[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2017191117A1 - Antagonistes du récepteur v1a destinés à une utilisation dans le traitement de maladies rénales - Google Patents

Antagonistes du récepteur v1a destinés à une utilisation dans le traitement de maladies rénales Download PDF

Info

Publication number
WO2017191117A1
WO2017191117A1 PCT/EP2017/060386 EP2017060386W WO2017191117A1 WO 2017191117 A1 WO2017191117 A1 WO 2017191117A1 EP 2017060386 W EP2017060386 W EP 2017060386W WO 2017191117 A1 WO2017191117 A1 WO 2017191117A1
Authority
WO
WIPO (PCT)
Prior art keywords
triazol
subject
copeptin
receptor antagonist
chlorophenyl
Prior art date
Application number
PCT/EP2017/060386
Other languages
English (en)
Inventor
Peter Kolkhof
Marie-Pierre Collin
Karoline DRÖBNER
Axel Kretschmer
Original Assignee
Bayer Pharma Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma Aktiengesellschaft filed Critical Bayer Pharma Aktiengesellschaft
Publication of WO2017191117A1 publication Critical patent/WO2017191117A1/fr

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the present invention relates to Via receptor antagonists for use in the treatment and/or prevention of a renal disease, in particular of acute and chronic kidney disease.
  • the invention furthermore relates to the use of arginine vasopressin (AVP) level and/or copeptin as biological markers to detect a renal disease or emerging onset of renal impairment in a patient and also to select patients for treatment options with a Via antagonist.
  • AVP arginine vasopressin
  • kidney disease AKI
  • CKD chronic kidney disease
  • CKD is defined as a gradual and permanent loss of kidney function that usually happens over months or years, potentially resulting in ESRD (end stage renal disease). Multiple ethiologies can lead to CKD and the condition is associated to several potential complications that may each require specific therapy.
  • CKD is usually characterized by reduction in GFR (glomerular filtration rate) and increase in proteinuria, which are the main criteria used to follow progression of the disease. It leads to a variety of metabolic disturbances and symptoms that can greatly affect quality of life even before reaching ESRD.
  • GFR glomerular filtration rate
  • GFR glomerular filtration rate
  • CKD has been classified into five stages, as follows:
  • CKD is clearly associated to adverse outcomes: mortality from any cause, the rate of cardiovascular events and the rate hospitalization all increase as GFR declines. The large majority of patients will die, most of them from cardiovascular complications, before reaching ES D and before RRT (renal replacement therapy: dialysis or transplantation) will become necessary. In most patients with CKD stages 1 to 3 FR declines slowly. However, the rate of decline varies among individuals, and many factors appear to impact progression. Because CKD stages 1 and 2 usually progress asymptomatically, detection of early- stage CKD requires laboratory testing.
  • Kidney Disease Improving Global Outcomes (KDIGO) recommends screening of all patients with hypertension, diabetes, or cardiovascular disease.
  • the American Diabetes Association recommends annual screening of all adults with diabetes, based on "expert consensus or clinical experience”.
  • the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) recommends annual screening of all patients with combined hypertension and diabetes.
  • JNC7 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
  • the National Kidney Foundation sponsors free CKD screening for all adults with hypertension, diabetes, or a primary relative with a history of kidney disease, hypertension, or diabetes. Also monitoring for changes in kidney function or damage in patients with CKD has been recommended.
  • Kidney Disease Outcomes Quality Initiative recommends at least annual estimated GFR measurement in adults with CKD in order to predict onset of ESRD and evaluate the effect of CKD treatments.
  • JNC7 recommends annual quantitative measurement of albuminuria in all patients with "kidney disease”.
  • KDOQI also recommends more frequent monitoring of CKD patients with worsening kidney function.
  • Angiotensin -Converting-Enzyme- (ACE-) inhibitors and Angiotensin-II-Receptor- Blockers (ARBs) are used to slow down or halt the progression of CKD to ESRD in patients with hypertension and albumin creatinine ratio (ACR) > 30 mg/mmol.
  • ACR albumin creatinine ratio
  • the beneficial effects appear to be in addition to their antiproteinuric effects and their reductions in blood pressure.
  • these drugs represent the current standard of care for patients with CKD, patients progressively lose kidney function while they are on these medications at a rate that is significantly faster than normal age-related decline. No new disease modifying treatments for chronic kidney disease have been approved by the FDA in the last decade.
  • CKD is a major health problem in today's society and available treatments are only partially effective. There is therefore a great need for new medicines to treat CKD.
  • Vasopressin is a neurohormone which basically regulates water homeostasis and vascular tone. It is produced in specialized endocrine neurons in the Nucleus supraopticus and N. paraventricularis in the wall of the third ventricle (hypothalamus) and is transported from there along the neural processes into the posterior lobes of the hypophysis (neurohypophysis).
  • the hormone is released into the bloodstream in response to different physiological and pathophysiological stimuli together with the stoichiometrically formed polypeptides copeptin and neurophysin, which are also constituents of the vasopressin (A VP) gene.
  • a disturbed neurohormonal regulation essentially manifests itself in an elevation of the sympathetic tone and inappropriate activation of the renin- angiotensin-aldosterone system (RAAS). While the inhibition of these components by beta- receptor blockers on the one hand and by ACE inhibitors or angiotensin-receptor blockers on the other is now an inherent part of the pharmacological treatment of cardiovascular diseases, the inappropriate elevation of vasopressin secretion is at present still not adequately treatable.
  • Vasopressin exerts its action mainly via binding to three receptors, which are classified as Via (AVPRla), Vlb (AVPRlb) and V2 (AVPR2) receptors and which belong to the family of G protein-coupled receptors.
  • AVPRla Via
  • Vlb Vlb
  • AVPR2 V2 receptors
  • V2 receptors are located in the distal tubular epithelium and the epithelium of the collecting tubules in the kidney. Their activation renders these epithelia permeable to water. This phenomenon is due to the incorporation of aquaporins (special water channels) in the luminal membrane of the epithelial cells. Consequently, pharmacological inhibition of the action of vasopressin on the V2 receptor results in increased urine excretion. Hence, drugs with V2 antagonistic activity appear particularly suitable for the treatment of all disease conditions which are associated with an overloading of the body with water.
  • Vlb receptors are mainly detectable in the central nervous system. Together with corticotropin-releasing hormone (CRH), vasopressin regulates the basal and stress - induced secretion of adr eno corticotropi c hormone (ACTH) via the Vlb receptor.
  • CHL corticotropin-releasing hormone
  • ACTH adr eno corticotropi c hormone
  • Via receptors are mainly located on vascular smooth muscle cells (VSMC) but also on cardiomyocytes, fibroblasts and specialized renal cells like glomerular mesangial cells or cells of the macula densa which control the release of renin [Wasilewski MA, Myers VD, Recchia FA, Feldman AM, Tilley IX i. Cell Signal, 28(3), 224-233, (2016)].
  • VSMC Via receptor by vasopressin gives rise to intracellular calcium release and according vasoconstriction. Therefore, stimulation of VSMC Via receptors causes increased vascular resistance and increased cardiac afterload. Cardiac output is adversely affected by Vla-mediated vasoconstriction.
  • Via receptor is also expressed in the renal cortical and medullary vasculature, where it mediates vasoconstriction of renal vessels and affecting overall renal blood flow.
  • the activation of Via receptor can decrease renal medullary blood flow inducing further pathological processes as tissue hypoxia, reduced oxygen and accordingly energy supply for tubular transport processes as well as direct damages of mesangial and macula densa cells. It has been demonstrated that mesangial Via receptor activation mediates TGF signaling and causes an increase in production of collagen IV.
  • Via receptors are also expressed on human platelets and in the liver.
  • the meaning of platelet Via receptors is not fully understood although vasopressin induces aggregation of human platelets via Via receptor at high concentrations ex vivo. Therefore, inhibition of vasopres sin-indue ed platelet aggregation by Via receptor antagonists is a useful pharmacological ex vivo assay making use of human tissue endogenously expressing the Via receptor [Thibonnier M. Roberts JM, J Clin Invest., 76, 1857-1864, (1985)].
  • Vasopressin stimulates gluconeogenesis and glycogenolysis via activation of the hepatic Via receptor.
  • Animal studies have shown that vasopressin impairs glucose tolerance which could be inhibited by a Via receptor antagonist thereby providing a link of vasopressin receptor Via to diabetes mellitus.
  • vasopressin also seems to play a causal role in the development of preeclampsia.
  • Chronic infusion of vasopressin during pregnancy in mice is sufficient to induce all of the major maternal and fetal phenotypes associated with human preeclampsia, including pregnancy-specific hypertension [Santillan MK, Santillan DA, Scroggins SM, Min JY, Sandgren JA, Pearson NA, Leslie KK, Hunter SK, Zamba GK, Gibson-Corley KN, Grobe .1 L.
  • Vasopressin in preeclampsia a novel very early human pregnancy biomarker and clinically relevant mouse model. Hypertension. 64(4), 852-859, (2014)].
  • Vasopressin levels can be elevated in women with dysmenorrhoea (a gynecological disorder which is characterised by cyclical cramping pelvic pain) during menstruation, which appear to increase myometrial smooth muscle contraction. It was found recently that a selective vasopressin Via receptor antagonist (relcovaptan/SR-49059) can reduce intrauterine contractions elicited by vasopressin.
  • Vasopressin and copeptin are derived from a pre -pro -hormone synthesized in the hypothalamus in a one-to-one molar ratio. Vasopressin has a very short half-life (ca. 20 min) in the circulation while copeptin is much more stable and relatively easy to measure. Therefore, it has gained a popular surrogate measure for vasopressin secretion.
  • Copeptin levels were associated with the development of microalbuminuria in a large prospective population based cohort [Kidney International, 2010, 77, 29-36].
  • albumin/creatinine values the measure for albuminuria, i.e. kidney injury
  • eGFR estimated glomerular filtration rate, the measure for renal function
  • the present invention therefore aims at identifying and providing new options for the treatment and/or prevention of renal diseases, in particular for patient groups suffering from CKD.
  • Vasopressin Via receptor antagonists can be used for the treatment of patients who suffer from a renal disease.
  • Successful Via receptor antagonism in any of the clinical settings (e.g., CKD, progression to CKD) described herein will be a major advance for renal disease therapy.
  • the inventors have made the surprising discovery that there is an association between renal disorders and the level of arginine vasopressin (A VP) and/or copeptin, as well as the predictive clinical value of these markers for response to a Via receptor antagonist.
  • the genetic identification, biochemical identification, or combination thereof, of one of these markers, in a sample from a subject may be useful in predicting whether the subject will respond to treatment with a Via receptor antagonist, screening subject for eligibility for a clinical trial, stratifying randomization of subjects for a clinical trial, or stratifying analysis of a clinical trial.
  • the ability to target populations expected to show the highest clinical benefit, based on the marker profile, may improve the utilization of a drug for the benefit of a subject.
  • the invention pertains to the use of Via receptor antagonists in the treatment and/or prevention of a renal disease in a subject.
  • the invention further pertains to the use of VI a receptor antagonists for the preparation of a medicament for the treatment and/or prevention a renal disease in a subject.
  • the invention further pertains to a Via receptor antagonist for use in the treatment and/or prevention a renal disease in a subject.
  • the invention further pertains to a method for the treatment and/or prevention of a renal disease in a subject using a therapeutically effective amount of a Via receptor antagonist.
  • the invention further pertains to a method for determining whether a subject is a suitable candidate for the treatment with a Via receptor antagonist.
  • the invention further pertains to a method for monitoring a subject's response to treatment with a Vi a antagonist.
  • the invention further pertains to identify subjects who are at risk to develop a renal disease or progress to further loss of renal function.
  • treatment includes inhibiting, delaying, relieving, mitigating, arresting, reducing, or causing the regression of a disease, disorder, condition, or state, the development and/or progression thereof, and/or the symptoms thereof.
  • prevention includes reducing the risk of having, contracting, or experiencing a disease, disorder, condition, or state, the development and/or progression thereof, and/or the symptoms thereof.
