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WO2006041763A1 - Inhibiteurs de renine pour le traitement de maladies induites par transplantation - Google Patents

Inhibiteurs de renine pour le traitement de maladies induites par transplantation Download PDF

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Publication number
WO2006041763A1
WO2006041763A1 PCT/US2005/035433 US2005035433W WO2006041763A1 WO 2006041763 A1 WO2006041763 A1 WO 2006041763A1 US 2005035433 W US2005035433 W US 2005035433W WO 2006041763 A1 WO2006041763 A1 WO 2006041763A1
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Prior art keywords
renin inhibitor
transplantation
formula
treatment
immunosuppressive
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PCT/US2005/035433
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English (en)
Inventor
Olivier Grenet
Margaret Forney Prescott
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Novartis Ag
Novartis Pharma Gmbh
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Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Publication of WO2006041763A1 publication Critical patent/WO2006041763A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • Renin inhibitors e.g. Aliskiren inhibit the action of the natural enzyme renin.
  • the latter passes from the kidneys into the blood where it effects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to form the octapeptide angiotensinogen II.
  • the octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone, accompanied by an increase in extracellular fluid volume. That increase can be attributed to the action of aldosterone.
  • Inhibitors of the enzymatic activity of renin bring about a reduction in the formation of angiotensin I. As a result a proportionately smaller amount of angiotensin Il is produced.
  • the reduced concentration of that active peptide hormone is the direct cause of, e.g., the hypotensive effect of renin inhibitors.
  • renin inhibitors can be used for the prevention of, delay progression or treatment of a condition or disease selected from transplantation-induced hypertension transplantationinduced nephrotoxicity, and allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis.
  • vascular effects in the kidney lead to reduced glomerular filtration and impaired sodium excretion. Many of these changes affect local regulation of vascular tone, including stimulation of endothelin and suppression of vasodilating prostaglandins. Allograft vasculopathy also develops, sometimes over a prolonged period of time, which includes endothelial dysfunction (often leading to atherosclerosis) and vascular sclerosis, which is distinct from atherosclerosis.
  • the invention relates to the use of renin inhibitors, for the preparation of a medicament, for the prevention of, delay progression or treatment of a condition or disease selected from: transplantation-induced hypertension, transplantation-induced nephrotoxicity, and allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis, preferably transplantation-induced hypertension and transplantation-induced nephrotoxicity
  • a condition or disease selected from: transplantation-induced hypertension, transplantation-induced nephrotoxicity, and allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis, preferably transplantation-induced hypertension and transplantation-induced nephrotoxicity
  • the invention relates to the use of renin inhibitors or a pharmaceutically acceptable salt thereof for the preparation of a medicament, for the prevention of, delay progression or treatment of transplantation induced hypertension.
  • the invention relates to the use of renin inhibitors or a pharmaceutically acceptable salt thereof for the preparation of a medicament, for the prevention of, delay progression or treatment of and transplantation induced nephrotoxicity.
  • the invention relates to the use of renin inhibitors or a pharmaceutically acceptable salt thereof for the preparation of a medicament, for the prevention of, delay progression or treatment of allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis.
  • the invention relates to the use of the renin inhibitor of formula (I) (aliskiren) or a pharmaceutically acceptable salt thereof, for the preparation of a medicament, for the prevention of, delay progression or treatment of a condition or disease selected from: transplantation- induced hypertension, transplantation induced nephrotoxicity, and allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis, preferably transplantation-induced hypertension and transplantation-induced nephrotoxicity.
  • a condition or disease selected from: transplantation- induced hypertension, transplantation induced nephrotoxicity, and allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis, preferably transplantation-induced hypertension and transplantation-induced nephrotoxicity.
  • the invention relates to the use of renin inhibitors or a pharmaceutically acceptable salt thereof, for the prevention of, delay progression or treatment of a condition or disease selected from: transplantation- induced hypertension, transplantation- induced nephrotoxicity, and allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis, preferably transplantation-induced hypertension and transplantation-induced nephrotoxicity.
  • a condition or disease selected from: transplantation- induced hypertension, transplantation- induced nephrotoxicity, and allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis, preferably transplantation-induced hypertension and transplantation-induced nephrotoxicity.
  • the invention also relates to a method for the prevention of, delay of progression or treatment of a condition or disease selected from: transplantation- induced hypertension, transplantation- induced nephrotoxicity, and allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis, preferably transplantation-induced hypertension and transplantation-induced nephrotoxicity, comprising administering to a warm-blooded animal an effective amount of a renin inhibitor or a pharmaceutically acceptable salt thereof.
  • a condition or disease selected from: transplantation- induced hypertension, transplantation- induced nephrotoxicity, and allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis, preferably transplantation-induced hypertension and transplantation-induced nephrotoxicity
  • a method for the prevention of, delay of progression or treatment of transplantation induced hypertension comprising administering to a warm-blooded animal an effective amount of a renin inhibitor or a pharmaceutically acceptable salt thereof.
