Europaisches
`
`Patentamt
`European
`Patent Office
`Office européen
`des brevets
`
`Bescheinigung
`
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`Attestation
`
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`geltenden Fassung der auf
`dem nachsten Blatt
`bezeichneten europaischen
`Patentanmeldung Uberein.
`
`The attached documents are
`exact copies of the text in
`which the European patent
`application described on the
`following page is deemed to
`have been filed.
`
`Les documentsjoints a la
`présente attestation sont
`conformesautexte,
`considéré comme
`initialement déposé, de la
`demande de brevet
`européen qui est spécifiée a
`la page suivante.
`
`
`
`Patentanmeldung Nr.
`
`Patent application No.
`
`Demande de brevet n°
`
`18179319.1 / EP18179319
`
`The organisation code and number of your priority application, to be used for filing abroad under the Paris
`Convention, is EP18179319.
`
`Der Prasident des Europaischen Patentamts;
`Im Auftrag
`For the President of the European Patent Office
`Le President de l'Office européen des brevets
`p.o.
`
`EPA/EPO/OEB Form 1014
`
`05.17
`
`V. Joseph
`
`

`

`
`
`Anmeldung Nr:
`Application no.:
`Demande no :
`
`18179319.1
`
`Anmelder/ Applicant(s) / Demandeur(s):
`
`SynAct Pharma ApS
`Dronninggards Allé 136
`2840 Holte/DK
`
`Anmeldetag:
`Date offiling:
`Date de dépét :
`
`22.06.18
`
`Bezeichnung der Erfindung / Title of the invention / Titre de I'invention:
`(Falls die Bezeichnung der Erfindung nicht angegeben ist, oder falls die Anmeldung in einer Nicht-Amtssprache des EPA eingereicht
`wurde, siehe Beschreibung beztglich urspriinglicher Bezeichnung.
`If no title is shown, orif the application has been filed in a non-EPO language, please refer to the description for the originaltitle.
`Si aucun titre n'est indiqué, ou si la demande a été déposée dans une langue autre qu'une langue officielle de l'OEB, se référer ala
`description pour le titre original.)
`
`TREATMENT OF PROTEINURIA
`
`In Anspruch genommenePrioritat(en) / Priority(Priorities) claimed / Priorité(s) revendiquée(s)
`Staat/Tag/Aktenzeichen / State/Date/File no. / Pays/Date/Numéro de dépét:
`
`Am Anmeldetag benannte Vertragstaaten / Contracting States designated at date offiling / Etats contractants désignés lors du dépét:
`
`AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LILT LU LV MC MK MT NL NO PL
`PT RO R&SSE SI SK SMTR
`
`EPA/EPO/OEB Form 1014
`
`05.17
`
`2
`
`

`

`P4934EP00
`
`Treatment of Proteinuria
`
`Technical field
`
`The present invention relates to a composition comprising a compound of formula (I),
`
`(la) or (Il), or a pharmaceutically acceptable derivative thereof, for use in a method of
`
`treating kidney disease, especially proteinuric kidney diseases, such as nephrotic
`
`syndromes.
`
`10
`
`Background
`
`Proteinuria, the hallmark of glomerular injury, is a common finding on urinalysis, and is
`
`by itself a strong, independent and modifiable risk factor for end stage renal disease,
`
`premature death of cardiovascular origin, and ischemic stroke in patients with diabetes.
`
`15
`
`Despite recent advancesrefractory proteinuria continues to be a challenge in clinical
`
`practice. It is imperative to develop more effective modalities to ameliorate glomerular
`
`injury and induce remission of proteinuria. Recent evidence points to melanocortin
`
`system as a novel target for treatment of proteinuria.
`
`20
`
`MN is one of the most common causes of nephrotic syndrome in adults. One-third of
`
`the patients have a good prognosis with spontaneous remission. Even so,
`
`approximately 50% of the remainder manifest an unchanged disease state, whereas
`
`50% progress into ESRD (end-stage renal disease) and dialysis. The nephrotic
`
`syndrome is a glomerular disease characterized by proteinuria, edema,
`
`25
`
`hypoalbuminemia, and hyperlipidemia. Most MN casesare idiopathic and the
`
`mechanisms underlying the diseasearestill largely unknown. Treatments have
`
`classically been nonspecific and often include steroids with anti-inflammatory actions,
`
`sometimes in combination with cytotoxic agents. These drugs affect multiple tissues,
`
`causing cytotoxic effects, osteoporosis, adrenal insufficiency, hypertension, peptic
`
`30
`
`ulcers, and increased risk of glucose intolerance and infections. Therefore, more
`
`effective and specific treatment options are needed.
`
`The melanocortin system is a set of neuropeptidergic and immunoendocrine signaling
`
`pathwaysthat play an integral role in the homeostatic control of a diverse array of
`
`35
`
`physiological functions, including melanogenesis, stress response, inflammation,
`
`

