GB2394223A - Peripherally-selective imidazole inhibitors of dopamine-beta-hydroxylase - Google Patents

Peripherally-selective imidazole inhibitors of dopamine-beta-hydroxylase Download PDF

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GB2394223A
GB2394223A GB0224306A GB0224306A GB2394223A GB 2394223 A GB2394223 A GB 2394223A GB 0224306 A GB0224306 A GB 0224306A GB 0224306 A GB0224306 A GB 0224306A GB 2394223 A GB2394223 A GB 2394223A
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dihydroimidazole
aminoethyl
hydrochloride
group
thione hydrochloride
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GB2394223B (en
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David Alexander Learmonth
Da Silva Patricio Manue Soares
Alexander Beliaev
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Bial Portela and Cia SA
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Bial Portela and Cia SA
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    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
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Abstract

Compounds of formula I <EMI ID=1.1 HE=45 WI=60 LX=759 LY=809 TI=CF> <PC>where R1, R2 and R3 are various optional substituents, R4 is H, alkyl or alkylaryl, X is CH2, O or S, and n is 1, 2 or 3, with the proviso that if X is CH2, n is not 1, have potentially valuable pharmaceutical properties for the treatment of cardiovascular disorders such as hypertension and chronic heart failure. Intermediates in their preparation are also novel compounds.

Description

PERIPHERALLY-SELECTIVE INHIBITORS OF DoPAMINE--HYDROXYLAsE AND METHOD OF
THEIR PREPARATION
5 This invention relates to peripherally-selective inhibitors of dopamine-hydroxylase and method of their preparation.
In recent years, interest in the development of inhibitors of dopamine-hydroxylase (D,DH) has centred on the hypothesis that inhibition of this enzyme may provide 10 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 capacity to inhibit the biosynthesis of noradrenaline, which is achieved via enzymatic hydroxylation of dopamine Activation of neurohumoral systems, chiefly I the sympathetic nervous system, is the principal clinical manifestation of congestive 15 heart failure (Parmley, W.W., Clinical Cardiology, 18: 440445, 1995). Congestive heart failure patients have elevated concentrations of plasma noradrenaline (Levine, T. B. et al., Am. J. Cardiol., 49:1659-1666, 1982), increased central sympathetic outflow I (Leimbach, W.N. et al., Circulation, 73: 913-919, 1986) and augmented cardiorenal noradrenaline spillover (Hacking, G J et al, Circulation, 73:615-621, 1966). Prolonged 20 and excessive exposure of myocardium to noradrenaline may lead to down-regulation of cardiac,81adrenoceptors, remodelling of the left ventricle, arrhytmias and necrosis, all of which can diminish the functional integrity of the heart. Congestive heart failure patients who have high plasma concentrations of noradrenaline also have the most unfavourable long-term prognosis (Cohn, J N et al, N Engl. J. Med., 311:819-823, 25 1984). Of greater significance is the observation that plasma noradrenaline concentrations are already elevated in asymptomatic patients with no overt heart failure and can predict ensuing mortality and morbidity (Benedict, C.R. et al., Circulation, 94:690-697, 1996). This implies that the activated sympathetic drive is not merely a clinical marker of congestive heart failure, but may contribute to progressive worsening 30 of the disease.
Inhibition of sympathetic nerve function with adrenoceptor antagonists appeared a promising approach, however a significant proportion of patients do not tolerate the
immediate haemodynamic deterioration that accompanies p-blocker treatment (Pfeffer, M.A. et al., N. Engl. J. Med. 334:1396-7, 1996) An alternative strategy for directly modulating sympathetic nerve function is to reduce the biosynthesis of noradrenaline via inhibition of D0H, the enzyme responsible for conversion of dopamine to 5 noradrenaline in sympathetic nerves This approach has several merits including gradual modulation as opposed to abrupt inhibition of the sympathetic system, and causing increased release of dopamine, which can improve renal function such as renal vasodilation, diuresis and natriuresis. Therefore inhibitors of D0H may provide significant advantages over conventional p-blockers.
Several inhibitors of D0H have been thus far reported in the literature. Early first and second generation examples such as disulfiram (Goldstein, M. et al., Life Sci., 3:763, 1964) and diethyidithiocarbamate (Lippmann, W. et al., Biochem. Pharmacol., 18: 2507, 1969) or fusaric acid (Hidaka, H Nature, 231, 1971) and aromatic or alkyl 15 thioureas (Johnson, G A et al, J Pharmacol Exp. Ther, 171: 80, 1970) were found to be of low potency, exhibited poor selectivity for D0H and caused toxic side effects. The third generation of D0H inhibitors however, were found to have much greater potency, such as for example, nepicastat (RS-25560-197, lcso 9nM) (Stanley, W.C., et al., Br. J Pharmacol., 121: 1803-1809, 1997), which was developed to early clinical trials.
20 Although devoid of some of the problems associated with first and second generation D,BH inhibitors, a very important discovery was that nepicastat was found to cross the blood brain barrier (BBB), thereby able to cause central as well as peripheral effects, a situation which could lead to undesired and potentially serious CNS side-effects of the drug. Therefore there yet remains an unfulfilled clinical requirement for a potent, non 25 toxic and peripherally selective inhibitor of D0H, which could be used for treatment of certain cardiovascular disorders A DH inhibitor with similar or even greater potency than nepicastat, but devoid of CNS effects (inability to cross the BBB) would provide a significant improvement over all D0H inhibitor compounds thusfar described in the prior art. We have surprisingly found that incorporation of certain heteroatoms to the carbocyclic ring and/or elongation of the amino alkyl side-chain of the nepicastat core-structure
gives rise to a series of compounds possessing significant and pronounced effects of potential usefulness for DDH inhibition Many of these compounds are endowed with greater potency and significantly reduced brain access, giving rise to potent and peripherally selective D0H inhibitors Thus, the invention relates to compounds of 5 general formula l; R. S': NH
R2R'4HN)n where R., R2 and R3 are the same or different and signify hydrogens, halogens, alkyl, alkylaryl, alkyloxy, hydroxy, nitro, amino, alkylcarbonylamino, alkylamino or 10 dialkylamino group; R4 signifies hydrogen, alkyl or alkylaryl group; X signifies CH2, oxygen atom or sulphur atom; n is 1, 2 or 3, with the proviso that when n is 1, X is not CH2; and the individual (R)- and (S)-enantiomers or mixtures of enantiomers; and the pharmaceutically acceptable salts thereof.
15 Unless stated otherwise, in this specification the term alkyl (whether used on its own or
used in combination with other moieties) means hydrocarbon chains, straight or branched, containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxYcarbonyl groups; the term aryl (whether used on its own or used in combination with other moieties) means a phenyl or 20 naphthyl group, optionally substituted by alkyloxy, halogen or nitro group; and the term halogen means fluorine, chlorine, bromine or iodine.