  • a method for the prevention of, delay of progression or treatment of transplantation- induced nephrotoxicity comprising administering to a warm-blooded animal an effective amount of a renin inhibitor or a pharmaceutically acceptable salt thereof.
  • a method for the prevention of, delay of progression or treatment of allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis comprising administering to a warm-blooded animal an effective amount of a renin inhibitor or a pharmaceutically acceptable salt thereof.
  • a method for the prevention of, delay progression or treatment of transplantation induced hypertension comprising administering to a warm-blooded animal an effective amount of a renin inhibitor or a pharmaceutically acceptable salt thereof.
  • a method for the prevention of, delay progression or treatment of and transplantation induced nephrotoxicity there is provided a method for the prevention of, delay progression or treatment of and transplantation induced nephrotoxicity.
  • a method for the prevention of, delay progression or treatment of allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis is provided.
  • the invention also relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising a renin inhibitor, especially the renin inhibitor of formula (I)
  • the invention specifically relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising a renin inhibitor, especially the renin inhibitor of formula (I)
  • an immunosuppressive drugs e.g. a calcineurin inhibitor, e.g. cyclosporin A, FK 506 or ISATX247; a mTOR inhibitor, e.g. rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841 , TAFA-93, biolimus 7, biolimus 9, or everolimus, an ascomycin having immuno-suppressive properties, e.g.
  • a calcineurin inhibitor e.g. cyclosporin A, FK 506 or ISATX247
  • a mTOR inhibitor e.g. rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841 , TAFA-93, biolimus 7, biolim
  • ABT-281 e.g. ABT-281 , ASM981, etc.
  • corticosteroids cyclophosphamide
  • azathioprene methotrexate
  • a S1 P receptor agonist e.g. FTY720 or an analogue thereof
  • leflunomide e.g. FTY720 or an analogue thereof
  • mizoribine e.g. mycophenolic acid; mycophenolate mofetil; 15- deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof
  • immunosuppressive monoclonal antibodies e.g. monoclonal antibodies to leukocyte receptors, e.g.
  • CTLA4lg for ex. designated ATCC 68629
  • a renin inhibitor is a drug that pharmacologically effectively inhibits the enzyme renin resulting in prevention of, delay of progression of and treatment of conditions and diseases associated with the inhibition of renin, especially such conditions and diseases as specified hereinbefore and hereinafter.
  • Renin inhibitors comprise, e.g., peptidic and, preferably, non-peptidic renin inhibitors.
  • the class of renin inhibitors comprises compounds having differing structural features.
  • a non-peptidic renin inhibitor is, e.g., ditekiren, terlakiren, zankiren, SPP-100 or a compound of formula (I)
  • Non-peptidic renin inhibitor comprise those that are disclosed in WO 97/09311 , especially corresponding renin inhibitors as disclosed in the claims and working examples, especially SPP100 of the formula
  • renin inhibitors include those disclosed in WO 01/09083; WO 02/02508, WO 02/08172, WO 2004/002466, WO2005/037803, WO2005/061457, WO2005/070877, WO2005/070871 , WO2005/070870, especially those renin inhibitors as disclosed in the working examples and claims.
  • the corresponding subject matter of said WO applications is herein incorporated by reference into the present invention.
  • immunosuppressive drugs shall mean that in addition to the compound of formula (I) one or more, for example two, furthermore three, immunosuppressive drugs or immunomodulatory compounds as specified according to the present invention can be combined.
  • immunosuppressive drugs comprises e.g a calcineurin inhibitor, e.g. cyclosporin A, FK 506 or ISATX247; a mTOR inhibitor, e.g.
  • rapamycin 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841 , TAFA-93, biolimus 7 or biolimus 9; everolimus; an ascomycin having immuno-suppressive properties, e.g. ABT-281 , ASM981 , etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; a S1 P receptor agonist e.g.
  • FTY720 or an analogue thereof leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; immunosuppressive monoclonal antibodies, e.g. monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, CD 11a/CD18, CD7, CD25, CD 27, B7, CD40, CD45, CD58, CD 137, ICOS, CD150 (SLAM), OX40, 4-1 BB or their ligands, e.g. CD154".
  • Calcineurin inhibitors include e.g. cyclosporins and FK506.
  • Cyclosporins to which the present invention applies are any of those having pharmaceutical utility, e.g. as immunosuppressive agents, as known and described in the art, in particular Cyclosporin A (also known as Ciclosporin), Cyclosporin G, [O-(2-hydroxyethyl)- (D)Ser] 8 -Ciclosporin, and [3'-dehydroxy-3'-keto-MeBmt] 1 -[Val] 2 -Ciclosporin. Cyclosporin A is preferred.
  • Cyclosporin A may be used in the form of a microemulsion concentrate, e.g. as disclosed in US 5342625, US5741512, US5866159, US5916589, US5962014, US5962017, US6024978, US6007840, or in the form of soft gel capsules, e.g. as disclosed in EP649651 , or in the form of a hydrosol, e.g. as disclosed in US5389382, the contents thereof being incorporated herein by reference.
