RU2805150C2 - Proteinuria treatment - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.

SUBSTANCE: invention relates to the treatment of primary nephrotic syndrome. The use of a compound of formula (II), including its stereoisomeric forms, or a pharmaceutically acceptable salt thereof for the treatment of primary nephrotic syndrome, as well as for the manufacture of a medicament for the treatment of primary nephrotic syndrome is disclosed.

EFFECT: use of the compound makes it possible to effectively treat primary nephrotic syndrome.

9 cl, 3 dwg, 2 ex

Description

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a composition containing a compound of Formula (I), (Ia) or (II), or a pharmaceutically acceptable derivative thereof, for use in a method of treating kidney disease, in particular proteinuric kidney diseases such as nephrotic syndromes.

BACKGROUND OF THE INVENTION

Proteinuria, a feature of glomerular disorder, is usually detected by urinalysis and is itself a significant independent modifiable risk factor for end-stage renal disease, premature death from cardiovascular disease, and ischemic stroke in patients with diabetes. Despite recent advances, refractory proteinuria continues to be a problem in clinical practice. More effective techniques need to be developed to attenuate glomerular disorder and achieve remission of proteinuria. Recent evidence suggests that the melanocortin system is a new target for the treatment of proteinuria.

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. A third of such patients have a favorable prognosis with spontaneous remission. However, approximately 50% of the remaining cases will remain unchanged, and 50% will develop ESRD (end-stage renal disease) and require dialysis. Nephrotic syndrome is a glomerular disease characterized by proteinuria, edema, hypoalbuminemia and hyperlipidemia. In most cases, the cause of MN is idiopathic, and the mechanisms underlying this disease are largely unknown. Classic treatment is nonspecific and often involves anti-inflammatory steroids, sometimes in combination with cytotoxic agents. These drugs affect various tissues, causing cytotoxic effects, causing osteoporosis, adrenal insufficiency, hypertension, peptic ulcers, and increasing the risk of glucose intolerance and infections. Therefore, more effective and specific treatments are needed.

The melanocortin system is a set of neuropeptidergic and immunoendocrine signaling pathways that play an essential role in the homeostatic control of a wide range of physiological functions, including melanogenesis, stress response, inflammation, immunomodulation and adrenocortical steroidogenesis. It consists of several components, including five G-protein coupled melanocortin receptors: melanocortin receptors MC1R-MC5R; peptide ligands: α, β, γ-melanocyte-stimulating hormones (α, β, γ-MSH), adrenocorticotropic hormone (ACTH), secreted by the anterior pituitary gland; and endogenous antagonists. The biological functions of the melanocortin system are mediated by five melanocortin receptors (MCRs), which have an unequal distribution in tissues, are involved in the transmission of various signals and influence changes in biological activity in various organ systems.

Adrenocorticotropic hormone (ACTH) is an endogenous peptide hormone and agonist for all melanocortin receptors 1-5 (MC1-5R), of which MC2R specifically binds to ACTH; steroidogenesis is induced only by ACTH and is mediated by MC2R in the adrenal cortex. Alpha melanocyte stimulating hormone (α-MSH) is a small endogenous peptide hormone structurally related to ACTH that binds to all MCR receptors except MC2R. MC1R is abundantly expressed by melanocytes in the skin, represents a key control point in melanogenesis and determines hair color.

Melanocortin therapy using ACTH or nonsteroidogenic melanocortin peptides attenuates proteinuria and glomerular abnormalities in experimental models of glomerular diseases and induces remission of nephrotic syndrome in patients with various glomerulopathies, even steroid-resistant glomerulopathies, including membranous nephropathy (MN), minimal change disease (MCD) ), focal segmental glomerulosclerosis (FSGS) and IgA nephropathy. The underlying mechanism remains unclear, but the role of melanocortin receptor 1 (MC1R) has been implicated in this mechanism and is highly and specifically expressed in the human renal cortex and specific renal epithelial cell types, including podocytes (Lindskog et al . 2010). However, recent studies have shown the effectiveness of ACTH monotherapy and NDP-αMSH ([Nle4, D-Phe7]-αMSH) also in patients with dominant-negative MC1R mutations, which was also confirmed in mice with an MC1R null mutation and in vitro with using primary podocytes obtained from MC1R-null and wild-type MC1R mice. Thus, the antiproteinuric effect of the melanocortin signaling pathway appears to be steroidogenic-independent and does not necessarily require MC1R, and this melanocortin effect could, at least in part, involve a pathogenic pathway common to all proteinuric kidney diseases. Podocytes are a critical component of the glomerular filtration barrier, controlling glomerular permeability and selectivity, and are considered the main culprit responsible for massive proteinuria in various glomerular diseases. The beneficial effect of melanocortin therapy can probably be attributed to a direct effect on podocytes (Qiao et al . 2016 ).

Thus, it is currently impossible to predict which melanocortin agonists and which associated targets may be used as candidates for the treatment of proteinuric diseases such as kidney disease.

Phenyl pyrrole aminoguanidine derivatives having activity at melanocortin receptors are described in WO 2007/141343. One example of such a compound is the anti-inflammatory drug AP1189 (( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H -pyrrol-2-yl]allylidene}-aminoguanidinium acetate), which is known to was first shown to bind to MC1R (WO 2007/141343), and was later found to be a functionally selective dual agonist of the MC1R and MC3R receptors that does not cause classical cAMP generation (and hence MC1R-induced melanogenesis), but instead, appears to induce alternative pathways including ERK1/2 phosphorylation and Ca ²⁺ mobilization (Montero-Melendez et al . 2015 ).

SUMMARY OF THE INVENTION

The present inventors have found that the phenyl pyrrole aminoguanidine derivative AP1189 (( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H -pyrrol-2-yl]allylidene}-aminoguanidinium acetate) significantly weakens proteinuria in passive Heyman nephritis, an experimental model of nephropathy, compared with the vehicle, which is reflected in a significant decrease in the rate of albumin excretion and FRAlb (fractional albumin excretion); and is also characterized by a significantly higher GFR (glomerular filtration rate; creatinine clearance) and a significant decrease in FRAlb levels compared to the values obtained during treatment using ACTH (1-24). This means that AP1189 and related compounds are candidates for achieving more effective treatment of proteinuric kidney diseases.

According to one aspect of the present invention there is provided a composition containing a compound of Formula (I) or (Ia):

Formula (I),

Formula (Ia),

including its tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric forms and racemic forms,

Where

n has the value 1, 2 or 3;

each R ₁ , R ₂ , R ₃ , R ₄ and R ₅ is independently selected from the group consisting of a hydrogen atom, optionally substituted C _1-6 -alkyl, optionally substituted C _3-6 -cycloalkyl, optionally substituted C _2-6 - alkenyl, optionally substituted C _4-6 -alkadienyl, optionally substituted C _2-6 -alkynyl, hydroxy, optionally substituted C _1-6 -alkoxy, optionally substituted C _2-6 -alkenyloxy, carboxy, optionally substituted C _1-6 -alkoxycarbonyl , optionally substituted C _1-6 -alkylcarbonyl, formyl, C _1-6 -alkylsulfonylamino, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylamino, arylsulfonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxy carbonyl, optional substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylamino, heteroarylsulfonylamino, optionally substituted heterocyclyl, optionally substituted heterocyclyloxycarbonyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyl, optionally substituted heterocyclylamino, heterocyclylsulfonylamino, amino, mono- and di(C _1-6 -alkyl)amino , carbamoyl, mono- and di(C _1-6 -alkyl)aminocarbonyl, amino-C _1-6 -alkyl-aminocarbonyl, mono- and di(C _1-6 -alkylamino-C _1-6 -alkyl-aminocarbonyl, C _1-6 -alkylcarbonylamino, amino-C _1-6 -alkyl-carbonylamino, mono- and di(C _1-6 -alkyl)amino-C _1-6 -alkyl-carbonylamino, cyano, guanidino, urea, C _1-6 -alkanoyloxy, C _1-6 -alkylsulfonyl, C _1-6 -alkylsulfinyl, C _1-6 -alkylsulfonyl-oxy, aminosulfonyl, mono- and di(C _1-6 -alkyl)aminosulfonyl, nitro, optionally substituted C _1-6 -alkylthio and halogen atom, where any C _1-6 -alkyl linked to the nitrogen atom is optionally substituted with hydroxy, C _1-6 -alkoxy, C _2-6 -alkenyloxy, amino, mono- and di(C _1-6 -alkyl)amino, carboxy, C _1-6 -alkylcarbonylamino, halogen atom, C _1-6 -alkylthio, C _1-6 -alkyl-sulfonyl-amino or guanidine;

