-trichlorobenzaldehyde (20.9 g, 0.1 mol) and aminoacetaldehyde diethyl acetal (13.3 g, 0, 1 mole) mainly as

above gave 12 g (46%) of the title compound as white crystals, m.p. 240-244° (ethanol).

EXAMPLE 2 3

1-(3-Fluorobenzyl)-2-mercaptoimidazole

Reaction of 3-fluorobenzaldehyde (24.8 g, 0.2 mol) and aminoacetaldehyde diethyl acetal (26.6 g, 0.2 mol) essentially as above gave 28 g (67%) of the title compound as white crystals, m.p. 112.5-114° (2-propanol/water).

EXAMPLE 24

1-(3'.5'-Difluorobenzyl)-2-mercaptoimidazole

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

EXAMPLE 2 5

1-f 3-(3'.5'-Difluorophenyl)propyl]-2-mercaptoimidazole 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 at 155° for 1 hour. The reaction mixture was poured into cold 3 N aqueous hydrochloric acid and then filtered. Recrystallization from ethanol afforded 4.7 g (66%) of 3,5-difluorocinnamic acid as brown-yellow needles, m.p. 199-201°.

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

A solution of 3-(3',5'-difluorophenyl)propanoic acid (4.4 g, 0.024 mol) N,N-dimethylformamide (one drop) and thionyl chloride (15 ml) was heated at 60° for 3 hours. Excess thionyl chloride was removed by distillation under reduced pressure. Distillation

(Kugelrohr) at reduced pressure (ca. 33 Pa) gave 4.1 g (85%) of 3-(3',5<7->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 slowly added to a 0° solution of aminoacetaldehyde dimethyl acetal (4.3 g, 0, 0412 mol) in methylene chloride (100 ml) at a rate such that the temperature did not exceed 20°. 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, 0.05% aqueous hydrogen chloride and water and then dried over sodium sulfate and concentrated to obtain 5.5 g (103%) of 3-(3',5'-difluorophenyl)propanamide- N-acetaldehyde dimethyl acetal as an oil.

To a slurry 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. Then water (4.5 mL) was carefully added, followed by 10% aqueous sodium hydroxide (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'-(3',5'-difluorophenyl)propanamine-N-acetaldehyde-dimethyl acetal as a colorless oil.

A solution of 3-(3',5'-difluorophenyl)propanamine-N-acetaldehyde-dimethyl acetal (4.3 g, 0.0166 mol) and potassium thiocyanate (1.6 g, 0.0166 mol) in ethanol (12 ml), water (20 ml) and concentrated hydrochloric acid (4 ml) were refluxed for 1 hour and then cooled, and a large volume 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).

EXAMPLE 2 6

3-( 3' , 5'- Dichlorophenyl) propyl- 2- mercaptoimidazole Reaction of 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) essentially as above gave 22.9 g (69%) of 3,5-dichlorocinnamic acid as white needles, m.p. 169-170° (ethanol).

Reaction of 3,5-dichlorocinnamic acid (22.9 g, 0.106 mol) and 3 g of palladium/carbon essentially as above gave 23 g (99%) of 3-(3',5'-dichlorophenyl)propanoic acid as an oil.

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

Dimethyl sulfoxide (6.75 g, 0.083 mol) in dry methylene chloride (15 mL) was added dropwise to a solution of oxalyl chloride (6.2 g, 0.049 mol) in dry methylene chloride (15 mL) at -78°. The reaction mixture was stirred for 2 minutes. Then 1-[3-(3',5'-dichlorophenyl)]-propanol (5 g, 0.0245 mol) in dry methylene chloride (20 ml) was added slowly, keeping the temperature below -60°. After stirring for 15 min at -70°, triethylamine (16 g, 0.160 mol) was added dropwise. The reaction mixture was stirred for an additional 5 minutes at -60° and was then warmed to room temperature and diluted with water. The organic layer was separated, washed with 3 N hydrogen chloride and then with brine, and was dried over sodium sulfate. The solution was concentrated to give 5.0 g (100%) of 3-(3',5'-dichlorophenyl)propionaldehyde as a yellow oil.

