ES2309279T3 - DERIVATIVES OF IMIDAZOL AND ITS USE AS PERIFERICALLY SELECTIVE INHIBITORS OF BETA-HYDROXYLASE DOPAMINE. - Google Patents

Abstract

(S) -5- (2-Aminoethyl) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazol-2-thione hydrochloride.

Description

Imidazole derivatives and their use as inhibitors peripherally selective dopamine β-hydroxylase.

This invention relates to an inhibitor. peripherally selective of the dopamine-? -hydroxylase and its Preparation method.

In recent years, interest in the development of dopamine-β-hydroxylase (DβH) inhibitors has focused on the hypothesis that inhibition of this enzyme can provide significant clinical improvements in patients suffering from cardiovascular disorders such as hypertension or chronic heart failure. The rationale for the use of D? H inhibitors is based on their ability to inhibit the biosynthesis of norepinephrine, which is achieved via enzymatic hydroxylation of dopamine. The activation of neurohumoral systems, particularly the sympathetic nervous system, is the main clinical manifestation of congestive heart failure (Parmley, WW, Clinical Cardiology, 18: 440-445, 1995). Patients with congestive heart failure have elevated plasma concentrations of norepinephrine (Levine, TB et al ., Am. J. Cardiol., 49: 1659-1666, 1982), an increased central sympathetic flow (Leimbach, WN et al ., Circulation, 73: 913-919, 1986) and an increased overflow of cardiorenal norepinephrine (Hasking, GJ, et al ., Circulation 73: 615-621, 1966). Prolonged and prolonged exposure of the myocardium to norepinephrine can lead to downregulation of β1 cardiac adrenoceptors, remodeling of the left ventricle, arrhythmias and necrosis, all of which may decrease the functional integrity of the heart . Patients with congestive heart failure who have high concentrations of plasma norepinephrine also have the most unfavorable long-term prognosis (Cohn, JN, et al ., N. Engl. J. Med., 311: 819-823, 1984). Of greater significance is the observation that plasma concentrations of norepinephrine are already high in asymptomatic patients who do not have overt heart failure and can predict the resulting mortality and morbidity (Benedict, CR, et al ., Circulation, 94: 690- 697, 1996). This implies that the activated sympathetic tone is not only a marker of congestive heart failure, but could contribute to the progressive worsening of the disease.

Inhibition of sympathetic nerve function with adrenoceptor antagonists seemed a promising approach, however a significant proportion of patients do not tolerate the immediate hemodynamic deterioration that accompanies treatment with β-blockers (Pfeffer, MA, et al ., N. Engl J. Med., 334: 1396-7, 19996). An alternative strategy to directly modulate sympathetic nerve function is to reduce the biosynthesis of norepinephrine via the inhibition of D? H, the enzyme responsible for the conversion of dopamine to norepinephrine in sympathetic nerves. This approach has several merits that include gradual modulation as opposed to abrupt inhibition of the sympathetic system, and that causes increased dopamine release, which improves renal function such as vasodilation, diuresis and renal natriuresis. Therefore, DβH inhibitors can provide significant advantages over conventional β-blockers.

To date, some DβH inhibitors have been described in the literature. The first first and second generation examples such as disulfiram (Goldstein, M., et al ., Life Sci., 3: 763, 1964) and diethyldithiocarbamate (Lippmann, W., et al ., Biochem. Pharmacol., 18 : 2507, 1969) or fusaric acid (Hidaka, H. Nature, 231, 1971) and aromatic or alkyl thioureas (Johnson, GA, et al ., J. Pharmacol. Exp. Ther., 171: 80, 1970) they turned out to be of low potency, exhibited little selectivity for DβH and caused toxic side effects. However, the third generation of DβH inhibitors turned out to have a much higher potency, such as the nepicastate (RS-25560-197, IC 50 9 nM) (Stanley, WC, et al ., Br J. Pharmacol., 121: 1803-1809, 1997), which was developed for the first clinical trials. Although it lacks some of the problems associated with the first and second generations of DβH inhibitors, a very important finding was that the nepicastate crossed the blood brain barrier (BBB), therefore capable of causing central as well as peripheral effects, a situation that could lead to unwanted and potentially serious side effects of the drug in the central nervous system (CNS). Therefore, there is still an unmet clinical requirement for a potent, non-toxic, peripherally selective DβH inhibitor, which could be used for the treatment of certain cardiovascular disorders. A DβH inhibitor with similar or even greater potency than nepicastate, but devoid of effects on the CNS (unable to cross the BBB), could provide a significant improvement over all other DβH inhibitor compounds described up to the date in the prior art.

