US2006094715A1PendingUtilityA1

5-Ht4 receptor antagonists for the treatment of heart failure

47
Individually held — no corporate assignee on recordPriority: May 16, 2002Filed: May 16, 2003Published: May 4, 2006
Est. expiryMay 16, 2022(expired)· nominal 20-yr term from priority
Inventors:Finn Olav Levy
A61K 31/5365A61P 9/04A61K 31/454C07D 405/12A61K 2300/00A61K 31/445C07D 405/02A61P 9/00
47
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Claims

Abstract

This invention provides the use of a 5-HT 4 receptor antagonist in the manufacture of a medicament for treating or preventing heart failure. Particular heart disorders to be treated are selected from the group comprising chronic heart failure, congestive heart failure, chronic congestive heart failure and heart failure resulting from ischaemic heart disease. Methods of treating heart failure using 5-HT 4 receptor antagonists and pharmaceutical compositions containing 5-HT 4 receptor antagonists are also provided.

Claims

exact text as granted — not AI-modified
1 . A method for treating or preventing heart failure in a mammal comprising administering to said mammal a pharmaceutically effective amount of a 5-HT 4  receptor antagonist.  
     
     
         2 . The method of  claim 1  wherein the treatment or prevention of atrial arrhythmia is excluded.  
     
     
         3 . The method of  claim 1  wherein said heart failure is characterised by impaired cardiac function due to systolic or diastolic dysfunction.  
     
     
         4 . The method of  claim 1  wherein said heart failure is chronic heart failure.  
     
     
         5 . The method of  claim 1  wherein said heart failure is congestive heart failure.  
     
     
         6 . The method of  claim 5  wherein said congestive heart failure is chronic congestive heart failure.  
     
     
         7 . The method of  claim 1  wherein said heart failure results from ischaemic heart disease, or chronic non-ischaemic cardiomyopathy (IDCM), or cardiomyopathy due to hypertension.  
     
     
         8 . The method of  claim 1  wherein said heart failure is post-infarction heart failure.  
     
     
         9 . The method of  claim 1  wherein said 5-HT 4  receptor antagonist inhibits the inotropic response of the heart to 5-HT.  
     
     
         10 . The method of  claim 1  wherein said 5-HT 4  receptor antagonist is selected from compounds comprising an aromatic ring structure with a hydrogen-bond acceptor as one substituent and a hydrogen-bond acceptor as a second substituent and a tertiary amine spaced with at least three bonds away from the aromatic ring.  
     
     
         11 . The method of  claim 1  wherein said 5-HT 4  receptor antagonist comprises an aromatic ring to which a carbonyl group is attached, and a basic nitrogen in an appended side chain and an oxygen atom adjacent to the carbonyl group.  
     
     
         12 . The method of  claim 1 , wherein said 5-HT 4  receptor antagonist is selected from the group consisting of benzoate esters, benzoate amides, imidazolopyridines, aryl ketones, indoles, carbazimidamides, phenylcarbamates and phenylureas.  
     
