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

• US 9,630,951 B2
• Filed: 06/13/2013
• Issued: 04/25/2017
• Est. Priority Date: 05/08/2007
• Status: Active Grant

• Current Assignee: BIAL Portela & Ca, SA
• Original Assignee: BIAL Portela & Ca, SA
• Inventors: Soares Da Silva, Patricio Manuel Vieira Araujo, Learmonth, David Alexander, Beliaev, Alexander
• Primary Examiner(s): Javanmard, Sahar
• Application Number:
  US13/917,385
• Publication Number:
  US 20130345275A1
• Time in Patent Office: 1,412 Days
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond

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.

Claims

1. A method of treating anxiety disorders;

migraine;

cardiovascular disorders;

hypertension, chronic or congestive heart failure;

or 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 of formula X;

2. The method according to claim 1, 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.

3. The method according to claim 2, wherein the administration of the compound(s) selected from the listed classes of compounds is simultaneous to the administration of the compound according to claim 1.

4. The method according to claim 2, wherein the administration of the compound(s) selected from the listed classes of compounds is sequential to the administration of the compound according to claim 1.

5. The method according to claim 1, wherein the compound is the (R) enantiomer of the compound of formula X, or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1, wherein the compound is the hydrochloride salt of the compound of formula X, or a pharmaceutically acceptable salt thereof.

7. The method according to claim 5, wherein the compound is the hydrochloride salt of the (R) enantiomer of the compound of formula X.

8. The method according to claim 1, wherein the method is used for the treatment of anxiety disorders.

9. The method according to claim 1, wherein the method is used for the treatment of migraine.

10. The method according to claim 1, wherein the method is used for the treatment of cardiovascular disorders.

11. The method according to claim 1, wherein the method is used for the treatment of hypertension.

12. The method according to claim 1, wherein the method is used for the treatment of chronic heart failure.

13. The method according to claim 1, wherein the method is used for the treatment of congestive heart failure.

14. The method according to claim 1, wherein the method is used for the treatment of one or more of the following indications:

angina, arrhythmias, circulatory disorders and Raynaud'"'"'s phenomenon.