ES2384118T3 - 3,4-Dihydro-3-amino-2H-1-benzopyran and -benzothiopyran derivatives as dopamine-beta-hydroxylase inhibitors and methods for their preparation - Google Patents

Abstract

A compound of formula II: in which R1, R2 and R3 may be the same or different, and are fluorine or hydrogen, with the proviso that at least one of R1, R2 and R3 is fluorine, and in which X is a oxygen atom or a sulfur atom.

Description

3,4-Dihydro-3-amino-2H-1-benzopyran and -benzothiopyran derivatives as dopamine-β-hydroxylase inhibitors and methods for their preparation

This invention relates to the intermediates defined in claim 1, useful for preparing peripherally selective dopamine-β-hydroxylase inhibitors and a method for their preparation.

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 DβH inhibitors is based on its ability to inhibit norepinephrine biosynthesis, which is achieved through the enzymatic hydroxylation of dopamine. The activity of neurohumoral systems, mainly the sympathetic nervous system, is the main clinical manifestation of congestive heart failure (Parmley, W.W., Clinical Cardiology, 18: 440-445. 1995). Patients with congestive heart failure have high concentrations of plasma norepinephrine (Levine, TB et al., Am. J. Cardiol., 49: 1659-1666, 1982), greater central sympathetic external efflux (Leimbach, WN et al., Circulation , 73: 913-919. 1986) and higher surplus rate of 15 cardiorenal norepinephrine (Hasking, GJ et al., Circulation, 73: 615-621, 1966). Prolonged and excessive exposure of the myocardium to norepinephrine can lead to under-regulation of cardiac β-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 noradrenaline plasma concentrations also have the most unfavorable long-term prognosis (Cohn, J.N. et al., N. Engl. J. Med.,

20 311: 819-823, 1984). More important is the observation that noradrenaline plasma concentrations are already high in asymptomatic patients without overt heart failure and this can predict the consequent mortality and morbidity (Benedict, C.R. et al., Circulation, 94: 690-697, 1996). This implies that activated sympathetic transmission is not simply a clinical marker of congestive heart failure, but may contribute to the progressive worsening of the disease.

25 The inhibition of sympathetic nerve function with adrenoceptor antagonists seemed a promising strategy, but a significant proportion of patients does not tolerate the immediate hemodynamic deterioration that accompanies treatment with β-blocker (Pfeffer, MA et al., N. Engl. J. Med., 334: 1396-1397, 1996). An alternative strategy to directly modulate the function of sympathetic nerves is to reduce norepinephrine biosynthesis through the inhibition of DβH, the enzyme responsible for converting dopamine into

30 norepinephrine in sympathetic nerves. This strategy has several merits, including gradual modulation as opposed to abrupt inhibition of the sympathetic system, and causes an increase in the release of dopamine that can improve renal function, such as renal vasodilation, diuresis and natriuresis. Therefore, DβH inhibitors can provide significant advantages over conventional β-blockers.

Several DβH inhibitors have been indicated in the literature to date. It was discovered that the first examples

35 first and second generation, such as disulfiramo (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 alkylthioureas or thioureas (Johnson, GA et al., J. Pharmacol. Exp. Ther., 171: 80, 1970) had low potency, showed little DβH selectivity, and caused toxic side effects. However, it was discovered that the third generation of DβH inhibitors had much greater potency, such as

40 nepicastat (RS-25560-197, IC50 9 nM) (Stanley, W.C. et al., Br. J. Pharmacol., 121: 1803-1809, 1997), which was developed in the first clinical trials. Although it did not present some of the problems associated with the first and second generation DβH inhibitors, a very important discovery was that it was discovered that the nepicastat crossed the blood-brain barrier (BHE), which is capable of causing central and peripheral effects , a situation that can lead to the drug causing side effects in the CNS

45 undesirable and potentially serious. Therefore, there is still a clinical need for a peripherally selective, non-toxic and potent DβH inhibitor that can be used for the treatment of certain cardiovascular disorders. A DβH inhibitor with a similar or even greater potency than nepicastat but without effects on the CNS (inability to cross BHE) would provide a significant improvement over all DβH inhibitor compounds described to date in the prior art.