  • prevention includes prophylaxis. Treatment or prevention of a disorder, disease, condition, or state may be partial or complete.
  • kidney disease summarizes conditions in which the kidneys fail to filter and remove waste products from the blood in an organism, e.g. a human being.
  • the present invention pertains to the treatment and/or prevention of a renal disease, in particular of acute and chronic kidney disease.
  • Treatment and/or prevention of a renal disease includes, but is not limited to, treatment and/or prevention of sequelae of acute kidney injury arising from multiple insults such as ischemia- reperfusion injury, radiocontrast administration, cardiopulmonary bypass surgery, shock and sepsis.
  • renal failure or renal insufficiency comprises both acute and chronic manifestations of renal insufficiency, as well as underlying or related kidney diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, IgA nephropathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, Alport syndrome, kidney inflammation, immunological kidney diseases such as kidney transplant rejection, immune complex-induced kidney diseases, nephropathy induced by toxic substances, contrast medium-induced nephropathy; minimal change glomerulonephritis (lipoid); Membranous glomerulonephritis ; focal segmental glomerulosclerosis (FSGS); hemolytic uremic syndrome (HUS), amyloidosis, Goodpasture's syndrome, Wegener's
  • kidney diseases such as renal hypoperfusion
  • the present invention also comprises the treatment and/or prevention of sequelae of renal insufficiency, for example pulmonary edema, heart failure, uraemia, anaemia, electrolyte disturbances (e.g. hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism.
  • the present invention also comprises the treatment and/or prevention of polycystic kidney disease (PCKD) and of the syndrome of inadequate ADH secretion ( SIADH ).
  • PCKD polycystic kidney disease
  • SIADH syndrome of inadequate ADH secretion
  • the present invention further comprises treatment and/or prevention of the cardiorenal syndrome (CRS) and its various subtypes. This term embraces certain disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other.
  • the present invention further comprises the treatment and/or prevention of liver cirrhosis, ascites, diabetes mellitus and diabetic complications such as, for example, neuropathy and nephropathy.
  • Nephrotic syndrome collectively comprises a group of symptoms that include very high albuminuria (in the urine) and hypalbuminemia (low blood protein levels in the blood), and as compensatory consequences oedema (which is generalized and also known as anasarca or dropsy in these patients) and hyperlipidemia (high cholesterol and triglyceride levels).
  • Nephrotic syndrome has many causes and may either be the result of a glomerular disease that can be either limited to the kidney, called primary nephrotic syndrome, or a condition that affects several parts of the body including the kidney, called secondary nephrotic syndrome.
  • the nephrotic syndrome can occur from cancer, diabetes, systemic lupus erythematosus, multiple myeloma, amyloidosis, genetic and immune disorders, infections and use of certain drugs like non-steroidal antiinflammtory drugs.
  • the nephrotic syndrome therefore is to be distinguished from the etiology and pathophysiology of a renal disease within the context of the present invention, such as exemplary and preferably acute and chronic kidney disease or diabetic nephropathy.
  • a preferred embodiment of the present invention is the treatment and/or prevention of acute and chronic kidney diseases (including diabetic nephropathy).
  • the renal disease is chronic kidney disease stage 2 to 5d (CKD-2 to CKD-5d) according to Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines in Nephrology.
  • vasopressin Via receptor antagonist or “Via receptor antagonist” refers to a compound that functions by inhibiting (partially or completely) or blocking the vasopressin Via receptor, thereby preventing activation of the receptor by vasopressin.
  • Vasopressin Via receptor antagonist refers to any compound capable of binding directly or indirectly to a Via receptor so as to modulate the receptor mediated activity.
  • Vasopressin Via receptor antagonists as used herein include Via receptor antagonists which were tested in clinical trials as well as Via receptor antagonists which are currently tested in clinical trials or already admitted to the market. Various Via receptor antagonists have been described in the literature and tested in clinical trials.
  • Via receptor antagonists for use in the methods described herein include, but are not limited to, a small molecule antagonist, an antibody antagonist, a peptide antagonist and an oligonucleotide antagonist.
  • the Via antagonist is a small molecule.
  • a vasopressin Via receptor antagonist according to the present invention may be a Via receptor antagonist which also shows activity at other vasopressin receptors, such as the Vlb and/or V2 subtypes.
  • the Via receptor antagonist is a dual antagonist of the vasopressin Via receptor and V2 receptor ("dual Vla V2 antagonist").
  • dual Vla/V2 antagonist is Ribuvaptan (BAY 86-8050).
  • selective Via antagonist refers to selectivity of Via over other vasopressin receptors, such as the Vlb and/or V2 subtypes.
  • SR 49059 Relcovaptan
  • the Via receptor antagonist is a selective Via antagonist.
  • Possible Via antagonists may be identified in binding assays known to the skilled person by identifying their IC» values, e.g. the biological assays described in section B.
  • a Via receptor antagonist described herein may be at least 10-fold selective for the Via receptor compared to the V2 receptor as determined according to the study in B-l.
  • a Via receptor antagonist described herein may be at least 15 -fold selective for the Via receptor compared to the V2 receptor as determined according to the study in B-l.
  • a Via receptor antagonist described herein may be at least 20-fold selective for the Via receptor compared to the V2 receptor as determined according to the study in B- l . In another preferred embodiment, a Via receptor antagonist described herein may be at least 30-fold selective for the Via receptor compared to the V2 receptor as determined according to the study in B-l . in another preferred embodiment, a Via receptor antagonist described herein may be at least 40-fold selective for the Via receptor compared to the V2 receptor as determined according to the study in B-l.
  • the Via receptor antagonist is a small molecule.
  • Exemplary small molecules that inhibit the Via receptor include, but are not limited to the vasopressin antagonists disclosed in WO2007/134862, WO2010/063402, WO2010/105770, WO2010/105750, WO2011/104322, WO2011/023703, WO2012/028644, WO2012/035075, WO 2016/071212, WO 2015/091411, WO 2015/024819, WO 2011/120877, WO 2011/131596, WO 2010/054961, WO 2010/057795, WO 2010/060836, WO 2011/128265, WO 2011/141396, WO 2015/082370, WO 2015/091411, WO 2015/124541, WO 2016/075181.
  • the Via receptor antagonist is selected from the group consisting of Conivaptan (YM 087), YM 218, Relcovaptan ( SR 49059), Ribuvaptan (BAY 86-8050), R 7314, RG 7713, RO 5028442, RWJ 676070, SRX 246, SRX 251, VA 111913, PF 00738245 and PF 184563.
  • the Via receptor antagonist is a small molecule that selectively inhibits the Via receptor.
  • Exemplary small molecules that selectively inhibit the Via receptor include, but are not limited to Relcovaptan ( SR 49059), RG 7314, RWJ 676070, SRX 246, PF 184563.
  • a selective Via antagonist is particularly useful as a treatment option for patients who have no signs of congestion (which is mostly the case for CKD stage 1-3) to prevent forced diuresis and potentially causing plasma electrolyte disorders (e.g. hypernatremia) and aggravating thirst via V2 antagonistic activity.
  • the Via receptor antagonist is a compound of the general formula (I)
  • R represents a group of the formula
  • R represents a group of the formula
  • R 3 represents a group selected from a hydrogen atom and methyl
  • any phenyl group and any 5- or 6-membered heteroaryl group are each optionally substituted, identically or differently, with one or two groups selected from a halogen atom, nitro, cyano, (G-C4)-alkyl, (Ci-C4)-alkoxy, (C i -C4)-alkylsulfanyl, (Ci-C- -alkoxycarbonyl, aminocarbonyl and
  • said (G-C4)-alkyl group, said (G-C4)-alkoxy group and said (C1-C4)- alkylsulfanyl group are each optionally substituted with up to three fluorine atoms, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
  • 5- to 6-membered heteroaryl means a monovalent, monocyclic aromatic ring having 5 or 6 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from a nitrogen atom and a sulfur atom, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
  • Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.
  • a 5-membered heteroaryl group such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl
  • the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g. : tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • the heteroaryl group in substituent Ar in the general formula (I), supra is a pyridinyl group.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, or chlorine atom.
  • C1-C4 as used in the present text, e.g. in the context of the definition of "Ci-C4-alkyl", “Ci-C4-alkoxy”, “ or "Ci-C4-alkylsulfanyl”, means an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1 , 2, 3, or 4 carbon atoms.
  • Ci-C4-alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, or 4 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec -butyl, isobutyl, ferf-butyl, or an isomer thereof. Particularly, said group has 1 , 2, 3 or 4 carbon atoms (“Ci-C4-alkyl”), e.g.
  • Ci-C3-alkyl a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or teri-butyl group, more particularly 1 , 2 or 3 carbon atoms
  • Ci-C3-alkyl e.g. a methyl, ethyl, n -propyl or isopropyl group, even more particularly a methyl group.
  • C 1 -C4-alkylsulfanyl means a linear or branched, saturated, monovalent group of formula (Ci-C4-alkyl)-S-, in which the term "Ci-C4-alkyl" is as defined supra, e.g.
  • Ci-C4-alkoxy means a linear or branched, saturated, monovalent group of formula (C 1 -C4 -alkyl )-0-, in which the term "Ci-C4-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, iert-butoxy, or an isomer thereof.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds included in the formula (I) of the formulae mentioned in the following and their salts, solvates and solvates of the salts, and the compounds included in the formula (I) and mentioned in the following as process products and/or embodiment examples and their salts, solvates and solvates of the salts, where the compounds included in the formula (I) and mentioned in the following are not already salts, solvates and solvates of the salts.
  • Salts for the purposes of the present invention are preferably pharmaceutically acceptable salts of the compounds according to the invention (for example, see S. M. Berge et ah, "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19). Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation, purification or storage of the compounds according to the invention are also included.
  • Solvates in the context of the invention are designated as those forms of the compounds according to the invention which form a complex in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present invention.
  • the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers (enantiomers, diastereomers). Any isomer may be present in which the asymmetric center is in the (i?)-, (5)-, or (R,S)-configuration. It will also be appreciated that when two or more asymmetric centers are present in the compounds of the invention, several diastereomers and enantiomers of the exemplified structures will often be possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the invention.
  • the Via receptor antagonist is selected from the group consisting of 5-(4- chlorophenyl)-2-( ⁇ l-(3-fluorophenyl)-5-[(lR ⁇
  • the Via receptor antagonist is a compound of the general formula (I-A)
  • R 1 represents a group of the formula
  • #' represents the point of attachment to the nitrogen atom
  • Ar represents a group of the formula
  • # 3 represents the point of attachment to the nitrogen atom
  • R 4 represents a group selected from a chlorine atom, trifluoromethyl, and ethoxycarbonyl,
  • the Via receptor antagonist is a compound of the general formula (I-A), supra, wherein
  • R ! represents a group of the formula
  • #' represents the point of attachment to the nitrogen atom
  • Ar represents a group of the formula in which # 3 represents the point of attachment to the nitrogen atom
  • the Via receptor antagonist is a compound of the general formula (I-A), supra, wherein
  • R 1 represents a group of the formula
  • #' represents the point of attachment to the nitrogen atom
  • # 3 represents the point of attachment to the nitrogen atom
  • R 4A represents a group selected from a chlorine atom, trifluoromethyl and trifluoromethoxy
  • R 4C represents a group selected from trifluoromethyl and trifluoromethoxy
  • Therapeutically effective amount means an amount of a Via receptor antagonist that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.
  • the “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
  • the Via receptor antagonists can be used for the treatment of a patient suffering from a renal disease described herein showing an elevated arginine vasopressin (A VP) level and/or an elevated copeptin level.
  • a VP arginine vasopressin
  • the neuropeptide arginine vasopressin (also denoted as vasopressin, vasopressin argipressin or antidiuretic hormone (ADH)) is a nonapeptide which is produced in the paraventricular nucleus of the hypothalamus and the supraoptic nucleus.
  • Patients showing elevated arginine vasopressin levels as used herein include patients showing an increased gene activity of the gene coding for A VP.
