Patent Description:
The complement system is an important component of the innate immune system and comprises a cascade of proteases that are normally present in an inactive state. These proteases are organized in three activation pathways: the classical, the lectin, and the alternative pathways that all converge on C3 and C5 cleavage and a common terminal pathway (<NPL>). Molecules from microorganisms, antibodies or cellular components can activate these pathways resulting in the formation of protease complexes known as the C3-convertases and the C5-convertases. The classical pathway is a calcium/magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes. It can also be activated in an antibody-independent manner by the binding of C-reactive protein complexed to ligand and by many pathogens including gram-negative bacteria. The lectin pathway is also calcium and magnesium dependent and is normally stimulated by lectins. The alternative pathway is a magnesium-dependent cascade which is activated by deposition and activation of C3 on certain susceptible surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials). In addition to alternative pathway-specific stimulation, the alternative pathway also serves as an amplification loop for the other complement pathways.

Factor B is a key protease of the alternative pathway and may be a suitable target for the inhibition of the alternative pathway as well as the amplification of the other complement pathways. Its plasma concentration in humans is typically about <NUM>µg/mL (or about <NUM>), and it has been shown to be a critical enzyme for activation of the alternative complement pathway (<NPL>; <NPL>).

<CIT> describes the synthesis and some utilities of the piperidinyl-indole derivatives. The said compounds are powerful factor B inhibitors and suppress the amplification of the complement system caused by C3 activation irrespective of the initial mechanism of activation (including for example activation of the classical, lectin or alternative pathways).

<CIT> describes polypeptide inhibitors of C3/C5 convertase and their utility for the treatment of disorders related to the complement system.

Surprisingly, the present invention provides now a compound of Formula (I) to for use in a method of treating or preventing factor B mediated diseases, which consists of administering a compound of Formula (I) to a patient suffering from C3G (C3 glomerulopathy).

In a first embodiment, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of C3G (C3 glomerulopathy). Compounds of Formula (I) or pharmaceutically acceptable salts thereof, are represented by the following structure:
<CHM>
Wherein.

In a second embodiment, the invention provides compounds or pharmaceutically acceptable salts thereof for use in accordance to the first embodiment, wherein.

In a third embodiment, the invention provides compounds or pharmaceutically acceptable salts thereof for use in accordance to the first embodiment wherein.

In a forth embodiment, the invention provides compounds for use in accordance to the first embodiment, wherein the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:.

In a fifth embodiment, the invention provides a compound for use in accordance to the first embodiment, wherein the compound or a pharmaceutically acceptable salt thereof is <NUM>-((<NUM>,<NUM>)-<NUM>-ethoxy-<NUM>-((<NUM>-methoxy-<NUM>-methyl-<NUM>-indol-<NUM>-yl)methyl)piperidin-<NUM>-yl)benzoic acid.

In a further embodiment, the invention provides a compound for use in accordance to any one of claims <NUM> - <NUM>, wherein the use is in the treatment of C3G (C3 glomerulopathy).

In a further embodiment the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt therof in accordance to the definition of embodiment <NUM> and one or more pharmaceutically acceptable carriers, for use in the treatment of C3G (C3 glomerulopathy).

For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having up to <NUM> carbon atoms. Unless otherwise provided, alkyl refers to hydrocarbon moieties having <NUM> to <NUM> carbon atoms, <NUM> to <NUM> carbon atoms, <NUM> to <NUM> carbon atoms, or <NUM> to <NUM> carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, <NUM>-methylhexyl, <NUM>,<NUM>- dimethylpentyl, <NUM>,<NUM>-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

As used herein, the term "alkoxy" refers to alkyl-O-, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, <NUM>-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Typically, alkoxy groups have about <NUM>-<NUM>, more preferably about <NUM>-<NUM> carbons.

Pharmaceutically acceptable acid addition salts may be formed with inorganic acids and organic acids.

Pharmaceutically acceptable base addition salts may be formed with inorganic and organic bases.

Representative examples of pharmaceutically acceptable salts of compounds of formula (I) were already described in <CIT> and are likewise suitable for this invention.

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, <NPL>). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (<NUM>) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder, or a disease or biological process (e.g., tissue regeneration and reproduction) (i) mediated by Factor B, or (ii) associated with Factor B activity, or (iii) characterized by activity (normal or abnormal) of the complement alternative pathway; or (<NUM>) reducing or inhibiting the activity of Factor B; or (<NUM>) reducing or inhibiting the expression of Factor B; or (<NUM>) reducing or inhibiting activation of the complement system and particularly reducing or inhibiting generation of C3a, iC3b, C5a or the membrane attack complex generated by activation of the complement alternative pathway. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of Factor B and/or the complement alternative pathway; or at least partially reducing or inhibiting the expression of Factor B and/or the complement alternative pathway. The meaning of the term "a therapeutically effective amount" as illustrated in the above embodiment for Factor B and/or the complement alternative pathway.

As used herein, the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.

As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least <NUM> % enantiomeric excess, at least <NUM> % enantiomeric excess, at least <NUM> % enantiomeric excess, at least <NUM> % enantiomeric excess, at least <NUM> % enantiomeric excess, at least <NUM> % enantiomeric excess, or at least <NUM> % enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.

Accordingly, as used herein the use of a compound of the present invention may be in the form of one of the possible isomers such as rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. For clarity, positional isomer are not encompassed by the above.

Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-<NUM>-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) using a chiral adsorbent.

In another embodiment, the present invention provides methods of treating a renal disease or disorder, comprising administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof in accordance to the definition of any one of embodiments <NUM> - <NUM>, wherein said disease or disorder is C3G.

Compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered in unit dosage of about <NUM>-<NUM> of active ingredient(s) for a subject of about <NUM>-<NUM>, or about <NUM>-<NUM> or about <NUM>-<NUM> or about <NUM>-<NUM> or about <NUM>-<NUM>, or about <NUM>-<NUM> of active ingredients. The therapeutically effective dosage thereof, may depend on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill may readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

The efficacy of a compound according to embodiment <NUM> may be assessed by the following methods:.

Patients are recruited in accordance to the following criteria:.

For the trial patients are vaccinated to eliminate the risk of infections caused by encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Vaccination may be effected for example with <NUM>-valent polysaccharide (PS) vaccine, or with heptavalent protein-polysaccharide conjugate (PCV-<NUM>) vaccine.

Pursuant to vaccination, patients are then treated with a daily dosage of a compound of formula (I) of <NUM>, <NUM>, <NUM> and <NUM> given twice per day (BID). The blood pressure is monitored per standard practice and proteinuria is determined by regularly determining the low molecular weight proteins in the urine, such as albumines and globulines.

The duration of treatment with a compound of formula (I) is at least <NUM> months, and the primary endpoints for an effective treatment is achieved with a reduction of urine protein creatinine ratio (UPCR) being <NUM>% or more.

As secondary endpoints, a renal histology is carried out in selected patients, wherein a reduced complement activation, less inflammation, reduced mesangial expansion is aimed at in the histological scores.

For the trial, patients are vaccinated to eliminate the risk of infections caused by encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Vaccination may be effected for example with <NUM>-valent polysaccharide (PS) vaccine, or with heptavalent protein-polysaccharide conjugate (PCV-<NUM>) vaccine.

Pursuant to vaccination, patients are then treated with a daily dosage of a compound of formula (I) of <NUM>, <NUM>, <NUM> and <NUM> given twice per day (BID).

The duration of treatment with a compound of formula (I) is at least <NUM> months.

The primary endpoint for an effective treatment is achieved if proteinuria is reduced by more than <NUM>%.

A secondary endpoint for an effective treatment is an improved eGFR as well as an improved histology in renal biopsy, target effects in tissue after <NUM> months of treatment (if possible, after <NUM> months of therapy).

Compounds of formula (I) or pharmaceutically acceptable salts thereof as disclosed in embodiments <NUM> - <NUM> are potent inhibitors of factor B and are tested in the clinical trials (<NUM>) and (<NUM>) described above.

This assay is based on stabilized C3 convertase in patient serum. Patient serum is mixed <NUM>:<NUM> with normal serum and incubated for <NUM> minutes at <NUM>. Normal serum serves as source for C3, since patient C3 levels can be very low. Outcome is the proportion of C3 that is cleaved vs uncleaved C3. Maximal cleavage was determined by incubating serum in Mg<NUM>+ EGTA-PBS, background cleavage was determined by incubating the serum in EDTA-PBS. Inhibition by a test compound was calculated by the following formula: <MAT>.

The assay was performed in samples of <NUM> patients with C3G with the following causes for alternative pathway (AP) dysregulation:.

In this assay, we tested the compounds of embodiment <NUM>. For example, the compound of embodiment <NUM> inhibited C3 cleavage at a concentration of <NUM> micromolar by ><NUM>%, and in the presence of <NUM> micromolar by <NUM>%.

Inhibition of the preformed and stabilized C3 convertase was measured by C3 Convertase Stabilizing Assay (C3CSA) (described by <NPL>)). In this assay, C3 convertase is artificially constructed on the surface of sheep erythrocytes. While C3 convertase normally has a half-life of <NUM> seconds at <NUM>, the decay is delayed by addition of IgG purified from patients. Compounds were added at the same time as the patient derived IgG in order to inhibit convertase stabilization/convertase activity and allow its decay. After IgG (and compound) administration, convertase was allowed to decay for <NUM> minutes at <NUM>. Then, rat serum in EDTA was added for <NUM> minutes at <NUM> to allow the stabilized C3 convertases to activate the terminal complement pathway and lyse the erythrocytes. Erythrocyte lysis is associated with hemoglobin release and therefore was quantified via absorption in the supernatant at <NUM>. Maximal hemolysis was determined by lysis at time <NUM> and as a background, hemolysis in EDTA buffer (full inhibition of all complement pathways) was measured.

Claim 1:
A compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of C3G (C3 glomerulopathy),
<CHM>
wherein,
R is hydrogen, C<NUM>-C<NUM>alkyl, or C<NUM>-C<NUM>alkoxy;
R<NUM> is C<NUM>-C<NUM>alkoxy;
R<NUM> is C<NUM>-C<NUM>alkyl;
R<NUM> is C<NUM>-C<NUM>alkoxy, C<NUM>-C<NUM>alkyl, or hydroxyl;
R<NUM> is phenyl, optionally substituted by -C(O)R<NUM>; and
R<NUM> is hydroxy, C<NUM>-C<NUM>alkoxy, or amino.