Another aspect of the present invention is a process for the preparation of compounds of formula 1. Some compounds according to formula 11 where X signifies methylene 25 (CH2), oxygen or sulphur are known (Martinez, G R. et al, US Patent 5,538,988, Jul.
23, 1996; Eriksson, M., PCT Int. Appl WO 9959988A1, 25 Nov 1999; Napoletano, M., PCT Int. Appl. WO 9608489A1, 21 March 1996; Sarda, N. et al., Tetrahedron Lett., 17:271 -272, 1976; Neirabeyeh, M AI et al, Eur. J Med Chem., 26:497-504, 1991) in
the literature and others can be prepared by those skilled in the art. Compounds according to formula 11 are chiral, and formula 11 is therefore to be taken to represent both optically pure individual (R)- and (S)enantiomers or mixtures of enantiomers; R. R2 vNH2 À 11 5 Compounds of formula I are prepared by reacting a compound of formula 11 where X is CH2, oxygen or sulphur; R., R2 and R3 are the same or different and signify hydrogens, halogens, alkyl, alkylaryl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkylamino group with a compound of formula lil: \0- NR4FR6
o 1 0 III
where n signifies 1, 2 or 3; when n is 1 or 2, R4 signifies hydrogen, alkyl or alkylaryl group; R5 signifies a hydroxyl protecting group and R6 signifies an amino protecting group; when n signifies 3, Rs is defined as above but R4 and R6 taken together represent a phthalimido group; and with a water soluble thiocyanate salt in an inert 15 organic solvent and in the presence of an organic acid, wherein 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, 20 but potassium thiocyanate is preferred.
The compound of formula lil where n is 1 is known (Wolf, E. et al., Can. J. Chem., 75:942-948, 1997) and compounds of formula lil where n is 2 or 3 are new compounds that can be prepared by those skilled in the art (see examples). The preferred hydroxyl 25 protecting groups (Rs) include organosilyl compounds such as chosen from trialkysilyl, triphenylsilyl, phenyidialkylsilyl or alkyidiphenylsilyl group The tertbutyidimethylsilyl (TBDMS) group is especially preferred The preferred amino protecting groups (R6)
include carbamates such alkyl carbamates, in particular the t-butyl carbamate (Boc) group, and alkylaryl carbamates The reaction may be run with a small excess of the compound of formula lil and potassium thiocyanate (preferably 1.1-1.3 equivalents).
5 The invention also provides compounds of formula 11, where at least one of R., R2 and R3 is fluorine.
The reaction can be run in a substantially inert solvent (preferably ethyl acetate) and at different temperatures (preferably at the solvent reflex temperature). Preferred organic 10 acids include acetic acid When compounds of formula lil where n signifies 1 are used, the intermediate of formula IV is then treated with a mineral acid in a suitable solvent to I remove the Boc amino protecting group and provide the compounds of formula I (scheme 1). Preferred mineral acids include hydrochloric acid and preferred solvents include ethyl acetate.
When compounds of formula lil where n signifies 2 are used and R4 signifies hydrogen, the mixture of intermediate products of formula V and Vl is reacted with hydrochloric acid in ethyl acetate to afford the corresponding single compounds of formula I (scheme 2); where R4 signifies alkyl (including alkyl substituted by aryl), the single 20 intermediate product of formula V is reacted with hydrochloric acid in ethyl acetate to afford the compounds of formula 1.
When compounds of formula lil where n is 3 are used, the intermediate of formula Vll is then treated with sodium borohydride in a suitable solvent system followed by acetic 25 acid to remove the pthalimido amino protecting group as described in the literature (Osby et al., Tetrahedron Lett, 1984, 25(20), 2093-2096) to give the compounds of formula I (scheme 3). The compounds of formula I are obtained with good purity, but if preferred can be recrystallized from a suitable solvent.
Scheme 1 R R5ONR4R6 R
l; R2 = NO R3 / X KSCN, AcOH, EtOAc R3 X NR4R6 / HCI/EtOAc >> NH R < NHR4. HCI
R3 1
( Scheme 2 R R5O I / NR4R6 S)_ NH
R <// À R2 Hi, N. 5/X KSCN, AcOH, EtOAc X R3 11 R3
V NR4R6
HCI/EtOAc R -.\9NH
NHR4.HCI Vl Scheme 3 R;\: RsO NR4RdR S Nt:H X KSCN, AcOH, EtOAc R3 X R3 II J
1.NaBH4/i-PrOH, THF / NR6R4 2.AcOH / 3.HCI Hi/ Vl1 >_ NH R2 J' New HCI H2N
For the preparation of pharmaceutical compositions of compounds of formula 1, inert pharmaceutically acceptable carriers are admixed with the active compounds. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules and capsules. A solid 5 carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it may also be an encapsulating material.
Preferably the pharmaceutical preparation is in unit dosage form, e.g. packaged 10 preparation, the package containing discrete quantities of preparation such as Racketed tablets, capsules and powders in vials or ampoules.
The dosages may be varied depending on the requirement of the patient, the severity of the disease and the particular compound being employed. For convenience, the total 15 daily dosage nosy be divided and administered in portions throughout the day. It is expected that once or twice per day administration will be most suitable. Determination of the proper dosage for a particular situation is within the skill of those in the medical art. 20 Materials and Methods In vitro studies D,bH activity was evaluated by the ability to 0-hydroxylate dopamine to noradrenaline as 25 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 (ATCC HTB-11), a human neuroblastoma derived cell line, were used as a source of human D,BH. SK-N-
SH cells cultured in 24 well plates were preincubated for 20 min in a reaction medium 30 containing 200 mM sodium acetate, 30 mM Nethylmaleimide, 5 HM copper sulphate, 0.5 mg/ml catalase aqueous solution, 1 mM pargyline, 10 mM sodium fumarate and 20 mM ascorbic acid. Thereafter, cells were incubated for further 45 min in the reaction medium with added increasing concentrations of dopamine (0.5 to 100 mM). During
preincubation and incubation, the cells were continuously shaken and maintained at 37 C. The reaction was terminated by the addition of 0.2 M perchloric acid. The acidified samples were stored at 4 C before injection into the high pressure liquid chromatograph for the assay of noradrenaline. In experiments conducted with the aim 5 of studying the effects of new DISH inhibitors on enzyme activity, test compounds (0.3 to 10,000 nM) of interest were added to the preincubation and incubation solutions; the 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.
10 In viva studies Male NMRI mice or Wistar rats were obtained from Harlan-lnterfauna (Spain) and were kept 10 and 5 per cage respectively, under controlled environmental conditions (12 h lighWark cycle and room temperature 22 + 1 C). Food and tap water were allowed ad 15 libitum and experimentation was performed during daylight hours.