  • Cys A is administered (or used) in the form as commercially available under the Tradename Neoral or Sandimmun Neoral.
  • FK-506, also known as tacrolimus is a macrolide lactone produced from the fermentation broth of Streptomyces tsukubaensis and has e.g. been described in Journal of Antibiotics 1987, 40: p. 1249-1255 and in Journal of Antibiotics 1987, 40: p. 1256-1265.
  • a mTOR inhibitor is a compound which targets intracellular mTOR ("mammalian Target Of Rapamycin").
  • mTOR is a family member of phosphatidylinositol 3-kinase (PI3-kinase) related kinase.
  • PI3-kinase phosphatidylinositol 3-kinase
  • Rapamycin, rapamycin derivatives and rapamycin analogues inhibit the mTOR pathway via a complex with its intracellular receptor FKBP12 (FK506-binding protein 12).
  • Rapamycin is a known macrolide antibiotic produced by Streptomyces hygroscopicus.
  • rapamycin derivative and rapamycin analogues it is meant a substituted rapamycin having mTOR inhibiting properties, e.g. rapamycin substituted in position 40 and/or 16 and/or 32, for example a compound of formula I
  • R- I is CH 3 or C 3-6 alkynyl
  • R 2 is H, -CH 2 -CH 2 -OH, 3-hydroxy-2-(hydroxymethyl)-2-methyl-propanoyl or tetrazolyl, and
  • rapamycin derivatives of formula I are e.g. 32-deoxorapamycin, 16-pent-2- ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-rapamycin, 16-pent-2- ynyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy ⁇ 2- (hydroxymethyl)-2-methylpropanoate]-rapamycin (also called CCI779) or 40-epi-(tetrazolyl)- rapamycin (also called ABT578).
  • a preferred compound is e.g.
  • Rapamycin derivatives may also include the so-called rapalogs, e.g. as disclosed in WO 98/02441 and WO01/14387, e.g. AP23573, AP23464, AP23675 or AP23841.
  • rapamycin derivative examples are those disclosed under the name TAFA-93, biolimus-7, biolimus-9 or everolimus.
  • immunomodulatory compounds comprises e.g a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y".
  • the structure of the active agents identified hereinbefore or hereinafter by generic or tradenames may be taken from the actual edition of the standard compendium "The Merck Index” or from databases, e.g., Patent Focus, e.g. IMS Life Cycle - IMS World Publications. The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
  • the invention is dealing with a combination according to the invention wherein the renin inhibitor and the immunosuppresor agent is a calcineurin inhibitor.
  • the invention is dealing with a combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is a calcineurin inhibitor.
  • the invention is dealing with a combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is a calcineurin inhibitor selectred from the group of e.g. cyclosporin A, FK 506 and ISATX247.
  • the invention is dealing with a combination according to the invention wherein the renin inhibitor and the immunosuppresor agent is a mTOR inhibitor.
  • the invention is dealing with a combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is a mTOR inhibitor.
  • the invention is dealing with a combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is a mTOR inhibitor selected from the group of e.g. rapamycin, 40-O-(2-hydroxyethyl)- rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841 , TAFA-93, biolimus 7, biolimus 9 or everolimus.
  • the immunosuppresor agent is a mTOR inhibitor selected from the group of e.g. rapamycin, 40-O-(2-hydroxyethyl)- rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841 , TAFA-93, biolimus 7, biolimus 9 or everolimus.
  • the invention is dealing with a combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is an ascomycin having immunosuppressive properties, e.g. ABT-281 , ASM981 , etc or corticosteroids.
  • the immunosuppresor agent is an ascomycin having immunosuppressive properties, e.g. ABT-281 , ASM981 , etc or corticosteroids.
  • the invention is dealing with a combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent selected from the group of corticosteroids; cyclophosphamide; azathioprene; methotrexate; a S1 P receptor agonist e.g. FTY720 or an analogue thereof; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; immunosuppressive monoclonal antibodies, e.g. monoclonal antibodies to leukocyte receptors, e.g.
  • the immunosuppresor agent selected from the group of corticosteroids; cyclophosphamide; azathioprene; methotrexate; a S1 P receptor agonist e.g. FTY720 or an analogue thereof; leflunomide; mizoribine; mycophenolic acid;
  • the invention is dealing with a combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is selected from cyclosporin A and 40-O-(2-hydroxyethyl)-rapamycin.
  • the invention is dealing with the use of the combination according to the invention for the preparation of a medicament for the treatment of a disease or disorder which may be inhibited by a renin inhibitor, especially the renin inhibitor of formula (I) and/or for immunosuppressive therapy and management of organ transplant recipients.
  • a renin inhibitor especially the renin inhibitor of formula (I) and/or for immunosuppressive therapy and management of organ transplant recipients.
  • the invention is dealing with the use of the combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is selected from cyclosporin A and 40-O-(2-hydroxyethyl)- rapamycin.