Surprisingly it has been found that Compounds, according to claims 1 to 6, have effects significant and pronounced of potential utility for the DβH inhibition. These compounds offer greater power and significantly reduced brain access, giving instead of peripherally potent DβH inhibitors selective. Therefore, the invention relates to certain specific compounds of general formula I;

one

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where R 1, R 2 and R 3 they are the same or different and mean hydrogens, halogens, groups alkyl, alkylaryl, alkyloxy, hydroxy, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino; R_ {4} means hydrogen, alkyl or alkylaryl groups; X means CH2, oxygen or sulfur atom; n is 2 or 3; and the enantiomers (R) - and (S) - individual or mixture of enantiomers; and its salts pharmaceutically acceptable. More particularly, the invention is refers to the compounds as defined in claims 1 to 6.

Unless otherwise indicated, in this Descriptive report the term alkyl (either used alone or in combination with other residues) means hydrocarbon chains, linear or branched, containing from 1 to 6 atoms of carbon, optionally substituted by aryl, alkoxy groups, halogen, alkoxycarbonyl or hydroxycarbonyl; the term aryl (already be used by itself or used in combination with other remains) means a phenyl or naphthyl group, optionally substituted by alkyloxy, halogen or nitro groups; and the term halogen means fluorine, chlorine, bromine or iodine.

For the preparation of compositions Pharmaceutical compounds of claims 1 to 6, mixed pharmaceutically acceptable vehicles, inert with the compounds assets. Pharmaceutically acceptable vehicles can be solid or liquid Solid form preparations include powders, tablets, dispersible granules and capsules. A vehicle solid can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or agents tablet disintegrants; it can also be a material encapsulant

Preferably the pharmaceutical preparation is in the form of a single dose, for example a packaged preparation, the package containing discrete amounts of the preparation as packaged tablets, capsules and powders in vials or blisters

The doses can be varied depending on the patient requirements, the severity of the disease and the particular compound that is used. For convenience, the dose daily total can be divided and administered in portions at throughout the day It is expected that the most appropriate administration would be once or twice a day. The determination of the appropriate dose for each particular situation it is within the experience of Experts in medical practice.

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Materials and methods In vitro studies

DβH activity was evaluated by its ability to b-hydroxylate dopamine a norepinephrine as previously described (Kojima, K., Parvez, S. and Nagatsu, T. 1993. Analysis of enzymes in catecholamine Biosynthesis In Methods in Neurotransmitter and Neuropeptide Research, pp. 349-380: Elsiever Science Publishers).  SK-N-SH cells were used (ATCC HTB-11), a cell line derived from human neuroblastoma, as a source of human DβH. The SK-N-SH plated cells 24 wells were pre-incubated for 20 min in a medium of reaction containing 200 mM sodium acetate, 30 mM N-ethylmaleimide, 5 mM copper sulfate, 0.5 mg / ml aqueous catalase solution, 1 mM pargiline, fumarate 10 mM sodium and 20 mM ascorbic acid. Then the cells were incubated for an additional 45 min in the reaction medium with the addition of increasing amounts of dopamine (from 0.5 to 100 mM). During preincubation and incubation the cells were shaken continuously and kept at 37 ° C. The reaction is over by adding 0.2 M perchloric acid. Samples acidified were kept at 4 ° C before injection at high pressure liquid chromatograph for testing the norepinephrine In the experiments carried out in order to study the effects of new DβH inhibitors on their enzymatic activity, test compounds were added interest (from 0.3 to 10,000 nM) to solutions preincubation and incubation; incubation was performed in presence of a concentration (50 mM) of dopamine 2.5 times the corresponding K_ {m} value as determined in the saturation experiments

In vivo studies

Male NMRI mice or Wistar rats from Harlan-Interfauna (Spain) were obtained and kept 10 and 5 per cage, respectively, under controlled environmental conditions (12 h light / dark cycles and ambient temperature of 22 ± 1 ° C). Food and tap water was supplied ad libitum and experimentation was carried out during daylight hours.