each R ₆ and R ₇ is independently selected from the group consisting of a hydrogen atom, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _4-6 alkadienyl, optionally substituted C _2-6 - alkynyl, optionally substituted C _1-6 -alkoxycarbonyl, optionally substituted C _1-6 -alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- and di (C _1-6 -alkyl)aminocarbonyl, amino-C _1-6 -alkyl-aminocarbonyl and mono- and di(C _1-6 -alkyl)amino-C _1-6 -alkyl-aminocarbonyl; or R ₆ and R ₇ together may form a five- or six-membered nitrogen-containing ring;

or a pharmaceutically acceptable derivative of this compound, for use in the treatment of kidney disease.

According to one aspect of the present invention there is also provided a composition containing a compound of Formula (II):

Formula (II),

including its tautomeric and isomeric forms, such as enantiomeric forms, diastereoisomeric forms and racemic forms;

or a pharmaceutically acceptable derivative of this compound, for use in the treatment of kidney disease.

According to one aspect of the present invention, there is also provided a composition containing a compound selected from the group consisting of {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidine; {3-[1-(2-nitrophenyl)-1 H -pyrrol-2-yl]-allylidene}-aminoguanidinium acetate; ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidine and ( E ) -N - trans- {3-[1-( 2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidinium acetate, or a pharmaceutically acceptable derivative thereof, for use in the treatment of kidney disease.

According to one embodiment of the present invention, said kidney disease is a kidney disease that is accompanied by proteinuria.

According to one embodiment of the present invention, said kidney disease is a glomerular disease, such as a disease affecting glomerular podocytes.

According to one embodiment of the present invention, said kidney disease is a nephrotic syndrome (glomerulonephrosis), such as primary nephrotic syndrome or secondary nephrotic syndrome.

Definitions

The term "pharmaceutically acceptable derivative" as used herein includes pharmaceutically acceptable salts, which means a salt that is not harmful to the patient. Such salts include pharmaceutically acceptable base or acid addition salts, as well as pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. The pharmaceutically acceptable derivative further includes esters and prodrugs or other precursors of the compound that can be biologically metabolized to form the active compound, or crystalline forms of the compound.

The term "acid addition salt" is intended to include a "pharmaceutically acceptable acid addition salt" which means a salt that is not harmful to the patient. Acid addition salts include salts of inorganic acids as well as organic acids. Typical examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid and the like. Typical examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamic, bismethylene salicylic, ethanesulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA (ethylenediaminetetraacetic acid), glycolic, para -aminobenzoic, glutamic, benzenesulfonic, para -toluenesulfonic acids and the like. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 66, 2, (1977), which are incorporated herein by reference.

The term "therapeutically effective amount" of a compound as used herein means an amount sufficient to treat, alleviate, prevent, reduce the risk of onset of, or partially suppress the clinical manifestations of a given disease or disorder and its complications. An amount sufficient to achieve these purposes is defined as a "therapeutically effective amount." The effective amount in each case will generally depend on the severity of the disease or injury and the weight and general condition of the subject. It is generally understood that determination of the appropriate dose can be accomplished using standard experimentation, by constructing a matrix of values and testing various points on the matrix, which can be performed by a qualified physician or veterinarian of average competence.

The terms “treating” and “treating” as used herein refer to the provision of medical care and monitoring of a patient to combat a condition, disease or disorder. The term is intended to include the full spectrum of treatment for the pathological condition from which the patient suffers. The patient being treated is preferably a mammal, in particular a human. However, as used herein, the term “treating” also refers to animals such as mice, rats, dogs, cats, horses, cattle, sheep and pigs. The patients treated may be of different ages.

DESCRIPTION OF DRAWINGS

Figure 1. In rats treated with test compound 1 (AP1189; (( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene} -aminoguanidinium acetate), a significant reduction in proteinuria was recorded compared with control rats (received vehicle) on days 28 and 42. In control rats, the level of albumin excretion remained unchanged at all time points, whereas in rats that received the test compound 1, a decrease in the rate of albumin excretion was recorded by 31±8% on day 28 and a decrease in the rate of albumin excretion by 48±10% on day 42. See Examples for details.

Figure 2A. In rats treated with test compound 1 (AP1189; (( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidinium acetate ), recorded a significantly higher GFR (creatinine clearance) after 4 weeks of treatment than in rats that received positive control (ACTH 1-24) as treatment:

i) positive control 10 mg/day: 2.19 ±0.24 ml/min;

ii) test compound 1 20 mg/kg: 3.12±0.14 ml/min (p=0.002);

iii) test compound 1 40 mg/kg: 2.94±0.14 ml/24 min (p=0.01).

Figure 2B. In rats treated with test compound 1 (AP1189; (( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidinium acetate ), a significant decrease in fractional albumin excretion (FEAlb) was recorded compared to rats receiving positive control (ACTH 1-24):

i) positive control 10 mg/day: 0.59±0.02%;

ii) test compound 1 20 mg/kg: 0.045±0.04% (p=0.007);

iii) test compound 1 40 mg/kg: 0.35±0.05% (p=0.001).

DETAILED DESCRIPTION OF THE INVENTION

Melanocortin (MC) receptors (MC1R-MC5R), a family of class A G protein-coupled receptors (GPCRs), are promising therapeutic targets for a range of pathological conditions due to their wide distribution and the diversity of physiological processes they regulate. MC1R regulates skin tanning under UV light and other immune responses through its expression in white blood cells. MC2R regulates cortisol production by the adrenal glands, while MC5R is involved in exocrine gland secretion. MC3R and MC4R have nonredundant functions in energy homeostasis along with their specific anti-inflammatory actions; MC3R activation in particular protects against joint inflammation such as arthritis, MC4R is neuroprotective against brain inflammation. Accordingly, MCR drugs could be used to target a variety of pathological conditions, including skin conditions, cardiovascular pathologies, joint inflammation, obesity and cachexia.

Peripheral MC1R and MC3R receptors can be activated pharmacologically to induce an anti-inflammatory response. The endogenous agonist α-melanocyte stimulating hormone (αMSH), like other protective mediators, is released by immune cells to counterbalance proinflammatory signals and thereby prevent excessive tissue damage. In light of the inflammatory concept, therapies targeting MC1R and MC3R mimic the host's own defenses and might have less side effects.

The use of corticotropin, or adrenocorticotropic hormone (ACTH), which had been considered an effective treatment for rheumatic diseases since the early 1950s, was abandoned when synthetic glucocorticoids became available. However, the discovery of an alternative anti-inflammatory mechanism for ACTH, involving activation of peripheral MC receptors on immune cells, has renewed interest in the development of new ACTH-like molecules that are not steroidogenic for the treatment of joint diseases such as gout or RA (rheumatoid arthritis). However, the limitation associated with translational delivery of new MC drugs, with the exception of commercially available ACTH drugs, is compounded by the fact that receptor selectivity has not yet been achieved.