Aminoacetaldehyde 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). After stirring for 1 hour at room temperature, sodium borohydride (7.3 g, 0.193 mol) in ethanol (25 ml) was added. The reaction mixture was stirred for 18 hours and was then diluted with water and concentrated. The residue was taken up 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' ,5'-dichlorophenyl)propanamide-N-acetal-dehyde-dimethyl acetal and potassium thiocyanate (2.2 g, 0.0223 mol) in ethanol (20 mL), water (30 mL) and conc. hydrochloric acid was boiled under reflux for 1 hour. The reaction mixture was cooled and diluted with water. After standing for 3 hours, the crude product solidified and was filtered. Chromatography on silica eluting with 0.5-1% methanol in methylene chloride gave 2.0 g (31%) of 3-(3',5'-dichlorophenyl)propyl-2-mercaptoimidazole as white crystals, m.p. 98-99° (ethanol).

EXAMPLES 27-58

The compounds listed in Table IV below are prepared essentially by the methods illustrated in the preceding Examples, except that equivalent molar amounts of the appropriate starting compounds and other reactants and reagents are used.

The compounds where X and/or Y is -OH are prepared from corresponding methoxy-substituted compounds where protective groups are removed as illustrated above.

In particular, the compounds according to Examples 29, 32, 36 and 38 are prepared from mercaptoimidazoles as follows:

Example Mercaptoimidazoles

30 1-[3-(3-carboxamido-4-methoxyphenyl)-propyl]-2-mercaptoimidazole 33 1-[2-(2,3-di(trifluoromethyl)-4-methoxy-phenylethyl]-2-mercaptoimidazole 3 6 1-[2-(3-cyano-4-methoxyphenyl)ethyl]-2-mercaptoimidazole 38 1-[3-(2-methoxy-4-carbomethoxyphenyl)-propyl]-2-mercaptoimidazole

The compound according to Example 33 where R is -(CH 2 ) 3 CH 3 is prepared by allowing protective groups to be removed with BBr 3 i butanol while continuing to form butyl bromide. Butyl bromide alkylates the mercapto moiety as in Example 6 above.

EXAMPLES 59-68

The compounds shown in Table V below are prepared by alkylation of corresponding mercaptoimidazoles according to the invention with methyl iodide in methanol by known techniques. Methyl iodide is replaced by other alkyl halides, for example methyl bromide, methyl chloride and butyl iodide in a suitable solvent. The salts are neutralized to the free base with, for example, sodium hydroxide or sodium carbonate, and can be converted into another pharmacologically satisfactory acid addition salt.

EXAMPLE 69

The ingredients in Table VI below are sieved, mixed and filled into a hard gelatin capsule.

EXAMPLE 7 0

The sucrose, calcium sulfate dihydrate and imidazole shown in Table VII below are mixed and granulated with one 10% gelatin solution. The wet granules are sieved, dried, mixed with the starch, talc and stearic acid, sieved and compressed into a tablet.

EXAMPLE 71

1-[3-(4-Hydroxyphenyl)propyl]-2-thiomethylimidazole hydrochloride, 75 mg, is dissolved in 25 ml of normal saline to prepare an injectable preparation.

Although the preferred embodiments of the invention are illustrated by the above, it must be clear that the invention is not limited to the exact structures described herein and that one reserves the right to all modifications that fall within the scope of the following claims.

Claims (42)