At time = 0 h, animals were administered with either test compounds at a given dose or vehicle (water) delivered orally via gavage. At 2, 6, 9, 12, 18 and 24 h post dose, the animals were sacrificed by decapitation and heart (left atrium and left ventricle) and 20 brain (frontal and parietal cortex) were isolated, weighed and stored in a volume of 0.2 M perchloric acid for 12 h at 4 C in the dark Post incubation, the resulting supernatants were collected by centrifuge filtration of incubates (0.2 IBM / 10 min / 5000 rpm, 4 C). Supernatants were stored frozen at -80 C until analysis.
Quantification of dopamine and noradrenaline in supernatants was performed by high 25 pressure liquid chromatography with electrochemical detection.
Results In vitro studies Incubation of SK-N-SH cells in the presence of increasing concentrations of dopamine I resulted in a concentrationdependent formation of noradrenaline, yielding Km (in,uM) and Vma, (in nmol mg protein h) values of 206+1.6 and 153.84.4, respectively.
From these kinetic parameters, a concentration of dopamine approaching saturation 10 (50 mM) was chosen for use in inhibition studies As listed in Table 1 compounds 2,3,4,5,6,7,8,10,12,16,19,24,26,28 and 29 were found to markedly inhibit DISH activity.
Compounds 2, 3, 4 and nepicastat 1 (the reference compound) produced a concentration-dependent decrease in the B-hydroxylation of dopamine with IC50 values in the low nM range against human D0H activity (see Table 2). Compound 4 was 15 chosen for further in viva studies, being the compound most closely related to nepicastat 1 in order to provide conclusive evidence that the structural modifications made to the molecule as part of the present invention are responsible for the surprisingly markedly improved biological properties observed.
Table 1. Effect of selected compounds (5 AM) on D0H activity in SK-N-SH cells.
Values are quoted as % of control.
No. | Means SEM No. | Means SEM | O.OiO.3 24 1 O.Oi1.9 1.6+0.3 25 1 66.0+ 4-5
4.10.6 26 4.5i1.9 3.3iO.3 27 15.5+5.8 8.1+0.3 28 2.6i1.6 6.9iO.6 29 2.2i2. 5 7 8.00.1 30 99.4i2.8 8 9.4iO.7 31 27.3+0.4 50.2i1.9 10 8.2+0.7
11 36.7i4.4 12 3.00.5
13 94.0+3.1
14 77.9+2.2
15 86.1i2.7 16 O.OiO.6 17 53.2i3.9 18 94.81.2
19 6.90.5
20 16.8+4.8
21 124.86.5
22 17.8i2.1 23 54.5i9.9 Table 2. IC50 values (in nM) for inhibition of DDH in SK-N-SH cells.
Compound IC50 (in nM) 60 (14, 250j 91 (56, 147)
105 (69, 161)
Nepicastat 1 36 (28, 46)
In viva studies Mouse 5 The time course experiments for compound 4 and nepicastat (1) in the heart at 100 mg/kg suggests that both compounds are long acting. Time of maximum effect (Tmax) for noradrenaline tissue reduction by both 4 and 1 appears to be at 9 h post-dose (Figure 1). Thereafter, noradrenaline tissue levels recover, reaching 50% recovery of initial tissue levels at 24 h. At Tmax (9 h after administration), both 4 and 1 reduced noradrenaline levels in a dose dependent manner in left ventricle For both 4 and 1, the maximal inhibitory effect was I attained at a dose of 100 mg/kg In contrast to that found in the heart, 4 failed to affect! noradrenaline tissue levels in the brain parietal cortex, whereas 1 produced a dose 15 dependent decrease in noradrenaline levels in this area of the brain (Figure 2).
Rat As shown in the mouse, the effects of both 4 and 1 upon noradrenaline were 20 dependent on the dose administered and reached its maximum at 9 h (data not shown). However, as depicted in Figure 3, the inhibitory effects of 4 (100 mg/kg) upon noradrenaline levels in both the left atrium and the left ventricle were more pronounced than those elicited by 1 (100 mg/kg) Again, as observed in the mouse, 4 failed to affect noradrenaline tissue levels in the brain parietal cortex and the brain frontal cortex, 25 whereas 1 produced a marked decrease in noradrenaline levels in these brain areas.
It is concluded that 4, in stark contrast to nepicastat 1, exerts its inhibitory effects upon D0H exclusively in the periphery, being devoid of inhibitory effects in the brain.
30 Reference is now made to the accompanying drawings, in which: Figure 1 is a graph showing the time-dependent decrease of noradrenaline levels in the left ventricle of mice treated orally with 100 mg/kg of 4 or nepicastat 1. Symbols are means of 5 determinations per group; vertical lines indicate S.E.M.
l Figure 2 is two graphs showing noradrenaline levels in the mouse left ventricle and brain parietal cortex 9 h after oral administration of 4 or nepicastat 1. Symbols are means of 5 determinations per group; vertical lines indicate S.E.M.
Figure 3 is four graphs showing noradrenaline levels in the rat heart (left atrium and left ventricle) and brain (frontal and parietal cortex) 9 h after the oral administration of 4 or nepicastat 1. Columns are means of 5 determinations per group; vertical lines indicated S.E.M.
Conclusion
Some compounds of general formula I are very potent dopamine-,0hydroxylase inhibitors and have potentially valuable pharmaceutical properties in the treatment of some cardiovascular disorders, where a reduction in the enzymatic hydroxylation of 15 dopamine to noradrenaline may be of therapeutic benefit, such as hypertension and chronic heart failure. The possibility to use a long-acting D0H inhibitor with limited access to the brain (CNS), such as compound 4 opens new perspectives in the treatment of hypertension and chronic heart failure by improving potency and selectivity of D,BH inhibition in the periphery.
The invention disclosed herein is exemplified by the following examples of preparation, which should not be construed to limit the scope of the disclosure. Alternative pathways
and analogous structures may be apparent to those skilled in the art.
25 Examples
Example 1
(R)-5-aminomethyl-1 -(6,8-d ifluorochroman-3-yl)-1,3-d ihydroimidazole-2thione 30 hydrochloride compound 3, table 1) A stirred mixture of (R)-6,8difluorochroman-3-ylamine hydrochloride (0.22 g, 1.0 mmol), [3-(tertbutyidimethylsilanyloxy)-2-oxopropyl]carbamic acid tert-butyl ester (0.33 g, 1.1 mmol), potassium thiocyanate (011 g, 1 1 mmol) and acetic acid (0. 3 mL,
5.0 mmol) in ethyl acetate (3 mL) was reflexed for 2 hours, cooled to room temperature, then washed by sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated in vacua. The residue was purified by the column chromatography over silica gel using ethyl acetate - petroleum ether mixture as eluent.
5 The resulting oil (0.23 9) was dissolved in ethyl acetate (2 ml), whereupon 2M HCI solution in ethyl acetate was added (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 of m.p. 192 C (decomp.).