`

`P4934EP00
`
`immunomodulation and adrenocortical steroidogenesis. It consists of multiple
`
`components, including the five G protein-coupled melanocortin receptors: melanocortin
`
`receptor 1 (MC1R) to MC5R; peptide ligands: a, B, y-melanocyte stimulating hormone
`
`(a, B, Y- MSH), adrenocorticotropic hormone (ACTH) secreted by the anterior pituitary;
`
`and endogenous antagonists. The biological functions of melanocortin system are
`
`mediated by the five melanocortin receptors (MCRs), which have distinct tissue
`
`distribution, convey different signalling and exert varying biological activities in different
`
`organ systems.
`
`10
`
`Adrenocorticotropic hormone (ACTH) is an endogenous peptide hormone and agonist
`
`for all melanocortin receptors 1 to 5 (MC1-5R), of which MC2R specifically binds
`
`ACTH; steroidogenesis is triggered only by ACTH and mediated via MC2R in the
`
`adrenal cortex. Alpha-melanocyte stimulating hormone (aMSH) is a small endogenous
`
`peptide hormone, structurally related to ACTH, which binds all of the MCRs except
`
`15
`
`MC2R. MC1R, abundantly expressed by melanccytesin the skin, is a key control point
`
`in melanogenesis and determineshair colour.
`
`Melanocortin therapy by using ACTH or non-steroidogenic melanocortin peptides
`
`attenuates proteinuria and glomerular injury in experimental glomerular diseases and
`
`20
`
`induces remission of nephrotic syndrome in patients with diverse glomerulopathies,
`
`even those resistant to steroids, including membranous nephropathy (MN), minimal
`
`change disease (MCD), focal segmental glomerulosclerosis (FSGS) and IgA
`
`nephropathy. The underlying mechanism remains elusive, but the role of melanocortin
`
`1 receptor (MC1R) has been implicated and MC1R is heavily and specifically
`
`25
`
`expressed in human kidney cortex and specific renal cell types including podocytes
`
`(Lindskog et al. 2010). However, recent studies have found effects of ACTH
`
`monotherapy and NDP-aMSH ([Nle,, D-Phe7]-aMSH) also in patients bearing
`
`dominant-negative MC1R mutations, which was confirmed also in MC1R-null mice and
`
`in vitro in primary podocytes derived from MC1R-null and wildtype mice. The anti-
`
`30
`
`proteinuric effect of melanocortin signalling thus appears to be steroidogenic-
`
`independent and MC1R-dispensable, and the melanocortin effect might, at least in
`
`part, target a pathogenic pathway commontoall proteinuric kidney diseases.
`
`Podocytesas a critical component of the glomerular filtration barrier controlling
`
`glomerular permselectivity, is a major culprit accounting for massive proteinuria in
`
`

`

`P4934EP00
`
`diverse glomerular diseases, and the beneficial effect of melanocortin therapyis likely
`
`attributable to a direct action on podocytes (Qiao et al. 2016).
`
`It is at present therefore not possible to predict which melanocortin agonists and which
`
`associated targets will present as useful candidates for treatment of proteinuric
`
`diseases such as kidney diseases.
`
`Phenyl pyrrole aminoguanidine derivatives with activity on the melanocortin receptors
`
`are disclosed in WO 2007/141343. One example of such compound is the anti-
`
`10
`
`inflammatory AP1189 ((E)-N-trans-{3-[1 -(2-nitrophenyl)-1 H-pyrrol-2-yl]-allylidene}-
`
`aminoguanidium acetate) which was first shown to bind the MC1R (WO 2007/141343)
`
`and later wasidentified as a biased dual agonist at receptors MC1R and MC8R that
`
`does not provoke canonical cAMP generation (and hence no MC1R-induced
`
`melanogenesis) but instead appear to induce alternative pathways including ERK1/2-
`phosphorylation and Ca?" mobilization (Montero-Melendez et al. 2015).
`
`15
`
`Summary
`
`The present inventors have found that the phenyl pyrrole aminoguanidine derivative
`
`20
`
`AP1189 ((E)-N-trans-{3-[1-(2-nitrophenyl)-1 H-pyrrol-2-yl]-allylidene}aminoguanidium
`
`acetate) significantly reduces proteinuria in Passive Haymann Nephritis. a nephropathy
`
`model, as comparedto vehicle, measured as a significant reduction of aloumin
`
`excretion rate and FRaw (fraction albumin excretion); and also has a significantly higher
`
`GFR (glomerular filtration rate; creatinine clearance) and a significantly reduced FRaip
`
`25
`
`comparedto treatment with ACTH(1-24). This implies that AP1189 and related
`
`compounds are candidates for the improved treatment of proteinuric kidney diseases.
`
`It is an aspect of the present disclosure to provide a composition comprising a
`
`compound of formula(I) or (la):
`
`30
`
`