At the time equal to 0 h, either the compounds to be tested at a given dose or the vehicle (water) administered orally via forced feeding were administered to the animals. At 2, 6, 9, 12, 18 and 24 h after the dose, the animals were sacrificed by decapitation and isolated, weighed and stored in a volume of 0.2 M perchloric acid for 12 h at 4 ° C in the dark in the heart (right atrium and left ventricle) and the brain (frontal and parietal cortex). After incubation, the resulting supernatants were collected by centrifugal filtration of the incubated (0.2 mM / 10 min / ~ 5000 rpm, 4 ° C). The supernatants were stored frozen at -80 until analysis. The quantification of dopamine and norepinephrine in the supernatants was performed by high pressure liquid chromatography with electronic detection.

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Results In vitro studies

Incubation of SK-N-SH cells in the presence of increasing concentrations of dopamine resulted in a concentration-dependent norepinephrine formation, yielding values of K m (in mM) and v max (in nmol mg protein <-1> h <-1>) of 20.6 ± 1.6 and 153.8 ± 4.4, respectively. A concentration of dopamine close to saturation was chosen from these kinetic parameters for use in inhibition studies. As detailed in Table I, compounds 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 19, 24, 26, 28 and 29 are those that were found to markedly inhibit the activity of D βH. Compounds 2, 3, 4, and nepicastate 1 (reference compound) produced a concentration-dependent decrease in dopamine β-hydroxylation with IC 50 values in the low range of nM versus Human DβH activity (see Table 2). For subsequent in vivo studies, compound 4 was chosen, this being the compound most closely related to nepicastate 1, in order to provide conclusive evidence that structural modifications made to the molecule as part of the present invention are responsible for the marked and surprising improvement of the observed biological properties.

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(Table goes to page next)

TABLE 1 Effect of the chosen compounds (5 mM) on the DβH activity in cells SK-N-SH. The values are give as% of the witness

2

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TABLE 2 IC 50 values (in nM) for inhibition of DβH in the cells SK-N-SH

3

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In vivo studies Mouse

Experiments over time for the compound 4 and nepicastate (1) in the heart at 100 mg / kg suggest that both compounds are long lasting. Maximum time effect (T max) for the reduction of norepinephrine in tissue by 4 and 1 seems to be at 9 h post-dose (Figure 1). Afterwards, noradrenaline tissue levels recover, reaching 50% recovery of initial tissue levels at 24 h.

A T_ {max} (9 h after administration), 4 and 1 reduced norepinephrine levels in a manner dependent on the dose in the left ventricle. For both 4 and 1, the effect Maximum inhibitor was reached at a dose of 100 mg / kg. By contrast to what was found in the heart, 4 did not affect the tissue levels of norepinephrine in the cerebral parietal cortex, while 1 produced a dose-dependent decrease in levels of norepinephrine in this area of the brain (Figure 2).

Rat

As shown in the mouse, the effects of 4 and 1 on norepinephrine were dose dependent administered and reached their maximum at 9 h. (data not revealed). However, as shown in Figure 3, the effects 4 (100 mg / kg) inhibitors on norepinephrine levels, both in the atrium and in the left ventricle, they were more pronounced than those caused by 1 (100 mg / kg). How I know observed in the mouse, again 4 did not affect the tissue levels of norepinephrine in the parietal cortex and in the frontal cortex cerebral, while 1 produced a marked decrease in norepinephrine levels in these brain areas.

It is concluded that 4, in severe contrast with the nepicastato 1, exerts its inhibitory effects on DβH exclusively on the periphery, lacking inhibitory effects on brain.

Reference is now made to the drawings companions, in which:

Figure 1 is a graph showing the time-dependent decrease in norepinephrine levels in the left ventricle of mice treated orally with 100 mg / kg of 4 or nepicastate 1. The symbols are the means of 5 determinations per group; the vertical lines indicate the standard error of the mean (SEM) of the English S tandard E rror of the M edium).

