1,3-DIHYDROIMIDAZOLE-2-THIONE DERIVATIVES AS INHIBITORS OF DOPAMINE-BETA-HYDROXYLASE

• US 20190322648A1
• Filed: 05/03/2019
• Published: 10/24/2019
• Est. Priority Date: 05/08/2007
• Status: Abandoned Application

• Current Assignee: BIAL Portela & Ca, SA
• Original Assignee: BIAL Portela & Ca, SA
• Inventors: Soares Da Silva, Patricio Manuel V.A., Learmonth, David Alexander, Beliaev, Alexander
• Application Number:
  US16/402,454
• Publication Number:
  US 20190322648A1
• Time in Patent Office: 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 compound of formula I:

2. A compound according to claim 1, wherein n is 2 or wherein X is O.

4. A compound according to claim 1, wherein R₄ signifies —

CH₂-aryl or —

CH₂-heteroaryl.

5. A compound according to claim 1, wherein the aryl group of R₄ is unsubstituted or wherein the aryl group of R₄ is phenyl.

7. A compound according to claim 1, wherein one of R₁, R₂ and R₃ is hydrogen, and the others are fluorine.

8. A compound according to claim 1, wherein

said compound consists of the R-enantiomer.

9. A compound according to claim 1, 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

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 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.

32. A method of treating hypertension comprising administering a therapeutically effective amount of a compound according to claim 1 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 claim 1 to a patient in need thereof.

35. A method according to claim 32 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 or sequential to the administration of the compound of formula I.

3. (canceled)

6. (canceled)

11. A compound of formula X:

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 12, comprising the hydrochloride salt of the compound of formula X.

14. A process for the preparation of the compound of formula X of claim 11, 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 and the reducing reagent is sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, or hydrogen in the presence of a hydrogenation catalyst.

17. The process according to claim 14, wherein the treatment takes place in a mixture of methanol and dichloromethane or wherein the process further includes a purification step.

16. (canceled)

18. (canceled)

21-31. -31. (canceled)

33. (canceled)

37. (canceled)