`

`P4934EP00
`
`4
`
`Ro
`
`Rg
`
`HN Rs
`
`ee
`/
`——-N
`
`No R;
`
`formula (I)
`
`Ry
`
`Ry
`
`Ry
`
`—_—
`
`n
`
`Rs;
`
`Rs
`
`R;
`
`
`
`5
`
`10
`
`including tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`forms and racemic forms, thereof;
`
`formula (la)
`
`wherein
`
`nis 1, 2 or 3;
`
`15
`
`each R,, Re, Rs, R4 and Rs is independently selected from the group consisting of
`
`hydrogen, optionally substituted C1.-alkyl, optionally substituted Cz.¢-cycloalkyl,
`
`

`

`P4934EP00
`
`optionally substituted C2.-alkenyl, optionally substituted C4.-alkadienyl, optionally
`
`substituted C2.- alkynyl, hydroxy, optionally substituted C,-.-alkoxy, optionally
`
`substituted C2z.-alkenyloxy, carboxy, optionally substituted C..-alkoxycarbonyl,
`
`optionally substituted C,-.- alkylcarbonyl, formyl, C1.6-alkylsulphonylamino, optionally
`
`substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy,
`
`optionally substituted arylcarbonyl, optionally substituted arylamino,
`
`arylsulphonylamino, optionally substituted heteroaryl, optionally substituted
`
`heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted
`
`heteroarylcarbonyl, optionally substituted heteroarylamino, heteroarylsulphonylamino,
`
`10
`
`optionally substituted heterocyclyl, optionally substituted heterocyclyloxycarbonyl,
`
`optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyl,
`
`optionally substituted heterocyclylamino, heterocyclylsulphonylamino, amino, mono-
`
`and di(C,..-alkyl)amino, carbamoyl, mono- and di(C;.6-alkyl)aminocarbonyl, amino-C1..-
`
`alkyl-aminocarbonyl, mono- and di(C1-6- alkylamino-C,-<-alkyl-aminocarbonyl, C1-¢-
`
`15
`
`alkylcarbonylamino, amino-C..¢-alkyl- carbonylamino, mono- and di(C;.6-alkyl)amino-C4.
`
`s-alkyl-carbonylamino, cyano, guanidino, carbamido, Cj.s-alkanoyloxy, C4-6-
`
`alkylsulphonyl, C..¢-alkylsulphinyl, C1.¢-alkylsulphonyl- oxy, aminosulfonyl, mono- and
`
`di(C1.6-alkylaminosulfonyl, nitro, optionally substituted C,.-alkylthio and halogen,
`
`where any nitrogen-bound C;.-alkyl is optionally substituted with hydroxy, C1..-alkoxy,
`
`20
`
`C26-alkenyloxy, amino, mono- and di(C16-alkylamino, carboxy, C4-.-
`
`alkylcarbonylamino, halogen, C1.6-alkylthio, C1-.s-alkyl-sulphonyl-amino or guanidine:
`
`each Rg and R;is independently selected from the group consisting of hydrogen,
`
`optionally substituted C,-.-alkyl, optionally substituted C2-¢-alkenyl, optionally
`
`25
`
`substituted C4.- alkadienyl, optionally substituted Cz-¢-alkynyl, optionally substituted
`
`C,-¢-alkoxycarbonyl, optionally substituted C,.¢-alkylcarbonyl, optionally substituted
`
`aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl,
`
`optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl,
`
`optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- and di(C1-¢-
`
`30
`
`alkyl)aminocarbonyl, amino- C,-.-alkyl-aminocarbonyl and mono- and di(C4-.-
`
`alkyl)amino- C,.s-alkyl-aminocarbonyl; or Rg and R7 may together form a five- or six-
`
`membered nitrogen-containing ring;
`
`or a pharmaceutically acceptable derivative thereof, for use in the treatment of a kidney
`
`35
`
`disease.
`
`