1. Connection with the formula: where X is -H, -OH, halogen, C1 _4 <-> alkyl, -CN, -N02 , -S02 NH2 , -CO 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , C-4-Alkoxy, -SO 2 C 1_4-alkyl, -S02<C>1_4 -fluoroalkyl or -C02<C>1_4 -alkyl or any available combination thereof up to four substituents, Y is -H, -OH, C1 _4 -Alkoxy, Halogen, C1_4 -Alkyl, -CN, -NO2 , -S02 NH2 , -C02 H, -CONH2 , -CHO, -CH2 OH, -CF3 , -S02 C1_4 -alkyl, -S02 C1_4 -fluoroalkyl or -C02<C>1_4 -alkyl, R is -H or C1_4 -alkyl and n is 1-4, or a hydrate or, when R is C-L-4 alkyl, a pharmaceutically acceptable acid addition salt thereof, provided that when n is 1-3, at least one of Y and X is not -H. 2. Compound according to claim 1, where Y is -OH. 3. Compound according to claim 2, where R is -H, n is 1 or 3 and X is -H, -OH or halogen. 4. Compound according to claim 3, where X is -H, -OH, 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluorine. 5. Compound according to claim 4, where X is 3,5-difluoro and n is 1. 6. A compound according to claim 1, wherein Y is -H. 7. Compound according to claim 6, where R is -H, n is 1 or 3 and X is -OH or halogen. 8. Compound according to claim 7, where X is -OH, 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluoro. 9. Compound according to claim 8, where X is 3,5-difluoro and n is 1. 10. Compound according to claim 1, wherein X is -H, Y is -OH, R is -H and n is 0-4; X is 3-OH, 3-C1, 3-CH3, 3-Br, 3-F, 3-NO2, 3-CF3, 3,5-dichloro, 3,5-difluoro, 2,6-dichloro or 2, 3,5,6-tetrafluoro, Y is -OH, R is -H and n is 1; X is -H, Y is -OH, R is -CH 3 and n is 3; X is -H, Y is -F, R is -H and n is 1; X is 3-C1, Y is -Cl, R is -H and n is 1; X is 2,6-dichloro, 2-Cl, 2,5-dichloro, 2,3-dichloro, 3-C1, 3,5-dichloro, 3-F, 3,5-difluoro, Y is -H, R is -H and n is 1; X is -H, 3-C1, 2-Cl, 2,6-dichloro, Y is -Cl, R is -H and n is 1; X is 3,5-dichloro or 3,5-difluoro, Y is -H, R is -H and n is 3; or X is 3-OH, 2-OH, 2-OCH3, 3-OCH3 or -H, Y is -H, R is -h and n is 1. 11. Compound according to claim 1, where Y is -OCH3. 12. Compound according to claim 11, where X is 3-F, R is H and n is 1, or X is 3,5-F2, R is H and n is 1. 13. A pharmaceutical composition for inhibiting DBH activity in mammals, comprising an amount effective to effect inhibition, of a compound of the formula: where X is -H, -OH, halogen, C1 _4 -alkyl, -CN, -NO2 , -SO2 NH2 , -CO2 H, -CONH2 , -CHO, -CH2 OH, -CF3 , C1_4-Alkoxy, -SO2C1_4-Alkyl, -S <0>2 C1 _4 -fluoroalkyl, -C <0>2 <C>1 _4 -alkyl or any available combination thereof up to four substituents, Y is -H, -OH, <C>1_4 -Alkoxy, halogen, C1_4 -alkyl, -CN, -NO2, -S02 NH2 , -C02 H, -CONH2 , -CHO, -CH2 OH, -CF3 , -S02 C1 _4 -alkyl, -S <0>2 C1_4 -fluoroalkyl or -C02<C>1_4 -alkyl, R is -H or C 2 -alkyl and n is 0-4, or a hydrate or, when R is C 1 -4 -alkyl, a pharmaceutically acceptable acid addition salt thereof, provided that when n is 0, Y is -OH or C -L -4 alkoxy, and a suitable carrier. 14. Pharmaceutical mixture according to claim 13, where Y is -OH. 15. Pharmaceutical mixture according to claim 14, where R is -H, n is 1 or 3 and X is -H, -OH or halogen. 16. Pharmaceutical mixture according to claim 15, where X is -H, -OH, 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluorine. 