Figure 2 contains two graphs that show norepinephrine levels in the left ventricle and the cerebral parietal cortex of the mouse, 9 hours after oral administration of 4 or nepicastate 1. The symbols are the averages of 5 determinations per group; vertical lines indicate the SEM.

Figure 3 contains four graphs that show norepinephrine levels in the heart (atrium and left ventricles) and brain (frontal and parietal cortex) of the rat, 9 hours after oral administration of 4 or nepicastato 1. The columns are the means of 5 determinations by group; the vertical lines indicate the SEM.

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conclusion

Some compounds of general formula I are very potent inhibitors of dopamine-? -hydroxylase and they have potentially valuable pharmaceutical properties in the treatment of some cardiovascular disorders, where a reduction of enzymatic hydroxylation of dopamine a norepinephrine may be of therapeutic benefit, as is the hypertension and chronic heart failure. The possibility of use a durable DβH inhibitor with limited access to brain (CNS), as compound 4 opens up new perspectives in the treatment of hypertension and heart failure chronic for improvement of the potency and selectivity of the inhibition of DβH in the periphery.

The invention described herein is exemplified. by the following preparation examples, which should not be interpreted to limit the scope of the description. They may be obvious alternative pathways and analogous structures for those subject matter experts. Only examples 14, 15, 16, 36, 44 and 45 are examples of this invention as claimed.

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Examples Example 1

(Comparative)

(R) -5-Aminomethyl-1- (6,8-difluorochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride, compound 3, table 1)

A stirred mixture of (R) -6,8-difluorochroman-3-ylamine hydrochloride (0.22 g, 1.0 mmol), tert-butyl ester of [3- (tert-butyldimethylsilyloxy) -2-oxopropyl] Carbamic acid (0.33 g, 1.1 mmol), potassium thiocyanate (0.11 g, 1.1 mmol) and acetic acid (0.3 ml, 5 mmol) in ethyl acetate (0.3 ml) was maintained at reflux for 2 hours, it was cooled to room temperature, then washed with a solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using the ethyl acetate-petroleum ether mixture as eluent. The resulting oil (0.23 g) was dissolved in ethyl acetate (2 ml), at this point a solution of 2M HCl in ethyl acetate (2 ml, 4 mmol) was added and the mixture was stirred for 2 hours at room temperature. The precipitate was removed by filtration and washed with ethyl acetate to give melting point crystals 192 ° C (decomposition).

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Examples 2-3

(Comparative)

By applying the technique described above and related procedures known to experts in the art and using the hydrochlorides of Appropriate chroman-3-ylamine, se They prepared the following compounds:

(R) -5-Aminomethyl-1-chroman-3-yl-1,3-dihydroimidazol-2-thione hydrochloride (compound 24, table 1).

(R) -5-Aminomethyl-1- (6-hydroxychroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 22, table 1).

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Example 4

(Comparative)

(R, S) -5-Aminomethyl-1- (6-hydroxythiochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride

A stirred mixture of hydrochloride 6-hydroxythiochroman-3-ylamine (0.22 g, 1.0 mmol), tert-butyl acid ester [3- (tert-Butyldimethylsilyloxy) -2-oxopropyl] carbamic (0.33 g, 1.1 mmol), potassium thiocyanate (0.11 g, 1.1 mmol) and acetic acid (0.3 ml, 5 mmol) in ethyl acetate (0.3 ml) it was refluxed for 2 hours, then cooled to room temperature, and washed with a bicarbonate solution sodium, dried over anhydrous magnesium sulfate and evaporated to empty. The residue was purified by column chromatography on silica gel using the ethyl acetate-petroleum ether mixture as eluent. The resulting oil (0.25 g) was dissolved in acetate of ethyl (2 ml), at this point a solution of 2M HCl was added in ethyl acetate (2 ml, 4 mmol) and the mixture was stirred for 2 hours at room temperature. The precipitate was removed by filtration and washed with ethyl acetate to give crystals, the which decomposed without fusion.