The inventors have surprisingly discovered that the incorporation of certain heteroatoms into the carbocyclic ring and / or the lengthening of the aminoalkyl side chain of the central structure of the nepicastat produces a series of compounds that have significant and pronounced effects of potential utility. for the inhibition of DβH. Many of these compounds are endowed with greater potency and significantly reduced access to the brain, producing potent and peripherally selective DβH inhibitors. Therefore, the invention relates to

Intermediates as defined in the claims, useful for the preparation of compounds of general formula I:

wherein R1, R2 and R3 are the same or different, and are hydrogen, halogen, an alkyl, alkyloxy, hydroxy, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R4 means a hydrogen, alkyl or alkylaryl group; X means CH2, an oxygen atom or a sulfur atom; n is 2 or 3; and the (R) -and (S) -enantiomeric mixtures or mixtures of enantiomers; and its pharmaceutically acceptable salts.

Unless otherwise indicated, in this specification, the term "alkyl" (whether it is used as such or combined with other moieties) means hydrocarbon chains, linear or branched, containing one to six carbon atoms, optionally substituted with aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl; the term aryl (whether used as such or in combination with other moieties) means a phenyl or naphthyl group, optionally substituted with an alkyloxy, halogen or nitro group; and the term halogen means fluorine, chlorine, bromine or iodine.

Some compounds according to formula II are known in the literature, in which X means methylene (CH2), oxygen

or sulfur, for example, 5,7-difluoro-1,2,3,4-tetrahydrofantalen-2-ylamine, of WO 95/29165 (Martinez, GR et al., U.S. Patent 5,538,988, July 23 , 1996; Eriksson, M., PCT international application WO 9959988A1, November 25, 1999; Napoletano, M., PCT international application WO 9608489A1, March 21, 1996; Sarda, N. et al., Tetrahedron Lett., 17 : 271-272, 1976; Neirabeyeh, M.AI et al., Eur. J. Med. Chem., 26: 497-504, 1991), and others that can be prepared by those skilled in the art. The compounds according to formula II are chiral and, therefore, formula II represents both optically pure (R) -y (S) -enantiomers or mixtures of enantiomers:

Compounds of formula I are prepared by reacting a compound of formula II, wherein X is CH2, oxygen or sulfur; R1, R2 and R3 are the same or different, and are hydrogen, halogen, an alkyl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkylamino group, with a compound of formula III:

in which n is 2 or 3; when n is 2, R4 is a hydrogen, alkyl or alkylaryl group; R5 is a hydroxyl protecting group, and R6 is an amino protecting group; when n is 3, R5 is defined as above, but NR4R6 taken together represents a phthalimido group; and with a water-soluble thiocyanate salt in an inert organic solvent and in the presence of an organic acid, in which the water-soluble thiocyanate salt is an alkali metal thiocyanate salt or a tetraalkylammonium thiocyanate salt.

Suitable alkali metal thiocyanate salts include sodium, lithium and cesium thiocyanates, but potassium thiocyanate is preferred.

The compound of formula III, in which n is 1, is known (Wolf, E. et al., Can. J. Chem., 75: 942-948, 1997), and the compounds of formula III, in which n is 2 or 3, they are new compounds that can be prepared by those skilled in the art (see examples). Preferred hydroxyl protecting groups (R5) include organosilyl compounds, such as a trialkylsilyl, triphenylsilyl, phenyldialkylsilyl or alkyldiphenylsilyl group. The tert-butyldimethylsilyl group (TBDMS) is especially preferred. Preferred amino (R6) protecting groups include carbamates, such as alkyl carbamates, in particular the t-butyl carbamate (Boc) group, and alkylaryl carbamates. The reaction can be carried out with a small excess of the compound of formula III and potassium thiocyanate (preferably 1.1-1.3 equivalents).

The reaction can be carried out in a substantially inert solvent (preferably ethyl acetate) and at different temperatures (preferably at the reflux temperature of the solvent). Preferred organic acids include acetic acid.

When the compounds of formula III, in which n is 2, and R4 is hydrogen, are used, the mixture of the intermediates of formula V and VI is reacted with hydrochloric acid in ethyl acetate to produce the

10 corresponding individual compounds of formula I (scheme 1); when R4 is alkyl (including alkyl substituted with aryl), the individual intermediate of formula V is reacted with hydrochloric acid in ethyl acetate to produce the compounds of formula I.

When the compounds of formula III, in which n is 3, are used, the intermediate of formula VII found is treated with sodium borohydride in a suitable solvent system, followed by acetic acid to remove the protecting group

15 of amino phthalimido, as described in the literature (Osby et al., Tetrahedron Lett., 1984, 25 (20), 2093-2096) to produce the compounds of formula I (scheme 2). The compounds of formula I are obtained with good purity, but if preferred they can be recrystallized from a suitable solvent.