17. Pharmaceutical mixture according to claim 16, where X is 3,5-difluoro and n is 1. 18. Pharmaceutical mixture according to claim 13, where Y is -H. 19. Pharmaceutical mixture according to claim 18, where R is -H, n is 1 or 3 and X is -OH or halogen. 20. Pharmaceutical mixture according to claim 19, where X is -OH, 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluoro. 21. Pharmaceutical mixture according to claim 20, where X is 3,5-difluoro and n is 1. 22. Pharmaceutical mixture according to claim 13, where X is -H, Y is -OH, R is -H and n is 0-4; X is 3-OH, 3-C1, 3-CH3, 3-Br, 3-F, 3-NO2, 3-CF3, 3,5-dichloro, 3,5-difluoro, 2,6-dichloro or 2, 3 ,5 , 6-t'etraf luor , Y is -OH, R is -H and n is 1; X is -H, Y is -OH, R is -CH 3 and n is 3; X is -H, Y is -F, R is -H and n is 1; X is 3-C1, Y is -Cl, R is -H and n is 1; X is 2,6-dichloro, 2-Cl, 2,5-dichloro, 2,3-dichloro, 3-C1, 3,5-dichloro, 3-F, 3,5-difluoro, Y is -H, R is -H and n is 1; X is -H, 3-C1, 2-Cl, 2,6-dichloro, Y is -Cl, R is -H and n is i; X is 3,5-dichloro or 3,5-difluoro, Y is -H, R is -H and n is 3; or X is 3-OH, 2-OH, 2-OCH3, 3-OCH3 or -H, Y is -H, R is -H and n is 1. 23. Pharmaceutical mixture according to claim 13, where Y is -OCH3. 24. Pharmaceutical mixture according to claim 23, where X is 3-F, R is H and n is 1, or X is 3,5-F2, R is H and n is 1. 25. Method for inhibiting the DBH activity in mammals, wherein one administers internally to an individual an effective amount of a compound of the formula where X is -H, -OH, halogen, C1 _4 -alkyl, -CN, -NO2 , -SO2 NH2 , -C02 H, -C0NH2 , -CHO, -CH2 0H, -CF3 , C1_4 -Alkoxy, -S02<C>1_4 -Alkyl, -S <0>2<C>1 _4 -fluoroalkyl, -C <0>2 <C>1 _4 -alkyl or any available combination thereof up to four substituents, Y is -H, -OH, C-L-4-Alkoxy, Halogen, C1-4-Alkyl, -CN, -NO2, -S02 NH2 , -C02 H, -C0NH2 , -CHO, -CH2 0H, -CF3 , -S02 C1 _4 -alkyl, -S <0>2 C1_4 -fluoroalkyl or -C02<C>1_4 -alkyl, R is -H or C1_4 -alkyl and n is 0-4, or a hydrate or, when R is C 1 -4 alkyl, a pharmaceutically acceptable acid addition salt thereof. 26. Method according to claim 25, where Y is -OH. 27. Method according to claim 26, where R is -H, n is 1 or 3 and X is -H, -OH or halogen. 28. Method according to claim 27, where X is -H, -OH, 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluorine. 29. Method according to claim 28, where X is 3,5-difluoro and n is 30. Method according to claim 25, where Y is -H. 31. Method according to claim 30, where R is -H, n is 1 or 3 and X is -OH or halogen. 32. Method according to claim 31, where X is -OH, 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluorine. 33. Method according to claim 32, where X is 3,5-difluoro and n is 1. 34.. Method according to claim 25, where X is -H, Y is -OH, R is -H and n is 0-4; X is 3-OH, 3-Cl, 3-CH3 , 3-Br, 3-F, 3-NO2 , 3-CF3 , 3,5-dichloro, 3,5-difluoro, 2,6-dichloro or 2, 3,5,6-tetrafluoro, Y is -OH, R is -H and n is 1; X is -H, Y is -OH, R is -CH 3 and n is 3; X is -H, Y is -F, R is -H and n is 1; X is 3-Cl, Y is -Cl, R is -H and n is 1; X is 2,6-dichloro, 2-Cl, 2,5-dichloro, 2,3-dichloro, 3-Cl, 3,5-dichloro, 2,4,6-trichloro, 3-F, 3,5- difluoro, Y is -H, R is -H and n is 1; X is -H, 3-Cl, 2-Cl, 2,6-dichloro, Y is -Cl," R is -H and n is i; X is 3,5-dichloro or 3,5-difluoro, Y is -H, R is -H and n is 3; X is 3-OH, 2-OH, 2-OCH 3 , 3-OCH 3 or -H, Y is -H, R is -H and n is 1; or X is -H, Y is -H, R is -H and n is 0. 