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Example 5 Tert-butyl acid ester (3,4-dihydroxybutyl) carbamic

To a stirred solution of 4-amino-1,2-propanediol (2.10 g, 20 mmol) in ethanol (50 ml) at room temperature added di-tert-butyldicarbonate (4.80 g, 22 mmol) in one serving. The resulting mixture was stirred at room temperature for two hours, then evaporated under vacuum and purified by column chromatography on silica using mixture ethyl acetate-petroleum ether as eluent to obtain a colorless oil

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Examples 6-7

By applying the technique described above and related procedures known to experts in the art and using the 4-amino-1,2-propanediols Appropriate N-substituted, the following compounds:

Tert-butyl acid ester (3,4-dihydroxybutyl) methylcarbamic.

Tert-butyl acid ester (3,4-dihydroxybutyl) benzylcarbamic.

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Example 8 Tert-butyl acid ester [4- (tert-Butyldimethylsilyloxy) -3-hydroxybutyl] carbamic

To a stirred ester solution tert-butyl acid (3,4-dihydroxybutyl) carbamic (2.60 g, 12.7 mmol), triethylamine (2.03 ml, 14.50 mmol) and 4- (dimethylamino) pyridine (0.05 g, 0.4 mmol) in anhydrous dichloromethane (40 ml) at temperature ambient, tert-butylmethylchlorosilane was added (2.0 g, 13.17 mmol) in one portion. The resulting mixture was stirred at room temperature for 18 hours, washed with water, brine and dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo resulted in an oil which was purified by column chromatography on silica using acetate mixture of ethyl-petroleum ether as eluent to obtain an oil colorless.

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Examples 9-10

By applying the technique described above and related procedures known to experts in the art and using the compounds of examples 6 and 7, They prepared the following compounds:

Tert-butyl acid ester [4- (tert-Butyldimethylsilyloxy) -3-hydroxybutyl] methylcarbamic

Tert-butyl acid ester [4- (tert-Butyldimethylsilyloxy) -3-hydroxybutyl] benzylcarbamic

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Example 11 Tert-butyl acid ester [4- (tert-Butyldimethylsilyloxy) -3-oxobutyl] carbamic

To a periodinan solution Dess-Martin (5.0 g, 11.8 mmol) in dichloromethane Anhydrous (35 ml) at room temperature was added a solution of tert-butyl acid ester [4- (tert-Butyldimethylsilyloxy) -3-hydroxybutyl] carbamic  (3.77 g, 11.8 mmol) in anhydrous dichloromethane. The resulting mixture stirred at room temperature for one hour, evaporated at empty up to one third of the initial volume and applied to a column filled with silica Elution with ethyl acetate-petroleum ether as solvent gave a colorless oil.

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Examples 12-13

By applying the technique described above and related procedures known to experts in the art and using the compounds of examples 9 and 10, They prepared the following compounds:

Tert-butyl acid ester [4- (tert-Butyldimethylsilyloxy) -3-oxobutyl] methylcarbamic.

Tert-butyl acid ester [4- (tert-Butyldimethylsilyloxy) -3-oxobutyl] benzylcarbamic.

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Example 14 (S) -5- (2-aminoethyl) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazol-2-thione hydrochloride, compound 2 , Table 1)

A stirred mixture of (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl amine hydrochloride (0.17 g, 0.79 mmol), tert-butyl acid ester [4 - (tert-Butyldimethylsilyloxy) -3-oxobutyl] carbamic (0.28 g, 0.87 mmol), potassium thiocyanate (0.085 g, 0.85 mmol), water (0.014 ml, 0.80 mmol) and acetic acid ( 0.2 ml, 3.3 mmol) in ethyl acetate (2 ml) was refluxed for 7 hours, cooled to room temperature, washed with a solution of sodium bicarbonate and dried over anhydrous magnesium sulfate and evaporated empty The residue was purified by column chromatography on silica using the ethyl acetate-petroleum ether mixture as eluent. The resulting oil (0.24 g) was dissolved in ethyl acetate (2 ml), a solution of 2M HCl in ethyl acetate (2 ml, 4 mmol) was added and the mixture was stirred for two hours at room temperature. The precipitate was isolated by filtration and washed with ethyl acetate to give crystals, which decomposed without melting.

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Example 15

By applying the technique described above and related procedures known to experts in the art and using the hydrochlorides of 1,2,3,4-tetrahydronaphthalen-2-ylamine appropriate, the following compounds were prepared:

(S) -5- (2-Aminoethyl) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 20, table 1).