  • the invention is dealing with the use of the combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is a calcineurin inhibitor.
  • the invention is dealing with the use of the combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is a calcineurin inhibitor selectred from the group of e.g. cyclosporin A, FK 506 and ISATX247.
  • the invention is dealing with the use of the combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is a mTOR inhibitor.
  • the invention is dealing with the use of the combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor is a mTOR inhibitor selected from the group of e.g. rapamycin, 40-O-(2- hydroxyethyO-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841 , TAFA-93, biolimus 7 or biolimus 9.
  • the renin inhibitor is the one of formula (I)
  • the immunosuppresor is a mTOR inhibitor selected from the group of e.g. rapamycin, 40-O-(2- hydroxyethyO-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841 , TAFA-93, biolimus 7 or biolimus 9.
  • the invention is dealing with the use of the combination according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is selected from cyclosporin A and 40-O-(2-hydroxyethyl)- rapamycin.
  • the invention is dealing with a method for the prevention, delay of progression or treatment of a disease or disorder which may be inhibited by a renin inhibitor, especially the renin inhibitor of formula (1) and/or for immunosuppressive therapy and management of organ transplant recipients comprising administering to a warm ⁇ blooded animal, including man, in need thereof jointly therapeutically effective amounts of (i) a renin inhibitor, especially the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof; (ii) an immunosuppressor or immunomodulator agent.
  • the invention is dealing with a method according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is selected from cyclosporin A and 40-O-(2-hydroxyethyl)-rapamycin.
  • the invention is dealing with a method according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is a calcineurin inhibitor.
  • the invention is dealing with a method according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is a calcineurin inhibitor selected from the group of e.g. cyclosporin A, FK 506 and ISATX247.
  • the immunosuppresor agent is a calcineurin inhibitor selected from the group of e.g. cyclosporin A, FK 506 and ISATX247.
  • the invention is dealing with a method according to the invention wherein the renin inhibitor- is the one of formula (1) and the immunosuppresor agent is a mTOR inhibitor.
  • the invention is dealing with a method according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor is a mTOR inhibitor selected from the group of e.g. rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, TAFA-93, biolimus 7, biolimus 9 or everolimus.
  • the renin inhibitor is the one of formula (I) and the immunosuppresor is a mTOR inhibitor selected from the group of e.g. rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, TAFA-93, biolimus 7, biolimus 9 or everolimus.
  • the invention is dealing with a method according to the invention wherein the renin inhibitor is the one of formula (I) and the immunosuppresor agent is selected from cyclosporin A and 40-O-(2-hydroxyethyl)-rapamycin.
  • the combination according to the present invention may be used, e.g., for the prevention, delay of progression or treatment of diseases and disorders that may be inhibited by the renin inhibitior of formula (I), for immunosuppressive therapy and management of organ transplant recipients.
  • the combination according to the present invention may be used, e.g., for the prevention, delay of progression or treatment of diseases and disorders selected from the group consisting of hypertension, transplantation- induced hypertension, congestive heart failure, diabetes, especially type 2 diabetes mellitus, diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, syndrome X, coronary heart disease, angina pectoris, myocardial infarction, stroke, vascular restenosis.
  • diseases and disorders selected from the group consisting of hypertension, transplantation- induced hypertension, congestive heart failure, diabetes, especially type 2 diabetes mellitus, diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, syndrome X, coronary heart disease, angina pectoris, myocardial infarction, stroke, vascular restenosis.
  • the combination according to the present invention may be used, e.g., for the prevention, delay of progression or treatment of diseases and disorders selected from the group consisting of hypertension, transplantation- induced hypertension, transplantation-induced nephropathy, allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis, congestive heart failure, diabetes, especially type 2 diabetes mellitus, mature onset diabetes of the young (MODY), diabetic retinopathy, macular degeneration, diabetic nephropathy, hypertensive or non-hypertensive nephropathy, IgA nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, cardiac syndrome X, atherosclerosis,, coronary- heart disease, angina pectoris, myocardial infarctionischemic or hemorrhagic stroke, vascular restenosis, hyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertryglyceridemia, insulin resistance,
  • said combination may be used for the treatment of hypertension, especially, transplantation- induced hypertension, isolated systolic hypertension, congestive heart failure, but also cerebrovascular events including transient ischemic attack, ischemic and hemorrhagic stroke.
  • said combination may be used for the treatment of nephrotoxicity, especially immunosuppressor- or immuno- modulator- induced nephrotoxicity , for example cyclosporine A nephrotoxicity.
  • said combination may be used for the treatment of allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis.