10 Examples 2-3 By the application of the above described technique and related procedures known to those skilled in the art and using the appropriate chroman-3-ylamines hydrochlorides, the following compounds were prepared: 15 (R)-5-aminomethyl-1-Chroman-3-yl-1,3-dihydroimidazole-2thione hydrochloride (compound 24, table 1) (R)-5-aminomethyl-1 -(6hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride (compound 22, table 1)
Example 4
(R,S)-5-aminomethyl-1 -(6-hydroxythiochroman-3-yl)-1,3-dihydroimidazole-2 thione hydrochloride 5 A stirred mixture of 6-hydroxythiochroman-3ylamine hydrochloride (0.22 9, 1.0 rnmol), [3-(tertbutyidimethylsilanylOxy)-2-oxopropyl]carbamic acid tert-butyl ester (0.33 9, 1.1 mmol), potassium thiocyanate (011 g, 11 mmol) and acetic acid (0.3 mL, 5.0 mmol) in ethyl acetate (3 mL) was reflexed for 2 hours, then cooled to room temperature, and washed by sodium bicarbonate solution, dried over anhydrous 10 magnesium sulphate and evaporated in vacua The residue was purified by column I chromatography on silica using ethyl acetate- petroleum ether mixture as eluent. The resulting oil (0.25 9) was dissolved in ethyl acetate (2 ml), whereupon 2M HCI solution in ethyl acetate was added (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 15 acetate to give crystals, which decomposed without melting.
Examole 5 (3,4-Dihydroxybutyl)carbamic acid tert-butyl ester 20 To a stirred solution of 4-amino-1,2-propanediol (2.10 9, 20 mmol) in ethanol (50 mL) at room temperature was added di-tert-butyidicarbonate (4.80 g, 22 mmol) in one portion. The resulting mixture was stirred at room temperature for two hours, then evaporated in vacua and purified by column chromatography on silica using ethyl acetate - petroleum ether mixture as eluent to afford colourless oil.
Examples 6-7
By the application of the above described technique and related procedures known to those skilled in the art and using the appropriate N- substituted 4-amino-1,2 30 propanediols, the following compounds were prepared: (3,4-Dihydroxybutyl)methylcarbamic acid tert-butyl ester (3,4Dihydroxybutyl)benzylcarbamic acid tert-butyl ester
! Example 8
[4-(tert-butyidimethylsilanyloxy)-3-hydroxybutyl]carbamic acid tert-butyl ester To a stirred solution of (3,4-dihydroxybutyl)carbamic acid tertbutyl ester (2.60 9, 5 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- butyidimethylchlorosilane (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 vacua gave an oil which 10 was purified by column chromatography on silica using ethyl acetate - petroleum ether mixture as eluent to afford a colourless oil.
Example 9-10
15 By the application of the above described technique and related procedures known to those skilled in the art and using compounds from examples 6 and 7, the following compounds were prepared: [4-(tertbutyidimethylsilanYloxy)-3-hydroxybutyl]methylcarbamic acid tert-butyl ester 20 [4-(tert-butyidimethylsilanyloxy)-3-hydroxybutyl]benzylcarbamic acid tert-butyl ester Example 1 1
25 [4-(tert-butyidimethylsilanylOXY)-3-oxobutyl]carbamic acid tert-butyl ester To a solution of Dess-Martin periodinane (5.0 9, 11.8 mmol) in anhydrous dichloromethane (35 mL) at room temperature was added a solution of [4-(tert butyidimethylsilanyloxY)-3-hydroxybutyl]carbamic acid tert-butyl ester (3.77 g, 11.8 mmol) in anhydrous dichloromethane The resulting mixture was stirred at room 30 temperature for one hour, evaporated in vacua to one third of the initial volume and applied to a column packed with silica Elution with ethyl acetate - petroleum ether solvent mixture afforded a colourless oil.
Example 12-13
By the application of the above described technique and related procedures known to those skilled in the art and using compounds from examples 9 and 10, the 5 following compounds were prepared: [4-(tertbutyidimethylsilanYloxy)-3-oxobutyl]methylcarbamic acid tert-butyl ester [4-(tert-butyidimethylsilanyloxy)-3-oxobutyl]benzylcarbamic acid tertbutyl ester.
Example 14
(S)-5-(2-aminoethyl)-1 -(5,7-difluoro-1,234-tetrahydronaphthalen-2-yl)-1, 3-
dihydroimidazole-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), [4-(tert-butyidimethylsilanyloxy)-3oxobutyl]carbamic 15 acid tert-butyl ester (0.28 g, 0 87 mmol), potassium thiocyanate (0.085 9, 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 reflexed for 7 hours, cooled to the room temperature, washed by sodium bicarbonate solution and dried over anhydrous magnesium sulphate and evaporated In vacua. The residue was purified by column chromatography on silica using ethyl 20 acetate - petroleum ether mixture as eluent The resulting oil (0.24 9) was dissolved in ethyl acetate (2 ml), 2M HCI solution in ethyl acetate was added (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, which decomposed without melting. Example 15
By the application of the above described technique and related procedures known to those skilled in the art and using the appropriate 1, 2,3,4 30 tetrahydronaphthalen-2-Ylamines hydrochlorides, the following compounds were prepared: (S)-5-(2-aminoethyl)-1 -(1,2,3,4tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole 2-thione hydrochloride (compound 20, table 1)
! Example 16
(R)-5-(2-aminoethyl)-1 -(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2thione hydrochloride (compound 4, table 1) 5 A stirred mixture of (R)-6,8difluorochroman-3-ylamine hydrochloride (1.68 g 7.58 mmol), [4-(tertbutyidimethylsilanYloxy)-3-oxobutyl]carbamic acid tert-butyl ester (3.13 9, 9.85 mmol), potassium thiocyanate (0 96 9, 9 85 mmol), water (0.18 mL, 10 mmol) and acetic acid (3 0 mL, 50 mmol) in ethyl acetate (30 mL) was reflexed for 7 hours, cooled to room temperature, washed by sodium bicarbonate solution, dried over 10 anhydrous magnesium sulphate and evaporated in vacua The residue was purified by column chromatography on silica using ethyl acetate - petroleum ether mixture as eluent. The resulting oil (2 15 g) was dissolved in ethyl acetate (20 ml), 2M HCI solution in ethyl acetate was added (20 mL, 40 mmol) and the mixture was stirred for 2 hours at room temperature. The precipitate was removed by filtration and washed with ethyl 15 acetate to give crystals, which decomposed without melting.