  • patients showing elevated A VP levels as used herein may include patients showing a combination of the presence or absence of at least one polymorphic variant of genes coding for the arginine vasopressin receptors (AVPPv), in particular for the arginine vasopressin receptor Via (AVPR1A), with the presence or absence of at least one polymorphic variant in the patient's genome excluding the AVPR ! A gene.
  • Patients showing elevated arginine vasopressin levels also include patients showing elevated levels of A VP in serum, plasma or urine.
  • the present invention relates to a Via receptor antagonist for use as described herein, wherein an elevated A VP level in said patient is determined by means of A VP or copeptin or neurophysin-2 measurement.
  • the measurement of AVP or copeptin or neurophysin-2 may be performed in a sample of blood of said patient.
  • Methods for determination of AVP or copeptin or neurophysin-2 levels in a sample of blood of a patient are known in the art and include immunoassays, e.g. radioimmunoassay or Time Resolved Amplified Cryptate Emission (TRACE) immunoassay, or Enzyme Linked Immunosorbent Assay (ELISA).
  • Copeptin (also denoted as C -terminal proAVP) is a glycopeptide of a length of 39 amino acids which is produced from the C-terminal part of the AVP precursor. AVP and copeptin are released from the AVP precursor in an equimolar amount. Since copeptin is stable in blood (i.e. blood plasma, blood serum and/or whole blood) it provides the advantage that it may be used as surrogate marker for AVP levels in the blood plasma, blood serum and/or whole blood.
  • blood i.e. blood plasma, blood serum and/or whole blood
  • the present invention thus relates to a Via receptor antagonist for use as described herein, wherein an elevated copeptin level in said patient is determined by means of copeptin measurement.
  • Methods for determination of co e tin levels in a blood sample derived from a patient are known in the art and include immunoassays, e.g. sandwich immunoassays. Examples of such immunoassays are the Copeptin EI A Kit provided by BioSupply UK and the ⁇ ! ⁇ I'M'S copeptin Kryptor assay provided by ThermoScientific.
  • Copeptin may be measured in plasma or serum by use of the established Time Resolved Amplified Cryptate Emission (TRACE) immunocomplex energy transfer assay (Thermo Scientific B s R*A e H e M e S Kryptor compact PLUS).
  • TRACE Time Resolved Amplified Cryptate Emission
  • the A VP level and/or copeptin level of the renal di ease patient is determined by means of an immunoassay, optionally by means of a radioimmunoassay or Time Resolved Amplified Cryptate Emission (TRACE) immunoassay, or Enzyme Linked Immunosorbent Assay (ELISA).
  • the copeptin level is determined in a blood sample of the patient as defined herein.
  • blood sample relates to whole blood, blood serum and/or blood plasma.
  • the blood sample can be obtained from the patient by any method known in the art, e.g. with a sterile needle.
  • the copeptin level is determined in the blood plasma derived from the blood sample of said patient. It is known in the art that blood plasma may be obtained by centrifugation of a blood sample to which an anti-coagulant has been added.
  • an elevated copeptin level denotes any copeptin level higher than the mean copeptin level measured in blood samples of healthy individuals.
  • an elevated copeptin level and therefore also an elevated A VP level in a patient with a renal disease is indicated by a copeptin blood concentration of at least 5 pmol/1, at least 6 pmol/1, at least 7 pmol/1, at least 8 pmol/1, at least 9 pmol/1, at least 10 pmol/1, at least 20 pmol/1, at least 30 pmol/1, at least 40 pmol/1, at least 50 pmol/1, at least 60 pmol 1, at least 70 pmol/1, at least 80 pmol/1, at least 90 pmol/1 or at least 100 pmol/1.
  • Elevated copeptin levels and therefore also elevated A VP levels may be indicated by a copeptin blood concentration in the range from 5 to 200 pmol/1, optionally in the range from 5 to 100 pmol/1.
  • the elevated copeptin level is at least 8.0 pmol/1 for a male subject or at least 6.0 pmol/1 for a female subject.
  • copeptin is surprisingly significantly elevated in patients characterized by mild impairment of renal function (This mild or mild-to-moderate renal impairment is categorized as chronic kidney disease (CKD) grades CKD-1, CKD-2, and CKD-3a according to the classification published by Kidney Disease Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of the International Society of Nephrology.
  • CKD chronic kidney disease
  • KDIGO Kidney Disease Improving Global Outcomes
  • vasopressin that are concomitant with increased levels of copeptin, act in a vasoconstrictive mode of renal cortical or medullary vasculature thus reducing renal blood flow and subsequently impair renal functions.
  • the vaso - constri ctive action of vasopressin resulting in loss of organ functions is being documented [Meijer e, Boertien W E, Zietse R. Gansevoort R T, Potential deleterious effects of vasopressin in chronic kidney disease and particularly autosomal dominant polycystic kidney disease, Kidney Blood Press Res 2011, 34:235-244].
  • a V R l a function blocking medications in particular to those patients of initial emerge of signs of loss of renal function, who are characterized by symptomatically elevated copeptin, or vasopressin, or neurophysin levels may be beneficial and of therapeutic relevance.
  • the invention may also involve comparing the level of AVP and/or copeptin for the individual with a predetermined value.
  • Predetermined cutoff and predetermined level refer generally to an assay cutoff value that is used to assess diagnostic/prognostic/therapeutic efficacy results by comparing the assay results against the predetermined cutoff/level, where the predetermined cutoff/level already has been linked or associated with various clinical parameters (e.g., severity of disease, progression/nonprogression/improvement, etc.).
  • the present disclosure provides exemplary predetermined levels.
  • cutoff values may vary depending on the nature of the immunoassay (e.g., antibodies employed, etc.).
  • the predetermined cutoff/level may vary between assays, the correlations as described herein should be generally applicable.
  • the predetermined value can vary among particular populations selected, depending on their habits, ethnicity, genetics etc. For example, an apparently healthy, non-smoker population (no detectable disease, particularly no diabetes mellitus) might have a different 'normal' range of markers than a smoking population or a population the members of which have diabetes mellitus. Accordingly, the predetermined values selected may take into account the category in which an individual falls.
  • the use of said level of arginine vasopressin pro -hormone or fragments thereof comprises comparing said the level of AVP and/or copeptin to a threshold level, whereby, when said the level of A VP and/or copeptin exceeds said threshold level, a renal disease is predicted in a subject or a subject having an enhanced risk for getting a renal disease is identified.
  • the predetermined value can take a variety of forms. It can be single cut-off value, such as for instance a median or mean or the 60th, 65th, 70th, 75th, 90th, 95th or 99th percentile of a population. It can be established based upon comparative groups, such as where the risk in one defined group is double the risk in another defined group. It can be a range, for example, where the tested population is divided equally (or unequally) into groups, such as a low-risk group, a medium-risk group and a high-risk group, or into quartiles, the lowest quartile being individuals with the lowest risk and the highest quartile being individuals with the highest risk.
  • cut-off values are for instance the 90th, 95th or 99th percentile of a normal population.
  • a higher percentile than the 75th percentile one reduces the number of false positive subjects identified, but one might miss to identify subjects, who are at moderate, albeit still increased risk.
  • a copeptin level of 5.0 pmol/L (i.e. exceeding the median concentration of a reference population of apparently healthy subjects) or above, preferably above 8.0 pmol/L (i.e. the Q3/Q4 border concentration of a reference population of apparently healthy subjects) in the sample may be indicative for an elevated risk of the patient to contract a renal disease or being at risk for progression of a renal disease.
  • Ql, Q2, Q3 and Q4 herein refer to quartiles of a reference population of apparently healthy subjects.
  • a VP and/or copeptin as marker may indicate that the subject is a suitable candidate for treatment with a Via antagonist.
  • the marker may be present at a level greater than about the 60 th percentile, particularly greater than about the 65 th , 70 th , 75 th , 80 th , 85 th , 90 th , or 95 th percentile, of the distribution of the marker in a normal subject sample.
  • the copeptin level may be at least 5 pmol/1, in particular at least 8.0 pmol/1 for a male subject or at least 6.0 pmol/1 for a female subject.
  • Healthy subject denotes any person not suffering from a renal disease as defined herein, in a particular embodiment said subject does not have any acute or chronic observable other disease.
  • the methods as described herein may be applied to a method for the treatment and/or prevention of a renal disease in a subject using a therapeutically effective amount of a Via receptor antagonist, said method comprising the steps of:
  • the methods as described herein may be applied to a method for determining whether a subject is a suitable candidate for the treatment with a Via receptor antagonist and treating a subject identified as a suitable candidate for said treatment, the method comprising the steps of:
  • the subject has a renal disease
  • an elevated A VP level and/or an elevated copeptin level in particular at a level above about the 60th percentile of the distribution of the marker in a normal subject sample, in said subject indicates that the subject is a suitable candidate for treatment with a Via antagonist and
  • step (c) treating a subject that is identified as a suitable candidate in step (b) with a Via antagonist.
  • the methods as described herein may be applied to screen subjects for eligibility for a clinical trial and/or stratify groups of subjects for a clinical trial.
  • the methods as described herein may be applied to a method for for monitoring a subject's response to treatment with a Via antagonist, comprising
  • the subject has a renal disease; and wherein a change in the A VP level and/or an copeptin level as compared to a baseline, indicates that the Via receptor antagonist is useful for treating the subject;
  • step (c) continuing or discontinuing treatment with the Via receptor antagonist in the subject based on the change in the level of the marker as compared to baseline detected in step (b).
  • Via antagonists according to the present invention may be administered as the sole pharmaceutical agent or in combination with one or more additional therapeutic agents as long as this combination does not lead to undesirable and/or unacceptable side effects.
  • Such combination therapy includes administration of a single pharmaceutical dosage formulation, e.g. which contains a compound of formula (I), as defined above, and one or more additional therapeutic agents, as well as administration e.g. of a compound of formula (I) and each additional therapeutic agent in its own separate pharmaceutical dosage formulation.
  • a compound of formula (I) and a therapeutic agent may be administered to the patient together in a single (fixed) oral dosage composition such as a tablet or capsule, or each agent may be administered in separate dosage formulations.
  • the compound of formula (I) and one or more additional therapeutic agents may be administered at essentially the same time (i.e., concurrently) or at separately staggered times (i.e., sequentially).
  • the inventors have surprisingly found that a substantial proportion of chronic kidney disease patients have elevated copeptin levels despite the fact that they are under continuous standard of care treatment regimes like angiotensin receptor blocker (ARB) and/or angiotensin converting enzyme inhibitor (ACEi), and/or calcium antagonist applications. It is even more surprising, that additional diuretic therapies on top of these anti -hyp ertensive therapies by application of thiazides or loop diuretics do not reduce this proportion of patients characterized by elevated copeptin levels. This observation holds true even for mildly to moderately affected CKD-3 patients. As a consequence of this finding, blocking of Via receptor activity in these patients is expected to be beneficial for ameliorating renal functions.
  • ARB angiotensin receptor blocker
  • ACEi angiotensin converting enzyme inhibitor
  • Via antagonists according to the present invention may be used in fixed or separate combination with
  • antithrombotic agents for example and preferably from the group of platelet aggregation inhi- bitors, anticoagulants and pro fibrinolytic substances;
  • blood pressure lowering agents for example and preferably from the group of calcium antagonists, angiotensin All antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-blockers, beta-blockers, mineralocorticoid receptor antagonists and diuretics; • antidiabetic agents (hypoglycemic or antihyp ergly cemic agents), such as for example and preferably insulin and derivatives, sulfonylureas, biguanides, thiazolidinediones, acarbose, DPP4 inhibitors, GLP-1 analogues, or SGLT inhibitors (gliflozins).
  • antidiabetic agents hyperoglycemic or antihyp ergly cemic agents
  • organic nitrates and NO-donors for example sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhalational NO;
