1,3-dihydroimidazole-2-thione derivatives as inhibitors of dopamine-beta-hydroxylase

Abstract

Compounds of formula I and a method for their preparation are described, where R1, R2 and R3 are the same or different and signify hydrogens, halogens, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R4 signifies -alkyl-aryl or alkyl heteroaryl; X signifies CH2, oxygen atom or sulphur atom; n is 2 or 3; including the individual (R)- and (S)-enantiomers or mixtures of enantiomers thereof; and including pharmaceutically acceptable salts and esters thereof. The compounds have potentially valuable pharmaceutical properties for the treatment of cardiovascular disorders such as hypertension and chronic heart failure.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         where R 1 , R 2  and R 3  are the same or different and signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R 4  signifies -alkyl-aryl or -alkyl-heteroaryl; X signifies CH 2 , oxygen atom or sulphur atom; n is 2 or 3; the individual (R)- and (S)-enantiomers or mixtures of enantiomers thereof; or pharmaceutically acceptable salts or esters thereof, wherein the term alkyl 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 means a phenyl or naphthyl group, optionally substituted by alkyl, alkyloxy, halogen or nitro group; the term halogen means fluorine, chlorine, bromine or iodine; the term heteroaryl means heteroaromatic group. 
       
     
     
         2 . A compound according to  claim 1 , wherein n is 2. 
     
     
         3 . A compound according to  claim 1  or  2 , wherein X is O. 
     
     
         4 . A compound according to any preceding claim, wherein R 4  signifies —CH 2 -aryl or —CH 2 — heteroaryl. 
     
     
         5 . A compound according to any preceding claim, wherein the aryl group of R 4  is unsubstituted. 
     
     
         6 . A compound according to any preceding claim, wherein the aryl group of R 4  is phenyl. 
     
     
         7 . A compound according to any preceding claim, wherein one of R 1 , R 2  and R 3  is hydrogen, and the others are fluorine. 
     
     
         8 . A compound according to any preceding claim, wherein said compound consists of the R-enantiomer. 
     
     
         9 . A compound according to any preceding claim, comprising the hydrochloride salt of the compound of formula I. 
     
     
         10 . A process for the preparation of the individual (R)- and (S)-enantiomers or mixtures of enantiomers and pharmaceutically acceptable salts or esters of a compound of formula I, which comprises reacting the individual (R)- or (S)-enantiomers or mixtures of enantiomers of a compound of Formula III 
       
         
           
           
               
               
           
         
       
       where X, R 1 , R 2 , R 3  and n have the same meaning as in  claim 1 , with a compound of formula IV 
       
         
           
           
               
               
           
         
       
       where R 5  signifies aryl or heteroaryl, wherein the term aryl means a phenyl or naphthyl group, optionally substituted by alkyl, alkyloxy, halogen or nitro group; the term halogen means fluorine, chlorine, bromine or iodine; the term heteroaryl means heteroaromatic group; under reductive alkylation conditions. 
     
     
         11 . A compound of formula X: 
       
         
           
           
               
               
           
         
       
       its (R) or (S) enantiomer, or mixture of (R) and (S) enantiomer, or pharmaceutically acceptable salts or esters thereof. 
     
     
         12 . A compound according to  claim 11 , wherein the compound is the (R) enantiomer of the compound of Formula X. 
     
     
         13 . A compound according to  claim 11  or  12 , comprising the hydrochloride salt of the compound of formula X. 
     
     
         14 . A process for the preparation of the compound of formula X of any of  claims 11  to  13 , which comprises treatment of (R)-5-(2-aminoethyl)-1-(6,8-difluoro-chroman-3-yl)-1,3-dihydroimidazole-2-thione and benzaldehyde under reductive alkylation reaction conditions. 
     
     
         15 . The process according to  claim 14  wherein the reductive alkylation is performed in the presence of a reducing reagent. 
     
     
         16 . A process according to  claim 15  wherein the reducing reagent is sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, or hydrogen in the presence of a hydrogenation catalyst. 
     
     
         17 . The process according to any of  claims 14  to  16  wherein the treatment takes place in a mixture of methanol and dichloromethane. 
     
     
         18 . The process according to any of  claims 14  to  17  wherein the process further includes a purification step. 
     
     
         19 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of  claims 1  to  9 ,  11  to  13  in combination with a pharmaceutically effective carrier. 
     
     
         20 . A pharmaceutical composition according to  claim 19  further comprising a compound selected from one or more of the following classes of compounds:
 diuretics; beta-adrenergic antagonists; alpha2-adrenergic agonists; alpha1-adrenergic antagonists; dual beta- and alpha-adrenergic antagonists; calcium channel blockers; potassium channel activators; anti-arrhythmics; ACE inhibitors; AT1 receptor antagonists; renin inhibitors; lipid lowerers, vasopeptidase inhibitors; nitrates; endothelin antagonists; neutral endopeptidase inhibitors; anti-angiotensin vaccines; vasodilators; phosphodiesterase inhibitors; cardiac glycosides; serotonin antagonists; CNS acting agents; calcium sensitisers; HMG CoA reductase inhibitors; vasopressin antagonists; adenosine A1 receptor antagonists; atrial natriuretic peptide (ANP) agonists; chelating agents; corticotrophin-releasing factor receptor; glucagon-like peptide-1 agonists; sodium, potassium ATPase inhibitors; advanced glycosylation end-products (AGE) crosslink breakers; mixed neprilysin/endotheliin-converting enzyme (NEP/ECE) inhibitors; nociceptin receptor (ORL-1) agonists; xanthine oxidase inhibitors; benzodiazepine agonists; cardiac myosin activators; chymase inhibitors; endothelial nitric oxide synthase (ENOS) transcription enhancers; and neutral endopeptidase inhibitors. 
 