35. Method according to claim 25, where Y is OCH3. 36. Method according to claim 35, where X is 3-F, R is H and n is 1, or X is 3,5-F2, R is H and n is 1. 37. Connection with the formula: where Y<1> is -H, halogen, C1_4 -alkyl, -CN, -NO2 , -SO2 NH2 , -CO2 H, -CONH2 , -CHO, -CH2 0H, -CF3 , C1_4 -Alkoxy, -SO2<C>1_4 -Alkyl, -S <0> 2 <C>1_4 -fluoroalkyl or -C02<C>1_4 -alkyl and X<1> is -H, halogen, C1 _4 -alkyl, -CN, -NO2 , -SO2 NH2 , -C02 H, -CONH2 , -CHO, -CH2 OH, -CF3 , <C>1_4 -Alkoxy, -S02<C>1_4 -Alkyl, -SO2 C1 _4 -fluoroalkyl or -C <0> 2 <C>1 _4 -alkyl or any available combination thereof up to four substituents, and n is 0-4, provided that when n is 0, Y <1 > -0CH3 and when n is 1-3, at least one of Y and X is not -H. 38. Compound according to claim 37, where n is 1-4. 39. Connection with the formula: where Y<1> is C1_4 -Alkoxy, X<1> is -H, halogen, C1_4 -alkyl, -CN, -NO2 , -SO2NH2 , -CO 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , C-4-Alkoxy, -SO 2 C 1_4-alkyl, -S <0> 2 <C>1 _4 -fluoroalkyl or -C <0> 2 <C>1 _4 -alkyl or any available combination thereof up to four substituents, and n is 0. 40. Method for producing a compound according to the formula: where X is -H, -OH, halogen, C1_4-alkyl, -CN, -NO2 , -SO2 NH2 , -C02 H, -C0NH2 , -CHO, -CH2 0H, -CF3 , C-1-4-Alkoxy, -S02C1_4-alkyl , -S <0>2 C1 _4 -fluoroalkyl, -C <0>2 <C>1 _4 -alkyl or any available combination thereof up to four substituents, Y is -H, -OH, <C>1_4 -Alkoxy, Halogen, C1_4 -Alkyl, -CN, -NO2 , -S02 HN2 , -C02 H, -CONH2 , -CHO, -CH2 OH, -CF3 , -S02 C1 _4 -alkyl, -S <0> 2 <C>1_4 -fluoroalkyl or -C02<C>1_4 -alkyl, R is -H or C-L-4-alkyl and n is 0-4, or a hydrate or, when R is C 1 -4 alkyl, a pharmaceutically acceptable acid addition salt thereof, where a connection with the formula where Y <1> is Y but not -OH, X <1> is X but not -OH and n is 0-4, is contacted with and reacted with acid thiocyanate, and when Y <1> and/or X < 1> is C1_4 -Alkoxy, the protective alkoxy group is optionally removed during the preparation of the compound where Y and/or X is -OH. 41. Method according to claim 40, where n is 1-4. 42. Method for producing the compound according to the formula where X is -H, -OH, halogen, C1 _4 -alkyl, -CN, -NO2 , -SO2 NH2 , -CO2 H, -CONH2 , -CHO, -CH2 0H, -CF3 , <C>1_4 -Alkoxy, -SO2<C>1_4 -Alkyl, -S <0>2 C1 _4 -fluoroalkyl, -C <0>2 <C>1 _4 -alkyl or any available combination thereof up to four substituents, Y is -H, -OH, <C>1_4 -Alkoxy, Halogen, C1_4 -Alkyl, -CN, -NO2 , -S02 NH2 , -C02 H, -C0NH2 , -CHO, -CH2 OH, -CF3 , -S02 C1 _4 -alkyl, -S <0>2 C1_4 -fluoroalkyl or -C02<C>1_4 -alkyl, R is -H or C1_4 -alkyl and n is 0-4, or a hydrate or, when R is C-L-4 alkyl, a pharmaceutically acceptable acid addition salt thereof, wherein n is 0, where a connection with the formula where Y <1> is C1_4 - alkoxy, X <1> is X but not -OH and n is 0, is contacted with and reacted with an acid to cyclize the compound and remove the protecting alkoxy group.