  • a "disease or condition which may be inhibited by the renin inhibitior of formula (I)" as defined in this application comprises, but is not limited to hypertension, transplantation- induced hypertension, transplantation-induced nephropathy, allograft vasculopathy, including endothelial dysfunction and/or vascular sclerosis, congestive heart failure, diabetes, especially type 2 diabetes mellitus, mature onset diabetes of the young (MODY), diabetic retinopathy, macular degeneration, diabetic nephropathy, hypertensive or non-hypertensive nephropathy, IgA nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, cardiac syndrome X, atherosclerosis,, coronary heart disease, angina pectoris, myocardial infarctionischemic or hemorrhagic stroke, vascular restenosis, hyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertryglyceridemia, insulin resistance, impaired
  • nephrotoxicity is the quality of being toxic or destructive to kidney cells.
  • hypertension used according to the invention comprises several features notably severe hypertension , pulmonary hypertension malignant hypertension , isolated systolic hypertension , familial dyslipidemic hypertension and renovascular hypertension
  • Hypertension is a disorder in which blood pressure remains abnormally high (a reading of 140/90 mm Hg or greater).
  • Severe hypertension is characterized by a characterized by a systolic blood pressure of >180 mm Hg and a diastolic blood pressure of ⁇ 110 mm Hg.
  • Pulmonary hypertension is a blood vessel disorder of the lung in which the pressure in the pulmonary artery rises above normal level of ⁇ 25/10 (especially primary and secondary PH), e.g., because the small vessels that supply blood to the lungs constrict or tighten up.
  • PH may be divided into five categories: pulmonary arterial hypertension (PAH), a PH occurring in the absence of a known cause is referred to as primary pulmonary hypertension, while secondary PH is caused by a condition selected, e.g., from emphysema; bronchitis; collagen vascular diseases, such as scleroderma, Crest syndrome or systemic lupus erythematosus (SLE); PH associated with disorders of the respiratory system; PH due to chronic thrombotic or embolic disease; PH due to disorders directly affecting the pulmonary blood vessels; and pulmonary venous hypertension (PVH).
  • PH pulmonary arterial hypertension
  • Malignant hypertension is usually defined as very high blood pressure with swelling of the optic nerve behind the eye, called papilledema (grade IV Keith-Wagner hypertensive retinopathy). This also includes malignant HTN of childhood. Isolated systolic hypertension is characterized by a systolic blood pressure of ⁇ 140 mm Hg and a diastolic blood pressure of ⁇ 90 mm Hg.
  • Familial dvslipidemic hypertension is characterized by mixed dyslipidemic disorders.
  • Biomarkers include oxidized LDL, HDL, glutathione and homocysteine LPa.
  • Renovascular hypertension is a condition where the narrowing of the renal artery is significant which leads to an increase of the blood pressure resulting from signals sent out by the kidneys.
  • Biomarkers include renin, PRA and prorenin.
  • Allograft Vasculopathy (allograft vascular sclerosis) is generally a diffuse process that starts in small distal vessels, ultimately involving the entire intramyocardial and epicardial arteries of the allograft. It often begins with endothelial injury and dysfunction. Late after transplantation, focal atherosclerotic plaques are found in addition to the vasculosclerosis.
  • prevention means prophylactic administration to healthy patients to prevent the outbreak of the conditions mentioned herein. Moreover, the term “prevention” means prophylactic administration to patients being in a pre-stage of the conditions, to be treated.
  • delay of progression means administration to patients being in a pre-stage of the condition to be treated in which patients a pre-form of the corresponding condition is diagnosed.
  • treatment is understood the management and care of a patient for the purpose of combating the disease, condition or disorder.
  • an “effective amount” shall mean that amount of compound that will elicit the biological or medical response of a tissue, system or animal (including man) that is being sought by a researcher or clinician.
  • warm-blooded animal or patient include, but are not limited to, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits, mice and laboratory animals.
  • the preferred mammals are humans.
  • pharmaceutically acceptable salt refers to a non-toxic salt commonly used in the pharmaceutical industry, which are prepared by methods well-known in the art.
  • the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, e.g. separately or in a fixed combination.
  • renin inhibitor especially the renin inhibitor of formula (l)immunosuppressive or immunomodulator drug, or, in each case, a pharmaceutically acceptable form thereof
  • additional benefits resulting from combined treatment can be achieved such as a surprising prolongation of efficacy, a broader variety of therapeutic treatment and surprising beneficial effects on diseases and conditions associated with hypertension , isolated systolic hypertension , transplantation induced hypertension and immunosuppressive or immunomodulator drug nephrotoxicity, especially cyclosporin A cytotoxicity .
  • An additional and preferred aspect of the present invention is the prevention, delay of progression or treatment of the condition of hypertension, transplantation induced hypertension and immunosuppressive or immunomodulator drug nephrotoxicity, especially cyclosporin A .
  • Potentiation shall mean an increase of a corresponding pharmacological activity or therapeutical effect, respectively. Potentiation of one component of the combination according to the present invention by co-administration of another component according to the present invention means that an effect is being achieved that is greater than that achieved with one component alone.
  • the term “synergistic” shall mean that the drugs, when taken together, produce a total joint effect that is greater than the sum of the effects of each drug when taken alone.