     
     
         21 . A compound according to any one of  claims 1  to  9 ,  11  to  13 , for use as a medicament. 
     
     
         22 . The use of a compound according to any one of  claims 1  to  9 ,  11  to  13 , in the manufacture of a medicament for treating disorders where a reduction in the hydroxylation of dopamine to noradrenaline is of therapeutic benefit. 
     
     
         23 . The use of a compound according any one of  claims 1  to  9 ,  11  to  13 , in the manufacture of a medicament for treating a subject afflicted by anxiety disorders. 
     
     
         24 . The use of a compound according any one of  claims 1  to  9 ,  11  to  13 , in the manufacture of a medicament for treating migraine. 
     
     
         25 . The use of a compound according any one of  claims 1  to  9 ,  11  to  13 , in the manufacture of a medicament for treating a subject afflicted by cardiovascular disorders. 
     
     
         26 . The use of a compound according any one of  claims 1  to  9 ,  11  to  13 , in the manufacture of a medicament for treating hypertension, or chronic or congestive heart failure. 
     
     
         27 . The use of a compound according any one of  claims 1  to  9 ,  11  to  13 , in the manufacture of a medicament for treating one or more of the following indications: angina, arrhythmias, and circulatory disorders such as Raynaud's phenomenon. 
     
     
         28 . The use of a compound according any one of  claims 1  to  9 ,  11  to  13 , in the manufacture of a medicament for use in inhibiting dopamine-β-hydroxylase. 
     
     
         29 . A method of treating anxiety disorders comprising administering a therapeutically effective amount of a compound according to any one of  claims 1  to  9 ,  11  to  13  to a patient in need thereof. 
     
     
         30 . A method of treating migraine comprising administering a therapeutically effective amount of a compound according to any one of  claims 1  to  9 ,  11  to  13  to a patient in need thereof. 
     
     
         31 . A method of treating cardiovascular disorders comprising administering a therapeutically effective amount of a compound according to any one of  claims 1  to  9 ,  11  to  13  to a patient in need thereof. 
     
     
         32 . A method of treating hypertension comprising administering a therapeutically effective amount of a compound according to any one of  claims 1  to  9 ,  11  to  13  to a patient in need thereof. 
     
     
         33 . A method of treating chronic or congestive heart failure comprising administering a therapeutically effective amount of a compound according to any one of  claims 1  to  9 ,  11  to  13  to a patient in need thereof. 
     
     
         34 . A method of treating one or more of the following indications: angina, arrhythmias, and circulatory disorders such as Raynaud's phenomenon comprising administering a therapeutically effective amount of a compound according to any one of  claims 1  to  9 ,  11  to  13  to a patient in need thereof. 
     
     
         35 . A method according to any one of  claims 29  to  34  further comprising the administration of a compound selected from one or more of the following classes of compounds:
 diuretics; beta-adrenergic antagonists; alpha2-adrenergic agonists; alpha1-adrenergic antagonists; dual beta- and alpha-adrenergic antagonists; calcium channel blockers; potassium channel activators; anti-arrhythmics; ACE inhibitors; AT1 receptor antagonists; renin inhibitors; lipid lowerers, vasopeptidase inhibitors; nitrates; endothelin antagonists; neutral endopeptidase inhibitors; anti-angiotensin vaccines; vasodilators; phosphodiesterase inhibitors; cardiac glycosides; serotonin antagonists; CNS acting agents; calcium sensitisers; HMG CoA reductase inhibitors; vasopressin antagonists; adenosine A1 receptor antagonists; atrial natriuretic peptide (ANP) agonists; chelating agents; corticotrophin-releasing factor receptor; glucagon-like peptide-1 agonists; sodium, potassium ATPase inhibitors; advanced glycosylation end-products (AGE) crosslink breakers; mixed neprilysin/endotheliin-converting enzyme (NEP/ECE) inhibitors; nociceptin receptor (ORL-1) agonists; xanthine oxidase inhibitors; benzodiazepine agonists; cardiac myosin activators; chymase inhibitors; endothelial nitric oxide synthase (ENOS) transcription enhancers; and neutral endopeptidase inhibitors. 
 
     
     
         36 . A method according to  claim 35  wherein the administration of the compound(s) selected from the listed classes of compounds is simultaneous to the administration of the compound according to any one of  claims 1  to  9 ,  11  to  13 . 
     
     
         37 . A method according to  claim 35  wherein the administration of the compound(s) selected from the listed classes of compounds is sequential to the administration of the compound according to any one of  claims 1  to  9 ,  11  to  13 .