Scheme 1 Scheme 2

Inert pharmaceutical compositions of compounds of formula I are mixed inert pharmaceutically acceptable carriers with the active compounds. Pharmaceutically acceptable vehicles

5 can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules and capsules. A solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; They can also be an encapsulating material.

Preferably, the pharmaceutical preparation is in a unit dosage form, for example, a

10 packaged preparation, the package containing discrete amounts of preparation, such as tablets, capsules and powders packed in vials or ampoules.

Dosages may vary depending on the needs of the patient, the severity of the disease, and the specific compound being used. For convenience, the total daily dosage can be divided and administered in portions throughout the day. It is expected that a daily or twice daily administration will be the

15 more suitable. The determination of the appropriate dosage for a specific situation is within the knowledge of those skilled in the medical art.

Materials and methods

In Vitrr Studies

DβH activity was evaluated by the ability to β-hydroxylate dopamine to norepinephrine, as described

20 previously (Kojima, K., Parvez, S. and Nagatsu, T., 1993, Analysis of enzymes in catecholamine biosynthesis, in Methods in Neurotransmitter and Neuropeptide Research, pp. 349-380, Elsevier Science Publishers). SK-N-SH cells (ATCC HTB-11), a cell line derived from human neuroblastoma, were used as a source of human DβH. SK-N-SH cells grown in 24-well plates were pre-incubated for 20 min in a reaction medium containing 200 mM sodium acetate, 30 mM N-ethylmaleimide, 5 μM copper sulfate, aqueous solution

25 of 0.5 mg / ml catalase, 1 mM pargiline, 10 mM sodium fumarate, and 20 mM ascorbic acid. The cells were then incubated for an additional 45 min in the reaction medium with the addition of increasing concentrations of dopamine (0.5 to 100 mM). During pre-incubation and incubation, the cells were continuously shaken and kept at 37 AD. The reaction was terminated by the addition of 0.2 M perchloric acid. Acidified samples were

they kept 4 DC before the injection in the high pressure liquid chromatograph for the norepinephrine test. In experiments conducted with the objective of studying the effects of new DβH inhibitors on enzymatic activity, test compounds (from 0.3 to 10,000 nM) of interest were added to the pre-incubation and incubation solutions; incubation was performed in the presence of a concentration (50 mM) of dopamine 2.5 times the corresponding Km value as determined in saturation experiments.

Studies in vivr

MNRI mice or male Wistar rats from Harlan-Interfauna (Espara) were obtained and kept in a number of 10 and 5 per cage, respectively, under controlled environmental conditions (12 h light / dark cycle, and ambient temperature 22 ± 1 DC). They were allowed free access to water and food, and the experiment was carried out during daylight hours.

At the time = 0 h, the animals were administered the test compounds at a given dose or vehicle (water) orally through a probe. At 2, 6, 9, 12, 18 and 24 h after the dose, the animals were sacrificed by decapitation and the heart (left atrium and left ventricle) and the brain (frontal and parietal cortex) were weighed and weighed. they were stored in a volume of 0.2 M perchloric acid for 12 h at 4 DC in the dark. After incubation, the resulting supernatants were collected by centrifugation filtration of the incubations (0.2 μM / 10 min / approximately 5000 rpm, 4 DC). Supernatants were kept frozen at -80 DC until analysis. The quantification of dopamine and norepinephrine in the supernatants was carried out by means of a high pressure liquid chromatography with electrochemical detection.

Results

In Vitrr Studies

Incubation of SK-N-SH cells in the presence of increasing concentrations of dopamine results in the formation, dependent on concentration, of norepinephrine, producing values of Km (in μM) and Vmax (in nmol mg protein-1 h- 1) of 20.6 ± 1.6 and 153.8 ± 4.4, respectively. From these kinetic parameters, a concentration of dopamine that approaches saturation (50 mM) was chosen for use in inhibition studies. As listed in Table 1, it was found that compounds 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 19, 24, 26, 28 and 29 markedly inhibited DβH activity. Compounds 2, 3, 4 and nepicastat 1 (the reference compound) produce a dose-dependent decrease in dopamine β-hydroxylation with IC50 values in the low range of nM versus DβH activity human (see table 2). Compound 4 was chosen for further in vivo studies, being the compound most closely related to nepicastat 1, to provide conclusive evidence that the structural modifications produced in the molecule as part of the present invention are surprisingly very responsible for the biological properties. Improved observed.