`

`P4934EP00
`
`It is also an aspect of the present disclosure to provide a composition comprising a
`
`compound of formula (II):
`
`@
`
`aN
`
`NFb
`
`FEN
`
`formula (II)
`
`including tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`forms and racemic forms, thereof;
`
`10
`
`or a pharmaceutically acceptable derivative thereof, for use in the treatment of a kidney
`
`disease.
`
`It is also an aspect of the present disclosure to provide a composition comprising a
`
`compound selected from the group consisting of {3-[1-(2-nitrophenyl)-1 H-pyrrol-2-yl]-
`
`15
`
`allylidene}-aminoguanidine; {3-[1-(2-nitrophenyl)-1H-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 a kidney disease.
`
`20
`
`In one embodiment said kidney disease is a kidney disease that present with
`
`proteinuria.
`
`In one embodiment said kidney disease is a glomerular disease, such as a disease
`
`25
`
`affecting the podocytes of the glomeruli.
`
`

`

`P4934EP00
`
`In one embodiment said kidney disease is nephrotic syndrome (glomerulonephrosis),
`
`such as primary nephrotic syndrome or secondary nephrotic syndrome.
`
`Definitions
`
`The term “pharmaceutically acceptable derivative” in the present context includes
`
`pharmaceutically acceptable salts, which indicate a salt which is not harmful to the
`
`patient. Such salts include pharmaceutically acceptable basic or acid addition salts as
`
`well as pharmaceutically acceptable metal salts, ammonium salts and alkylated
`
`ammonium salts. A pharmaceutically acceptable derivative further includes esters and
`
`10
`
`prodrugs, or other precursors of a compound which may be biologically metabolized
`
`into the active compound, or crystal forms of a compound.
`
`The term “acid addition salt” is intended to include “pharmaceutically acceptable acid
`
`addition salt” which indicates salts which are not harmful to the patient. Acid addition
`
`salts include salts of inorganic acids as well as organic acids. Representative examples
`
`15
`
`of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric,
`
`sulfuric, nitric acids and the like. Representative 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, pamoic,
`
`20
`
`bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic,
`
`EDTA,glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids
`
`and the like. Further examples of pharmaceutically acceptable inorganic or organic acid
`
`addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 66,
`
`2, (1977) which is incorporated herein by reference.
`
`25
`
`The term "therapeutically effective amount” of a compound as used herein refers to an
`
`amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially arrest the
`
`clinical manifestations of a given disease or disorder and its complications. An amount
`
`adequate to accomplish this is defined as "therapeutically effective amount". Effective
`
`amounts for each purpose will depend on the severity of the disease or injury as well
`
`30
`
`as the weight and general state of the subject. It will be understood that determining an
`
`appropriate dosage may be achieved using routine experimentation, by constructing a
`
`matrix of values and testing different points in the matrix, whichis all within the ordinary
`
`skills of a trained physician or veterinary.
`
`

`

`P4934EP00
`
`The terms “treatment” and “treating” as used herein refer to the management and care
`
`of a patient for the purpose of combating a condition, disease or disorder. The term is
`
`intended to include the full spectrum of treatments for a given condition from which the
`
`patient is suffering. The patient to be treated is preferably a mammal, in particular a
`
`human being. Treatment of animals, such as mice, rats, dogs, cats, horses, cows,
`
`sheep and pigs, is, however, also within the scope of the present context. The patients
`
`to be treated can be of various ages.
`
`10
`
`Description of Drawings
`
`Figure 1: Rats treated with test compound 1 (AP1189; ((E)-N-trans-{3-[1-(2-
`
`nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidium acetate) have a significant
`
`reduction in proteinuria at day 28 and day 42 comparedto control rats (vehicle).
`
`Control rats maintained an unchanged albumin excretion at all time points, whereas
`
`15
`
`rats treated with test compound 1 show a 3148% reduction in albumin excretion rate at
`
`day 28 and a 48410% reduction in albumin excretion rate at day 482. See Examples
`
`for details.
`
`Figure 2A) Rats treated with test compound 1 (AP 1189; ((E)-N-trans-{3-[1-(2-
`
`20
`
`nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidium acetate) have a significantly
`
`higher GFR (creatinine clearance) following 4 weeks treatment than the rats treated
`
`with the positive control (ACTH 1-24):
`
`i)
`
`ii)
`
`iii)
`
`positive control at 10 mg/day: 2.19 £0.24 mL/min
`
`test compound1 at 20 mg/kg: 3.1240.14 mL/min (p=0.002)
`
`test compound 1 at 40 mg/kg: 2.944+0.14 mL/24 min (p=0.01).
`
`Figure 2B) Rats treated with test compound 1 (AP 1189; ((E)-N-trans-{3-[1-(2-
`
`nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidium acetate) have a significantly
`
`reducedfraction albumin excretion (FEAlb) comparedto positive control (ACTH 1-24):
`
`i)
`
`ii)
`
`iii)
`
`positive control at 10 mg/day: 0.59+0.02%
`
`test compound 1 at 20 mg/kg: 0.045+0.04% (p=0.007)
`
`test compound 1 at 40 mg/kg: 0.35+0.05% (p=0.001).
`
`25
`
`30
`
`