Innovative approaches to finding drugs that interact with G protein-coupled receptors could help overcome this limitation. Allosteric modulation refers to the ability of a molecule to enhance (positive modulation) or weaken (negative modulation) the effect of an endogenous ligand upon binding to a specific site on a receptor protein called an allosteric site. A higher degree of selectivity can be expected when the allosteric regions of the five MCR receptors are less conserved, and indeed allosteric modulators of the MC4R receptor are currently being developed for the treatment of obesity.

Another promising concept of significant therapeutic interest is the concept of functional-selective agonism. The outdated concept that a receptor can exist in only two possible conformations, an active conformation and an inactive conformation, has been replaced by the concept that there can be multiple active conformations, each producing a distinct signal, resulting in multiple functional responses. Receptor activation, instead of being linear and static, becomes a highly dynamic and multidimensional process in which a diversity of active conformations can be induced by different molecules causing distinct effects.

Small molecule AP1189 (( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H -pyrrol-2-yl]allylidene}-aminoguanidinium acetate) is characterized as a functionally selective agonist of the MC1R and MC3R receptors , which does not induce classical cAMP generation but instead induces ERK1/2 phosphorylation, a signaling pathway responsible for the proefferocytotic effect produced in primary murine macrophages. AP1189 has been shown to reduce cytokine release in macrophages, whereas AP1189 does not induce melanogenesis in melanocytes. In vivo, when administered orally, AP1189 has anti-inflammatory effects in peritonitis and accelerates the regression phase, and provides a significant reduction in macroscopic and histological parameters characterizing joint damage in an experimental model of inflammatory arthritis. Accordingly, AP1189 is a functionally selective dual agonist of the MC1R and MC3R receptors with anti-inflammatory properties and, at the same time, no effect on melanogenesis.

Melanocortin therapy using adrenocorticotropic hormone (ACTH) or nonsteroidogenic melanocortin peptides attenuates proteinuria and glomerular disorder in experimental models of glomerular diseases and induces remission of nephrotic syndrome in patients with various glomerulopathies, even in patients refractory to steroids.

Proteinuria, a sign of glomerular disorder, is usually detected by urinalysis and is itself a significant independent modifiable risk factor for end-stage renal disease, premature death from cardiovascular disease, and ischemic stroke in patients with diabetes. Despite recent advances, refractory proteinuria continues to be a problem in clinical practice.

According to one aspect of the present invention there is provided a composition containing a compound of Formula (I) or (Ia):

Formula (I),

Formula (Ia),

including its tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric forms and racemic forms,

Where

n has the value 1, 2 or 3;

each R ₁ , R ₂ , R ₃ , R ₄ and R ₅ is independently selected from the group consisting of a hydrogen atom, optionally substituted C _1-6 -alkyl, optionally substituted C _3-6 -cycloalkyl, optionally substituted C _2-6 - alkenyl, optionally substituted C _4-6 -alkadienyl, optionally substituted C _2-6 -alkynyl, hydroxy, optionally substituted C _1-6 -alkoxy, optionally substituted C _2-6 -alkenyloxy, carboxy, optionally substituted C _1-6 -alkoxycarbonyl , optionally substituted C _1-6 -alkylcarbonyl, formyl, C _1-6 -alkylsulfonylamino, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy, optionally substituted arylcarbonyl, optionally substituted arylamino, arylsulfonylamino, optionally substituted heteroaryl, optionally substituted heteroaryloxy carbonyl, optional substituted heteroaryloxy, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylamino, heteroarylsulfonylamino, optionally substituted heterocyclyl, optionally substituted heterocyclyloxycarbonyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyl, optionally substituted heterocyclylamino, heterocyclylsulfonylamino, amino, mono- and di(C _1-6 -alkyl)amino , carbamoyl, mono- and di(C _1-6 -alkyl)aminocarbonyl, amino-C _1-6 -alkyl-aminocarbonyl, mono- and di(C _1-6 -alkylamino-C _1-6 -alkyl-aminocarbonyl, C _1-6 -alkylcarbonylamino, amino-C _1-6 -alkyl-carbonylamino, mono- and di(C _1-6 -alkyl)amino-C _1-6 -alkyl-carbonylamino, cyano, guanidino, urea, C _1-6 -alkanoyloxy, C _1-6 -alkylsulfonyl, C _1-6 -alkylsulfinyl, C _1-6 -alkylsulfonyl-oxy, aminosulfonyl, mono- and di(C _1-6 -alkyl)aminosulfonyl, nitro, optionally substituted C _1-6 -alkylthio and halogen atom, where any C _1-6 -alkyl linked to the nitrogen atom is optionally substituted with hydroxy, C _1-6 -alkoxy, C _2-6 -alkenyloxy, amino, mono- and di(C _1-6 -alkyl)amino, carboxy, C _1-6 -alkylcarbonylamino, halogen atom, C _1-6 -alkylthio, C _1-6 -alkyl-sulfonyl-amino or guanidine;

each R ₆ and R ₇ is independently selected from the group consisting of a hydrogen atom, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _4-6 alkadienyl, optionally substituted C _2-6 - alkynyl, optionally substituted C _1-6 -alkoxycarbonyl, optionally substituted C _1-6 -alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl, optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- and di (C _1-6 -alkyl)aminocarbonyl, amino-C _1-6 -alkyl-aminocarbonyl and mono- and di(C _1-6 -alkyl)amino-C _1-6 -alkyl-aminocarbonyl; or R ₆ and R ₇ together may form a five- or six-membered nitrogen-containing ring;

or a pharmaceutically acceptable derivative of this compound, for use in the treatment of kidney disease.

According to one aspect of the present invention, the use of a composition containing a compound of Formula (I) or (Ia) is also provided:

Formula (I),

Formula (Ia),

including its tautomeric and isomeric forms, such as enantiomeric forms, diastereoisomeric forms and racemic forms, wherein each of n, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ , R ₆ and R ₇ is as defined herein described above, or a pharmaceutically acceptable derivative of this compound,

for the manufacture of a medicinal product for the treatment of kidney disease.

According to one aspect of the present invention there is also provided a method of treating kidney disease, comprising one or more steps of administering a composition containing a compound of Formula (I) or (Ia):

Formula (I),

Formula (Ia),

including its tautomeric and isomeric forms, such as enantiomeric forms, diastereoisomeric forms and racemic forms, wherein each of n, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ , R ₆ and R ₇ is as defined herein described above, or a pharmaceutically acceptable derivative of the compound, to an individual in need thereof.

The present invention also provides a composition containing a compound of Formula (II):

https://en.wikipedia.org/wiki/Kidneyhttps://en.wikipedia.org/wiki/Proteinuriahttps://en.wikipedia.org/wiki/Hypoalbuminemiahttps://en.wikipedia.org/wiki/Hyperlipidemiahttps: //en.wikipedia.org/wiki/Edemahttps://en.wikipedia.org/wiki/Blood_clotshttps://en.wikipedia.org/wiki/High_blood_pressure Formula (II),

including its tautomeric and isomeric forms, such as enantiomeric forms, diastereoisomeric forms and racemic forms, or a pharmaceutically acceptable derivative of the compound, for use in the treatment of kidney disease.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, for use in the treatment of kidney disease, wherein said kidney disease is accompanied by proteinuria.

Proteinuria means the presence of excess protein in the urine. In healthy subjects, urine contains very little protein; an excess suggests the presence of a disease. The main causes of proteinuria are kidney disease (especially glomerular) or kidney injury, increased amounts of serum proteins ("flood" proteinuria), low proximal tubular reabsorption, certain biological agents, and excess fluid intake.

Proteinuria can be defined as an amount of protein >3.5 g per 1.73 m ² body surface area per day, or >40 mg per square meter body surface area per hour in children.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, for use in the treatment of kidney disease, characterized in that said kidney disease is accompanied by proteinuria, defined as >3.5 g per 1.73 m ² body surface area per day, or >40 mg per square meter body surface area per hour in children.