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Example 16 (R) -5- (2-aminoethyl) -1- (6,8-difluorochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 4, table 1)

A stirred mixture of (R) -6,8-difluorochroman-3-ylamine hydrochloride (1.68g, 7.58 mmol), [4- (tert-butyldimethylsilyloxy) -3-oxobutyl] carbamic acid tert-butyl ester (3.13 g, 9.85 mmol), potassium thiocyanate (0.96 g, 9.85 mmol), water (0.18 ml, 10 mmol) and acetic acid (3 ml, 50 mmol) in ethyl acetate (30 ml) was refluxed for 7 hours, cooled to room temperature, washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica using the ethyl acetate-petroleum ether mixture as eluent. The resulting oil (2.15 g) was dissolved in ethyl acetate (20 ml), a solution of 2M HCl in ethyl acetate (20 ml, 40 mmol) was added and the mixture was stirred for two hours at room temperature. The precipitate was isolated by filtration and washed with ethyl acetate to give crystals, which decomposed without melting.

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Examples 17-37

By applying the technique described above and related procedures known to experts in the art and using the hydrochlorides of chroman-3-ylamine and esters tert-butyl acids [4- (tert-Butyldimethylsilyloxy) -3-oxobutyl]  appropriate carbamic, the following compounds were prepared:

(R) -5- (2-aminoethyl) -1-chroman-3-yl-1,3-dihydroimidazol-2-thione hydrochloride (compound 12, table 1)

(R) -5- (2-aminoethyl) -1- (6-hydroxychroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 16, table 1)

(R) -5- (2-aminoethyl) -1- (8-hydroxychroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 21, table 1)

(R) -5- (2-aminoethyl) -1- (6-methoxychroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 23, table 1)

(R) -5- (2-aminoethyl) -1- (8-methoxychroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 19, table 1)

(R) -5- (2-aminoethyl) -1- (6-fluorochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 7, table 1)

(R) -5- (2-aminoethyl) -1- (8-fluorochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 6, table 1)

(R) -5- (2-aminoethyl) -1- (6,7-difluorochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 8, table 1)

(S) -5- (2-aminoethyl) -1- (6,8-difluorochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 9, table 1)

(R) -5- (2-aminoethyl) -1- (6,7,8-trifluorochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 10, table 1)

(R) -5- (2-aminoethyl) -1- (6-chloro-8-methoxychroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 11, table 1)

(R) -5- (2-aminoethyl) -1- (6-methoxy-8-chlorochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 13, table 1)

(R) -5- (2-aminoethyl) -1- (6-nitrochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 18, table 1)

(R) -5- (2-aminoethyl) -1- (8-nitrochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 17, table 1)

(R) -5- (2-aminoethyl) -1- (6- (acetylamino) chroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 14, table 1)

(R) -5- (2-aminoethyl) -1- (6-hydroxy-7-benzylchroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound
15, table 1)

(R) -5- (2-Benzylaminoethyl) -1- (6-methoxychroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 25, table 1)

(R) -5- (2-benzylaminoethyl) -1- (6-hydroxychroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 26, table 1)

(R) -1- (6-hydroxychroman-3-yl) -5- (2-methylaminoethyl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 27, table 1)

(R) -1- (6,8-difluorochroman-3-yl) -5- (2-methylaminoethyl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 28, table 1)

(R) -1-Chroman-3-yl-5- (2-methylaminoethyl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 29, table 1)

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Example 38 (R, S) -5- (2-aminoethyl) -1- (6-methoxythiochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 30, table 1)

A stirred mixture of hydrochloride 6-methoxythiochroman-3-ylamine (0.12 g, 0.50 mmol), tert-butyl acid ester [3- (tert-Butyldimethylsilyloxy) -2-oxopropyl] carbamic (0.17 g, 0.55 mmol), potassium thiocyanate (0.055 g, 0.55 mmol), water (0.009 g, 0.5 mmol) and acetic acid (0.2 ml, 3.3 mmol) in acetate ethyl (2 ml) was refluxed for 7 hours, cooled to room temperature, washed with a bicarbonate solution sodium, dried over anhydrous magnesium sulfate and evaporated to empty. The residue was purified by column chromatography. on silica using the ethyl acetate-petroleum ether mixture as eluent The resulting oil (0.12 g) was dissolved in acetate ethyl (1 ml), a solution of 2M HCl in ethyl acetate was added (1 ml, 2 mmol) and the mixture was stirred for 2 hours at temperature ambient. The precipitate was isolated by filtration and washed with ethyl acetate to give crystals, which decomposed without melting.