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • ⁇ positive -inotropic agents such as for example cardiac glycosides (digoxin) and beta-adrenergic and dopaminergic agonists such as isoproterenol, adrenalin, noradrenalin, dopamine or dobut- amine;
  • natriuretic peptides such as for example atrial natriuretic peptide (ANP, anaritide), B-type natriuretic peptide or brain natriuretic peptide ( BN , nesiritide), C-type natriuretic peptide (CNP) or urodilatin;
  • sGC soluble guanylate cyclase
  • sGC guanylate cyclase
  • HNE human neutrophil elastase
  • ⁇ compounds influencing the energy metabolism of the heart such as for example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine, or full or partial adenosine Al receptor agonists as GS-9667 (previously known as CVT-3619), capadenoson and BAY 1067197;
  • anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid (aspirin), ibuprofen and naproxen, glucocorticoids, 5 -aminosalicylic acid derivatives, leukotriene antagonists, TNF-alpha inhibitors and chemokine receptor antagonists such as CCR1 , 2 and/or 5 inhibitors;
  • NSAIDs non-steroidal anti-inflammatory drugs
  • acetylsalicylic acid aspirin
  • ibuprofen and naproxen glucocorticoids
  • 5 -aminosalicylic acid derivatives 5 -aminosalicylic acid derivatives
  • leukotriene antagonists such as TNF-alpha inhibitors
  • chemokine receptor antagonists such as CCR1 , 2 and/or 5 inhibitors
  • fat metabolism altering agents for example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors, such as for example and preferably HMG-CoA- reductase or squalene synthesis inhibitors, AC AT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein ⁇ ) antagonists.
  • cholesterol synthesis inhibitors such as for example and preferably HMG-CoA- reductase or squalene synthesis inhibitors, AC AT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lip
  • Antithrombotic agents are preferably to be understood as compounds from the group of platelet aggregation inhibitors, anticoagulants and profibrinolytic substances.
  • Via antagonists according to the invention are administered in combination with a platelet aggregation inhibitor, for example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
  • Via antagonists according to the invention are administered in combination with a thrombin inhibitor, for example and preferably ximelagatran, dabigatran, melagatran, bivalirudin or enoxaparin.
  • Via antagonists according to the invention are administered in combination with a ( iPl lb Il ia antagonist, for example and preferably tirofiban or abcixi- mab.
  • Via antagonists according to the invention are administered in combination with a factor Xa inhibitor, for example and preferably rivaroxaban, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-I50, K FA- 1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR- 126512 or SSR-128428.
  • a factor Xa inhibitor for example and preferably rivaroxaban, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-I50, K FA- 1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 80
  • Via antagonists according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • Via antagonists according to the invention are administered in combination with a vitamin K antagonist, for example and preferably coumarin.
  • Blood pressure lowering agents are preferably to be understood as compounds from the group of calcium antagonists, angiotensin Al l antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-blockers, beta-blockers, mineralocorticoid receptor antagonists and diuretics.
  • Via antagonists according to the invention are administered in combination with a calcium antagonist, for example and preferably nifedipine, amlodipine, verapamil or diltiazem.
  • Via antagonists according to the invention are administered in combination with an alpha- 1 -receptor blocker, for example and preferably prazosin or tamsulosin.
  • Via antagonists according to the invention are administered in combination with a beta-blocker, for example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carve - dilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-blocker for example and preferably propranolol, atenolol, timolol, pindolol,
  • Via antagonists according to the invention are administered in combination with an angiotensin Ai l receptor antagonist, for example and preferably losartan, candesartan, valsartan, telmisartan, irbesartan, olmesartan, eprosartan or azilsartan.
  • angiotensin Ai l receptor antagonist for example and preferably losartan, candesartan, valsartan, telmisartan, irbesartan, olmesartan, eprosartan or azilsartan.
  • Via antagonists according to the invention are administered in combination with a vasopeptidase inhibitor or inhibitor of neutral endopeptidase (NEP), such as for example and preferably sacubitril, omapatrilat or AVE-7688.
  • NEP neutral endopeptidase
  • Via antagonists according to the invention are administered in combination with a dual angiotensin Al l receptor antagonist/NEP inhibitor (ARNI), for example and preferably LCZ696.
  • ARNI angiotensin Al l receptor antagonist/NEP inhibitor
  • Via antagonists according to the invention are administered in combination with an ACE inhibitor, for example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • Via antagonists according to the invention are administered in combination with an endothelin antagonist, for example and preferably bosentan, darusentan, ambrisentan, tezosentan, sitaxsentan or atrasentan.
  • an endothelin antagonist for example and preferably bosentan, darusentan, ambrisentan, tezosentan, sitaxsentan or atrasentan.
  • Via antagonists according to the invention are administered in combination with a renin inhibitor, for example and preferably aliskiren, SPP-600 or SPP-800.
  • Via antagonists according to the invention are administered in combination with a mineralocorticoid receptor antagonist, for example and preferably finerenone, spironolactone, canrenone, potassium canrenoate, eplerenone, CS-3150, or MT-3995.
  • a mineralocorticoid receptor antagonist for example and preferably finerenone, spironolactone, canrenone, potassium canrenoate, eplerenone, CS-3150, or MT-3995.
  • Via antagonists according to the invention are administered in combination with a diuretic, such as for example and preferably furosemide, bumetanide, piretanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, xipamide, indapamide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorothalidone, metolazone, quinethazone, acetazolamide, dichlorophenamide, methazolamide, glycerine, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic such as for example and preferably furosemide, bumetanide, piretanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, xipamide, indap
  • Fat metabolism altering agents are preferably to be understood as compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA-reductase or squalene synthesis inhibitors, AC AT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.
  • cholesterol synthesis inhibitors such as HMG-CoA-reductase or squalene synthesis inhibitors
  • AC AT inhibitors AC AT inhibitors
  • MTP inhibitors PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists
  • cholesterol absorption inhibitors polymeric bile acid adsorbers
  • bile acid reabsorption inhibitors lipase inhibitors and lipoprotein(a) antagonists
  • Via antagonists according to the invention are administered in combination with a CETP inhibitor, for example and preferably dalcetrapib, anacetrapib, BAY 60- 5521 or CETP-vaccine (Avant).
  • a CETP inhibitor for example and preferably dalcetrapib, anacetrapib, BAY 60- 5521 or CETP-vaccine (Avant).
  • Via antagonists according to the invention are administered in combination with a thyroid receptor agonist, for example and preferably D-thyroxin, 3,5,3'-triiodothyronin (T3), CGS 23425 or axitirome (CGS 26214).
  • Via antagonists according to the invention are administered in combination with an HMG-CoA-reductase inhibitor from the class of statins, for example and preferably lovastatin, simvastatin, pravastatin, fiuvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • an HMG-CoA-reductase inhibitor from the class of statins, for example and preferably lovastatin, simvastatin, pravastatin, fiuvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • Via antagonists according to the invention are administered in combination with a squalene synthesis inhibitor, for example and preferably BMS-188494 or TAK-475.
  • Via antagonists according to the invention are administered in combination with an AC AT inhibitor, for example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • Via antagonists according to the invention are administered in combination with an MTP inhibitor, for example and preferably implitapide, R- ! 03757, BMS- 201038 or JTT- 130.
  • Via antagonists according to the invention are administered in combination with a PPAR-gamma agonist, for example and preferably pioglitazone or rosiglitazone.
  • Via antagonists according to the invention are administered in combination with a PPAR-delta agonist, for example and preferably GW 501516 or BAY 68-5042.
  • Via antagonists according to the invention are administered in combination with a cholesterol absorption inhibitor, for example and preferably ezetimibe, tiqueside or pamaqueside.
  • Via antagonists according to the invention are administered in combination with a lipase inhibitor, for example and preferably orlistat.
  • Via antagonists according to the invention are administered in combination with a polymeric bile acid adsorber, for example and preferably cholestyr- amine, colestipol, colesolvam, CholestaGel or colestimide.
  • Via antagonists according to the invention are administered in combination with a lipoprotein(a) antagonist, for example and preferably gemcabene calcium (CI- 1027) or nicotinic acid.
  • Via antagonists according to the invention are administered in combination with antidiabetics (hypoglycemic or antihyperglycemic agents), such as for example and preferably insulin and derivatives, sulfonylureas such as tolbutamide, carbutamide, acetohexamide, chlorpropamide, glipizide, gliclazide, glibenclamide, glyburide, glibornuride, gliquidone, glisoxepide, glyclopyramide, glimepiride, JB253 and JB558, meglitinides such as repaglinide and nateglinide, biguanides such as metformin and buformin, thiazolidinediones such
  • Via antagonists of the present invention are administered in combination with one or more additional therapeutic agents selected from the group consisting of diuretics, angiotensin Al l antagonists, ACE inhibitors, beta-receptor blockers, mineralocorticoid receptor antagonists, antidiabetics, organic nitrates and NO donors, activators and stimulators of the soluble guanylate cyclase (sGC), and positive-inotropic agents.
  • additional therapeutic agents selected from the group consisting of diuretics, angiotensin Al l antagonists, ACE inhibitors, beta-receptor blockers, mineralocorticoid receptor antagonists, antidiabetics, organic nitrates and NO donors, activators and stimulators of the soluble guanylate cyclase (sGC), and positive-inotropic agents.
  • the present invention relates to pharmaceutical compositions comprising at least one Via antagonist according to the invention and one or more additional therapeutic agents for the treatment and/or prevention of renal diseases, especially of the aforementioned diseases.
  • Via antagonists of the present invention may be utilized, as such or in compositions, in research and diagnostics, or as analytical reference standards and the like, which are well known in the art.
  • the Via antagonists of the present invention are administered as pharmaceuticals, to humans and other mammals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 % to 99.5% (more preferably, 0.5%) to 90%o) of active ingredient in combination with one or more pharmaceutically acceptable excipients.
  • the present invention relates to pharmaceutical compositions comprising at least one Via antagonist according to the invention, conventionally together with one or more inert, nontoxic, pharmaceutically suitable excipients, and to the use thereof for the treatment and/ or prevention of renal diseases, especially of the aforementioned diseases.
  • the Via antagonists according to the invention can act systemically and/or locally.
  • they can be administered in a suitable way such as, for example, by the oral, parenteral, pulmonary, nasal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival, otic or topical route, or as an implant or stent.
  • the Via antagonists of the invention can be administered in suitable application forms.
  • Suitable for oral administration are application forms which function according to the state of the art and deliver the compounds according to the invention rapidly and or in modified fashion, and which contain the compounds according to the invention in crystalline, amorphous and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example having enteric coatings or coatings which are insoluble or dissolve with a delay and control the release of the compound according to the invention), tablets which disintegrate rapidly in the mouth, or films/ wafers, films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example having enteric coatings or coatings which are insoluble or dissolve with a delay and control the release of the compound according to the invention
  • tablets which disintegrate rapidly in the mouth or films/ wafers, films/lyophilisates
  • capsules e.g. hard or soft gelatin
  • Parenteral application can be carried out with avoidance of an absorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with inclusion of an absorption (intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • Suitable parenteral application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
  • Forms suitable for other application routes include, for example, inhalatory pharmaceutical forms (e.g. powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets or capsules to be administered lingually, sublingually or buccally (e.g.