"Kidney disease associated with proteinuria" means that the proteinuria is associated with a symptom or sign of said kidney disease. "Kidney disease associated with proteinuria" may also be described as kidney disease associated with proteinuria, or kidney disease with proteinuria, or proteinuric kidney disease.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, for use in the treatment of kidney disease, characterized in that said kidney disease is glomerular a disease such as a disease affecting glomerular podocytes.

Glomerular disease can also reflect any type of glomerular disorder caused by glomerular disease or any other stimuli, such as other causative diseases or exposures.

The term “caused by” a disease as used herein means that the disorder occurs or is detected as a cause or consequence of a disease, such as a causative disease, that is, as a consequence of a pathological condition.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, for use in the treatment of kidney disease, characterized in that said kidney disease is nephrotic syndrome (glomerulonephrosis).

Nephrotic syndrome is a collection of symptoms that develop as a result of kidney damage, including proteinuria, low blood albumin levels, high blood lipids, and severe swelling. Other symptoms may include weight gain, feeling tired, and foamy urine. Complications may include blood clots, infections, and high blood pressure. Causes include a number of kidney diseases, and complications such as diabetes or lupus may also occur. The mechanism of development of the disease usually involves damage to the renal glomeruli.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, for use in the treatment of kidney disease, characterized in that said kidney disease is a primary nephrotic syndrome (primary glomerulonephrosis).

According to one embodiment of the present invention, said primary nephrotic syndrome is membranous glomerulonephritis (MGN) (or membranous nephropathy (MN)).

According to one embodiment of the present invention, said primary nephrotic syndrome is focal segmental glomerulosclerosis (FSGS)

According to one embodiment of the present invention, said primary nephrotic syndrome is membranous proliferative glomerulonephritis (MPGN) (mesangiocapillary glomerulonephritis).

According to one embodiment of the present invention, said membranous proliferative glomerulonephritis (MPGN) is selected from MPGN type 1 and MPGN type 2.

According to one embodiment of the present invention, said primary nephrotic syndrome is rapidly progressive glomerulonephritis (RPGN) (crescentic GN).

According to one embodiment of the present invention, said primary nephrotic syndrome is minimal change disease (MCD).

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, for use in the treatment of kidney disease, characterized in that said kidney disease is a secondary nephrotic syndrome (secondary glomerulonephrosis).

According to one embodiment of the present invention, said secondary nephrotic syndrome is caused by a causative disease (or simply caused by a disease). The term “caused” by a disease as used herein means that the nephrotic syndrome occurs or is found to be a cause or consequence of a disease, such as a causative disease, that is, as a consequence of a pathological condition.

According to one embodiment of the present invention, said secondary nephrotic syndrome is caused by a causative autoimmune disease.

According to one embodiment of the present invention, said secondary nephrotic syndrome is caused by a causative cancer.

According to one embodiment of the present invention, said secondary nephrotic syndrome is caused by a causative hereditary disease.

According to one embodiment of the present invention, said secondary nephrotic syndrome is caused by a causative disease selected from the group consisting of systemic lupus erythematosus (SLE), diabetic nephropathy, sarcoidosis, Sjogren's syndrome, amyloidosis, multiple myeloma, vasculitis, cancer and hereditary diseases (such as congenital nephrotic syndrome).

Lupus nephritis is an inflammation of the kidneys caused by SLE. Thus, according to one embodiment of the present invention, secondary nephrotic syndrome is caused by lupus nephritis.

According to one embodiment of the present invention, said secondary nephrotic syndrome is caused by diabetic nephropathy.

According to one embodiment of the present invention, said secondary nephrotic syndrome is caused by infection.

According to one embodiment of the present invention, said secondary nephrotic syndrome is caused by a urinary tract infection.

According to one embodiment of the present invention, said secondary nephrotic syndrome is caused by an infection selected from the group consisting of HIV (human immunodeficiency virus), syphilis, hepatitis such as hepatitis A, B and C, post-streptococcal infection, genitourinary schistosomiasis and Ebola.

According to one embodiment of the present invention, said secondary nephrotic syndrome is caused by the action of a drug, that is, it is a drug-induced nephrotic syndrome.

According to one embodiment of the present invention, said drug-induced nephrotic syndrome is caused by a drug selected from the group consisting of antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), radiocontrast media, anti-cancer drugs, anti-rheumatic drugs, antibody therapy, anti-TNF-α therapy, penicillamine , nicotine, lithium carbonate, gold and other heavy metals, ACE (angiotensin converting enzyme) inhibitors and opiates (such as heroin).

The term “drug-induced,” as used herein, means that nephrotic syndrome occurs or is detected as a cause or consequence of the use or administration of the drug.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, for use in the treatment of kidney disease, characterized in that said kidney disease is an inflammatory kidney disease.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, for use in the treatment of a kidney disease, wherein said kidney disease is glomerulonephritis (GN).

According to one embodiment of the present invention, said glomerulonephritis is selected from the group consisting of IgA nephropathy (Berger's disease), IgM nephropathy, post-infectious glomerulonephritis and thin basement membrane disease.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I) or (Ia), as defined herein, for use in the treatment of kidney disease, where n = 1.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I) or (Ia), as defined herein, for use in the treatment of kidney disease, wherein R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of -H, -CH ₃ , -CF ₃ , -CCl ₃ , -OC _1-6 alkyl, -OH, -OCH ₃ , -NH-C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -SC _1-6 alkyl, - tert Bu, -CN, -SO ₃ -C _1-6 alkyl, -NH ₂ , -NO ₂ , -CO ₂ H, -CO ₂ -C _1-6 alkyl, - C(=O)-C _1-6 alkyl, -CHO, morpholine, pyrrolidine, pyrrole or halogen atom.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I) or (Ia), as defined herein, for use in the treatment of kidney disease, wherein each R ₁ and/or R ₂ represents an electron-withdrawing group.

An electron-withdrawing group is an electron-withdrawing element or functional group that shifts the electron density from neighboring atoms in its direction, usually through a resonance or inductive effect. Whether a functional group is electron-withdrawing or electron-donating can be determined using the Hammett equation, an equation known to one skilled in the art. Hammett substituent constants, also known as σ substituent constants, can be used as a measure of the ability of a functional group to shift the electron density from neighboring atoms towards itself. An electron-withdrawing group is an electron-withdrawing element or functional group with a substituent σ constant > 0, for example in the range from 0.01 to 0.9, in particular 0.78. These values are known in the art and can be found in tables published in the scientific literature, for example in J. Org. Chem. , 23, 420 (1958). Examples of electron-withdrawing groups are CF ₃ , CCl ₃ , F, Cl, CN and NO ₂ .

According to one embodiment of the present invention, said R ₁ is selected from the group consisting of CF ₃ , CCl ₃ , F, Cl, CN and NO ₂ .

According to one embodiment of the present invention, each of the specified R ₂ and/or R ₃ represents a hydrogen atom.

According to one embodiment of the present invention, each R ₄ and R ₅ is independently selected from the group consisting of -H, C _1-6 alkyl, halogen atom, -O(C _1-6 alkyl), -NH(C _1-6 alkyl ) and -C(=O)C _1-6 alkyl.

According to one embodiment of the present invention, each R ₆ and R ₇ is independently selected from the group consisting of hydrogen, methyl, ethyl and propyl.

According to one embodiment of the present invention, each of the specified R ₆ and R ₇ represents a hydrogen atom.

According to one embodiment of the present invention, said R ₆ represents a hydrogen atom and R ₇ represents methyl or ethyl. According to one embodiment of the invention, said R ₆ represents a hydrogen atom and R ₇ represents methyl. According to one embodiment of the invention, said R ₆ represents a hydrogen atom and R ₇ represents ethyl. According to one embodiment of the invention, both R ₆ and R ₇ are methyl. According to one embodiment of the invention, both R ₆ and R ₇ are ethyl.

According to one embodiment of the present invention, said R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ each represent a hydrogen atom and said R ₁ is selected from the group consisting of CF ₃ , CCl ₃ , F, Cl, NO ₂ and CN.