`

`P4934EP00
`
`Detailed description
`
`Melanocortin (MC) receptors (MC1R-—MC5R), a family of class A G protein-coupled
`
`receptors (GPCRs), are attractive therapeutic targets for a number of conditions due to
`
`their wide distribution and diversity of physiological processes they regulate. MC1R
`
`regulates UV light-induced skin tanning and other immune responsesbecause ofits
`
`expression on leukocytes. MC2R regulates cortisol production on the adrenal glands,
`
`whereas MCS5R plays a role on exocrine glands secretions. MC3R and MC4R exert
`
`non-redundant functions on energy homeostasis in addition to specific anti-
`
`inflammatory roles; whereas MC3R activation is particularly protective for joint
`
`10
`
`inflammation such asarthritis, MC4R provides neuroprotection in brain inflammation.
`
`Accordingly, an array of pathological situations could be targeted with MCR-drugs
`
`including skin conditions, cardiovascular pathologies, joint inflammation, obesity and
`
`cachexia.
`
`15
`
`Peripheral MC1R and MC3R can be pharmacologically activated to induce anti-
`
`inflammation. The endogenous agonist a-melanocyte—stimulating hormone (aMSH),
`
`like other protective mediators, is released by immune cells to counterbalance
`
`proinflammatory signals, thus preventing excessive tissue damage. In line with the
`
`resolution of inflammation concept, therapeutics targeting MC1R and MCS3R act by
`
`20
`
`mimicking the body’s own protective resources and might be characterized bya lighter
`
`burden of side effects.
`
`Shownto be effective in rheumatic diseases since the early 1950s, the use of
`
`corticotropin or adrenocorticotropin hormone (ACTH) declined when synthetic
`
`25
`
`glucocorticoids became available. However, the discovery of an alternative anti-
`
`inflammatory mechanism for ACTH involving activation of peripheral MC receptors on
`
`immune cells has revived the interest in developing novel ACTH-like molecules with no
`
`steroidogenic effects for the treatment of joint diseases such as gout or RA (rheumatoid
`
`arthritis). However, the limitation in the translational delivery of novel MC drugs besides
`
`30
`
`the marketed ACTH formulations is imposed by the lack of receptor selectivity achieved
`
`so far.
`
`Innovative approachesin G protein—coupled receptor drug discovery might help to
`
`overcome this limitation. Allosteric modulation consists in the ability of a molecule to
`
`35
`
`enhance (positive modulation) or reduce (negative modulation) the effect of the
`
`