  • ISH isolated systolic hypertension
  • elevated systolic blood pressure above 140 mm Hg
  • normal diastolic blood pressure below 90 mm Hg
  • Elevated systolic blood pressure is an independent risk factor for cardiovascular diseases and may lead e.g. to myocardial hypertrophy and heart failure.
  • ISH is furthermore characterized by an increased pulse pressure, defined as the difference between systolic and diastolic blood pressures. Elevated pulse pressure is being recognized as the type of hypertension the least likely to be well controlled. A reduction of elevated systolic blood perssure and correspondingly of pulse pressure is associated with a significant risk reduction in cardiovascular death.
  • an immunosuppressive or immunomodulator drug to that of a renin inhibitor , especially the renin inhibitor of formula (I) would potentiate the effect on systolic blood pressure and further improve vascular stiffness/compliance.
  • the proven antihypertensive effects of a renin inhibitor, especially the renin inhibitor of formula (I) on systolic and diastolic blood pressure may be potentiated by the addition of an immunosuppressive or immunomodulator drug.
  • the benefit of these combinations may also extend to an additional or potentiated effect on endothelial function, and improve vascular function and structure in various organs/tissues including the kidney, heart, eye and brain.
  • lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects.
  • This is in accordance with the desires and require ⁇ ments of the patients to be treated.
  • the combination according to the present invention provides benefit especially in the treatment of modest hypertension , isolated systolic hypertension , transplantation induced hypertension and immunosuppressive or immunomodulator drug nephrotoxicity, especially cyclosporin A cytotoxicity .
  • the present invention relates to the use of a combination comprising as active ingredients (i) a renin inhibitor, especially the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof;
  • an immunosuppressive or immunomodulator drug for the manufacture of a medicament for the prevention, delay of progression or treatment of a disease and disorder which may be inhibited by a renin inhibitor, especially the renin inhibitor of formula (I) and by an immonusuppressive or immunomodulator drug , for example, for the prevention, delay of progression or treatment of hypertension, transplantation induced hypertension, modest hypertension , isolated systolic hypertension, congestive heart failure, diabetes, especially type 2 diabetes mellitus, diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, renal failure, especially chronic renal failure, diabetic neuropathy, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, myocardial infarction, stroke, vascular restenosis, endothelial dysfunction and the like and immunosuppressive drug or immonumodulatory drug toxicity, especially cyclosporine A nephrotoxicity.
  • a renin inhibitor especially the ren
  • the present invention also relates to a method for the prevention, delay of progression or treatment of a disease and disorder which may be inhibited by a renin inhibitor, especially the renin inhibitor of formula (I) and/or by an immonusuppressive or immunomodulator drug comprising administering to a warm-blooded animal, including man, in need thereof jointly therapeutically effective amounts of
  • renin inhibitor especially the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof;
  • an immunosuppressive drug selected from calcineurin inhibitor, e.g. cyclosporin A, FK
  • a mTOR inhibitor e.g. rapamycin, 40-O-(2-hydroxyethyl)-rapamycin,
  • FTY720 or an analogue thereof leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; immunosuppressive monoclonal antibodies, e.g. monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, CD 11a/CD18, CD7, CD25, CD 27, B7, CD40, CD45, CD58, CD 137, ICOS, CD150 (SLAM), OX40 and 4-1BB or their ligands, e.g.
  • CD154 or an immunomodulatory drug selected from: e.g a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y".
  • a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y.
  • composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.
  • the pharmaceutical composition according to-the present-invention comprises a "kit of parts" in the sense that the components can be dosed independently or by use of different fixed combinations with distinguished amounts of the components at different time points.
  • the parts of the "kit of parts” can then e.g. be administered simultaneously or chrono ⁇ logically staggered, that is at different time points and with equal or different time intervals for any part of the "kit of parts".
  • the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components.
  • there is at least one beneficial effect e.g.
  • a mutual enhancing of the effect of (i) a renin inhibitor, especially the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof; (ii) immunosuppressive or immunomodulator drug; in particular a potentiation or a synergism, e.g. a more than additive effect, additional advantageous effects, less side effects, a combined therapeutical effect in a non-effective dosage of one or each of the components, especially a potentiation or a strong synergism.
  • a potentiation or a synergism e.g. a more than additive effect, additional advantageous effects, less side effects, a combined therapeutical effect in a non-effective dosage of one or each of the components, especially a potentiation or a strong synergism.
  • the invention furthermore relates to a commercial package comprising the combination according to the present invention together with instructions for simultaneous, separate or sequential use.
  • the compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
  • the compounds having an acid group for example COOH can also form salts with bases.
  • the corresponding active ingredients or a pharmaceutically acceptable salts thereof may also be used in form of a solvate, such as a hydrate or including other solvents, used for crystallization.
  • the combination according to the present invention may be used for the treatment of congestive heart failure, for example, the methods as disclosed by Smith HJ, Nuttall A: Experimental models of heart failure. Cardiovasc Res 1985, 19, 181-186 may be applied.