According to one embodiment of the present invention, said R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ each represent a hydrogen atom, said R ₁ selected from the group consisting of CF ₃ , CCl ₃ , F, Cl, NO ₂ or CN, and n = 1.

According to one embodiment of the present invention, said R ₃ is in position 4.

According to one embodiment of the present invention, said R ₃ is selected from the group consisting of F, Cl and Br.

According to one embodiment of the present invention, said compound is {3-[1-(2-nitrophenyl) -1H -pyrrol-2-yl]allylidene}-aminoguanidine, preferably ( E ) -N - trans- {3- [1-(2-nitrophenyl) -1H- pyrrol-2-yl]-allylidene}-aminoguanidine, or a pharmaceutically acceptable salt thereof.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, for use in the treatment of kidney disease, characterized in that a pharmaceutically acceptable derivative of said compound is is a pharmaceutically acceptable salt of an inorganic acid or an organic acid.

According to one embodiment of the present invention, the organic acid is selected from the group consisting of formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid , malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamic acid, bismethylene salicylic acid, ethane disulfonic acid, gluconic acid, citraconic acid acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p -aminobenzoic acid, glutamic acid, benzenesulfonic acid and p -toluenesulfonic acid.

According to one embodiment of the present invention, said organic acid is acetic acid, succinic acid, tartaric acid or propionic acid.

According to one embodiment of the present invention, said inorganic acid is selected from the group consisting of: hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid and nitric acid.

According to one embodiment of the present invention, said pharmaceutically acceptable acid is acetic acid.

According to one embodiment of the present invention, said compound is {3-[1-(2-nitrophenyl) -1H -pyrrol-2-yl]allylidene}-aminoguanidinium acetate, preferably ( E ) -N - trans- {3 -[1-(2-nitrophenyl)-1 H -pyrrol-2-yl]-allylidene}-aminoguanidinium acetate.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (Ia), wherein each R ₂ , R ₃ , R ₄ and R ₅ is a hydrogen atom, each R ₆ and R ₇ is independently selected from the group consisting of hydrogen, methyl, ethyl and propyl, said R ₁ selected from the group consisting of CF ₃ , CCl ₃ , F, Cl, NO ₂ or CN, and n = 1, for use in the treatment of kidney disease.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (Ia), wherein each of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ is a hydrogen atom, and said R ₁ is selected from the group consisting of of CF ₃ , CCl ₃ , F, Cl, NO ₂ or CN, and n = 1, for use in the treatment of kidney disease.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (Ia), wherein each of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ is a hydrogen atom, and said R ₁ is selected from the group consisting of of CF ₃ , CCl ₃ , F, Cl, NO ₂ or CN, and n = 1, for use in the treatment of a kidney disease, wherein said kidney disease is proteinuria.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (Ia), wherein each of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ is a hydrogen atom, and said R ₁ is selected from the group consisting of of CF ₃ , CCl ₃ , F, Cl, NO ₂ or CN, and n = 1, for use in the treatment of nephrotic syndrome. According to one embodiment of the invention, said nephrotic syndrome is selected from the group consisting of primary nephrotic syndrome and secondary nephrotic syndrome.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (Ia), wherein each of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ is a hydrogen atom, and said R ₁ is selected from the group consisting of of CF ₃ , CCl ₃ , F, Cl, NO ₂ or CN, and n = 1, for use in the treatment of primary nephrotic syndrome (primary glomerulonephrosis), characterized in that said primary nephrotic syndrome is selected from the group consisting of membranous glomerulonephritis ( MGN) (or membranous nephropathy (MN)), focal segmental glomerulosclerosis (FSGS), membranous proliferative glomerulonephritis (MPGN) (mesangiocapillary glomerulonephritis), selected from the group consisting of MPGN type 1 and MPGN type 2, rapidly progressive glomerulonephritis (RPGN) (crescentic GN) and minimal change disease (MCD).

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (Ia), wherein each of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ is a hydrogen atom, and said R ₁ is selected from the group consisting of of CF ₃ , CCl ₃ , F, Cl, NO ₂ or CN, and n = 1, for use in the treatment of secondary nephrotic syndrome (secondary glomerulonephrosis), characterized in that said secondary nephrotic syndrome is caused by a disease selected from the group consisting of causative autoimmune disease, systemic lupus erythematosus (lupus nephritis), diabetic nephropathy, sarcoidosis, Sjogren's syndrome, amyloidosis, multiple myeloma, vasculitis, cancer, hereditary diseases (such as congenital nephrotic syndrome), infection and diabetic nephropathy.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (Ia), wherein each of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ is a hydrogen atom, and said R ₁ is selected from the group consisting of of CF ₃ , CCl ₃ , F, Cl, NO ₂ or CN, and n = 1, for use in the treatment of drug-induced nephrotic syndrome. According to one embodiment of the invention, said drug-induced nephrotic syndrome is caused by a drug selected from the group consisting of antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), radiocontrast media, anti-cancer drugs, anti-rheumatic drugs, antibody-based therapy, anti-TNF-α therapy, penicillamine, nicotine, lithium carbonate, gold and other heavy metals, ACE inhibitors and opiates (especially heroin).

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (Ia), wherein each of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ is a hydrogen atom, and said R ₁ is selected from the group consisting of of CF ₃ , CCl ₃ , F, Cl, NO ₂ or CN, and n = 1, for use in the treatment of a kidney disease, characterized in that said kidney disease is selected from the group consisting of a glomerular disease, a disease affecting glomerular podocytes, inflammatory kidney disease and glomerulonephritis (GN), such as glomerulonephritis selected from the group consisting of IgA nephropathy (Berger's disease), IgM nephropathy, post-infectious glomerulonephritis and thin basement membrane disease.

According to one embodiment of the present invention, there is provided a composition containing a compound selected from the compound of Formula (II), {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidine, {3 -[1-(2-nitrophenyl) -1H -pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H -pyrrole -2-yl]-allylidene}-aminoguanidine and ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, or pharmaceutically acceptable a derivative of the said compound for use in the treatment of kidney disease. According to one embodiment of the invention, said kidney disease is proteinuria.

According to one embodiment of the present invention, there is provided a composition containing a compound selected from the compound of Formula (II), {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidine, {3 -[1-(2-nitrophenyl) -1H -pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H -pyrrole -2-yl]-allylidene}-aminoguanidine and ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, or pharmaceutically acceptable a derivative of the said compound for use in the treatment of nephrotic syndrome. According to one embodiment of the invention, said nephrotic syndrome is selected from the group consisting of primary nephrotic syndrome and secondary nephrotic syndrome.

According to one embodiment of the present invention, there is provided a composition containing a compound selected from the compound of Formula (II), {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidine, {3 -[1-(2-nitrophenyl) -1H -pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H -pyrrole -2-yl]-allylidene}-aminoguanidine and ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, or pharmaceutically acceptable a derivative of said compound for use in the treatment of primary nephrotic syndrome (primary glomerulonephrosis), characterized in that said primary nephrotic syndrome is selected from the group consisting of membranous glomerulonephritis (MGN) (or membranous nephropathy (MN)), focal segmental glomerulosclerosis (FSGS ), membranous proliferative glomerulonephritis (MPGN) (mesangiocapillary glomerulonephritis), selected from the group consisting of MPGN type 1 and MPGN type 2, rapidly progressive glomerulonephritis (RPGN) (crescentic GN) and minimal change disease (MCD).

According to one embodiment of the present invention, there is provided a composition containing a compound selected from the compound of Formula (II), {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidine, {3 -[1-(2-nitrophenyl) -1H -pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H -pyrrole -2-yl]-allylidene}-aminoguanidine and ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, or pharmaceutically acceptable a derivative of said compound, for use in the treatment of secondary nephrotic syndrome (secondary glomerulonephrosis), characterized in that said secondary nephrotic syndrome is caused by a disease selected from the group consisting of a causative autoimmune disease, systemic lupus erythematosus (lupus nephritis), diabetic nephropathy, sarcoidosis, Sjogren's syndrome, amyloidosis, multiple myeloma, vasculitis, cancer, hereditary diseases (such as congenital nephrotic syndrome), infection and diabetic nephropathy.