ExamoIe 17-37 By the application of the above described technique and related procedures 20 known to those skilled in the art and using the appropriate chroman-3-ylamine hydrochlorides and [4-(tertbutyidimethylsilanyloxy)-3-oxobutyl]carbamic acid tert-butyl esters, the following compounds were prepared: (R)-5-(2-aminoethyl)-1-chroman-3-yl-1, 3-dihydroimidazole-2-thione hydrochloride (compound 12, table 1) 25 (R)-5(2-aminoethyl)-1-(6-hYdroXYchr man-3-yl)-13-dihydroimidazole-2-thione hydrochloride (compound 16, table 1) (R)-5-(2-aminoethyl)-1 -(8hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride (compound 21, table 1) (R)-5-(2-aminoethyl)-1 -(6-methoxychroman-3-yl)-1,3-dihydroimidazole-2-thione 30 hydrochloride (compound 23, table 1) (R)-5(2-aminoethyl)-1 -(8-methoxychroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride (compound 19, table 1) (R)-5-(2-aminoethyl)-1 -(6fluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride (compound 7, table 1)
it (R)-5-(2-aminoethyl)-1 -(8-fluorochroman-3-yl)-1,3-dihydroimidazole-2thione hydrochloride (compound 6, table 1) (R)-5-(2-aminoethyl)-1 -(6,7difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride (compound 8, table 1) 5 (5)-5-(2-aminoethyl)-1-(6,8-diflUorochroman-3-yl)13-dihydroimidazole-2-thione hydrochloride (compound 9, table 1) (R)-5-(2aminoethyl)-1 -(6,7,8-trifluorochroman-3-yl)-1,3-dihydroimidazole-2-th lone hydrochloride (compound 10, table 1) (R)-5-(2-aminoethyl)-1 -(6chloro-8-methoxychroman-3-yl)-1,3-dihydroimidazole-2 10 thione hydrochloride (compound 11, table 1) (R)-5-(2-aminoethyl)-1-(6-meth XY-8chlorochroman-3-yl)-13-dihydroimidazole-2- l thione hydrochloride (compound 13, table 1) (R)-5-(2-aminoethyl)-1 -(6-nitrochroman-3-yl)-1,3dihydroimidazole-2-thione hydrochloride (compound 18, table 1) 15 (R)-5(2-aminoethyl)-1-(8-nitrochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride (compound 17, table 1) (R)-5-(2-aminoethyl)-1 -[6(acetylamino)chroman-3-yl]-1,3-dihydroimidazole-2-thione hydrochloride (compound 14, table 1) (R)-5-(2-aminoethyl)-1 -(6-hydroxy-7-benzylchroman3-yl)-1,3-dihydroimidazole-2-thione 20 hydrochloride (compound 15, table 1) (R)-5-(2-BenzylaminoethYI)-1 -(6-methoxychroman-3-yl)-1,3dihydroimidazole-2-thione hydrochloride (compound 25, table 1) (R)-5-(2BenzylaminoethYI)-1 -(6-hydroxychroman-3-yl)-1,3-dihydroimidazole-2thione hydrochloride (compound 26, table 1) 25 (R)-1-(6-Hydroxychroman-3YI)-5-(2-methylaminoethyl)-193-dihydroimidazole-2-thione hydrochloride (compound 27, table 1) (R)-1 -(6,8-Difluorochroman-3-YI)-5-(2methYlaminoethyl)-1,3-dihydroimidazole-2-thione hydrochloride (compound 28, table 1) (R)-1 -Chroman-3-yl-5-(2-methylaminoethyl)-1,3dihydroimidazole-2-thione 30 hydrochloride (compound 29, table 1) Example 38
(R,5)-5-(2-aminoethyl)-1-(6-meth xYthiochroman-3-yl)-13-dihydroimidazole2 thione hydrochloride (compound 30, table 1) A stirred mixture of 6methoxythiochroman-3-ylamine hydrochloride (0.12 g, 0.50 mmol), [3-(tertbutyidimethylsilanyloxY)-2-OXOprOpyl]carbamic acid tert-butyl ester (0.17 5 9, 0.55 mmol), potassium thiocyanate (0 055 g, 0 55 mmol), water (0.009 9, 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 by sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated In vacua. The residue was purified by column chromatography on silica using ethyl acetate - petroleum ether mixture as 10 eluent. The resulting oil (012 9) was dissolved in ethyl acetate (1 ml), 2M HCI solution in ethyl acetate was added (1 mL, 2 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 which decomposed without melting.
15 ExamoIe 39 By the application of the above described technique and related procedures known to those skilled in the art and using the appropriate chroman-3-ylamine hydrochlorides, the following compounds were prepared: 20 (R. SJ-5-(2-a minoethyl)-1 -(6-hydroxythiochroman-3-yl)1,3-dibydroimidazole-2 thione hydrochloride (compound 31, table 1) Example 40
25 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 9, 6.60 mmol) and carboethoxyphthalimide (145 9, 660 mmol) in acetonitrile (10 mL) at room temperature was added triethylamine (0 92 mL, 6 60 mmol) in one portion and the resuting mixture was stirred at room temperature for 18 hours, evaporated in vacua 30 and the residue was dissolved in ethyl acetate (50 mL) The solution was washed with brine, 10% citric acid solution and brine, then dried over anhydrous magnesium sulfate.
Filtration and concentration in vacua gave an oil which was purified by column
( chromatography on silica using ethyl acetate - petroleum ether mixture as eluent to afford a colourless oil.
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 THE (20 mL) at room temperature was added 2N HCI solution (15 mL, 30 mmol) in one portion and the resulting mixture was stirred at room 10 temperature for two hours and then evaporated in vacua to half of the initial volume.
The residue was saturated with NaCI and extracted with ethyl acetate. The organic phase was dried by anhydrous magnesium sulfate Filtration and concentration In vacuo afforded a colourless oil.
15 Example 42
By the application of the technique described in example 8 to 2-(4,5-
dihydroxypentyl)isoindole-1,3-diOne, the following compound was prepared: 2-[5-(tert-ButyidimethylsilanYlaxYf4-hydroxYPentyl]isoindole-1,3-dione Example 43
By the application of the technique described in example 11 to 2-[5-(tert-
butyidimethylsilanyloxY)4-hydroxypentyl]isoindole-13-dione, the following compound 25 was prepared: 2-[5-(tert-ButyidimethylsilanYiOxy)-4-oxopentyl] isoindole-1,3-dione Example 44
(S)-5-(3-aminopropyl)-1 -(5,7-difluoro-1,234-tetrahydronaphthalen-2-yl)-1, 3-
30 dihydroimidazole-2-thione hydrochloride (compound 5, table 1) A stirred mixture of (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl amine hydrochloride (0.22 9, 10 mmol), 2-[5-(tert-butyidimethylsilanyloxy) -4 oxopentyl]isoindole-1,3-dione (0 38 g, 1 05 mmol), potassium thiocyanate (0.11 g, 1.10 mmol), water (0.18 9, 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 by sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated In vacuo. The residue was purified by column chromatography on silica using ethyl acetate - petroleum ether mixture as eluent The resulting oil (0.18 g) was dissolved in 5 a mixture of isopropanol (5 mL) and THE (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 reflexed for two hours then evaporated in vacua to dryness. The residue was taken up into acetone, the solid was filtered off, and the filtrate was acidified with 2N HCI solution 10 in ethyl acetate. The precipitate was collected and washed with acetone to afford crystals, which decomposed without melting.
