US2022362251A1PendingUtilityA1
Treatment of tachycardia
Est. expiryNov 23, 2037(~11.3 yrs left)· nominal 20-yr term from priority
A61K 31/4985A61K 31/135A61K 31/44A61K 31/5517A61K 31/5513A61K 31/522A61K 31/52A61K 31/53A61K 31/5025A61P 9/06
47
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Claims
Abstract
The invention provides compounds which are selective PDE2 inhibitors for use in the treatment of tachycardia or tachyarrhythmia. Such compounds are particularly suitable for use in the treatment of any of the following conditions: atrial tachycardia, atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, premature ventricular contractions (PVCs), ventricular fibrillation and ventricular tachycardia, and may be used alone or in combination therapy with other conventional cardiovascular drugs, e.g. beta-blockers. In particular, the invention provides compounds which are selective PDE2 inhibitors for use in the treatment of ventricular tachycardia in patients who are suffering from, or who are at risk of suffering from heart failure, CPVT or long QT syndrome.
Claims
exact text as granted — not AI-modified1 . A compound which is a selective PDE2 inhibitor for use in the treatment or prevention of ventricular tachycardia in a subject.
2 . A compound for use as claimed in claim 1 , wherein said compound has a selectivity for inhibiting the activity of PDE2 (e.g. human PDE2) which is at least 10-fold compared to at least one other PDE type (e.g. at least one other human PDE type).
3 . A compound for use as claimed in claim 2 , wherein said compound has a selectivity for inhibiting the activity of PDE2 (e.g. human PDE2) which is at least 10-fold compared to all other PDE types (e.g. compared to all other human PDE types).
4 . A compound for use as claimed in claim 2 or claim 3 , wherein said selectivity is at least 20-fold, preferably at least 30-fold, more preferably at least 50-fold, e.g. at least 100-fold.
5 . A compound for use as claimed in any one of the preceding claims, wherein said compound inhibits PDE2, e.g. human PDE2, with an IC 50 value of less than about 100 nM, preferably less than about 50 nM, e.g. less than about 10 nM.
6 . A compound for use as claimed in any one of the preceding claims, wherein said compound is selected from any of the following, their pharmaceutically acceptable salts or prodrugs thereof:
Compound
Name
BAY 60-7550 2-(3,4- dimethoxybenzyl)-7- [(2R,3R)-2-hydroxy- 6-phenylhexan-3-yl]- 5-methylimidazo[5,1- f][1,2,4]triazin-4(3H)- one
Lu AF64280
PF-05180999
TAK-915 N-((1S)-1-(3-fluoro-4- (trifluoromethoxy) phenyl)-2- methoxyethyl)-7- methoxy-2-oxo-2,3- dihydropyrido[2,3- b]pyrazine-4-(1H)- carboxamide
N-(1S)-2-hydroxy-2- methyl-1-(4- (trifluoromethoxy)- phenyl)propyl)-5-(1H- pyrazol-1-yl) pyrazolo[1,5- a]pyrimidine-3- carboxamide
N-(1S)-2-hydroxy-2- methyl-1-(4- (trifluoromethoxy)- phenyl)propyl)-5-(4- methyl-1H-1,2,3- triazol-1- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
N-(1S)-2-hydroxy-2- methyl-1-(4- (trifluoromethoxy)- phenyl)propyl)-5-(3- methyl-1H-1,2,4- triazol-1- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
ND-7001 3-(8-methoxy-1- methyl-2-oxo-7- phenyl-2,3-dihydro- 1H-benzo[e]- [1,4]diazepin-5- yl)benzamide
PDM-631 ((S)-3-cyclopropyl-6- methyl-1-(1-(4- (trifluoromethoxy) phenyl)propan-2-yl)- 1,5-dihydro-4H- pyrazolo[3,4-d] pyrimidin-4-one
DNS-8254 (5S)-1-[(3-bromo-4- fluorophenyl) carbonyl]-3,3- difluoro-5-{5-methyl- [1,2,4]triazolo[1,5- a]pyrimidin-7- yl}piperidine
1-[2,3-dihydro-1- benzofuran-5- yl)carbonyl]-3-{5- methyl-[1,2,4]- triazolo[1,5- a]pyrimidin-7- yl}piperidine
6-[(3-{5-methyl- [1,2,4]triazolo[1,5- a]pyrimidin-7- yl}piperidin-1- yl)carbonyl]quinolone
EHNA (erythro-9-(2- hydroxy-3- nonyl)adenine)
7 . A compound for use as claimed in claim 1 , wherein said compound is selected from TAK-915 (N-((1S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4-(1H)-carboxamide); ND-7001 (3-(8-methoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e]-[1,4]diazepin-5-yl)benzamide); PF-05180999 or Lu AF64280 as defined in claim 6 ; and their pharmaceutically acceptable salts and prodrugs thereof.
8 . A compound for use as claimed in claim 1 , wherein said compound is TAK-915 (N-((1S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4-(1H)-carboxamide), or PF-05180999 as defined in claim 6 , or a pharmaceutically acceptable salt or prodrug thereof.
9 . A compound for use as claimed in claim 1 , wherein said compound is BAY 60-7550 (2-(3,4-dimethoxybenzyl)-7-[(2R,3R)-2-hydroxy-6-phenylhexan-3-yl]-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one), ND-7001 (3-(8-methoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e]-[1,4]diazepin-5-yl)benzamide), PF-05180999 as defined in claim 6 , or Lu AF64280 as defined in claim 6 , or a pharmaceutically acceptable salt or prodrug thereof.