According to one embodiment of the present invention, there is provided a composition containing a compound selected from the compound of Formula (II), {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidine, {3 -[1-(2-nitrophenyl) -1H -pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H -pyrrole -2-yl]-allylidene}-aminoguanidine and ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, or pharmaceutically acceptable a derivative of the said compound for use in the treatment of secondary nephrotic syndrome caused by diabetic nephropathy.

According to one embodiment of the present invention, there is provided a composition containing a compound selected from the compound of Formula (II), {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidine, {3 -[1-(2-nitrophenyl) -1H -pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H -pyrrole -2-yl]-allylidene}-aminoguanidine and ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, or pharmaceutically acceptable a derivative of the said compound for use in the treatment of drug-induced nephrotic syndrome. According to one embodiment of the invention, said drug-induced nephrotic syndrome is caused by a drug selected from the group consisting of antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), radiocontrast media, anti-cancer drugs, anti-rheumatic drugs, antibody-based therapy, anti-TNF-α therapy, penicillamine, nicotine, lithium carbonate, gold and other heavy metals, ACE inhibitors and opiates (especially heroin).

According to one embodiment of the present invention, there is provided a composition containing a compound selected from the compound of Formula (II), {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidine, {3 -[1-(2-nitrophenyl) -1H -pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H -pyrrole -2-yl]-allylidene}-aminoguanidine and ( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]-allylidene}-aminoguanidinium acetate, or pharmaceutically acceptable derivative of the said compound, for use in the treatment of a kidney disease selected from the group consisting of glomerular disease, a disease affecting glomerular podocytes, inflammatory kidney disease, and glomerulonephritis (GN), such as glomerulonephritis selected from the group consisting of IgA nephropathy (a disease Berger), IgM nephropathy, post-infectious glomerulonephritis and thin basement membrane disease.

Without being bound by any theory, according to one embodiment of the invention, the compounds of the present invention produce beneficial effects by acting as an agonist at one or more MC receptors, such as MC1R and MC3R, such as the MC1R receptor. In one embodiment, the compounds of the present invention produce beneficial effects by acting as a functionally selective agonist at the MC1R and MC3R receptors.

According to one embodiment of the present invention, there is provided a composition containing a compound of Formula (I), (Ia) or (II) as defined herein, including tautomeric and isomeric forms thereof, such as enantiomeric forms, diastereomeric forms and racemic forms , for use in the treatment of kidney disease, characterized in that said compound is

i) an agonist of one or more MC receptors,

ii) agonist of MC1R and MC3R receptors,

iii) MC1R receptor agonist,

iv) an agonist of the MC1R and/or MC3R receptor, but not an agonist of the MC2R and MC4R receptors,

v) functionally selective agonist of MC1R and MC3R receptors,

vi) a functionally selective agonist of the MC1R and MC3R receptors, which mainly induces ERK1/2 phosphorylation and slightly induces cAMP generation,

vii) a functionally selective agonist of the MC1R and MC3R receptors that does not stimulate melanogenesis through its effect on MC1R, and/or

viii) an MC1R and/or MC3R receptor agonist that has no effect on energy homeostasis, such as food intake.

In one embodiment, the compound of the present invention does not reduce food intake, eg, does not reduce food intake by affecting MC3R and/or MC4R.

According to one embodiment of the invention, the compound of the present invention does not induce melanogenesis.

Combination therapy

The compounds or compositions of the present invention may be combined with or contain one or more additional active ingredients that are considered to be another therapeutically effective compound or a pharmaceutically acceptable derivative of the compound.

According to one embodiment of the present invention, a composition containing a compound of Formula (I), (Ia) or (II), or a pharmaceutically acceptable derivative thereof, contains, alone or together (with said compound), one or more additional active pharmaceutical ingredients .

According to one embodiment of the present invention, a composition containing a compound of Formula (I), (Ia) or (II), or a pharmaceutically acceptable derivative thereof, contains, alone or together (with said compound), one or more additional active pharmaceutical ingredients , used to treat kidney disease.

According to one embodiment of the present invention, the one or more additional active pharmaceutical ingredients include ingredients used for the treatment of kidney disease.

According to one embodiment of the present invention, said one or more additional active pharmaceutical ingredients include ingredients used to treat the underlying cause of said kidney disease.

According to one embodiment of the present invention, said one or more additional active pharmaceutical ingredients include ingredients used to treat the underlying cause of said kidney disease, such as ingredients for the treatment of high blood pressure, high blood cholesterol and infection, low-salt diet and dietary restriction liquids.

According to one embodiment of the present invention, the one or more additional active pharmaceutical ingredient used for the treatment of kidney disease is selected from the group consisting of an angiotensin converting enzyme (ACE) inhibitor, an aldosterone antagonist and an angiotensin receptor blocker (ARB).

According to one embodiment of the present invention, the one or more additional active pharmaceutical ingredients used for the treatment of kidney disease and proteinuria caused by an autoimmune disease are used together with steroids or a steroid-sparing agent in combination with ACE inhibitors.

According to another embodiment of the present invention, the one or more additional active pharmaceutical ingredients include ingredients used to treat the underlying cause of kidney disease.

According to one embodiment of the invention, the combination of additional drugs allows for a gentle dosing regimen that reduces the required dose of the drug used in combination with the compound of the present invention.

According to one embodiment of the present invention, a composition comprising a compound of Formula (I), (Ia) or (II), as defined herein, and an additional active ingredient is administered simultaneously, sequentially or separately.

According to one embodiment of the present invention, a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, is administered before the additional active ingredient is administered. According to another embodiment of the invention, a composition containing a compound of Formula (I), as defined herein, is administered simultaneously with an additional active ingredient. According to yet another embodiment of the invention, a composition containing a compound of Formula (I), as defined herein, is administered after administration of the additional active ingredient.

Routes of administration

It should be understood that the preferred route of administration will generally depend on the general condition and age of the subject being treated, the nature of the pathological condition being treated, the location of the tissue being treated in the body of the subject, and the active ingredient selected.

According to one embodiment of the present invention, a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, is administered using systemic administration, local administration, enteral administration or parenteral administration. Suitable dosage forms for such administration can be prepared using standard techniques.

Systemic administration

Systemic administration allows for the introduction of a compound into the bloodstream to ultimately target desired targets.

Such routes of administration include any suitable route of administration, such as the enteral route, oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.

According to one embodiment of the present invention, a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, is administered using systemic administration.

Oral administration

Oral administration is commonly used for enteral drug delivery, where the compound is delivered through the mucosa of the digestive tract. Typically, syrups and solid oral dosage forms such as tablets, capsules and the like are used.

According to one embodiment of the present invention, a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, is administered using oral administration.

Parenteral administration

Parenteral administration refers to any route of administration other than the oral/enteral route, in which the drug does not undergo first-pass metabolism in the liver. Accordingly, parenteral administration includes any injections and infusions, such as bolus injection or continuous infusion, performed, for example, by intravenous administration, intramuscular administration, subcutaneous administration. In addition, parenteral administration includes inhalation and topical administration.

Accordingly, the compound can be administered topically and passes through the mucous membrane of the animal to which the biologically active substances are administered, for example, the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract or rectum, preferably through the nasal or oral mucosa , and accordingly, parenteral administration may also include buccal, sublingual, nasal, rectal, vaginal and intraperitoneal administration, as well as pulmonary and bronchial administration by inhalation or using medical equipment. Also, the compound can be administered topically such that it passes through the skin.

Generally, subcutaneous and intramuscular parenteral forms are preferred.