`

`P4934EP00
`
`10
`
`endogenous ligand by binding to a distinct site of the receptor protein, termed allosteric
`
`site. A higher degree of selectivity is expected as allosteric regions are less conserved
`
`among the five MCRs, and indeed, allosteric modulators at MC4R are currently under
`
`developmentfor the treatment of obesity.
`
`Another emerging concept of significant therapeutic interest is the one of biased
`
`agonism. The obsolete notion that receptors could exist in two unique conformations,
`
`the active one and the inactive one, has been replaced with the conception that
`
`multiple active conformations can exist, each one creating a distinct signal yielding
`
`10
`
`multiple functional outcomes. Receptor activation, rather than linear and static, is
`
`emerging as a highly dynamic and multidimensional processin which a diversity of
`
`active conformations may be induced bydifferent molecules leading to distinct effects.
`
`The small molecule AP1189 ((E)-N-trans-{8-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-
`
`15
`
`allylidene}-aminoguanidium acetate) has been characterized as a biased agonistat
`
`receptors MC1R and MC3R, which does not induce canonical cAMP generation, but
`
`cause ERK1/2 phosphorylation, a signaling responsible for the proefferocytic effect
`
`evoked in mouse primary macrophages. AP1189 was shownto reduce cytokine
`
`release in macrophages, whereas no melanogenesis was induced by AP1189in
`
`20
`
`melanocytes.
`
`In vivo, oral AP1189 elicits anti-inflammatory actions in peritonitis and
`
`accelerated the resolution phase, and afforded significant reduction of macroscopic
`
`and histological parameters ofjoint disruption in experimental inflammatory arthritis.
`
`AP1189 is thus a biased dual agonist at MC1R and MC3R with anti-inflammatory
`
`properties together with a lack of effect on melanogenesis.
`
`25
`
`30
`
`Melanocortin therapy by using adrenocorticotropic hormone (ACTH) or non-
`
`steroidogenic melanocortin peptides attenuates proteinuria and glomerular injury in
`
`experimental glomerular diseases and induces remission of nephrotic syndrome in
`
`patients with diverse glomerulopathies, even those resistant to steroids.
`
`Proteinuria, the hallmark of glomerular injury, is a common finding on urinalysis, and is
`
`by itself a strong, independent and modifiable risk factor for end stage renal disease,
`
`premature death of cardiovascular origin, and ischemic stroke in patients with diabetes.
`
`Despite recent advancesrefractory proteinuria continues to be a challenge in clinical
`
`35
`
`practice.
`
`

`

`P4934EP00
`
`11
`
`It is an aspect of the present disclosure to provide a composition comprising a
`
`compound of formula (I) or (la):
`
`HNTS+ ;
`
`Ro
`
`Rg
`
`Ry
`
`Rs
`
`R,
`
`Ry
`
`N
`mL
`
`Rs
`
`i
`—— _=N
`n
`
`Nn Ry
`
`formula (I)
`
`XY
`
`_
`0 SON lh
`
`rN
`
`R
`
`formula (la)
`
`10
`
`15
`
`including tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`forms and racemic forms, thereof;
`
`wherein
`
`nis1,2or3;
`
`

`

`P4934EP00
`
`12
`
`each Rz, Re, Rs, Ra and Rs is independently selected from the group consisting of
`
`hydrogen, optionally substituted C,..-alkyl, optionally substituted C3..-cycloalkyl,
`
`optionally substituted C2.-alkenyl, optionally substituted C4..-alkadienyl, optionally
`
`substituted Co.¢- alkynyl, hydroxy, optionally substituted C)-¢-alkoxy, optionally
`
`substituted C2z..-alkenyloxy, carboxy, optionally substituted C,..-alkoxycarbonyl,
`
`optionally substituted C,-.- alkylcarbonyl, formyl, C1.6-alkylsulphonylamino, optionally
`
`substituted aryl, optionally substituted aryloxycarbonyl, optionally substituted aryloxy,
`
`optionally substituted arylcarbonyl, optionally substituted arylamino,
`
`10
`
`arylsulphonylamino, optionally substituted heteroaryl, optionally substituted
`
`heteroaryloxycarbonyl, optionally substituted heteroaryloxy, optionally substituted
`
`heteroarylcarbonyl, optionally substituted heteroarylamino, heteroarylsulphonylamino,
`
`optionally substituted heterocyclyl, optionally substituted heterocyclyloxycarbonyl,
`
`optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyl,
`
`15
`
`optionally substituted heterocyclylamino, heterocyclylsulphonylamino, amino, mono-
`
`and di(C,..-alkyl)amino, carbamoyl, mono- and di(C;.6-alkyl)aminocarbonyl, amino-C1..-
`
`alkyl-aminocarbonyl, mono- and di(C1.¢- alkylamino-C,.<-alkyl-aminocarbonyl, C1-¢-
`
`alkylcarbonylamino, amino-C...-alkyl- carbonylamino, mono- and di(C;.6-alkyl)amino-C4.
`
`s-alkyl-carbonylamino, cyano, guanidino, carbamido, C1-.-alkanoyloxy, C4-6-
`
`20
`
`alkylsulphonyl, Cy.¢-alkylsulphinyl, C1.¢-alkylsulphonyl- oxy, aminosulfonyl, mono- and
`
`di(C..6-alkyl)aminosulfonyl, nitro, optionally substituted C1.6-alkylthio and halogen,
`
`where any nitrogen-bound C;..-alkyl is optionally substituted with hydroxy, C1..-alkoxy,
`
`C2.6-alkenyloxy, amino, mono- and di(C4-6-alkylamino, carboxy, C1-.-
`
`alkylcarbonylamino, halogen, C..¢-alkylthio, C1-¢-alkyl-sulphonyl-amino or guanidine;
`
`25
`
`each Rg and R; is independently selected from the group consisting of hydrogen,
`
`optionally substituted C,-¢-alkyl, optionally substituted C2-¢-alkenyl, optionally
`
`substituted C,4.<- alkadienyl, optionally substituted Cz-¢-alkynyl, optionally substituted
`
`C,-¢-alkoxycarbonyl, optionally substituted C,.¢-alkylcarbonyl, optionally substituted
`
`30
`
`aryl, optionally substituted aryloxycarbonyl, optionally substituted arylcarbonyl,
`
`optionally substituted heteroaryl, optionally substituted heteroaryloxycarbonyl,
`
`optionally substituted heteroarylcarbonyl, aminocarbonyl, mono- and di(C4-.6-
`
`alkyl)aminocarbonyl, amino- C,.¢-alkyl-aminocarbonyl and mono- and di(C4-.-
`
`alkyl)amino- C,-¢-alkyl-aminocarbonyl; or Rg and R; may together form a five- or six-
`
`

