ENDOTHELIN RECEPTOR ANTAGONIST DERIVATIVES 22.10.2009

ENDOTHELIN RECEPTOR ANTAGONIST DERIVATIVES

Publication Number: US20090263472
Application Number: US12300026
Filing date: 05/23/2007
PCT 371 date: 11/07/2008
Publication date: 10/22/2009
Predicted expiration date: 05/23/2027
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Inventor(s): Nicoletta Almirante · Stefano Biondi · Ennio Ongini ·
Assignee(s): NICOX S.A. · View assignee updates
Correspondent: ARENT FOX LLP ·


U.S. Classifications: 424/450 · 424/45 · 514/18 · 530/331 · 514/269 · 424/463 · 424/474 · 544/296 ·
International Classifications: A61K9127 · C07D40304 · A61K31506 · A61K3806 · C07K5097 · A61K912 · A61K948 · A61K928 · A61P900 ·
PCT Application Number: WO20PCTEP0755012 - 05/23/2007
Foreign Priority: EP06114617.1 - 05/29/2006 ·
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USPTO · PAIR · esp@cenet · Patent Family


Abstract
Endothelin receptor antagonist nitroderivatives of general formula (I): having an improved pharmacological activity compared with their parent compounds. They can be employed for treating or preventing endothelial-related disorders, renal, pulmonary, cardiac and vascular diseases, and inflammatory processes.
References Cited
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Referenced By
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Patent Family
The current document is not in a family.Claims
1. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: wherein: m, m′ and m″ are equal to 0 or 1; n, n′ and n″ are equal to 0 or 1; s, s′ and s″ are equal to 0 or 1; A is selected from the group consisting of: wherein: N1 is —O—, —OH; N2 is —N—, —NH—; N3 is —C(O)O—, —C(O)NH—; B, B′ and B″ are —CO—, —C(O)O—, —C(O)NH; C, C′ and C″ are: with the proviso that: 1) when A is selected from the group consisting of: (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il) and (Im), at least one of m, m′, m″, n, n′ or n″ is 1; 2) when A is selected from the group consisting of: (In), (Io), (Ip), (Iq), (Ir), (Is) and (Iu), then s′, s″ and m are 0; while n is 0 or 1; 3) when A is (It), then m, m′ and s″ are 0; while n and n′ are 0 or 1; 4) at least one of N1 or N2 is a group —O— or —N— able to bind at least one of the groups —[(B)m—(C)n—(Y—ONO2)], —[(B′)m, —(C′)n′, —(Y′—ONO2)] or [(B″)m″—(C″)n″—(Y″—ONO2)]; Y, Y′ and Y″ are a bivalent radical having the following meaning: a) straight or branched C1-C20 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO2 or Ta, wherein Ta is —OC(O)(C1-C10 alkyl)-ONO2 or —O(C1-C10 alkyl)-ONO2; cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T, wherein T is straight or branched alkyl with from 1 to 10 carbon atoms; wherein n0 is an integer from 0 to 20, and n1 is an integer from 1 to 20; wherein: n1 is as defined above and n2 is an integer from 0 to 2; X1=—OCO— or —COO— and R2 is H or CH3; wherein: n1, n2, R2 and X1 are as defined above; Y1 is —CH2—CH2— or —CH═CH—(CH2)n2—; wherein: n1 and R2 are as defined above, R3 is H or —COCH3; with the proviso that when Y is selected from the bivalent radicals mentioned under b)-f), the —ONO2 group is linked to a —CH2 group; wherein X2 is —O— or —S—, n3 is an integer from 1 to 6, R2 is as defined above; wherein: n4 is an integer from 0 to 10; n5 is an integer from 1 to 10; R4, R5, R6, R7 are the same or different, and are H or straight or branched C1-C4 alkyl; wherein the —ONO2 group is linked to wherein n5 is as defined above; Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of:
2. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein Y, Y′ and Y″ are a bivalent radical having the following meaning: a) straight or branched C1-C10 alkylene, being optionally substituted with one —ONO2 group; wherein n0 is an integer equal to 0 or 1, and n1 is an integer equal to 1; with the proviso the —ONO2 group is linked to a —CH2 group; wherein X2 is —O— or —S—, n3 is an integer equal to 1 and R2 is H.
3. A compound according to claim 1, selected from the group consisting of:
4. A compound of general formula (I) according to claim 1 for use as a medicament.
5. Use of a compound according to claim 1, for preparing a drug that can be employed in the treatment or prophylaxis of endothelial-related disorders, renal, pulmonary, cardiac and vascular diseases, and inflammatory processes.
6. Use of a compound according to claim 5, for preparing a drug that can be employed in the treatment or prophylaxis of congestive heart failure, coronary diseases, left ventricular dysfunction and hypertrophy, cardiac fibrosis, myocardial ischemia, stroke, subarachnoid hemorrhage, cerebrovascular vasospasm, coronary vasospasm, atherosclerosis, restenosis post angioplasty, renal ischemia, renal failure, renal and pulmonary fibrosis, glomerulonephritis, renal colic, ocular hypertension, glaucoma, systemic hypertension, pulmonary arterial hypertension (PAH), diabetic complications such as nephropathy, vasculopathy and neuropathy, peripheral vascular diseases, liver fibrosis, portal hypertension, metabolic syndromes, erectile dysfunction, complications after vascular or cardiac surgery, complications of treatment with immunosuppressive agents after organ transplantation, hyperaldosteronism, lung fibrosis, scleroderma, sickle cell disease, benign prostatic hyperplasia, cancer, anxiety, cognitive disorders.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of general formula (I) or a salt or stereoisomer thereof according to claim 1.
8. A pharmaceutical composition according to claim 7 in a suitable form for the oral, parenteral, rectal, topic and transdermic administration, by inhalation spray or aerosol or iontophoresis devices.
9. Liquid or solid pharmaceutical composition for oral, parenteral, rectal, topic and transdermic administration or inhalation in the form of tablets, capsules and pills eventually with enteric coating, powders, granules, gels, emulsions, solutions, suspensions, syrups, elixir, injectable forms, suppositories, in transdermal patches or liposomes, containing a compound of formula (I) or a salt or stereoisomer thereof according to claim 1 and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising a compound of general formula (I) according to claim 1, at least a compound used to treat cardiovascular disease and a pharmaceutically acceptable carrier.
11. Pharmaceutical composition according to claim 10 wherein the compound used to treat cardiovascular disease is selected from the group consisting of: aldosterone antagonists, angiotensin II receptor blockers, ACE inhibitors, HMGCoA reductase inhibitors, beta-adrenergic blockers, alpha-adrenergic antagonists, sympatholytics, calcium channel blockers, renin inhibitors, neutral endopeptidase inhibitors, potassium activators, diuretics, vasodilators, antithrombotics such as aspirin or nitrosated compounds thereof.
12. A pharmaceutical kit comprising a compound of general formula (I) as defined in claim 1, a compound used to treat cardiovascular disease as combined preparation for simultaneous, separated or sequential use for the treatment of cardiovascular disease.
13. A pharmaceutical kit according to claim 12 wherein the compound used to treat cardiovascular disease is selected from the group consisting of: aldosterone antagonists, angiotensin II receptor blockers, ACE inhibitors, HMGCoA reductase inhibitors, beta-adrenergic blockers, alpha-adrenergic antagonists, sympatholytics, calcium channel blockers, renin inhibitors, neutral endopeptidase inhibitors, potassium activators, diuretics, vasodilators, antithrombotics such as aspirin or nitrosated compounds thereof.
Full Specification
The present invention relates to Endothelin receptor antagonist derivatives. More particularly, the present invention relates to Endothelin receptor antagonist nitroderivatives, pharmaceutical compositions containing them and their use for the treatment of endothelial-related disorders, renal, pulmonary, cardiac and vascular diseases, and inflammatory processes.