  • the pharmaceutical composition comprising a Via antagonist as defined above is provided in a form suitable for oral administration.
  • the pharmaceutical composition comprising a Via antagonist as defined above is provided in a form suitable for intravenous administration.
  • Via antagonists according to the invention can be converted into the recited application forms in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include, inter alia, carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), surfactants (e.g. polyoxysorbitan oleate), dispersants (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colorants (e.g. inorganic pigments such as, for example, iron oxides), and flavour and/or odour masking agents.
  • carriers e.g. microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid poly
  • a preferred dose of Vi a antagonists of the present invention is the maximum that a patient can tolerate and not develop serious side effects.
  • the compound of the present invention may be administered parenterally at a dose of about 0.001 mg/kg to about 10 nig kg, preferably of about 0.01 mg/kg to about 1 mg kg of body weight.
  • an exemplary dose range is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg, and more preferably about 0.1 to 10 mg/kg of body weight. Ranges intermediate to the above -recited values are also intended to be part of the invention.
  • actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient.
  • Treatment can be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in individual portions spread over the day.
  • Figure 1-1 Induction of mRNA formation of pro-fibrotic genes PAI- I and osteopontin by exposure of renal NRK-49F cells to 1 nM Arg-vasopressin for 5 hours.
  • FIG. 1 Copeptin quantification in serum samples of unilaterally nephrectomized Spraque- Dawley rats (Sham) demonstrate elevated copeptin levels in rats that are additionally affected by ischemia reperfusion injury (Placebo).
  • FIG. 1 Receiver operating characteristic (ROC) curves of copeptin in C D-3 patients.
  • Figure 3-4 Gender effect on copeptin levels in diabetic C D patients.
  • NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
  • Chemical names were generated using the ACD/Name software from ACD/Labs. in some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.
  • NMR nuclear magnetic resonance spectroscopy chemical shifts ( ⁇ ) are given in ppm. The chemical shifts were corrected by setting the DM SO signal to 2.50 ppm unless otherwise stated.
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
  • Instrument MS Thermo Scientific FT-MS; Instrument type UHPLC+: Thermo Scientific UltiMate 3000; Column: Waters, H SST3. 2.1 x 75 mm, C18 1.8 ⁇ ; eluent A: 1 I, water + 0.01% formic acid; eluent B: 1 L acetonitrile + 0.01 % formic acid; gradient: 0.0 min 10% B ⁇ 2.5 min 95% B ⁇ 3.5 min 95% B; oven: 50°C; flow rate: 0.90 ml/min; UV detection: 210 nm/ optimum integration path 210-300 nm.
  • the resulting mixture was heated under reflux for 3 h and then cooled down to room temperature.
  • the reaction mixture was then diluted with I N hydrochloric acid (70 ml).
  • the organic phase was washed twice with IN hydrochloric acid.
  • the aqueous phase was extracted twice with ethyl acetate.
  • the combined organic phases were evaporated.
  • the residue was retaken in methanol (22.5 ml) and the resulting suspension was heated to 60°C until the solid was completely dissolved.
  • I N hydrochloric acid (22.5 ml) was added and the resulting suspension was heated at 78°C for 10 min and then cooled down to room temperature. The solid was filtered off and dried under vacuum.
  • the resulting solution was treated at 5 °C with 52.8 g (438 mmol) of 2,2-dimethylpropanoylchloride over 15 minutes and the resulting mixture was stirred at room temperature for 2.5 hours.
  • 183 ml of 28 > aqueous ammonia solution was added over 1 h while the solution temperature was kept between 10 °C and 20 °C and at the resulting mixture then stirred at 5 °C for an additional time period of 1 h.
  • 500 ml methyl tert- butyl ether and 300 ml 20%o aqueous citric acid were then added while keeping the internal temperature between 10 °C and 20 °C.
  • the phases were the separated and the organic phase was washed with 300 ml of 20%> aqueous citric acid followed by 300 ml saturated aqueous sodium hydrogencarbonate solution and finally with 300 ml of 10%> aqueous sodium chloride solution.
  • the organic phase was evaporated at 60 °C under reduced pressure until an oily residue was obtained.
  • 300 ml THF was then added and the solution was evaporated again until an oily solution was obtained. This operation was repeated a second time.
  • the oil residue was retaken in 360 ml THF and treated with 172 g (820 mmol) trifluoroacetic acid anhydride over 20 min at a temperature between 10 °C and 20 °C. The resulting solution was then stirred at room temperature for 1 h.
  • the formed suspension was cooled to 20 °C and a solid formed which was filtered off and washed with 200 ml n-heptane and then dried under reduced pressure (50°C, 30 mbar) affording 88 g (93 % of th.) of ⁇ 3-(4-chlorophenyl)-5-oxo-4-[(2.S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-l /-l,2,4-triazol- l-yl ⁇ acetonitrile as a solid.
  • Example 12A A mixture of 142 mg (0.25 mmol) of Example 12A in an ammonia solution (7N in methanol, 2 ml, 14 mmol) was stirred overnight at room temperature and the mixture was then evaporated. The obtained residue was purified by preparative HPLC (Chromatorex CI 8, 10 ⁇ , 125 x 30 mm, water/ac etonitrile-gradient 0.1 % formic acid) affording 107 mg (74% of th.) of the title compound.
  • the precipitate was filtered off and washed with water, which afforded 3.5 g of crude product.
  • the aqueous phase was extraced with ethyl acetate.
  • the organic phase was dried over magnesium sulfate, filtered and the solvent was removed in vacuo.
  • the crude product was purified by flash chromatography (silica gel, dichloromethane/methanol, 97/3), affording 4.00 g (81 % of th.) of the title compound as a solid.
  • Example 16 A dihydro-lH-l,2,4-triazol-l-yl ⁇ methyl)-l-[3-(trifluoromethoxy)pyridin-2-yl]-lH-l,2,4-triazole- carboxylate (Example 16 A, 84 ⁇ ) was dissolved in 5.0 mL of an ammonia solution (7N in methanol, 35.0 mmol). The resulting mixture was stirred for 1 h at room temperature. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 44.2 mg (89% of th.) of the title compound as a solid.
  • Example 18A (84 ⁇ ) was dissolved in 1 .25 mL of an ammonia solution (7N in methanol, 0.175 mmol). The resulting mixture was stirred for 1 h at room temperature. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 27.8 mg (57% of th.) of the title compound as a solid.
  • Example 19A (0.179 mmol) was dissolved in 1.0 mL of an ammonia solution (7N in methanol, 7.09 mmol). The resulting mixture was stirred for 16 h at room temperature. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 76.7 mg (79% of th.) of the title compound as a solid.
  • Example 20A (0.133mmol) was dissolved in 8.0 mL of an ammonia solution (7N in methanol, 1.14 mmol). The resulting mixture was stirred for 1 h at room temperature. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 49.7 mg (77% of th.) of the title compound as a solid.
  • Example 21A (151 ⁇ ) was dissolved in 1.0 mL NIL in EtOH (2.00 mmol, 2 N). The resulting mixture was stirred for 16 h at room temperature and another 1.0 mL of an ammonia solution (7N in methanol, 2.00 mmol) was added and stirring was continued for 16 h at room temperature. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 46.0 mg (49% of th.) of the title compound as a solid.
  • Example 18A (134 ⁇ ) was dissolved in 10 mL of an ammonia solution (7N in methanol, 70.0 mmol). The resulting mixture was stirred for 10 min at 70 °C, solvent was removed in vacuo and the residue was dissolved 10 mL of an ammonia solution (7N in methanol, 70.0 mmol) stirred for 3 h at 120 °C in the microwave. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 22.0 mg (28% of th.) of the title compound as a solid.
  • Example 22 A (0.197 mmol) was dissolved in 1.0 mL of an ammonia solution (7N in methanol, 7.09 mmol). The resulting mixture was stirred for 1 h at room temperature. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 92.0 mg (86%o of th.) of the title compound as a solid.
  • Example 23A (270 ⁇ ) was dissolved in 5.0 liiL of an ammonia solution (7N in methanol, 2.00 mmol). The resulting mixture was stirred for 1.5 h at room temperature. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 162.1 mg (quant.) of the title compound as a solid.
  • Example 24 A (21 1 ⁇ ) was dissolved in 5.0 mL of an ammonia solution (7N in methanol, 35.0 mmol). The resulting mixture was stirred for 1 h at room temperature. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 1 1 1 mg (97% of th.) of the title compound as a solid.
  • Example 2 A (199 ⁇ ) was dissolved in 5.0 mL of an ammonia solution (7N in methanol, 2.00 mmol). The resulting mixture was stirred for 20 min at room temperature. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Method 5). Lyophilisation of the product containing fractions afforded 99.5 mg (87% of th.) of the title compound as a solid.
  • PAI-1 Plasminogen activator inhibitor- 1
  • Demonstration of the activity of the Via antagonists of the present invention and the impact on response-to-treatment by raised vasopressin or copeptin may be accomplished through in vitro, ex vivo, and in vivo assays, and diagnostic means to quantify vasopressin or copeptin that are well known in the art. For example, the following assays may be used.
  • Example B-l Cellular in vitro assay for determining vasopressin receptor activity
  • the identification of agonists and antagonists of the Via and V2 vasopressin receptors from humans, rats and dogs as well as the quantification of the activity of the compounds of the invention is carried out using recombinant cell lines. These cell lines originally derive from a hamster's ovary epithelial cell (Chinese Hamster Ovary, CHO Kl, ATCC: American Type Culture Collection, Manassas, VA 20108, USA). The test cell lines constitutively express the human, rat or dog Via or V2 receptors.
  • cells are also stably transfected with a modified form of the calcium-sensitive photoproteins aequorin (human and rat Via) or obe- lin (dog Via), which, after reconstitution with the cofactor coelenterazine, emit light when there are increases in free calcium concentrations [Rizzuto R. Simpson AW, Brini M, Pozzan T, Nature 358. 325-327 (1992); Illarionov HA, Bondar VS, Illarionova VA, Vysotski ES, Gene 153 (2), 273- 274 (1995)].
  • aequorin human and rat Via
  • obe- lin dog Via
  • the resulting vasopressin receptor cells react to stimulation of the recombinantly expressed Via receptors by intracellular release of calcium ions, which can be quantified by the resulting photoprotein luminescence.
  • the G s -coupled V2 receptors are stably transfected into cell lines expressing the gene for firefly luciferase under control of a C RE -responsible promoter. Acti- vation of V2 receptors induces the activation of the C E -responsive promoter via cAMP increase, thereby inducing the expression of firefly luciferase.
  • the light emitted by photoproteins of Via cell lines as well as the light emitted by firefly luciferase of V2 cell lines corresponds to the activation or inhibition of the respective vasopressin receptor.
  • the bioluminescence of the cell lines is detected using a suitable luminometer [Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 17, 235-237 (1996)].
  • the cells are plated out in culture medium (DMEM/F12, 2% PC ' S, 2 mM glutamine, 10 mM H E PES. 5 ⁇ g/ml coelenterazine) in 384-well microtiter plates and kept in a cell incubator (96% humidity, 5% v/v CO -. 37°C).
  • culture medium DMEM/F12, 2% PC ' S, 2 mM glutamine, 10 mM H E PES. 5 ⁇ g/ml coelenterazine
  • test compounds in various concentrations are placed for 10 minutes in the wells of the microtiter plate before the agonist [ Arg 8 ] - vasopres sin at EC50 concentration is added. The resulting light signal is measured immediately in a luminometer.
  • Vasopressin V2 receptor cell lines are vascularlypressin V2 receptor cell lines.
  • the cells are plated out in culture medium (DMEM/F12, 2% FCS, 2 mM glutamine, 10 mM H E PES) in 384-well microtiter plates and kept in a cell incubator (96% humidity, 5% v/v CO2, 37°C).
  • test compounds in various concentrations and the agonist [Arg 8 ]-vasopressin at EC50 concentration are added together to the wells, and plates are incubated for 3 hours in a c ell incubator.
  • TritonTM and the substrate luciferin luminescence of firefly luciferase is measured in a luminometer.
  • Table 1A lists individual IC50 values for the compounds of general formula (I) (including racemic mixtures as well as separated enantiomers) that were obtained from cell lines transfected with the human Via or V2 receptor:
  • IC and i values can be determined in radioactive binding assays using membrane fractions of recombinant human embryonic kidney cell line 293 (HEK293) or CHO-K1 cell lines expressing the respective human vasopressin Via and V2 receptors.
  • Human recombinant vasopressin Via receptors expressed in HEK293 cells are used in 50 mM Tris-HCl buffer, pH 7.4, 5 mM MgCb, 0.1% BSA using standard techniques. Aliquots of prepared membranes are incubated with test compounds in various concentrations in duplicates and 0.03nM [ 125 I]Phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH 2 for 120 minutes at 25°C. Nonspecific binding is estimated in the presence of 1 ⁇ [Arg 8 ]Vasopressin.
  • Receptors are filtered and washed, the filters are then counted to determine [ !25 I]Phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg- Pro-Arg-Tyr-Nl h specifically bound.