`

`P4934EP00
`
`13
`
`memberednitrogen-containing ring;
`
`or a pharmaceutically acceptable derivative thereof, for use in the treatment of a kidney
`
`disease.
`
`It is also an aspect to provide use of a composition comprising a compound of formula
`
`(I) or (la):
`
`Ro
`
`mf
`
`Rg
`
`ns
`
`—<—=>a
`
`N
`
`H
`
`Rs
`
`10
`
`n
`
`formula (I)
`
`AfRR;
`Ytae
`
`Rs
`
`Fe
`
`Yh
`
`rN
`
`R,
`
`formula (la)
`
`including tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`15
`
`forms and racemic forms, thereof; wherein each of n, R:, Re, R3, Ra and Rs, Re and
`
`R; are as defined herein above, or a pharmaceutically acceptable derivative thereof,
`
`

`

`P4934EP00
`
`14
`
`for the manufacture of a medicament for the treatment of a kidney disease.
`
`It is also an aspect to provide a method for treating a kidney disease, said method
`
`comprising one or more steps of administration of a composition comprising a
`
`compound of formula (I) or (la):
`
`Ro
`
`Rs
`
`HN Fs
`
`a
`/
`—<—_— ——N
`n
`
`No Ry
`
`formula (I)
`
`Ry
`
`Ry
`
`Ry
`
`Rs
`
`Rs
`
`R;
`
`
`
`10
`
`formula (la)
`
`including tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`forms and racemic forms, thereof; wherein each of n, Ri, R2, Rs, Ra and Rs, Re and
`
`15
`
`R; are as defined herein above, or a pharmaceutically acceptable derivative thereof, to
`
`an individual in need thereof.
`
`

`

`P4934EP00
`
`15
`
`The present disclosure also provides a composition comprising a compound of formula
`
`(IN):
`
`@
`
`aN
`
`NFb
`
`FEN
`
`formula (II)
`
`including tautomeric and isomeric forms, such as enantiomeric forms, diastereomeric
`
`forms and racemic forms, thereof; or a pharmaceutically acceptable derivative thereof,
`
`for use in the treatmentof a kidney disease.
`
`10
`
`In one embodiment there is provided a composition comprising a compound of formula
`
`(I), (la) or (II) as defined herein for use in the treatment of a kidney disease, wherein
`
`said kidney disease present with proteinuria.
`
`15
`
`Proteinuria is the presence of excessproteins in the urine. In healthy persons, urine
`
`contains verylittle protein; an excess is suggestive of illness. The main mechanisms to
`
`cause proteinuria is disease in the kidney (esp. the glomerulus) or kidney damage,
`
`increased quantity of proteins in serum (overflow proteinuria), low reabsorption at
`
`proximal tubule, certain biological agents and excessive fluid intake.
`
`20
`
`Proteinuria may be defined as defined as >3.5 g per 1.73 m’* body surface area per
`
`day, or > 40 mg per square meter body surface area per hour in children.
`
`In one embodiment there is provided a composition comprising a compound of formula
`
`25
`
`(I), (la) or (Il) as defined herein for use in the treatment of a kidney disease, wherein
`
`said kidney disease present with proteinuria defined as >3.5 g per 1.73 m* body
`
`