Table 1. Effect of selected compounds (5 μM) on DβH activity in SK-N-SH cells. The values are indicated as a percentage of the control. Table 2. IC50 values (in nM) for the inhibition of DβH in SK-N-SH cells.

no

Mean ± MEE  no Mean ± MEE

one

0.0 ± 0.3 24 0.0 ± 1.9

2

1.6 ± 0.3 25 66.0 ± 4.5

3

4.1 ± 0.6 26 4.5 ± 1.9

4

3.3 ± 0.3 27 15.5 ± 5.8

5

8.1 ± 0.3 28 2.6 ± 1.6

6

6.9 ± 0.6 29 2.2 ± 2.5

7

8.0 ± 0.1 30 99.4 ± 2.8

8

9.4 ± 0.7 31 27.3 ± 0.4

9

50.2 ± 1.9

10

8.2 ± 0.7

eleven

36.7 ± 4.4

12

3.0 ± 0.5

13

94.0 ± 3.1

14

77.9 ± 2.2

fifteen

86.1 ± 2.7

16

0.0 ± 0.6

17

53.2 ± 3.9

18

94.8 ± 1.2

19

6.9 ± 0.5

twenty

16.8 ± 4.8

twenty-one

124.8 ± 6.5

22

17.8 ± 2.1

2. 3

54.5 ± 9.9

Compound

IC50 (in nM)

2

60 (14, 250)

3

91 (56, 147)

4

105 (69, 161)

Nepicastat 1

36 (28, 46)

Studies in vivr

5 Mouse

The time evolution experiments for compound 4 and nepicastat (1) in the heart at 100 mg / kg suggest that both compounds are long-term action. The time of maximum effect (Tmax) for the reduction of tissue norepinephrine by 4 and 1 appears to be at 9 h after the dose (Figure 1). Then the levels of tissue norepinephrine recover, reaching 50% recovery from the initial tissue levels at 24 h.

10 In Tmax (9 h after administration), both 4 and 1 reduce norepinephrine levels in a dose-dependent manner in the left ventricle. For 4 and 1, the maximum inhibitory effect is achieved at a dose of 100 mg / kg. In contrast to what is obtained in the heart, 4 does not affect tissue norepinephrine levels in the cerebral parietal cortex, while 1 produces a dose-dependent decrease in norepinephrine levels in this area of the brain (Figure 2). .

15 rat

As demonstrated in the mouse, the effects of 4 and 1 on norepinephrine depend on the dose administered and reach their maximum at 9 o'clock (data not shown). However, as shown in Figure 3, the inhibitory effects of 4 (100 mg / kg) on norepinephrine levels in the left atrium and left ventricle were more pronounced than those produced by 1 (100 mg / kg) . Again, as noted

20 in the mouse, 4 does not affect tissue norepinephrine levels in the cerebral parietal cortex and the cerebral frontal cortex, while 1 produces a marked decrease in norepinephrine levels in these brain areas.

It is concluded that 4, in stark contrast to nepicastat 1, exerts its inhibitory effects on DβH exclusively on the periphery and has no inhibitory effects on the brain.

25 Reference is made below to the accompanying drawings, 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 nepicastat 1. The symbols are the average of 5 determinations per group; the vertical lines indicate the M.E.E.

-

Figure 2 are two graphs showing noradrenaline levels in the left mouse ventricle and cerebral parietal cortex 9 h after oral administration of 4 or nepicastat 1. The symbols are the average of 5 determinations per group; the vertical lines indicate the M.E.E.

-

Figure 3 are four graphs showing the levels of norepinephrine in the heart (left atrium and left ventricle) and rat brain (frontal and parietal cortex) 9 h after oral administration of 4 or nepicastat 1. The columns are the average of 5 determinations per group; the vertical lines indicate the M.E.E.

Conclusion

Some compounds of general formula I are very potent dopamine-β-hydroxylase inhibitors and have potentially valuable pharmaceutical properties for the treatment of some cardiovascular disorders, in which a reduction in the enzymatic hydroxylation of dopamine to norepinephrine may have a therapeutic benefit. , such as hypertension and chronic heart failure. The possibility of using a long-term action DβH inhibitor with limited access to the brain (CNS), such as compound 4, opens up new perspectives in the treatment of hypertension and chronic heart failure, improving potency and selectivity. of inhibition of DβH in the periphery.