     
         13 . The method of  claim 1  wherein said 5-HT 4  receptor antagonist is selected from the group consisting of 1-piperidinyl-ethyl-1H-indole-3-carboxylate, SB203186; (1 butyl 4 piperidinyl)methyl 8 amino 7 iodo-1,4 benzodioxan 5 carboxylate, SB207710; [1 [2 methylsulphonylamino ethyl] 4-piperidinyl]-methyl]methyl 1H indole 3 carboxylate, GR113808; 2 diethylaminoethyl (2 methoxy 4 amino 5 chloro)benzoate, SDZ205557; endo 8 methyl 8 azabicyclo[3.2.1]oct 3 yl 2,3 dihydro 6 methoxy 2 oxo 1H benzimidazole 1 carboxylate, DAU 6285; 1 [4 amino 5 chloro 2 (3,5 dimethoxybenzyl-oxy)phenyl] 3[1 [2 [(methylsulfonyl)amino]ethyl] 4 piperidinyl] 1 propanone hydrochloride, RS 39604; (1 n butyl 4 piperidinyl)methyl 8 amino 7 chloro 1,4 benzodioxane 5 carboxylate, SB 204070; N [(1 butyl 4 piperidinyl)-methyl] 3,4dihydro 2H [1,3]oxazino[3,2 a]indole10-carboxamide hydrochloride, SB 207266; (endo 3,9 dimethyl 3,9 diazabicyclo[3,3,1]non 7 yl 1H indazole 3 carboxamide dihydrochloride), N 3389; [(+) 8,9 dihydro 10 methyl 7 [(5 methyl 4 imidazolyl)methyl]pyrido [1,2 a] indole 6(7H) one hydrochloride], FK1052; 2 (cis 3,5 dimethyl-piperidino)ethyl 4 amino 5 chloro 2 methoxybenzoate, ML10375; [3 (piperidine 1 yl)propyl 4 amino 5 chloro 2 methoxybenzoate hydrochloride], RS 23597 190; (1-[2-[(methyl-sulphonyl)amino]-ethyl]-4-piperidinyl-methyl-5-fluoro-2-methoxy-1H-indole-3-carboxylate), GR125487; R50595 (FR76530); RS100302; 1-(1-methylethyl)-N-[2-[4-[tricyclo[3.3.1.1 (3,7)]dec-1-ylcarbonyl)amino]-1-piperidinyl]ethyl-1H-indazole-3-carboxamide, LY353433; A-85380; SB205800; SB 207058; SB 207226; SC-53606 and SC 56184.  
     
     
         14 . The method of  claim 1  wherein said 5-HT 4  receptor antagonist is an antibody or fragment or derivative thereof.  
     
     
         15 . The method of  claim 1  wherein said 5-HT 4  receptor antagonist is formulated as a physiologically acceptable salt.  
     
     
         16 . The method of  claim 1  wherein said 5-HT 4  receptor antagonist is formulated for oral administration or parenteral administration.  
     
     
         17 . The method of  claim 1  wherein the 5-HT 4  receptor antagonist blocks a response to 5-HT.  
     
     
         18 . (canceled)  
     
     
         19 . The method of  claim 1 , wherein said mammal does not have atrial arrhythmia.  
     
     
         20 . The method of  claim 1  wherein cardiac performance is improved.  
     
     
         21 . The method of  claim 20  wherein ventricular ejection fraction is increased.  
     
     
         22 . The method of  claim 21  wherein left ventricular ejection fraction is increased.  
     
     
         23 . The method of  claim 20  wherein the improvement in cardiac performance is one or more of the following: New York Heart Association (NYHA) functional class is reduced, exercise capacity is improved, pulmonary capillary wedge pressure is decreased, peak heart rate is increased, peak systolic blood pressure is increased and neutral velocity deceleration time is increased.  
     
     
         24 . The method of  claim 1  wherein the plasma level of Nt-proANP is reduced.  
     
     
         25 . A pharmaceutical composition comprising a 5-HT 4  receptor antagonist and a pharmaceutically acceptable carrier diluent or excipient, wherein said 5-HT 4  receptor antagonist is present in said composition in an amount sufficient for the treatment or prevention of heart failure.  
     
     
         26 . The pharmaceutical composition of  claim 25  further comprising a second agent effective for the treatment of heart failure.  
     
     
         27 . A composition comprising 
 (a) a 5-HT 4  receptor antagonist, and    (b) a second agent effective for the treatment of heart failure as a combined preparation for simultaneous, separate or sequential use in the treatment of heart failure or in improving cardiac function.    
     
     
         28 . The pharmaceutical composition of claims  26  or  27  wherein said second agent is selected from the group consisting of diuretics, vasodilators, inotropic drugs, anticoagulants, β blockers, angiotension II blockers and angiotension converting enzyme inhibitors.  
     