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Example 39

By applying the technique described above and related procedures known to experts in the art and using the hydrochlorides of Appropriate chroman-3-ylamine, se They prepared the following compounds:

(R, S) -5- (2-aminoethyl) -1- (6-hydroxythiochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 31, table 1).

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Example 40 2- [3- (2,2-dimethyl [1,3] dioxolan-4-yl) propyl] isoindole-1,3-dione

To a stirred solution of 3- (2,2-dimethyl [1,3] dioxolan-4-yl) propylamine (1.05 g, 6.60 mmol) and carboethoxyphthalimide (1.45 g, 6.60 mmol) in acetonitrile (10 ml) at room temperature triethylamine was added (0.92 ml, 6.60 mmol) in one portion and the resulting mixture was stirred at room temperature for 18 hours, it was evaporated under vacuum and the residue was dissolved in ethyl acetate (50 ml). The solution is washed with brine, 10% citric acid solution and brine, then dried over anhydrous magnesium sulfate. Filtration and vacuum concentration resulted in an oil that was purified by column chromatography on silica using the mixture ethyl acetate-petroleum ether as eluent to obtain a colorless oil

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Example 41 2- (4,5-dihydroxypentyl) isoindole-1,3-dione

To a stirred solution of 2- [3- (2,2-dimethyl [1,3] dioxolan-4-yl) propyl] isoindole-1,3-dione (1.65 g, 5.70 mmol) in THF (20 ml) at room temperature was added a solution of 2N HCl (15 ml, 30 mmol) in one portion and the mixture resulting was stirred at room temperature for two hours, and It was then evaporated in vacuo to half the initial volume. He residue was saturated with NaCl and extracted with ethyl acetate. The Organic phase was dried over anhydrous magnesium sulfate. The filtration and concentration in vacuo resulted in an oil colorless.

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Example 42

By applying the technique described in example 8 to the 2- (4,5-dihydroxypentyl) isoindole-1,3-dione,  The following compound was prepared:

2- [5- (tert-Butyldimethylsilyloxy) -4-hydroxypentyl] isoindole-1,3-dione.

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Example 43

By applying the technique described in example 11 to 2- [5- (tert-Butyldimethylsilyloxy) -4-hydroxypentyl] isoindole-1,3-dione,  The following compound was prepared:

2- [5- (tert-Butyldimethylsilyloxy) -4-oxopentyl] isoindole-1,3-dione.

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Example 44 (S) -5- (3-Aminopropyl) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazol-2-thione hydrochloride (compound 5 , Table 1)

A stirred mixture of (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride (0.22 g, 1.0 mmol), 2- [5- (tert-butyldimethylsilyloxy) ) -4-oxopentyl] isoindole-1,3-dione (0.38 g, 1.05 mmol), potassium thiocyanate (0.11 g, 1.10 mmol), water (0.18 g, 1.0 mmol ) and acetic acid (0.3 ml, 5.0 mmol) in ethyl acetate (3 ml) was refluxed for 7 hours, cooled to room temperature, washed with a sodium bicarbonate solution, dried over sulfate anhydrous magnesium and evaporated in vacuo. The residue was purified by column chromatography on silica using the ethyl acetate-petroleum ether mixture as eluent. The resulting oil (0.18 g) was dissolved in a mixture of isopropanol (5 ml) and THF (2 ml). Water (0.8 ml) and sodium borohydride (0.066 g, 1.74 mmol) were added at room temperature and the mixture was stirred for 1.5 hours. Acetic acid (0.6 ml, 10 mmol) was added and the solution was refluxed for two hours and then evaporated in vacuo to dryness. The residue was taken up in acetone, the solid was filtered to remove it, and the filtrate was acidified with a solution of 2N HCl in ethyl acetate. The precipitate was collected and washed with acetone to give crystals, which decomposed without melting.