The invention described herein is exemplified by the following preparation examples, which should not be considered as limiting the scope of the description. Other routes and analog structures may be apparent to those skilled in the art.

Examples (none of these examples are examples of intermediates according to claim 1)

Example 1

(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 the acid [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, 5.0 mmol) in ethyl acetate (3 ml) is refluxed for 2 hours, cooled to room temperature, then washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate-petroleum ether as eluent. The resulting oil (0.23 g) was dissolved in ethyl acetate (2 ml), after which 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 yield crystals of m.p. 192 DC (decomp.).

Examples 2-3

The following compounds were prepared by applying the technique described above and related procedures known to those skilled in the art and using the appropriate chroman-3-ylamine hydrochlorides:

(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)

Example 4

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

A stirred mixture of 6-hydroxythiochroman-3-ylamine hydrochloride (0.22 g, 1.0 mmol), tert-butyl ester of the acid [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, 5.0 mmol) in ethyl acetate (3 ml) was refluxed for 2 hours, then it was cooled to room temperature, and 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 a mixture of ethyl acetate-petroleum ether as eluent. The resulting oil (0.25 g) was dissolved in ethyl acetate (2 ml), after which 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 produce crystals, which decomposed without melting.

Example 5

Tert-Butyl ester of the (3,4-dihydroxybutyl) carbamic acid A stirred solution of 4-amino-1,2-butane (2.10 g, 20 mmol) in ethanol (50 ml) at room temperature was digested. -terc-butyldicarbonate (4.80 g, 22 mmol) in one portion. The resulting mixture was stirred at room temperature for two hours, then evaporated in vacuo and purified by column chromatography on silica using a mixture of ethyl acetate-petroleum ether as eluent to yield a colorless oil.

Examples 6-7

By applying the technique described above and related procedures known to those skilled in the art and using the appropriate N-substituted 4-amino-1,2-butane, the following compounds were prepared:

Tert-Butyl ester of (3,4-dihydroxybutyl) methylcarbamic acid

Tert-Butyl ester of (3,4-dihydroxybutyl) benzylcarbamic acid

Example 8

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

At a stirred solution of the tert-butyl ester of (3,4-dihydroxybutyl) carbamic acid (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 room temperature was added tert-butyldimethylchlorosilane (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 vacuum concentration produced an oil that was purified by column chromatography on silica using a mixture of ethyl acetate-petroleum ether as eluent to yield a colorless oil.

Examples 9-10

By applying the technique described above and related procedures known to those skilled in the art and using the compounds of Examples 6 and 7, the following compounds were prepared:

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

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

Example 11

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

A solution of the tert-butyl ester of the acid [4- (tert-butyldimethylsilyloxy) acid was added to a solution of Dess-Martin periododyne (5.0 g, 11.8 mmol) in anhydrous dichloromethane (35 ml) at room temperature -3hydroxybutyl] carbamic (3.77 g, 11.8 mmol) in anhydrous dichloromethane. The resulting mixture was stirred at room temperature for one hour, evaporated in vacuo to a third of the initial volume and applied to a column loaded with silica. An elution with a solvent mixture of ethyl acetate-petroleum ether produced a colorless oil.

Examples 12-13

By applying the technique described above and related procedures known to those skilled in the art and using the compounds of Examples 9 and 10, the following compounds were prepared:

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

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

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-ylamine hydrochloride (0.17 g, 0.79 mmol), tert-butyl ester of the acid [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 sodium bicarbonate solution, and dried over magnesium sulfate anhydrous and evaporated in vacuo. The residue was purified by column chromatography on silica using a mixture of ethyl acetate-petroleum ether as eluent. The resulting oil (0.24 g) was dissolved in ethyl acetate (2 ml), 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 produce crystals that decomposed without melting.

Example 15

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

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

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 (1.68 g, 7.58 mmol), tert-butyl ester of the acid [4- (tert-butyldimethylsilyloxy) -3-oxobutyl] carbamic (3.13 g, 9.85 mmol), potassium thiocyanate (0.96 g, 9.85 mmol), water (0.18 ml, 10 mmol) and acetic acid (3.0 ml, 50 mmol) in ethyl acetate (30 ml), it was refluxed for 7 hours, cooled to room temperature, washed with a solution of sodium bicarbonate, and dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica using a mixture of ethyl acetate-petroleum ether 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 scratched and the mixture was stirred for 2 hours at room temperature . The precipitate was removed by filtration and washed with ethyl acetate to produce crystals that decomposed without melting.