  • Molecular approaches such as transgenic methods are also described, for example by Lucas et al.: Hypertension-induced end-organ damage. "A new transgemic approach for an old problem.” Hypertension 1999, 33, 212-218.
  • Dosaging may depend on various factors, such as mode of application, species, age and/or individual condition.
  • the doses to be administered daily are between 10 mg to 1 g.
  • the present data indicate a statistically significant increase in the level of renin mRNA after high dose (20mg) of Neoral treatment for 2 weeks. These results show that the inhibition of renin could have a beneficial effect on the kidney during immunosuppressive treatment.
  • the renin mRNA localization is restricted to the juxta-glomerular apparatus (JG) (figure 2).
  • the juxtaglomerular apparatus is a collective term referring to the cells near a structure called the glomerulus in the kidney.
  • the juxtaglomerular cells are specialized cells that stimulate the secretion of the adrenal hormone aldosterone and play a major role in renal autoregulation, the kidney's self-governance. Renin is released into the blood from the JG cells. Recent evidence shows that the JG cells have all the necessary enzyme pathways to produce angiotensin themselves using this renin-angiotensin l-angiotensin Il cascade.
  • the juxtaglomerular apparatus can release active angiotensin Il into the local area, and regulate glomerular blood flow by inducing localized vasoconstriction possibly involved in renal toxicity.
  • Renin over expression due to renal toxicity induced by Neoral may also result in endothelial injury and dysfunction that leads to allograft vasculopathy as a significant improvement of endothelial function as assessed by brachial artery ultrasound is induced by administration of a renin inhibitor, especially the renin inhibitor of formula (I) or a pharmaceutically accepted salt thereof, either as monotherapy or in combination with an immunosuppressor agent, preferably a calcineurin inhibitor or an mTOR inhibitor.
  • a renin inhibitor especially the renin inhibitor of formula (I) or a pharmaceutically accepted salt thereof, either as monotherapy or in combination with an immunosuppressor agent, preferably a calcineurin inhibitor or an mTOR inhibitor.
  • compositions are for enteral, such as oral, and also rectal or parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances.
  • the pharmaceutical preparations consist of from about 0.1-90%, preferably of from about 1 % to about 80%, of the active compound.
  • Pharmaceutical preparations for enteral or parenteral, and also for ocular, administration are, e.g., in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner that is known perse, e.g., using conventional mixing, granulation, coating, solubulizing or lyophilizing processes.
  • compositions for oral use can be obtained by combining the active compound with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.
  • the dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
  • Preferred dosages for the active ingredients of the pharmaceutical combination according to Jthe present invention are therapeutically effective dosages, especially those which are commercially-available.
  • an approximate daily dose of from about 1 mg to about 360 mg is to be estimated, e.g., for a patient of approximately 75 kg in weight.
  • the dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
  • the pharmaceutical preparation will be supplied in the form of suitable dosage unit form, e.g., a capsule or tablet, and comprising an amount, being together with the further component(s) jointly effective.
  • a renin inhibitor, especially the renin inhibitor of formula (I) will be supplied in the form of suitable dosage unit form, for example, a capsule or tablet, and comprising a therapeutically effective amount, e.g. from about 10 to about 500 mg, of the renin inhibitor of formula (I) which may be applied to patients.
  • Corresponding doses may be taken, for example, in the morning, at mid-day or in the evening. Preferred is q.d. administration.
  • the doses of renin inhibitor of formula (I) to be administered to warm-blooded animals, e.g., human beings, of, e.g., approximately 70 kg body weight, especially the doses effective in the inhibition of the enzyme renin, e.g., in lowering blood pressure and/or in improving the symptoms of glaucoma, are from approximately 3 mg to approximately 3 g, preferably from approximately 10 mg to approximately 1 g, e.g., approximately from 20-600 , e.g. 20 -200, mg/person/day, divided preferably into 1-4 single doses which may, e.g., be of the same size. Usually, children receive about half of the adult dose.
  • the dose necessary for each individual can be monitored, e.g., by measuring the serum concentration of the active ingredient, and adjusted to an optimum level.
  • Single doses comprise, e.g., 75 mg, 150 mg, 300 or 600 mg per adult patient.
  • hemi-fumarate of the compound of formula (I) 1000 g corn starch 680 g colloidal silicic acid 200 g magnesium stearate 20 g stearic acid 50 g sodium carboxymethyl starch 250 g water quantum satis A mixture of one of the compounds of formula I mentioned in the preceding Examples as active ingredient, 50 g of corn starch and the colloidal silicic acid is processed into a moist mass with starch paste prepared from 250 g of corn starch and 2.2 kg of demineralised water. The mass is forced through a sieve having a mesh size of 3 mm and dried at 45° for 30 minutes in a fluidised bed drier.
  • the dried granules are pressed through a sieve having a mesh size of 1 mm, mixed with a previously sieved mixture (1 mm sieve) of 330 g of com starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch, and compressed to form slightly biconvex tablets.