  • CHO- 1 cells stably transfected with a plasmid encoding human vasopressin V2 receptor are used to prepare membranes in 50 mM Tris-HCl buffer, pH 7.4, 10 mM MgCh, 0.1% BSA using standard techniques. Aliquots of prepared membrane are incubated with test compounds in various concentrations in duplicates and 4 nM [ 3 H](Arg 8 )- Vasopressin for 120 minutes at 25°C.
  • Non-specific binding is estimated in the presence of 1 mM (Arg 8 )- vasopressin.
  • Membranes are filtered and washed 3 times and the filters are counted to determine [ 3 H](Arg 8 )-Vasopressin specifically bound.
  • IC50 values are determined by a non-linear, least squares regression analysis using MathlQTM (ID Business Solutions Ltd., UK).
  • the inhibition constant K is calculated using the equation of Cheng and Prusoff (Cheng, Y., Prusoff, W.H.. Biochem. Pharmacol. 22:3099-3108, 1973).
  • Example C-l Tissue culture testing of a compound which antagonizes AVPRla activity in vasopressin exposed renal cells
  • a method to demonstrate the prevention of deleterious fibrotic gene expression in vasopressin exposed renal NRK-49F cells by use of compounds blocking AV R I a dependent cellular processes is being conducted as follows.
  • Rat renal NRK-49F cells [(ATCC CRL 1 570. American Type Culture Collection Manassas, VA 20108 USA, www.atcc.org] which express native AVPRla at a high level and diminishing amounts of AVPR2 are being seeded in 6 -well microtiter plates for cell culture, at a cell density of 50.000 cells/well, in 2.0 ml of Opti-MEM medium (Cat. No. 31985070, Thermo Fisher Scientific Inc). Cells are being cultured in a cell incubator (96% humidity, 8% v/v carbon dioxide, 37°C).
  • vasopressin solution [Arg8 ] -vasopressin acetate, Sigma, Cat. No. V9879
  • additional test substances dissolved in vehicle: water with 20% by volume ethanol
  • vasopressin solution is regularly 5.0 nM if not indicated differently.
  • the test substance solution is added to the cell culture in small volumes (5 ⁇ /well), in order to keep a final concentration of ethanol below 0.03% vol/vol.
  • AVPRla antagonists are being added to wells at concentrations spanning a range of 1.0 nM to 1000 nM final concentration.
  • the culture supernatant is separated by suction for protein quantification by enzyme linked immune sorbent assays (ELISA).
  • ELISA enzyme linked immune sorbent assays
  • the adherent cells are lysed in 350 ⁇ of RLT buffer (Qiagen, Ratingen, Cat. No. 79216), and the RNA is isolated from this lysate using the RNeasy kit (Qiagen, Cat. No. 74104). This is followed by DNAse digestion (Invitrogen, Cat. No. 18068-015), cDNA synthesis (Promaga, ImProm-Ii Reverse Transcription System, Cat. No. A3800) and RTPCR (pPCR MasterMix RT-QP2X-03-075 from Eurogentec, Seraing, Belgium).
  • the primer sets for the RTPCR are selected on the basis of published mRNA gene sequences (NCBI Genbank Entrez Nucleotide Data Base) using the Prim er3 Plus program.
  • the RTPC for determining the relative mRNA expression in the cells of the various assay batches is carried out using 6-FAM TAMRA-labelied probes (manufactured by Sigma-Aldrich Co. LLC) and read-out by the Applied Biosystems ABi Prism 7900HT Sequence Detector in 384-well microtiter plate format in accordance with the instrument operating instructions.
  • the relative gene expression is represented by the delta-delta Ct value [Applied Biosystems, User Bulletin No.
  • Fig. 1-1 shows the induction of in RNA formation of pro-fibrotic genes PAI- 1 and osteopontin by exposure of renal NRK-49F cells to 1 nM Arg-vasopressin for 5 hours.
  • This gene induction is dose dependently attenuated in the presence of AVPRla antagonists.
  • the selective AVPRV2 antagonist Satavaptan does not inhibit the induction of these genes.
  • AVPRla antagonists prevent decrease of renal function in kidney ischemia reperfusion injury model in unilaterally nephrectomized copeptin-prone Spraque-Dawley rats (SD UNX IRI rat model)
  • Spraque-Dawley rats may benefit from treatment by AVPR l a antagonist after ischemia reperfusion injury due to raised vasopressin levels.
  • the beneficial effect of Via antagonists on kidney function is being investigated in a kidney ischemia-reperfusion injury model in rats as follows. Laboratory bred male 6-8 weeks old Sprague Dawley® rats are obtained from Charles River. Rats are maintained under standard laboratory conditions, 12 hour light-dark cycles with access to normal chow and drinking water at libitum. For the ischemia reperfusion injury model a total of 10- 12 rats is used in each control and experimental group. Animals are anesthetized with continuous inhaled isoflurane.
  • Right nephrectomy is performed through a right flank incision 7 days before the ischemic procedures in the contralateral kidneys.
  • a left flank incision is made. Renal vessels are exposed by dissection of the left renal pedicle.
  • Non-traumatic vascular clamps are used to stop blood flow (artery and vein) during 45 min of ischemia. Reperfusion is established by removing the clamps.
  • the abdominal wall (muscular layer and skin) is closed with 5.0 polypropylene sutures. Temgesic® (Buprenorphin, 0.025 mg/kg s.c.) is applied as an analgesic.
  • Copeptin in rat serum samples is being quantified using an ELISA kit manufactured by Peninsula Laboratories International, Inc. San Carlos, ( A 94070, USA.
  • the copeptin ELISA is conducted according to the assay protocol provided by the manufacturer.
  • Fig. 2-1 shows a typical copeptin assay result showing elevated serum copeptin levels in unilaterally nephrectomized Spraque-Dawley rats with (Placebo) and without ischemia reperfusion injury (Sham).
  • Urine of each animal is collected in metabolic cages over night before sacrifice at 24h post ischemia. Upon sacrifice, blood samples are obtained under terminal anesthesia. After centrifugation of the blood samples, serum is isolated. Both serum creatinine and serum urea are measured via clinical biochemistry analyzer (Pentra 400). Both urinary creatinine and albumin are measured to determine Albuminuria (albumin/creatinine ratio, ACR) via clinical biochemistry analyzer (Cobas Integra).
  • ACR albumin/creatinine ratio
  • Fig. 2-2 shows the reduction of serum creatinine (A) and serum urea (B) after treatment with different doses of a Via receptor antagonist (Relcovaptan, grey bars) in comparison to placebo treated (white bar) and sham operated animals (black bar).
  • a Via receptor antagonist Relcovaptan, grey bars
  • Fig. 2-3 shows the increase of ACR (urinary creatinin/ albumin ratio) in unilaterally nephrectomized Spraque-Dawley rats with (white bar) and without ischemia reperfusion injury (black bar ). Treatment with a Via receptor antagonist (Relcovaptan) in ischemic rats reduces ACR (grey bars).
  • ACR urinary creatinin/ albumin ratio
  • RNA is isolated from kidneys. Left kidneys are snap-frozen in liquid nitrogen at sacrifice. Kidney tissue is then homogenized and RNA is obtained. Total R A is transcribed to cDNA. Using TaqMan real-time PC R renal Nephrin and Podocin mRNA expression is analyzed in whole kidney tissue.
  • Copeptin is being measured in plasma or serum of subjects by use of a Time Resolved Amplified Cryptate Emission (TRACE) immunocomplex energy transfer assay (Thermo Scientific B'RrA'H'M'S Kryptor compact PLUS, Heringsdorf, Germany). Plasma or serum copeptin levels were investigated by epidemiological studies including healthy control subjects and patient cohorts representing diabetic patients, heart failure patients, hypertensive patients or patients suffering from different kinds of kidney disease. These study results reveal, that elevated copeptin levels can be detected even in mildly affected kidney disease patients or otherwise asymptomatic individuals. These individuals are supposed being at risk to develop kidney disease or to be exposed to accelerated decrease of kidney function due to the known deleterious action of excessive AVPRla activation.
  • TRACE Time Resolved Amplified Cryptate Emission
  • Example C-3.1; Fig. 3-1 Receiver operating characteristic (ROC) cu rves of copeptin in CKD- 3 patients
  • copeptin levels which are exceeding a concentration that is defined by the mean copeptin level of a healthy age and gender matched control cohort plus the addition of the standard deviation of the assay results of that reference cohort are being strongly correlated with indicators for renal disease.
  • Copeptin, cystatin C and NGAL plasma levels of CKD-3 patients are being analyzed by the receiver operating characteristic test to rank test results for specificity and sensitivity versus the healthy control group.
  • the Area (A) under the curves indicates the discriminatory power of the analyzed biomarkers.
  • Figs. 3-2 and 3-3 show copeptin plasma levels of healthy subjects together with copeptin levels which were found in patients who are affected by a mild degree of renal impairment, i.e. KDK iO grades Gl and Al - A3, or G2 and Al - A3, or G3a and Al - A2, commonly referred to as CKD1 , CKD2, or CKD-3a. It was found by the inventors, that a substantial proportion of these mildly affected CKD patients have elevated copeptin levels exceeding 8.0 pmol/L.
  • KDK iO grades Gl and Al - A3, or G2 and Al - A3, or G3a and Al - A2, commonly referred to as CKD1 , CKD2, or CKD-3a commonly referred to as CKD1 , CKD2, or CKD-3a. It was found by the inventors, that a substantial proportion of these mildly affected CKD patients have elevated copeptin levels exceeding 8.0 pmol/L
  • the graphical plots of the copeptin data clearly show that a sizable proportion of patients can be identified even in the groups of low grade kidney disease, who are characterized by copeptin concentrations exceeding 8.0 pmol/L, and therefore qualify particularly for treatment by a AVPR l a antagonist.
  • CKD classification CKD-3b, CKD-4, and CKD-5 frequency of elevated copeptin levels increases in these patients as well as the conc entration of the copeptin levels found in these patients.
  • Copeptin plasma levels shown in Fig. 3-2 were measured in diabetic CKD patients and healthy controls: Copeptin concentrations in healthy subjects (Controls) and diabetic patients of non- impaired renal function (Diabetics) and diabetic nephropathy patients representing the sub-group classifications of chronic kidney disease CKD-1, CKD-2, CKD-3a, CKD-3b, CKD-4, CKD-5, and CKD5d according to KDK iO criteria.
  • the numbers shown in the top line enumerate the number of individuals per group. Each circle assigns the copeptin concentration of an individual in the given sub-group. Group differences according to two-sided t-tests versus the Controls are presented by p values.
  • the dashed line dissects individual copeptin values above and below a concentration of 8.0 pmol/L.
  • a substantial proprotion of CKD-2 and CKD-3 patients show elevated copeptin levels above 8.0 pmol/L. All patients show cop ep tin levels above 8.0 pmol/L at advanced degrees of CKD-4 and CKD-5 in this study.
  • Copeptin plasma levels shown in Fig. 3-3 were measured in non-diabetic CKD patients and healthy controls: Copeptin concentrations in healthy subjects (Controls) and non-diabetic nephropathy patients representing the sub-group classifications of chronic kidney disease CKD-3, CKD-4, CKD-5, and CKD5d according to KDIGO criteria.
  • the numbers shown in the top line enumerate the number of individuals per group. Each circle assigns the copeptin concentration of an individual in the given sub-group.
  • the dashed line assigns the concentration of 8.0 pmol/L. More than one third of mild-to-moderate non-diabetic CKD-3 patients show elevated copeptin levels above 8.0 pmol/L. All patients show copeptin levels above 8.0 pmol/L at advanced degrees of CKD-4 and CKD-5 in this study.
  • Example C-2 As outlined by preclinical study results of Example C-2 it can be assumed that individuals characterized by abnormally increased copeptin level will most likely benefit from treatment regimes using an AVPRla antagonistic compound.
  • Figs. 3-4 shows a detailed plasma copeptin quantification which shows in particular, for one cohort of diabetic mild to moderate CKD patients, that these abnormal high copeptin levels were determined to be at 8.0 pmol/L for males and for females.
  • Copeptin mean values of the sub-groups are presented in the top line. Gender differences of copeptin leves for male and female subgroups are presented by p values of a two-sided t-test.
  • Chronic kidney disease patients of grade CKD-3 show no difference of mean copeptin levels with or without additional treatment by loop diuretics or thiazides.
  • the patients are being characterized by elevated copeptin levels despite standard of care treatment of these patients by angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker and/or calcium antagonist.
  • the top line enumerates the number of patients per group and the mean copeptin level of the group.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des antagonistes du récepteur V1a destinés à une utilisation dans le traitement et/ou la prévention de maladies rénales, en particulier de maladies rénales aiguës et chroniques. L'invention concerne en outre l'utilisation du niveau d'arginine vasopressine (AVP) et/ou de la copeptine comme marqueurs biologiques pour détecter une maladie rénale ou le début de l'apparition d'une insuffisance rénale chez un patient, ainsi que pour sélectionner les patients auxquels il sera possible de proposer des options thérapeutiques utilisant un antagoniste de V1a.
PCT/EP2017/060386 2016-05-03 2017-05-02 Antagonistes du récepteur v1a destinés à une utilisation dans le traitement de maladies rénales WO2017191117A1 (fr)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
EP16168163 2016-05-03
EP16168165 2016-05-03
EP16168165.5 2016-05-03
EP16168166 2016-05-03
EP16168169.7 2016-05-03
EP16168172.1 2016-05-03
EP16168166.3 2016-05-03
EP16168169 2016-05-03
EP16168163.0 2016-05-03
EP16168172 2016-05-03
EP16186839 2016-09-01
EP16186839.3 2016-09-01