Examples 17-37

By applying the technique described above and related procedures known to those skilled in the art and using the appropriate chroman-3-ylamine hydrochlorides and tert-butyl esters of the acid [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) (R) -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

one) (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)

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 6-methoxythiochroman-3-ylamine hydrochloride (0.12 g, 0.50 mmol), tert-butyl ester of the acid [3- (tert-butyldimethylsilyloxy) -2-oxopropyl] carbamic acid (0.17 g , 0.55 mmol), potassium thiocyanate (0.055 g, 0.55 mmol), water (0.009 ml, 0.50 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 sodium bicarbonate solution, and dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica using a mixture of ethyl acetate-petroleum ether as eluent. The resulting oil (0.12 g) was dissolved in ethyl acetate (1 ml), a solution of 2M HCl in ethyl acetate (1 ml, 2 mmol) was scratched and the mixture was stirred for 2 hours at room temperature . The precipitate was removed by filtration and washed with ethyl acetate to produce crystals that decomposed without melting.

Example 39

The following compounds were prepared by applying the technique described above and related procedures known to those skilled in the art and using the appropriate chroman-3-ylamine hydrochlorides:

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

Example 40

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

At 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 (0.92 ml, 6.60 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 18 hours, evaporated in vacuo and the residue dissolved in ethyl acetate (50 ml). The solution was washed with brine, a 10% citric acid solution and brine, then dried over anhydrous magnesium sulfate. Filtration and vacuum concentration produced an oil that was purified by column chromatography on silica using a mixture of ethyl acetate-petroleum ether as eluent to yield a colorless oil.

Example 41

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

At 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 a solution of 2N HCl (15 ml, 30 mmol) was added in one portion and the resulting mixture was stirred at room temperature for two hours and then evaporated in vacuo to half the initial volume. The residue was saturated with NaCl and extracted with ethyl acetate. The organic phase was dried by anhydrous magnesium sulfate. Filtration and vacuum concentration produced a colorless oil.

Example 42

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

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

Example 43

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

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

Example 44

(S) -5- (2-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 ml, 1.0 mmol ) and acetic acid (0.3 ml, 5.0 mmol) in ethyl acetate (3 ml) was refluxed

for 7 hours, it was cooled to room temperature, washed with a solution of sodium bicarbonate, and dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica using a mixture of ethyl acetate-petroleum ether 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 scratched and the solution was refluxed for two hours and then evaporated in vacuo to dryness. The residue was suspended in acetone, the solid was removed by filtration, and the filtrate was acidified with a solution of 2N HCl in ethyl acetate. The precipitate was collected and washed with acetone to produce crystals that decomposed without melting.

Example 45

(S) -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 ml, 0.50 mmol) and acetic acid (0.15 ml, 2.5 mmol) in ethyl acetate (1.5 ml) it 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 a mixture of ethyl acetate-petroleum ether as eluent. The resulting oil (0.10 g) was dissolved in a 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 scratched and the solution was refluxed for two hours and then evaporated in vacuo to dryness. The residue was suspended in acetone, the solid was removed by filtration, and the filtrate was acidified with a solution of 2N HCl in ethyl acetate. The precipitate was collected and washed with acetone to produce crystals that decomposed without melting.

Example 46

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

A stirred mixture of 6-hydroxythiochroman-3-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 ml, 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 solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica using a mixture of ethyl acetate-petroleum ether as eluent. The resulting oil (0.17 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 scratched and the solution was refluxed for two hours and then evaporated in vacuo to dryness. The residue was suspended in acetone, the solid was removed by filtration, and the filtrate was acidified with a solution of 2N HCl in ethyl acetate. The precipitate was collected and washed with acetone to produce crystals that decomposed without melting.

Claims (1)

1.-A compound of formula II: wherein R1, R2 and R3 may be the same or different, and are fluorine or hydrogen, with the proviso that at least one of R1, R2 and R3 is fluorine, and in which X is an oxygen atom or a sulfur atom. 2. A compound of claim 1, wherein X is an oxygen atom. 3. A compound of claim 1, wherein X is a sulfur atom. 4.- (R) -6,8-Difluoro-3,4-dihydro-2H-1-benzopyran-3-amine.