Example 45
15 (R)-5-(3-aminopropyl)-1-(6,8-difluorochroman-3-yl)-1,3dIhydroimidazole-2 thione hydrochloride A stirred mixture of (R)-6,8difluorochroman-3-ylamine hydrochloride (0.11 g, 0.50 mmol), 2-[5-(tertButyidimethylsilanyloxy)-4-oxopentyl]isoindole-113-dione (0.19 g, 0.55 mmol), potassium thiocyanate (0055 9, 0 55mmol), water (0.009 9, 0.50 mmol) 20 and acetic acid (0.15 mL, 25 mmol) in ethyl acetate (1 5 mL) was refluxed for 7 hours, cooled to the room temperature, washed by sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated in vacua The residue was purified by column chromatography on silica using ethyl acetate - petroleum ether mixture as eluent. The resulting oil (010 9) was dissolved in the mixture of isopropanol (2.5 mL) 25 and THE (1 mL). Water (0 4 mL) and sodium borohydride (0.038 9, 1.0 mmol) were added at room temperature and the mixture was stirred for 1.5 hours. Acetic acid (0.3 ml, 5 mmoj) was added and the solution was reflexed for two hours and evaporated In vacuo to dryness. The residue was taken up in acetone, the solid was filtered off, and the filtrate was acidified with 2N HCI solution in ethyl acetate. The precipitate was 30 collected and washed with acetone to afford crystals, which decomposed without melting.
Example 46
(R,5)-5-(3-aminoproPYI)-1 -(6-hydroxythiochroman-3-yl)-1,3dihydroimidazole-2 thione hydrochloride 5 A stirred mixture of 6hydroxythiochroman-3-ylamine hydrochloride (0.22 g, 1.
mmol), 2-[5-(tert-ButyidimethYlsilanyloxy)-4-oxopentyl]isoindole-173dione (0.38 g, 1.05 mmol), potassium thiocyanate (0 11 9, 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 by sodium bicarbonate solution, dried over anhydrous 10 magnesium sulphate and evaporated in vacua The residue was purified by column chromatography on silica using ethyl acetate- petroleum ether mixture as eluent. The resulting oil (0.17 9) was dissolved in the mixture of isopropanol (5 mL) and THE (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 15 hours. Acetic acid (0.6 ml, 10 mmoj) 15 was added and the solution was reflexed for two hours and evaporated in vacua to dryness. The residue was taken up into acetone, the solid was filtered off and the filtrate was acidified with 2N HCI solution in ethyl acetate. The precipitate was collected and washed with acetone to afford crystals, which decomposed without melting.

Claims (16)

Claims
1.A compound of formula l: R. S) NH
>N R3 X R4HN
where R., R2 and R3 are the same or different and signify hydrogens, halogens, alkyl, alkyloxy, hydroxy, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; 10 R4 signifies hydrogen, alkyl or alkylaryl group; X signifies CH2, oxygen atom or sulphur atom; n is 1, 2 or 3, with the proviso that when n is 1, X is not CH2; and the individual (R)- and (S)-enantiomers or mixtures of enantiomers and pharmaceutically acceptable salts thereof; wherein the term alkyl means hydrocarbon chains, straight or branched, containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, 15 alkoxycarbonyl or hydroxycarbonyl groups; the term aryl means a phenyl or naphthyl group, optionally substituted by alkyloxy, halogen or nitro group; the term halogen means fluorine, chlorine, bromine or iodine.
2. A compound according to claim 1, comprising: (S)-5-(2-aminoethyl)-1-(1, 2,3,4 20 tetrahydronaphthalen-2-YI)-1.3-dihydroimidazole-2-thione hydrochloride; (S)-5-(2-
aminoethyl)-1 -(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3dihydroimidazole-2 thione hydrochloride; (R)-5-(2-aminoethyl)-1-chroman-3yl-13-dihydroimidazole-2 thione hydrochloride; (R)-5-(2-aminoethyl)-1-(6hydroxychroman-3-yl)-1,3-
dihydroimidazole-2-thione hydrochloride; (R)-5-(2-aminoethyl)-1-(8hydroxychroman-3 25 yl)-1,3-dihydroimidazole-2-thione hydrochloride; (R)5-(2-aminoethyl)-1-(6-
methoxychroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride; (R)-5(2-
aminoethyl)-1-(8-methOxychroman-3-yl)-13-dihydroimidazole-2-thione hydrochloride; (R)-5-(2-aminoethyl)-1 -(6-fluorochroman-3-yl)-1,3dihydroimidazole-2-thione
( hydrochloride; (R)-5-(2-aminoethyl)-1-(8-0uorochroman-3-yl)-1,3dihydroimidazole-2 thione hydrochloride; (R)-5-(2-aminoethyl)-1-(6,7difluorochroman-3-yl)-1,3-
dihydroimidazole-2-thione hydrochloride; (R)-5-(2-aminoethyl)-1-(68difluorochroman 3-yl)-1,3-dihydroimidazole-2-thione hydrochloride; (S)-5(2-aminoethyl)-1-(6,8 5 difluorochroman-3-yl)-1,3-dihydroimidazole-2thione hydrochloride; (R)-5-(2-
aminoethyl)-1 -(6,7,8-trifluorochroman-3-yl)-1,3-dihydroimidazole-2thione hydrochloride; (R)-5-(2-aminoethyl)-1-(6-chloro-8-methoxychroman-3yl)-1,3-
dihydroimidazole-2-thione hydrochloride; (R)-5-(2-aminoethyl)-1-(6methoxy-8-
ch lorochroman-3-yl)- 1,3-dihydroimidazole-2-thione hydrochloride; (R)-5(2-aminoethyl) 10 1-(6-nitrochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride; (R)-5-(2 aminoethyl)-1 -(8-nitrochroman-3-yl)-1,3dihydroimidazole-2-th lone hydrochloride; (R)-5- l (2-aminoethyl)- 1 -[6(acetylamino)chroman-3-yl]- 1,3-dihydroimidazole-2-thione l hydrochloride; (R)-5-aminomethyl-1-chroman-3-yl-1,3-dihydroimidazole-2-thione hydrochloride; (R)-5-aminomethyl-1-(6-hydroxYchroman-3-yl)-1,3dihydroimidazole-2 15 thione hydrochloride; (R)-5-(2-aminoethyl)-1-(6hydroxy-7-benzylchroman-3-yl)-13 dihydroimidazole-2-thiOne hydrochloride; (R)-5-aminomethyl-1-(68-difluorochroman-3 yl)-1,3-dihydroimidazole-2thione hydrochloride; (R)-5-(3-aminopropyl)-1-(6,8-
difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride; (5)-5 (3 aminopropyl)-1 -(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3dihydroimidazole-2 20 thione hydrochloride; (R,s)-5-(2-aminoethyl)-1-(6hydroxythiochroman-3-yl)-13 dihydroimidazole-2-thione hydrochloride; (R,S) -5-(2-aminoethyl)-1-(6-
methoxythiochroman-3-yl)-13-dihydroimidazole-2-thione hydrochloride; rR)5-(2-
benzylaminoethyl)-1 -(6-methoxychroman-3-yl)-1,3-dihydroimidazole-2thione hydrochloride; (R)-5-(2-benzylaminoethyl)-1-(6-hydroxychroman-3-yl) -1,3 25 dihydroimidazole-2-thione hydrochloride; (R)-1-(6-hydroxychroman3-yl)-5-(2-
methylaminoethyl)-1,3-dihydroimidazole-2-thione hydrochloride; (R)-1-(6,8 difluorochroman-3-yl)-5-(2-methYlaminoethyl)-13-dihydroimidazole 2 thione hydrochloride or (R)-1-chroman-3-yl-5-(2-methylaminoethyl)-1,3dihydroimidazole 2 thione hydrochloride.