Local treatment

According to one embodiment of the present invention, the compound described in this application is used for topical treatment, that is, administered directly to the site(s) of its action. Accordingly, the compound may be administered directly into the skin or mucosa, or the compound may be administered by injection into the site of its action, such as into diseased tissue, or into a terminal artery leading directly to diseased tissue.

Doses

In accordance with the present invention, a composition containing a compound of Formula (I), (Ia) or (II) is administered to individuals in need of treatment in pharmaceutically effective doses. A therapeutically effective amount of a compound is an amount sufficient to treat, prevent, reduce the risk of occurrence or partially suppress the clinical manifestations of a given disease and its complications. The amount that will be effective to achieve a particular therapeutic result depends on the severity and type of disorder, as well as the weight and general condition of the subject. The compound may be administered once or more times per day, for example 1 to 8 times per day, for example 1 to 6 times per day, for example 1 to 5 times per day, for example 1 to 4 times per day, for example 1 up to 3 times a day, for example 1 to 2 times a day, for example 2 to 4 times a day, for example 2 to 3 times a day. Alternatively, the compound can be administered less than once a day, for example once a day, for example once every two days, for example once every three days, for example once every four days, for example once every five days, for example once every six days , for example once a week.

According to one embodiment of the present invention, a composition containing a compound of Formula (I), as defined herein, is administered in a therapeutically effective amount, for example, in an amount of from 1 mg to 1000 mg of a compound of Formula (I), (Ia) or ( II) per day.

Hence, according to one embodiment of the present invention, the compound is administered in an amount of 1 mg to 1000 mg, for example 1 to 5 mg, 5 to 10 mg, 10 to 15 mg, 15 to 20 mg, 20 mg, 20 to 30 mg, from 30 to 60 mg, from 60 to 80 mg, from 80 to 100 mg, from 100 to 130 mg, from 130 to 160 mg, from 160 to 200 mg, from 200 to 240 mg, from 240 to 280 mg , from 280 to 320 mg, from 320 to 360 mg, from 360 to 400 mg, from 400 to 440 mg, from 440 to 500 mg, from 500 to 560 mg, from 560 to 620 mg, from 620 to 680 mg, from 680 to 740 mg, 740 to 800 mg, 800 to 860 mg, 860 to 920 mg, 920 to 980 mg, 980 to 1000 mg, for example 500 to 1000 mg per day.

"Per day" means that the dose may be given as a single dose or divided into multiple doses over the course of a day, including once daily (QD), twice daily (BID), and/or three times daily (TID).

According to another embodiment of the present invention, the compound is administered in an amount of from 0.01 mg/kg body weight to 40 mg/kg body weight, for example from 0.01 mg/kg body weight to 0.05 mg/kg body weight, from 0. 05 to 0.1 mg/kg body weight, from 0.1 to 0.5 mg/kg body weight, from 0.5 mg to 1 mg/kg body weight, from 1 to 2 mg/kg body weight, from 2 up to 3 mg/kg body weight, from 3 to 5 mg/kg body weight, from 5 to 10 mg/kg body weight, from 10 to 15 mg/kg body weight, from 15 to 20 mg/kg body weight, from 20 up to 30 mg/kg body weight, for example 30 to 40 mg/kg body weight.

Drugs

According to one embodiment of the present invention, a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, is a pharmaceutical composition, such as a pharmaceutically safe composition. A composition containing a compound of Formula (I), (Ia) or (II), as defined herein, may be administered by any suitable route, for example orally, sublingually or parenterally, and may be in any form suitable for such administration , for example in the form of solutions, suspensions, aerosols, tablets, capsules, powders, syrups, implants or dispersions intended for injection.

According to one embodiment of the present invention, a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, is formulated as a suspension.

According to one embodiment of the present invention, a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, is formulated in an oral dosage form, such as a solid oral dosage form, or a pharmaceutical unit, such as tablets or capsules, or liquid oral dosage form. Techniques for preparing solid pharmaceutical preparations are well known in the art.

According to another embodiment of the present invention, a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, is formulated in an injectable dosage form.

According to one embodiment of the present invention, a composition containing a compound of Formula (I), (Ia) or (II), as defined herein, is formulated in the form of a solid pharmaceutical unit, preferably in the form of a tablet or capsule.

Compound (I), (Ia) or (II) as a free base or salt may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in a single dose or multiple doses. Pharmaceutical compositions may be formulated further containing pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients, in accordance with standard techniques, such as those described in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

Bibliography

Lindskog et al . 2010 "Melanocortin 1 Receptor Agonists Reduce Proteinuria." J Am Soc Nephrol 21: 1290-1298, 2010.

Qiao et al . 2016 "MC1R is dispensable for the proteinuria reducing and glomerular protective effect of melanocortin therapy." Nature Scientific Reports 6:27589.

Montero-Melendez et al . 2015 "Biased Agonism as a Novel Strategy To Harness the Proresolving Properties of Melanocortin Receptors without Eliciting Melanogenic Effects." J Immunol 2015; 194:3381–3388.

EXAMPLES

Techniques

In male Sprague-Dawley rats anesthetized with isoflurane, passive Heymann's nephritis was induced by slow injection into the jugular vein of antiFx1A serum (PTX-002S, Probetex, San Antonio, TX, USA, Probetex, lot 169-6H) in the 0th day of the study (1 ml of serum) and on the 7th day of the study (0.25 ml of serum). It has previously been shown (Lindskog et al. , J Am Soc Nephrol. 2010; 21:1290-1298) that this administration regimen induces significant proteinuria. Pharmacological intervention using control compound or test compound was initiated on day 14.

In one experiment (Experiment 1), test compound 1, dissolved in isotonic solution, was administered once daily by intraperitoneal (ip) injection at a dose of 10 mg/kg (n=12), animals (n=12) were used as control. who received injections of isotonic solution.

In another experiment (Experiment 2), test compound 1 was administered once daily via gastric tube. Test compound 1 was administered as a suspension in 10% hydroxypropyl-beta-cyclodextrin in water. Two doses of test compound 1 were tested: 20 mg/kg/day (n=8) and 40 mg/kg/day (n=8). In this experiment, the therapeutic effect of the test compound 1 was compared with the effect of ACTH(1-24), since the literature describes that ACTH has a therapeutic effect on proteinuria in the experimental model used. As a positive control, rats (n=6) were treated with ACTH(1-24) (Bachem, catalog number H-1150) at a dose of 10 μg/kg per day by continuous subcutaneous infusion using Alzet osmotic minipumps for 4 weeks . This treatment regimen has previously been shown to result in approximately 50% reduction in proteinuria compared to controls when animals receive no treatment (Lindskog et al. , J Am Soc Nephrol . 2010;21:1290-1298).

In Experiment 1, twenty-four-hour urine volumes were collected three times, on day 14 after nephritis induction, which is the time when pharmacological intervention was initiated, on day 28, and on day 42 after nephritis induction. To collect urine, rats were placed in metabolic cages and blood samples were then collected to measure plasma creatinine and albumin concentrations. The concentrations of creatinine and albumin in urine were also determined, and then the volume of urine excreted over a twenty-four hour period was determined.

In Experiment 2, a twenty-four-hour urine volume was collected on day 42 after nephritis induction, that is, after 28 days of treatment with test compound 1 or ACTH(1-24). As in Experiment 1, rats were placed in metabolic cages and blood samples were then collected to measure plasma creatinine and albumin concentrations. The concentrations of creatinine and albumin in urine were also determined, and then the volume of urine excreted over a twenty-four hour period was determined.

Blood samples were collected from the abdominal vein of rats anesthetized with pentobarbital (0.2–0.3 ml/rat intraperitoneally; Dolethal, Vetoquinol via Centravet, Lapalisse, France). The collected blood samples were transferred into EDTA-coated tubes and centrifuged (10 min, 1000 g, 4°C) to collect plasma. Prior to quantitation of creatinine and albumin, plasma samples were stored at -80°C.