     
         29 . The pharmaceutical composition of  claim 28  wherein said second agent is a β blocker.  
     
     
         30 . The method of  claim 7 , wherein said ischaemic heart failure is a chronic ischaemic heart failure.  
     
     
         31 . The method of  claim 7 , wherein said chronic non-ischaemic cardiomyopathy is idiopathic dilated cardiomyopathy.  
     
     
         32 . The pharmaceutical composition of  claim 25 , wherein said 5-HT 4  receptor antagonist is selected from compounds comprising an aromatic ring structure with a hydrogen-bond acceptor as one substituent and a hydrogen-bond acceptor as a second substituent and a tertiary amine spaced with at least three bonds away from the aromatic ring.  
     
     
         33 . The pharmaceutical composition of  claim 25 , wherein said 5-HT 4  receptor antagonist comprises an aromatic ring to which a carbonyl group is attached, and a basic nitrogen in an appended side chain and an oxygen atom adjacent to the carbonyl group.  
     
     
         34 . The pharmaceutical composition of  claim 25 , wherein said 5-HT 4  receptor antagonist is selected from the group consisting of benzoate esters, benzoate amides, imidazolopyridines, aryl ketones, indoles, carbazimidamides, phenylcarbamates and phenylureas.  
     
     
         35 . The pharmaceutical composition of  claim 25 , wherein said 5HT 4  receptor antagonist is selected from the group consisting of 1-piperidinyl-ethyl-1H-indole-3-carboxylate, SB203186; (1 butyl 4 piperidinyl)methyl 8 amino 7 iodo-1,4 benzodioxan 5 carboxylate, SB207710; [1 [2 methylsulphonylamino ethyl] 4-piperidinyl]-methyl]methyl 1H indole 3 carboxylate, GR113808; 2 diethylaminoethyl (2 methoxy 4 amino 5 chloro)benzoate, SDZ205557; endo 8 methyl 8 azabicyclo[3.2.1]oct 3 yl 2,3 dihydro 6 methoxy 2 oxo 1H benzimidazole 1 carboxylate, DAU 6285; 1 [4 amino 5 chloro 2 (3,5 dimethoxybenzyloxy)phenyl] 3[1 [2 [(methylsulfonyl)amino]ethyl] 4 piperidinyl] 1 propanone hydrochloride, RS 39604; (1 n butyl 4 piperidinyl)methyl 8 amino 7 chloro 1,4 benzodioxane 5 carboxylate, SB 204070; N [(1 butyl 4 piperidinyl)-methyl] 3,4dihydro 2H [1,3]oxazino[3,2 a]indole10-carboxamide hydrochloride, SB 207266; (endo 3,9 dimethyl 3,9 diazabicyclo[3,3,1]non 7 yl 1H indazole 3 carboxamide dihydrochloride), N 3389; [(+) 8,9 dihydro 10 methyl 7 [(5 methyl 4 imidazolyl)methyl]pyrido [1,2 a] indole 6(7H) one hydrochloride], FK1052; 2 (cis 3,5 dimethylpiperidino)ethyl 4 amino 5 chloro 2 methoxybenzoate, ML10375; [3 (piperidine 1 yl)propyl 4 amino 5 chloro 2 methoxybenzoate hydrochloride], RS 23597 190; (1-[2-[(methylsulphonyl)amino]-ethyl]-4-piperidinyl-methyl-5-fluoro-2-methoxy-1H-indole-3-carboxylate), GR125487; R50595 (FR76530); RS100302; 1-(1-methylethyl)-N-[2-[4-[tricyclo[3.3.1.1 (3,7)]dec-1-ylcarbonyl)amino]-1-piperidinyl]ethyl-1H-indazole-3-carboxamide, LY353433; A-85380; SB205800; SB 207058; SB 207226; SC-53606 and SC 56184.

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