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Example 45 (R) -5- (3-aminopropyl) -1- (6,8-difluorochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride

A stirred mixture of (R) -6,8-difluorochroman-3-ylamine hydrochloride (0.11 g, 0.50 mmol), 2- [5- (tert-butyldimethylsilyloxy) -4-oxopentyl] isoindole-1, 3-dione (0.19 g, 0.55 mmol), potassium thiocyanate (0.055 g, 0.55 mmol), water (0.009 g, 0.50 mmol) and acetic acid (0.15 ml, 2.5 mmol ) in ethyl acetate (1.5 ml) was refluxed for 7 hours, cooled to room temperature, washed with a solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica using the ethyl acetate-petroleum ether mixture as eluent. The resulting oil (0.10 g) was dissolved in the mixture of isopropanol (2.5 ml) and THF (1 ml). Water (0.4 ml) and sodium borohydride (0.038 g, 1.0 mmol) were added at room temperature and the mixture was stirred for 1.5 hours. Acetic acid (0.3 ml, 5 mmol) was added and the solution was refluxed for two hours and evaporated in vacuo to dryness. The residue was taken up in acetone, the solid was filtered to remove it, and the filtrate was acidified with a solution of 2N HCl in ethyl acetate. The precipitate was collected and washed with acetone to give crystals, which decomposed without melting.

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Example 46 (R, S) -5- (3-aminopropyl) -1- (6-hydroxythiochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride

A stirred mixture of hydrochloride 6-hydroxythiochroman-3-ylamine (0.22 g, 1.0 mmol), 2- [5- (tert-Butyldimethylsilyloxy) -4-oxopentyl] isoindole-1,3-dione  (0.38 g, 1.05 mmol), potassium thiocyanate (0.11 g, 1.10 mmol), water (0.18 g, 1.0 mmol) and acetic acid (0.3 ml, 5.0 mmol) in acetate ethyl (3 ml) was refluxed for 7 hours, cooled to room temperature, washed with a bicarbonate solution sodium, dried over anhydrous magnesium sulfate and evaporated to empty. The residue was purified by column chromatography. on silica using the ethyl acetate-petroleum ether mixture as eluent. The resulting oil (0.17 g) was dissolved in the mixture of isopropanol (5 ml) and THF (2 ml). Water was added (0.8 ml) and sodium borohydride (0.066 g, 1.74 mmol) at room temperature and the mixture was stirred for 1.5 hours. Acetic acid was added (0.6 ml, 10 mmol) and the solution was refluxed for two hours and then evaporated in vacuo to dryness. The residue is collected in acetone, the solid was filtered to remove it, and the filtrate was acidified with a solution of 2N HCl in acetate ethyl. The precipitate was collected and washed with acetone to give crystals, which decomposed without melting.

Claims (12)

1. (S) -5- (2-Aminoethyl) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazol-2-thione hydrochloride. 2. (S) -5- (2-Aminoethyl) -1- (1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazol-2-thione hydrochloride. 3. (R) -5- (2-Aminoethyl) -1- (6,8-difluorochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride. 4. (R) -1- (6,8-Difluorochroman-3-yl) -5- (2-methylaminoethyl) -1,3-dihydroimidazol-2-thione hydrochloride. 5. (S) -5- (3-Aminopropyl) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-dihydroimidazol-2-thione hydrochloride. 6. (R) -5- (3-Aminopropyl) -1- (6,8-difluorochroman-3-yl) -1,3-dihydroimidazol-2-thione hydrochloride. 7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, in combination with a pharmaceutically effective vehicle. 8. A compound according to any one of the requirements from 1 to 6, to use as a medicine. 9. The use of a compound according to any one of claims 1 to 6, in the manufacture of a  medication to treat disorders where a reduction in hydroxylation of dopamine to norepinephrine is beneficial therapeutic. 10. The use of a compound according to a any of claims 1 to 6, in the manufacture of a medicine to treat a subject affected with disorders cardiovascular 11. The use of a compound according to a any of claims 1 to 6, in the manufacture of a medicine to treat hypertension or insufficiency chronic heart 12. The use of a compound according to a any of claims 1 to 6, in the manufacture of a medication to use in the inhibition of dopamine-? -hydroxylase.