An ABX Pentra 400 clinical chemistry analyzer (HORIBA) was used to quantify albumin and creatinine in urine and plasma.

The albumin excretion rate was determined as follows:

24-hour urine volume x urine albumin concentration.

Creatinine clearance as an estimate of glomerular filtration rate was determined as follows:

(urinary creatinine concentration x 24-hour urine volume)/plasma creatinine concentration.

Fractional albumin excretion was determined as follows:

((urinary albumin concentration x 24-hour urine volume)/plasma albumin concentration)/creatinine clearance x100

All data are presented as mean ± standard error of the mean (SE). Statistical analysis was performed using a standard unpaired t test, with the statistical significance level considered at p < 0.05.

results

Test compound 1 = AP1189 = (( E ) -N - trans- {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidinium acetate.

ACTH(1-24) = human adrenocorticotropic hormone fragment 1-24; tetracosactide.

Potent ACTH/MC2R agonist (EC ₅₀ = 5.5 nM). Stimulates the release of glucocorticoids from the adrenal glands. Sequence: Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-Gly-Lys-Lys-Arg-Arg-Pro-Val-Lys-Val-Tyr-Pro.

Experiment 1

Compared with control rats, rats treated with Test Compound 1 showed significant reduction in proteinuria on day 28 and day 42. In rats treated with test compound 1, a decrease in the rate of albumin excretion by 31 ± 8% was recorded on day 28 and a statistically significant decrease in the rate of albumin excretion by 48 ± 10% on day 42. In control rats, the rate of albumin excretion did not change throughout the experiment (on the 28th day this value was 96±11% of the corresponding value recorded on the 14th day, and on the 42nd day - 102±14% of the value recorded registered on the 14th day) (see Fig. 1).

A similar picture was observed when assessing fractional albumin excretion: on day 28, FEAlb was reduced by 48±5% and on day 42 by 45±11% (illustration not available).

Experiment 2

Animals treated with test compound 1 had a significantly higher GFR (glomerular filtration rate; creatinine clearance) after 4 weeks of treatment than rats treated with positive control (ACTH 1-24 at 10 mg/day): The GFR in rats treated with positive control was 2.19 ± 0.24 ml/min, while in rats treated with test compound 1 at 20 mg/kg, the corresponding value was 3.12 ± 0.14 ml /min (p=0.002 vs positive control) and in rats receiving test compound 1 in an amount of 40 mg/kg - 2.94±0.14 ml/24 min (p=0.01 vs positive control). (see Fig. 2A).

Treatment with test compound 1 significantly reduced the excretion of fractional albumin (FEAlb) compared to treatment with the positive control (ACTH 1-24 at 10 mg/day): FEAlb in rats treated with the positive control was 0.59 ± 0 .02%, while in rats receiving test compound 1 in an amount of 20 mg/kg, the corresponding value was 0.045 ± 0.04% (p = 0.007 vs positive control) and in rats receiving test compound 1 in an amount of 40 mg/kg kg, - 0.35±0.05% (p=0.001 vs positive control) (see Fig. 2B).

Claims (37)

1. Use of the compound of formula (II) formula (II), including its stereoisomeric forms, or a pharmaceutically acceptable salt thereof, for the treatment of primary nephrotic syndrome. 2. Use of a compound of formula (II) formula (II), including its stereoisomeric forms, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicinal product for the treatment of primary nephrotic syndrome. 3. Application according to any one of paragraphs. 1, 2, characterized in that the specified compound is a functionally selective agonist of the MC1R and MC3R receptors, which does not stimulate melanogenesis through its effect on MC1R. 4. Application according to any one of paragraphs. 1, 2, characterized in that said primary nephrotic syndrome is membranous glomerulonephritis (MGN) (or membranous nephropathy (MN)). 5. Application according to any one of paragraphs. 1, 2, characterized in that the specified primary nephrotic syndrome is focal segmental glomerulosclerosis (FSGS). 6. Application according to any one of paragraphs. 1, 2, characterized in that the specified primary nephrotic syndrome is membranous proliferative glomerulonephritis (MPGN) (mesangiocapillary glomerulonephritis). 7. Use according to claim 6, characterized in that said membranous proliferative glomerulonephritis (MPGN) is selected from MPGN type 1 and MPGN type 2. 8. Application according to any one of paragraphs. 1, 2, characterized in that the specified primary nephrotic syndrome is rapidly progressive glomerulonephritis (RPGN) (crescentic GN). 9. Application according to any one of paragraphs. 1, 2, characterized in that the specified primary nephrotic syndrome is a minimal change disease (MCD). 10. Application according to any one of paragraphs. 1, 2, characterized in that said compound is selected from the group consisting of {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidine and ( E ) -N - trans -{3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidine, or a pharmaceutically acceptable salt of these compounds. 11. Application according to any one of paragraphs. 1, 2, characterized in that said pharmaceutically acceptable salt is a pharmaceutically acceptable salt of an inorganic acid or an organic acid. 12. Use according to claim 11, characterized in that said organic acid is selected from the group consisting of formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid , lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamic acid, bismethylene salicylic acid, ethanesulfonic acid acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p -aminobenzoic acid, glutamic acid, benzenesulfonic acid and p -toluenesulfonic acid. 13. Use according to claim 12, characterized in that said organic acid is acetic acid, succinic acid, tartaric acid or propionic acid. 14. Use according to claim 11, characterized in that said inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid and nitric acid. 15. Use according to claim 13, characterized in that said organic acid is acetic acid. 16. Application according to any one of paragraphs. 1, 2, characterized in that said compound is selected from the group consisting of {3-[1-(2-nitrophenyl) -1H- pyrrol-2-yl]allylidene}-aminoguanidinium acetate and ( E ) -N- trans -{3-[1-(2-nitrophenyl)-1 H -pyrrol-2-yl]-allylidene}-aminoguanidinium acetate. 17. Application according to any one of paragraphs. 1, 2, characterized in that said connection: i) is an agonist of one or more MC receptors, ii) is an agonist of MC1R and MC3R receptors, iii) is an agonist of the MC1R receptor, iv) is an agonist of the MC1R and/or MC3R receptor, but is not an agonist of the MC2R and MC4R receptors, v) is a functionally selective agonist of MC1R and MC3R receptors, vi) is a functionally selective agonist of MC1R and MC3R receptors, which mainly induces ERK1/2 phosphorylation and slightly induces cAMP generation, vii) is a functionally selective agonist of the MC1R and MC3R receptors, which does not stimulate melanogenesis through its effect on MC1R, viii) is an MC1R and/or MC3R receptor agonist with no effect on energy homeostasis, such as food intake, ix) does not reduce food intake, e.g. does not reduce food intake by affecting MC3R and/or MC4R, and/or x) does not induce melanogenesis. 18. Application according to any one of paragraphs. 1, 2, characterized in that the specified compound is administered in an amount from 1 mg to 1000 mg per day, for example from 1 to 5 mg, from 5 to 10 mg, from 10 to 15 mg, from 15 to 20 mg, from 20 to 30 mg, from 30 to 60 mg, from 60 to 80 mg, from 80 to 100 mg, from 100 to 130 mg, from 130 to 160 mg, from 160 to 200 mg, from 200 to 240 mg, from 240 to 280 mg , from 280 to 320 mg, from 320 to 360 mg, from 360 to 400 mg, from 400 to 440 mg, from 440 to 500 mg, from 500 to 560 mg, from 560 to 620 mg, from 620 to 680 mg, from 680 to 740 mg, 740 to 800 mg, 800 to 860 mg, 860 to 920 mg, 920 to 980 mg, 980 to 1000 mg, for example 500 to 1000 mg per day. 19. Application according to any one of paragraphs. 1, 2, characterized in that said compound is presented in a pharmaceutical composition that is pharmaceutically safe.