Endothelins are a family of closely related 21-amino acid peptides (ET-1, ET-2, and ET-3) with ET-1 being one of the most potent vasoconstrictors identified to date. These peptides cause numerous biological effects in addition to vasoconstriction. The endothelins have been implicated in a variety of disease states including hypertension, congestive heart failure, renal failure, pulmonary hypertension, and metastatic prostate cancer. The endothelins exert their physiological activities via two specific G-protein coupled receptors termed ETA and ETB. The ETA receptor is selective for ET-1 and is expressed predominately in vascular smooth muscle cells where it mediates vasoconstrictive and proliferative responses. The ETB receptor is nonselective and binds all three ET isopeptides with equal affinity. The ETB receptors are mostly found on endothelial cells and mediate ET-1-induced vasodilation possibly through the release of nitric oxide. A small population of ETB receptors is also found on some smooth muscle cells where their activation leads to vasoconstriction (J. Med. Chem. 2000, 43, 3111).

With the Endothelin receptor antagonist derivatives a class of compounds is intended, comprising as main components Ambrisentan, Atrasentan, Avosentan, Bosentan, Clazosentan, Darusentan, Tezosentan, Sitaxsentan etc.

U.S. Pat. No. 6,635,273 discloses methods for treating vascular diseases characterized by nitric oxide insufficiency by administering to a patient a therapeutically effective amount of at least one antioxidant, or a pharmaceutically acceptable salt thereof, and at least one of isosorbide dinitrate and isosorbide mononitrate, and, optionally, at least one nitrosated angiotensin-converting enzyme inhibitor, nitrosated beta-adrenergic blocker, nitrosated calcium channel blocker, nitrosated endothelin antagonist, nitrosated angiotensin II receptor antagonist, nitrosated renin inhibitor, and/or at least one compound used to treat cardiovascular diseases.

WO 2005/023182 describes novel nitrosated and/or nitrosylated cardiovascular compounds or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated and/or nitrosylated cardiovascular compound, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The nitrosated and/or nitrosylated cardiovascular compounds are selected from: aldosterone antagonists, angiotensin II antagonists, calcium channel blockers, nitrosated and/or nitrosylated endothelin antagonists, hydralazine compounds, neutral endopeptidase inhibitors and renin inhibitors.

CA 2391818 discloses methods for treating physiological conditions in which NO production is at least partially inhibited, such as erectile dysfunction, by administering to a patient an effective amount of endothelin antagonists.

It was now object of the present invention to provide new derivatives of Endothelin receptor antagonists having an improved pharmacological activity compared with their parent compounds.

In particular, it has been recognized that the Endothelin receptor antagonist nitroderivatives of the present invention can be employed for treating or preventing congestive heart failure, coronary diseases, left ventricular dysfunction and hypertrophy, cardiac fibrosis, myocardial ischemia, stroke, subarachnoid hemorrhage, cerebrovascular vasospasm, coronary vasospasm, atherosclerosis, restenosis post angioplasty, renal ischemia, renal failure, renal and pulmonary fibrosis, glomerulonephritis, renal colic, ocular hypertension, glaucoma, systemic hypertension, pulmonary arterial hypertension (PAH), diabetic complications such as nephropathy, vasculopathy and neuropathy, peripheral vascular diseases, liver fibrosis, portal hypertension, metabolic syndromes, erectile dysfunction, complications after vascular or cardiac surgery, complications of treatment with immunosuppressive agents after organ transplantation, hyperaldosteronism, lung fibrosis, scleroderma, sickle cell disease, benign prostatic hyperplasia, cancer, anxiety, cognitive disorders.

Object of the present invention are, therefore, Endothelin receptor antagonist nitroderivatives of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof:

MERCI SIMIS
Tu nous les sort en rafale cette fois

Pour une boite ,qui pour certain dépose bientôt le bilan
je trouve qu'elle bosse fort et qu'elle phosphore

A quand le remède universel ?