Publications (1)

Publication Number Publication Date
WO2017191117A1 true WO2017191117A1 (fr) 2017-11-09

Family

ID=58640902

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/060386 WO2017191117A1 (fr) 2016-05-03 2017-05-02 Antagonistes du récepteur v1a destinés à une utilisation dans le traitement de maladies rénales

Country Status (1)

Country Link
WO (1) WO2017191117A1 (fr)

Citations (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2000006568A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues
WO2001019355A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique presentant de nouvelles proprietes pharmaceutiques
WO2001019776A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide dicarboxylique presentant des proprietes pharmaceutiques
WO2001019780A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarboxylique presentant des proprietes pharmaceutiques
WO2001019778A1 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique a proprietes pharmaceutiques
WO2002042301A1 (fr) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Nouveaux derives de pyrazolopyridine a substitution pyridine
WO2002070510A2 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques
WO2002070462A1 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Derives d'acide aminodicarboxylique
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2007134862A1 (fr) 2006-05-23 2007-11-29 Bayer Healthcare Ag Imidazolones et triazolones d'aryle substitués comme inhibiteurs des récepteurs de vasopressine
WO2009045309A2 (fr) * 2007-09-28 2009-04-09 Ferring B.V. Utilisation d'antagonistes des récepteurs v2 en combinaison avec des agonistes vasopressinergiques
WO2010054961A1 (fr) 2008-11-13 2010-05-20 F. Hoffmann-La Roche Ag Spiro-5,6-dihydro-4h-2,3,5,10b-tétraza-benzo[e]azulènes
WO2010057795A1 (fr) 2008-11-18 2010-05-27 F. Hoffmann-La Roche Ag Alkylcyclohexyléthers de dihydrotétrazabenzoazulènes
WO2010060836A1 (fr) 2008-11-28 2010-06-03 F. Hoffmann-La Roche Ag Arylcyclohexyléthers de dihydrotétrazabenzoazulènes pour emploi en tant qu'antagonistes du récepteur v1a de la vasopressine
WO2010063402A1 (fr) 2008-12-06 2010-06-10 Bayer Schering Pharma Aktiengesellschaft Benzyltriazolones et phénylsulfonyltriazolones substituées et leur utilisation
WO2010105770A1 (fr) 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft 2-acétamido-5-aryl-1,2,4-triazolones substitués et leur utilisation
WO2010105750A1 (fr) 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft Dérivés de triazole en tant qu'inhibiteurs des récepteurs de vasopressine pour le traitement de l'insuffisance cardiaque
WO2011023703A1 (fr) 2009-08-27 2011-03-03 Bayer Schering Pharma Aktiengesellschaft 2-acetamido-5-aryl-1,2,4-triazolones hétérocycliquement substituées et leur utilisation
WO2011104322A1 (fr) 2010-02-27 2011-09-01 Bayer Pharma Aktiengesellschaft Aryltriazolone liée à un bis-aryle et son utilisation
WO2011120877A1 (fr) 2010-03-31 2011-10-06 F. Hoffmann-La Roche Ag Aryl-cyclohexyl-tétraazabenzo[e]azulènes
WO2011128265A1 (fr) 2010-04-13 2011-10-20 F. Hoffmann-La Roche Ag Aryl-/hétéroaryl-cyclohexényl-tétraazabenzo[e]azulènes en tant qu'antagonistes de vasopressine
WO2011131596A1 (fr) 2010-04-21 2011-10-27 F. Hoffmann-La Roche Ag Hétéroaryl-cyclohexyl-tétraazabenzo[e]azulènes comme antagonistes des récepteurs de la vasopressine v1a
WO2011141396A1 (fr) 2010-05-10 2011-11-17 F. Hoffmann-La Roche Ag Hétéroaryl-cyclohexyl-tétraazabenzo[e]azulènes
WO2011147809A1 (fr) 2010-05-26 2011-12-01 Bayer Pharma Aktiengesellschaft 5-fluoro-1h-pyrazolopyridines substituées et leur utilisation
WO2012004258A1 (fr) 2010-07-09 2012-01-12 Bayer Pharma Aktiengesellschaft Pyrimidines et triazines annelées et leur utilisation pour traiter ou prévenir des affections du système cardio-vasculaire
WO2012028647A1 (fr) 2010-09-03 2012-03-08 Bayer Pharma Aktiengesellschaft Azahétérocycles bicycliques et leur utilisation
WO2012028644A1 (fr) 2010-09-02 2012-03-08 Bayer Pharma Aktiengesellschaft N-phénéthyl-triazolonacétamidessubstitués et leur utilisation
WO2012035075A1 (fr) 2010-09-16 2012-03-22 Bayer Pharma Aktiengesellschaft Phénylacétamides et phénylpropanamides substitués et leur utilisation
WO2012059549A1 (fr) 2010-11-04 2012-05-10 Bayer Pharma Aktiengesellschaft 6-fluoro-1h-pyrazolo[4,3-b]pyridines substituées et leur utilisation
WO2015024819A1 (fr) 2013-08-19 2015-02-26 F. Hoffmann-La Roche Ag Antagonistes de v1a pour traiter des troubles du sommeil impliquant un décalage de phase
WO2015082370A1 (fr) 2013-12-05 2015-06-11 F. Hoffmann-La Roche Ag Synthèse de trans-8-chloro-5-méthyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4 h-2,3,5,10b-tétraaza-benzo[e]azulène et leurs formes cristallines
WO2015091411A1 (fr) 2013-12-19 2015-06-25 F. Hoffmann-La Roche Ag Spiro-oxazolones
WO2015124541A1 (fr) 2014-02-20 2015-08-27 F. Hoffmann-La Roche Ag Spiro-oxazolones
WO2016071212A1 (fr) 2014-11-03 2016-05-12 Bayer Pharma Aktiengesellschaft Dérivés de phényltriazole à substitution hydroxyalkyle et utilisations associées
WO2016075181A1 (fr) 2014-11-14 2016-05-19 F. Hoffmann-La Roche Ag Spiro-thiazolones