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Abstract

L'invention concerne l'utilisation d'inhibiteurs de rénine pour l'élaboration de médicament, la prévention, le freinage de la progression ou le traitement d'état ou de maladie pouvant être : hypertension induite par transplantation, néphrotoxicité induite par transplantation, et vasculopathie d'allogreffe, y compris le dysfonctionnement endothélial et/ou la sclérose vasculaire.
PCT/US2005/035433 2004-10-04 2005-10-03 Inhibiteurs de renine pour le traitement de maladies induites par transplantation WO2006041763A1 (fr)

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US10933124B2 (en) 2015-07-16 2021-03-02 Yeda Research And Development Co. Ltd. Methods of transplantation and disease treatment
US11324777B2 (en) 2011-09-08 2022-05-10 Yeda Research And Development Co. Ltd. Anti third party central memory T cells, methods of producing same and use of same in transplantation and disease treatment
US11555178B2 (en) 2017-01-18 2023-01-17 Yeda Research And Development Co. Ltd. Genetically modified veto cells and use of same in immunotherapy

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EP3391878A1 (fr) * 2006-06-23 2018-10-24 Noden Pharma DAC Formulations galéniques de composants organiques
WO2007147596A1 (fr) * 2006-06-23 2007-12-27 Novartis Ag Formes galéniques associant aliskirène et hydrochlorothiazide
EP2311439A1 (fr) * 2006-06-23 2011-04-20 Novartis AG Formulation galénique contenant de l'aliskiren et l'hydrochlorothiazide
KR101442272B1 (ko) * 2006-06-23 2014-09-22 노파르티스 아게 알리스키렌 및 히드로클로로티아지드의 갈레닉 제제
JP2009541239A (ja) * 2006-06-23 2009-11-26 ノバルティス アクチエンゲゼルシャフト アリスキレンおよびヒドロクロロチアジドのガレヌス製剤
US8618172B2 (en) 2006-06-23 2013-12-31 Novartis Ag Galenical formulations of organic compounds
US9421228B2 (en) 2008-10-30 2016-08-23 Yeda Research And Development Co. Ltd. Use of anti third party central memory T cells for anti-leukemia/lymphoma treatment
US10196450B2 (en) 2010-08-23 2019-02-05 Board Of Regents, The University Of Texas System Anti-OX40 antibodies and methods of using the same
US9006399B2 (en) 2010-08-23 2015-04-14 Board Of Regents, The University Of Texas System Anti-OX40 antibodies and methods of using the same
US10851173B2 (en) 2010-08-23 2020-12-01 Board Of Regents, The University Of Texas System Anti-OX40 antibodies and methods of using the same
US9695246B2 (en) 2010-08-23 2017-07-04 Board Of Regents, The University Of Texas System Anti-OX40 antibodies and methods of using the same
US9163085B2 (en) 2010-08-23 2015-10-20 Board Of Regents, The University Of Texas System Anti-OX40 antibodies and methods of treating cancer
US9527917B2 (en) 2010-08-23 2016-12-27 Board Of Regents, The University Of Texas System Nucleic acid encoding anti-OX40 antibodies
CN103270050A (zh) * 2010-09-08 2013-08-28 耶达研究及发展有限公司 用于稳定和长期移植的免疫抑制药物组合
WO2012032525A3 (fr) * 2010-09-08 2012-08-09 Yeda Research And Development Co. Ltd. Combinaison de médicaments immunosuppresseurs pour une prise de greffe à long terme et stable
US12133866B2 (en) 2011-09-08 2024-11-05 Yeda Research And Development Co. Ltd. Anti third party central memory t cells, methods of producing same and use of same in transplantation and disease treatment
US11324777B2 (en) 2011-09-08 2022-05-10 Yeda Research And Development Co. Ltd. Anti third party central memory T cells, methods of producing same and use of same in transplantation and disease treatment
US10933124B2 (en) 2015-07-16 2021-03-02 Yeda Research And Development Co. Ltd. Methods of transplantation and disease treatment
US11179448B2 (en) 2015-07-16 2021-11-23 Yeda Research And Development Co. Ltd. Genetically modified anti-third party central memory T cells and use of same in immunotherapy
US11844827B2 (en) 2015-07-16 2023-12-19 Yeda Research And Development Co. Ltd. Genetically modified anti-third party central memory T cells and use of same in immunotherapy
US10751368B2 (en) 2017-01-18 2020-08-25 Yeda Research And Development Co. Ltd. Methods of transplantation and disease treatment
US11555178B2 (en) 2017-01-18 2023-01-17 Yeda Research And Development Co. Ltd. Genetically modified veto cells and use of same in immunotherapy
CN112367992A (zh) * 2018-03-29 2021-02-12 布鲁诺·瑞卡特 原位和异位异种心脏、肾脏、肺或肝脏移植后延长存活的组合物
WO2019185936A3 (fr) * 2018-03-29 2019-12-05 Bruno Reichart Procédés et compositions pour prolonger la survie après des xénogreffes orthotopiques et hétérotopiques de cœur, de rein, de poumon ou de foie

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