3. A process for the preparation of the individual (R)- and (S)enantiomers or mixtures of enantiomers and pharmaceutically acceptable salts of a compound of
l formula I of claim 1 which comprises reacting the individual (R)- or (S) -enantiomers or mixtures of enantiomers of a compound of Formula II R1 i N H2 R3 5 where X is CH2, oxygen or sulphur; R., R2 and R3 are the same or different and signify hydrogens, halogens, alkyl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkylamino group; with a compound of formula lil 5:o NR4R6 o 1 0 III
where n signifies 1, 2 or 3; when n is 1 or 2, R4 signifies hydrogen, alkyl group; R5 signifies a hydroxyl protecting group and R6 signifies an amino protecting group; when n signifies 3, Rs is defined as above but R4 and R6 taken together represent a 15 phthalimido group; and with a water soluble thiocyanate salt in the presence of an organic acid in a substantially inert solvent, followed by subsequent deprotection of the intermediate products IV-VII:
( NR4R6 IV V NR4R6
S NH
R: N NR6 R2 it 2 R3
R3 Vl NR6R4 Vl1 wherein the water soluble thiocyanate salt is an alkali metal thiocyanate salt or a tetrealkylammonium thiocyanate salt, and wherein the term alkyl means hydrocarbon 5 chains, straight or branched, containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups; the term aryl means a phenyl or naphthyl group, optionally substituted by alkyloxy, halogen or nitro group; the term halogen means fluorine, chlorine, bromine or iodine.
10
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or 2, in combination with a pharmaceutically effective carrier.
5. A compound according to claim 1 or 2, for use as a medicament.
6. The use of a compound according to claim 1 or 2, in the manufacture of a medicament for treating disorders where a reduction in the hydroxylation of dopamine to noradrenaline is of therapeutic benefit.
/
7. The use of a compound according to claim 1 or 2, in the manufacture of a medicament for treating a subject afflicted by cardiovascular disorders
8. The use of a compound according to claim 1 or 2, in the manufacture of a 5 medicament for treating hypertension or chronic heart failure.
9. The use of a compound according to claim 1 or 2, in the manufacture of a medicament for use in inhibiting dopamine--hydroxylase.
10 10. A compound of formula lil s \o'/\ NR4R6 o III 15 where n signifies 2, R4 signifies hydrogen or alkyl group; Rs signifies a hydroxyl protecting group and R6 signifies an amino protecting group, wherein the hydroxyl protecting group is a trialkysilyl, triphenylsilyl, phenyidialkylsilyl or alkyidiphenylsilyl group; and the amino protecting groups is an alkyl carbamate or alkylaryl carbamate group, and wherein the term alkyl means hydrocarbon chains, straight or branched, 20 containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups; the term aryl means a phenyl or naphthyl group, optionally substituted by alkyloxy, halogen or nitro group; the term halogen means fluorine, chlorine, bromine or iodine.
1 1. A compound of formula l l l \o'/\NR4R6 o III
( where n signifies 3, Rs signifies a hydroxyl protecting group; and R4 and R6 taken together represent a phthalimido group, wherein the hydroxyl protecting group is a trialkysilyl, triphenylsilyl, phenyidialkylsilyl or alkyidiphenylsilyl group.
12. A compound of formula 11 R1 R iNH2 R3 wherein R., R2 and R3 may be the same or different and signify fluorine or hydrogen 10 with the proviso that at least one R., R2 and R3 signfies fluorine where X is the same as defined in claim 1.
1 3. (R)-6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-amine.
15
14. A compound substantially herein described with reference to and as shown in the accompanying examples.
15. A pharmaceutical composition substantially herein described with reference to and as shown in the accompanying examples.
16. A process substantially herein described with reference to and as shown in the accompanying examples.
GB0224306A 2002-10-11 2002-10-18 Peripherally-selective inhibitors of dopamine-beta-hydroxylase and method of their preparation Expired - Lifetime GB2394223B (en)

Priority Applications (39)

Application Number Priority Date Filing Date Title
US10/681,578 US7125904B2 (en) 2002-10-11 2003-10-08 Peripherally-selective inhibitors of dopamine-β-hydroxylase and method of their preparation
SI200331986T SI1908760T1 (en) 2002-10-11 2003-10-10 Chromane and thiochromane-3-yl-1,3-dihydroimidazoles as inhibitors of dopamine-beta-hydroxylase and methods of their preparation
PL376224A PL218537B1 (en) 2002-10-11 2003-10-10 Imidazole derivatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase
PT103029A PT103029B (en) 2002-10-11 2003-10-10 DOPAMINE-BETA-HYDROXYLASE INHIBITORS SELECTIVELY PERIPHERED AND METHOD FOR THEIR PREPARATION
EP07076122A EP1914233B8 (en) 2002-10-11 2003-10-10 Silyl-protected hydroxymethyl-carbamoylalkyl-ketones as intermediates in the preparation of dopamine-beta-hydroxylase inhibitors
DE60322642T DE60322642D1 (en) 2002-10-11 2003-10-10 Imidazole derivatives and their use as peripheral-selective inhibitors of dopamine beta-hydroxylases
JP2004542666A JP4620464B2 (en) 2002-10-11 2003-10-10 Imidazole derivatives as peripherally selective inhibitors of dopamine-beta-hydroxylase and their use
PCT/GB2003/004430 WO2004033447A1 (en) 2002-10-11 2003-10-10 Imidazole derivatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase
CA2501819A CA2501819C (en) 2002-10-11 2003-10-10 Imidazole derivative and their use as peripherally-selective inhibitors of dopa nine-beta-hydroxylase
ARP030103711A AR041589A1 (en) 2002-10-11 2003-10-10 PERIPHERALLY SELECTIVE DOPAMINE-BETA-HYDROXYLASE INHIBITORS AND METHOD FOR PREPARATION
KR1020057006221A KR101155159B1 (en) 2002-10-11 2003-10-10 Imidazole derivatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase
ES03256420T ES2309279T3 (en) 2002-10-11 2003-10-10 DERIVATIVES OF IMIDAZOL AND ITS USE AS PERIFERICALLY SELECTIVE INHIBITORS OF BETA-HYDROXYLASE DOPAMINE.