Patent Citations (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2000006568A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues
WO2001019355A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique presentant de nouvelles proprietes pharmaceutiques
WO2001019776A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide dicarboxylique presentant des proprietes pharmaceutiques
WO2001019780A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarboxylique presentant des proprietes pharmaceutiques
WO2001019778A1 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique a proprietes pharmaceutiques
WO2002042301A1 (fr) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Nouveaux derives de pyrazolopyridine a substitution pyridine
WO2002070510A2 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques
WO2002070462A1 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Derives d'acide aminodicarboxylique
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2007134862A1 (fr) 2006-05-23 2007-11-29 Bayer Healthcare Ag Imidazolones et triazolones d'aryle substitués comme inhibiteurs des récepteurs de vasopressine
WO2009045309A2 (fr) * 2007-09-28 2009-04-09 Ferring B.V. Utilisation d'antagonistes des récepteurs v2 en combinaison avec des agonistes vasopressinergiques
WO2010054961A1 (fr) 2008-11-13 2010-05-20 F. Hoffmann-La Roche Ag Spiro-5,6-dihydro-4h-2,3,5,10b-tétraza-benzo[e]azulènes
WO2010057795A1 (fr) 2008-11-18 2010-05-27 F. Hoffmann-La Roche Ag Alkylcyclohexyléthers de dihydrotétrazabenzoazulènes
WO2010060836A1 (fr) 2008-11-28 2010-06-03 F. Hoffmann-La Roche Ag Arylcyclohexyléthers de dihydrotétrazabenzoazulènes pour emploi en tant qu'antagonistes du récepteur v1a de la vasopressine
WO2010063402A1 (fr) 2008-12-06 2010-06-10 Bayer Schering Pharma Aktiengesellschaft Benzyltriazolones et phénylsulfonyltriazolones substituées et leur utilisation
WO2010105770A1 (fr) 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft 2-acétamido-5-aryl-1,2,4-triazolones substitués et leur utilisation
WO2010105750A1 (fr) 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft Dérivés de triazole en tant qu'inhibiteurs des récepteurs de vasopressine pour le traitement de l'insuffisance cardiaque
WO2011023703A1 (fr) 2009-08-27 2011-03-03 Bayer Schering Pharma Aktiengesellschaft 2-acetamido-5-aryl-1,2,4-triazolones hétérocycliquement substituées et leur utilisation
WO2011104322A1 (fr) 2010-02-27 2011-09-01 Bayer Pharma Aktiengesellschaft Aryltriazolone liée à un bis-aryle et son utilisation
US20130190330A1 (en) * 2010-02-27 2013-07-25 Bayer Intellectual Property Gmbh Bisaryl-bonded aryltriazolones and use thereof
WO2011120877A1 (fr) 2010-03-31 2011-10-06 F. Hoffmann-La Roche Ag Aryl-cyclohexyl-tétraazabenzo[e]azulènes
WO2011128265A1 (fr) 2010-04-13 2011-10-20 F. Hoffmann-La Roche Ag Aryl-/hétéroaryl-cyclohexényl-tétraazabenzo[e]azulènes en tant qu'antagonistes de vasopressine
WO2011131596A1 (fr) 2010-04-21 2011-10-27 F. Hoffmann-La Roche Ag Hétéroaryl-cyclohexyl-tétraazabenzo[e]azulènes comme antagonistes des récepteurs de la vasopressine v1a
WO2011141396A1 (fr) 2010-05-10 2011-11-17 F. Hoffmann-La Roche Ag Hétéroaryl-cyclohexyl-tétraazabenzo[e]azulènes
WO2011147809A1 (fr) 2010-05-26 2011-12-01 Bayer Pharma Aktiengesellschaft 5-fluoro-1h-pyrazolopyridines substituées et leur utilisation
WO2012004258A1 (fr) 2010-07-09 2012-01-12 Bayer Pharma Aktiengesellschaft Pyrimidines et triazines annelées et leur utilisation pour traiter ou prévenir des affections du système cardio-vasculaire
WO2012028644A1 (fr) 2010-09-02 2012-03-08 Bayer Pharma Aktiengesellschaft N-phénéthyl-triazolonacétamidessubstitués et leur utilisation
WO2012028647A1 (fr) 2010-09-03 2012-03-08 Bayer Pharma Aktiengesellschaft Azahétérocycles bicycliques et leur utilisation
WO2012035075A1 (fr) 2010-09-16 2012-03-22 Bayer Pharma Aktiengesellschaft Phénylacétamides et phénylpropanamides substitués et leur utilisation
WO2012059549A1 (fr) 2010-11-04 2012-05-10 Bayer Pharma Aktiengesellschaft 6-fluoro-1h-pyrazolo[4,3-b]pyridines substituées et leur utilisation
WO2015024819A1 (fr) 2013-08-19 2015-02-26 F. Hoffmann-La Roche Ag Antagonistes de v1a pour traiter des troubles du sommeil impliquant un décalage de phase
WO2015082370A1 (fr) 2013-12-05 2015-06-11 F. Hoffmann-La Roche Ag Synthèse de trans-8-chloro-5-méthyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4 h-2,3,5,10b-tétraaza-benzo[e]azulène et leurs formes cristallines
WO2015091411A1 (fr) 2013-12-19 2015-06-25 F. Hoffmann-La Roche Ag Spiro-oxazolones
WO2015124541A1 (fr) 2014-02-20 2015-08-27 F. Hoffmann-La Roche Ag Spiro-oxazolones
WO2016071212A1 (fr) 2014-11-03 2016-05-12 Bayer Pharma Aktiengesellschaft Dérivés de phényltriazole à substitution hydroxyalkyle et utilisations associées
WO2016075181A1 (fr) 2014-11-14 2016-05-19 F. Hoffmann-La Roche Ag Spiro-thiazolones

Non-Patent Citations (30)

* Cited by examiner, † Cited by third party
Title
AM J NEPHROL., vol. 44, 2016, pages 22 - 28
BJORNSTAD PETTER ET AL: "Elevated copeptin is associated with atherosclerosis and diabetic kidney disease in adults with type 1 diabetes", JOURNAL OF DIABETES AND ITS COMPLICATIONS, ELSEVIER SCIENCE, NEW YORK, NY, US, vol. 30, no. 6, 19 April 2016 (2016-04-19), pages 1093 - 1096, XP029640460, ISSN: 1056-8727, DOI: 10.1016/J.JDIACOMP.2016.04.012 *
BOERTIEN W E ET AL: "Copeptin, a surrogate marker for arginine vasopressin, is associated with declining glomerular filtration in patients with diabetes mellitus (ZODIAC-33).", DIABETOLOGIA AUG 2013, vol. 56, no. 8, August 2013 (2013-08-01), pages 1680 - 1688, XP002766765, ISSN: 1432-0428 *
BOLIGNANO D ET AL: "Vasopressin beyond water: Implications for renal diseases", CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION 2010 LIPPINCOTT WILLIAMS AND WILKINS GBR, vol. 19, no. 5, September 2010 (2010-09-01), pages 499 - 504, ISSN: 1062-4821 *
CHENG, Y.; PRUSOFF, W.H., BIOCHEM. PHARMACOL., vol. 22, 1973, pages 3099 - 3108
DATABASE EMBASE [online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; September 2010 (2010-09-01), BOLIGNANO D ET AL: "Vasopressin beyond water: Implications for renal diseases", XP002766767, Database accession no. EMB-2010457739 *
DIABETES CARE, vol. 36, 2013, pages 3639 - 3645
DIABETOLOGIA, vol. 56, 2013, pages 1680 - 1688
DUFFIELD J S: "Cellular and molecular mechanisms in kidney fibrosis", J CLIN INVEST., vol. 124, no. 6, 2014, pages 2299 - 2306
ILLARIONOV BA; BONDAR VS; ILLARIONOVA VA; VYSOTSKI ES, GENE, vol. 153, no. 2, 1995, pages 273 - 274
INTERNATIONAL JOURNAL OF OBESITY, vol. 37, 2013, pages 598 - 603
JASN, vol. 25, no. 6, 2014, pages 1140 - 1147
JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 76, no. 7, 1979, pages 1411
KIDNEY INTERNATIONAL, vol. 77, 2010, pages 29 - 36
LI X; CHAN TO; MYERS V; CHOWDHURY I; ZHANG XQ; SONG J; ZHANG J; ANDREI J; FUNAKOSHI H; ROBBINS J, CIRCULATION, vol. 124, 2011, pages 572 - 581
MEIJER E; BOERTIEN W E; ZIETSE R; GANSEVOORT R T: "Potential deleterious effects of vasopressin in chronic kidney disease and particularly autosomal dominant polycystic kidney disease", KIDNEY BLOOD PRESS RES, vol. 34, 2011, pages 235 - 244
MILLIGAN G; MARSHALL F; REES S, TRENDS IN PHARMACOLOGICAL SCIENCES, vol. 17, 1996, pages 235 - 237
MORGENTHALER NILS G: "Copeptin: a biomarker of cardiovascular and renal function.", CONGESTIVE HEART FAILURE (GREENWICH, CONN.) JUL 2010, vol. 16 Suppl 1, July 2010 (2010-07-01), pages S37 - S44, XP002766766, ISSN: 1751-7133 *
NORBERTO PERICO ET AL: "V1/V2 Vasopressin receptor antagonism potentiates the renoprotection of renin-angiotensin system inhibition in rats with renal mass reduction", KIDNEY INTERNATIONAL, vol. 76, no. 9, 1 November 2009 (2009-11-01), LONDON, GB, pages 960 - 967, XP055342004, ISSN: 0085-2538, DOI: 10.1038/ki.2009.267 *
PENCINA MJ ET AL.: "Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond", STAT MED, vol. 27, 2008, pages 157 - 172, XP055399798, DOI: doi:10.1002/sim.2929
PORNPIMOL RIANTHAVORN ET AL: "Use of conivaptan to allow aggressive hydration to prevent tumor lysis syndrome in a pediatric patient with large-cell lymphoma and SIADH", PEDIATRIC NEPHROLOGY ; JOURNAL OF THE INTERNATIONAL PEDIATRIC NEPHROLOGY ASSOCIATION, SPRINGER, BERLIN, DE, vol. 23, no. 8, 24 April 2008 (2008-04-24), pages 1367 - 1370, XP019631977, ISSN: 1432-198X *
RIZZUTO R; SIMPSON AW; BRINI M; POZZAN T, NATURE, vol. 358, 1992, pages 325 - 327
S. M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: doi:10.1002/jps.2600660104
SANTILLAN MK; SANTILLAN DA; SCROGGINS SM; MIN JY; SANDGREN JA; PEARSON NA; LESLIE KK; HUNTER SK; ZAMBA GK; GIBSON-CORLEY KN: "Vasopressin in preeclampsia: a novel very early human pregnancy biomarker and clinically relevant mouse model", HYPERTENSION, vol. 64, no. 4, 2014, pages 852 - 859
TAHARA A ET AL: "Effects of YM218, a nonpeptide vasopressin V"1"A receptor-selective antagonist, on human vasopressin and oxytocin receptors", PHARMACOLOGICAL RESEARCH, ACADEMIC PRESS, LONDON, GB, vol. 51, no. 3, 1 March 2005 (2005-03-01), pages 275 - 281, XP004715283, ISSN: 1043-6618, DOI: 10.1016/J.PHRS.2004.09.006 *
TASEVSKA IRINA ET AL: "Increased Levels of Copeptin, a Surrogate Marker of Arginine Vasopressin, Are Associated with an Increased Risk of Chronic Kidney Disease in a General Population.", AMERICAN JOURNAL OF NEPHROLOGY 2016, vol. 44, no. 1, 28 June 2016 (2016-06-28), pages 22 - 28, XP002766764, ISSN: 1421-9670 *
TAVEAU C; CHOLLET C; WAECKEL L; DESPOSITO D; BICHET DG; ARTHUS MF; MAGNAN C; PHILIPPE E; PARADIS V; FOUFELLE F: "Vasopressin and hydration play a major role in the development of glucose intolerance and hepatic steatosis in obese rats", DIABETOLOGIA, vol. 58, no. 5, 2015, pages 1081 - 1090, XP035479142, DOI: doi:10.1007/s00125-015-3496-9
THIBONNIER M; ROBERTS JM, J CLIN INVEST, vol. 76, 1985, pages 1857 - 1864
WASILEWSKI MA; MYERS VD; RECCHIA FA; FELDMAN AM; TILLEY DG, CELL SIGNAL., vol. 28, no. 3, 2016, pages 224 - 233
WASILEWSKI MA; MYERS VD; RECCHIA FA; FELDMAN AM; TILLEY DG: "Arginine vasopressin receptor signaling andfunctional outcomes in heart failure", CELL SIGNAL., vol. 28, no. 3, 2016, pages 224 - 233, XP029388858, DOI: doi:10.1016/j.cellsig.2015.07.021

Similar Documents

Publication Publication Date Title
US11091463B2 (en) Amide-substituted pyridinyltriazole derivatives and uses thereof
EP3215498B1 (fr) Dérivés de phényltriazole à substitution hydroxyalkyle et utilisations associées
US10800746B2 (en) Oxoalkyl-substituted phenyltriazole derivatives and uses thereof
US10525041B2 (en) Fluoroalkyl-substituted aryltriazole derivatives and uses thereof
US10526314B2 (en) Hydroxyalkyl-substituted heteroaryltriazole derivatives and uses thereof
US10927098B2 (en) Hydroxyalkyl-substituted triazole derivatives and uses thereof
US10815205B2 (en) Amide-substituted phenyltriazole derivatives and uses thereof
US20190119251A1 (en) Amide-substituted aryltriazole derivatives and uses thereof
US20210253557A1 (en) Substituted triazole derivatives and uses thereof
US11230540B2 (en) Substituted triazole derivatives and uses thereof
US11331314B2 (en) Amine substituted triazole derivatives and uses thereof
WO2017191117A1 (fr) Antagonistes du récepteur v1a destinés à une utilisation dans le traitement de maladies rénales

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17720149

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17720149

Country of ref document: EP

Kind code of ref document: A1