10 . A compound for use as claimed in any one of the preceding claims in the treatment of a subject who has previously suffered a myocardial infarction, a subject who has heart failure, or a subject predisposed to tachycardia, e.g. a subject having a genetic predisposition to catecholaminergic polymorphic ventricular tachycardia (CPVT).
11 . A compound for use as claimed in any one of claims 1 to 9 in the treatment of a subject suffering from, or at risk of suffering from, heart failure, CPVT or long QT syndrome,
12 . A compound for use as claimed in claim 10 or claim 11 , wherein said subject is selected from any of the following:
a subject previously diagnosed with, and/or treated for, a cardiac arrhythmia, e.g. a subject undergoing treatment with an anti-arrhythmic drug such as a beta-blocker;
a subject who has an implanted cardiac defibrillator (ICD); and
a subject undergoing long term treatment for a cardiac arrhythmia, e.g. a subject that has been undergoing treatment with a beta-blocker for at least 6 months.
13 . A compound for use as claimed in 12 , wherein said subject has an implanted cardiac defibrillator (ICD) and is undergoing treatment with an anti-arrhythmic drug, e.g. a beta-blocker.
14 . A compound for use as claimed in claim 13 , wherein said beta-blocker is a β 1 -selective beta-blocker, e.g. Metoprolol.
15 . A compound for use as claimed in any one of the preceding claims, wherein said subject is a mammalian subject, preferably a human.
16 . A compound for use as claimed in any one of the preceding claims in a combination therapy with one or more cardiovascular drugs, preferably a drug for the treatment of hypertension, heart failure, arrhythmia and/or post infarction myocardial reperfusion syndrome, e.g. wherein said drug is selected from any of the following: beta-blockers, calcium antagonists, ACE-inhibitors, ATII/-blockers and anti-arrhythmic drugs.
17 . A compound for use as claimed in claim 16 , wherein the beta-blocker is a β 1 -selective beta-blocker, e.g. Metoprolol.
18 . A pharmaceutical composition comprising a selective PDE2 inhibitor as defined in any one of claims 1 to 9 , together with one or more cardiovascular drugs, e.g. an anti-arrhythmic drug, and optionally in combination with at least one pharmaceutically acceptable carrier or excipient.
19 . A composition as claimed in claim 18 , wherein the anti-arrhythmic drug is a beta-blocker, preferably a β 1 -selective beta-blocker, e.g. Metoprolol.
20 . A method of treatment of ventricular tachycardia in a subject in need of such treatment (preferably a mammalian subject, e.g. a human), said method comprising the step of administering to said subject a selective PDE2 inhibitor as defined in any one of claims 1 to 9 , or a pharmaceutical composition as claimed in claim 18 or claim 19 .
21 . A method of treatment as claimed in claim 20 , wherein said subject has previously suffered a myocardial infarction, has heart failure, or is predisposed to tachycardia, e.g. wherein said subject has a genetic predisposition to catecholaminergic polymorphic ventricular tachycardia (CPVT).
22 . A method of treatment as claimed in claim 20 , wherein said subject is suffering from, or is at risk of suffering from, heart failure, CPVT or long QT syndrome.
23 . A method of treatment as claimed in any one of claims 20 to 22 , wherein said subject is selected from any of the following:
a subject previously diagnosed with, and/or treated for, a cardiac arrhythmia, e.g. a subject undergoing treatment with an anti-arrhythmic drug such as a beta-blocker;
a subject who has an implanted cardiac defibrillator (ICD); and
a subject undergoing long term treatment for a cardiac arrhythmia, e.g. a subject that has been undergoing treatment with a beta-blocker for at least 6 months.
24 . A method of treatment as claimed in 23 , wherein said subject has an implanted cardiac defibrillator (ICD) and is undergoing treatment with an anti-arrhythmic drug, preferably a beta-blocker, e.g. a β 1 -selective beta-blocker such as Metoprolol.
25 . A method of treatment as claimed in any one of claims 20 to 24 , wherein said method additionally comprises the step of administering to said subject (e.g. simultaneously, separately or sequentially) one or more cardiovascular drugs, preferably a drug for the treatment of hypertension, heart failure, arrhythmia and/or post infarction myocardial reperfusion syndrome, e.g. wherein said drug is selected from any of the following: beta-blockers, calcium antagonists, ACE-inhibitors, ATII/-blockers and anti-arrhythmic drugs.
26 . A method of treatment as claimed in claim 25 , wherein the beta-blocker is a β 1 -selective beta-blocker, e.g. Metoprolol.
27 . Use of a selective PDE2 inhibitor as defined in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 18 or claim 19 in the manufacture of a medicament for use in the treatment of ventricular tachycardia in a subject.
28 . Use as claimed in claim 27 , wherein said subject is as defined in any one of claims 21 to 24 .
29 . Use as claimed in claim 27 or claim 28 , wherein said treatment additionally comprises administration to said subject (e.g. simultaneously, separately or sequentially) of one or more cardiovascular drugs, preferably a drug for the treatment of hypertension, heart failure, arrhythmia and/or post infarction myocardial reperfusion syndrome, e.g. wherein said drug is selected from any of the following: beta-blockers, calcium antagonists, ACE-inhibitors, ATII/-blockers and anti-arrhythmic drugs.
30 . Use as claimed in claim 29 , wherein the beta-blocker is a β 1 -selective beta-blocker, e.g. Metoprolol.Join the waitlist — get patent alerts
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