AT07076124T ATE500247T1 (en) 2002-10-11 2003-10-10 METHOD FOR PRODUCING 3-(1,3-DIHYDROIMIDAZOLE-2-THION-1-YL)-CHROMANES AND THIOCHROMANES AS A DOPAMINE BETA-HYDROXYLASE INHIBITOR
AT07076123T ATE550335T1 (en) 2002-10-11 2003-10-10 3,4-DIHYDRO-3-AMINO-2H-1-BENZOPYRAN AND - BENZOTHIOPYRAN DERIVATIVES AS DOPAMINE BETA-HYDROXYLASE INHIBITORS AND METHOD FOR THE PRODUCTION THEREOF
DK03256420T DK1408038T3 (en) 2002-10-11 2003-10-10 Imidazole derivatives and their use as peripherally selective inhibitors dopamine beta-hydroxylase
EP03256420A EP1408038B1 (en) 2002-10-11 2003-10-10 Imidazole deriviatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase
AT07076122T ATE500248T1 (en) 2002-10-11 2003-10-10 SILYL-PROTECTED HYDROXYMETHYL-CARBAMOYLALKYL KETONES AS INTERMEDIATE IN THE PRODUCTION OF DOPAMINE BETA-HYDROXYLASE INHIBITORS
KR1020127005102A KR101350741B1 (en) 2002-10-11 2003-10-10 Imidazole derivatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase
RU2005114021/04A RU2332416C2 (en) 2002-10-11 2003-10-10 Imidazole derivatives, method of their production, pharmaceutical composition on their basis, their use as peripherically selective inhibitors dophamine-beta-hydrolaze and intermediate compounds
AT03256420T ATE403652T1 (en) 2002-10-11 2003-10-10 IMIDAZOLE DERIVATIVES AND THEIR USE AS PERIPHERAL-SELECTIVE INHIBITORS OF DOPAMINE BETA-HYDROXYLASES
EP07076124A EP1911757B8 (en) 2002-10-11 2003-10-10 Method of preparation of 3-(1,3-Dihydroimidazole-2-thione-1-yl)-chromanes and thiochromanes as dopamine-beta-hydroxylase inhibitors
ES07076123T ES2384118T3 (en) 2002-10-11 2003-10-10 3,4-Dihydro-3-amino-2H-1-benzopyran and -benzothiopyran derivatives as dopamine-beta-hydroxylase inhibitors and methods for their preparation
AT07076125T ATE505465T1 (en) 2002-10-11 2003-10-10 CHROMAN- AND THIOCHROMAN-3-YL-1,3-DIHYDROIMIDAZOLE AS INHIBITORS OF DOPAMINE BETA-HYDROXYLASE AND METHOD FOR THE PRODUCTION THEREOF
EP07076125A EP1908760B1 (en) 2002-10-11 2003-10-10 Chromane and thiochromane-3-yl-1,3-dihydroimidazoles as inhibitors of dopamine-beta-hydroxylase and methods of their preparation
SI200331309T SI1408038T1 (en) 2002-10-11 2003-10-10 Imidazole deriviatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase
MXPA05003847A MXPA05003847A (en) 2002-10-11 2003-10-10 Imidazole derivatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase.
DE60336772T DE60336772D1 (en) 2002-10-11 2003-10-10 Chroman and thiochroman-3-yl-1,3-dihydroimidazoles as dopamine beta-hydroxylase inhibitors and methods for their preparation
DE60336275T DE60336275D1 (en) 2002-10-11 2003-10-10 Process for the preparation of 3- (1,3-dihydroimidazole-2-thion-1-yl) -chromans and thiochromans as dopamine-beta-hydroxylase inhibitor
BRPI0315143A BRPI0315143B8 (en) 2002-10-11 2003-10-10 compound, pharmaceutical composition, and use of a compound
DE60336276T DE60336276D1 (en) 2002-10-11 2003-10-10 Silyl-protected hydroxymethyl-carbamoylalkyl ketones as intermediates in the preparation of dopamine-beta-hydroxylase inhibitors
EP07076123A EP1908759B1 (en) 2002-10-11 2003-10-10 3,4-dihydro-3-amino-2H-1-benzopyrane and -benzothiopyrane derivatives as dopamine-beta-hydroxylase Inhibitors and methods of their preparation
AU2003271945A AU2003271945B2 (en) 2002-10-11 2003-10-10 Imidazole derivatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase
DK07076125.9T DK1908760T3 (en) 2002-10-11 2003-10-10 Chromatic and thiochroman-3-yl-1,3-dihydroimidazoles as inhibitors of dopamine beta-hydroxylase and methods for their preparation
US11/533,462 US7259271B2 (en) 2002-10-11 2006-09-20 Peripherally-selective inhibitors of dopamine-β-hydroxylase and method of their preparation
GB0702982A GB2432159B (en) 2002-10-11 2007-02-15 Intermediates for manufacturing peripherally-selective inhibitors of dopamine-beta-hydroxylase
GB0702981A GB2432158B (en) 2002-10-11 2007-02-15 Intermediates for manufacturing peripherally-selective inhibitors of dopamine-beta-hydroxylase and method of their preparation
HK08111214.9A HK1116188A1 (en) 2002-10-11 2008-10-09 Chromane and thiochromane-3-yl-1,3-dihydroimidazoles as inhibitors of dopamine-beta-hydroxylase and methods of their preparation
CY20081101204T CY1108452T1 (en) 2002-10-11 2008-10-24 IMIDAZOLI PRODUCTS AND USE THESE AS PERIODICALLY EXTRACTIVE INHIBITORS OF DOPOPAMIN-β-HYDROXYLUM
CY20111100639T CY1112457T1 (en) 2002-10-11 2011-07-01 CHROMO- AND THIROXROMANO-3-YlO-1,3-dihydro-imidazole as inhibitors of dopamine-B-hydroxylation, and their production methods

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Publication number Priority date Publication date Assignee Title
WO1995029165A2 (en) * 1994-04-26 1995-11-02 Syntex (U.S.A.) Inc. Benzocycloalkylaz0lethione derivatives as dopamin beta-hydroxylase inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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