`

`P4934EP00
`
`16
`
`surface area per day, or > 40 mg per square meter body surface area per hour in
`
`children.
`
`A ‘kidney disease presenting with proteinuria’ means that proteinuria is an associated
`
`symptom or sign of said kidney disease. A ‘kidney disease presenting with proteinuria’
`
`may also be described as a kidney disease associated with proteinuria or a kidney
`
`disease with proteinuria or a proteinuric kidney disease.
`
`In one embodiment there is provided a composition comprising a compound of formula
`
`10
`
`(1), (la) or (Il) as defined herein for use in the treatment of a kidney disease, wherein
`
`said kidney disease is a glomerular disease, such as a disease affecting the podocytes
`
`of the glomeruli.
`
`A glomerular disease mayalso reflect any type of glomerular injury caused by
`
`15
`
`glomerular disease or any other stimuli, such as other underlying diseases or
`
`influences.
`
`The term ‘caused by’ a disease in the present context means that the injury arises or
`
`emerges as a causeor result of a disease, such as an underlying disease, i.e. as a
`
`20
`
`result of the pathologic condition.
`
`In one embodiment there is provided a composition comprising a compound of formula
`
`(I), (la) or (Il) as defined herein for use in the treatment of a kidney disease, wherein
`
`said kidney disease is nephrotic syndrome (glomerulonephrosis).
`
`25
`
`Nephrotic syndrome is a collection of symptoms due to kidney damage, including
`
`proteinuria, low blood albumin levels, high bloodlipids, and significant swelling. Other
`
`symptoms mayinclude weight gain, feeling tired, and foamy urine. Complications may
`
`include blood clots, infections, and high blood pressure. Causes include a number of
`
`30
`
`kidney diseases and mayalso occur as a complication of for example diabetes or
`
`lupus. The underlying mechanism typically involves damageto the glomeruli of the
`
`kidney.
`
`

`

`P4934EP00
`
`17
`
`In one embodiment there is provided a composition comprising a compound of formula
`
`(1), (la) or (II) as defined herein for use in the treatment of a kidney disease, wherein
`
`said kidney disease is primary nephrotic syndrome (primary glomerulonephrosis).
`
`In one embodiment said primary nephrotic syndrome is membranous
`
`glomerulonephritis (MGN) (or membranous nephropathy (MN)).
`
`In one embodimentsaid primary nephrotic syndrome is focal segmental
`
`glomerulosclerosis (FSGS)
`
`10
`
`In one embodiment said primary nephrotic syndrome is membranoproliferative
`
`glomerulonephritis (MPGN) (mesangiocapillary glomerulonephritis).
`
`In one embodiment said membranoproliferative glomerulonephritis (MPGN) is selected
`
`15
`
`from Type 1 MPGN and Type 2 MPGN.
`
`In one embodiment said primary nephrotic syndrome is rapidly progressive
`
`glomerulonephritis (RPGN) (crescentic GN).
`
`20
`
`In one embodiment said primary nephrotic syndrome is minimal change disease
`
`(MCD).
`
`In one embodiment there is provided a composition comprising a compound of formula
`
`(I), (la) or (Il) as defined herein for use in the treatment of a kidney disease, wherein
`
`25
`
`said kidney disease is secondary nephrotic syndrome (secondary glomerulonephrosis).
`
`In one embodiment said secondary nephrotic syndrome is caused by an underlying
`
`disease (or simply caused by a disease). The term ‘caused by’ a disease in the present
`
`context means that the nephrotic syndrome arises or emerges as a cause or result of a
`
`30
`
`disease, such as an underlying disease, i.e. as a result of the pathologic condition.
`
`In one embodiment said secondary nephrotic syndrome is caused by an underlying
`
`autoimmune disease.
`
`

`

`P4934EP00
`
`18
`
`In one embodiment said secondary nephrotic syndrome is caused by an underlying
`
`cancer disease.
`
`In one embodiment said secondary nephrotic syndrome is caused by an underlying
`
`genetic disorder.
`
`In one embodiment said secondary nephrotic syndrome is caused by an underlying
`
`disease selected from the group consisting of: Systemic lupus erythematosus, Diabetic
`
`nephropathy, Sarcoidosis, Sj6gren's syndrome, Amyloidosis, Multiple myeloma,
`
`10
`
`Vasculitis, Cancer and Genetic disorders (such as congenital nephrotic syndrome).
`
`In one embodiment said secondary nephrotic syndrome is caused b