WO2015004089A1 - Losmapimod for use in treating glomerular disease - Google Patents

Losmapimod for use in treating glomerular disease Download PDF

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Publication number
WO2015004089A1
WO2015004089A1 PCT/EP2014/064508 EP2014064508W WO2015004089A1 WO 2015004089 A1 WO2015004089 A1 WO 2015004089A1 EP 2014064508 W EP2014064508 W EP 2014064508W WO 2015004089 A1 WO2015004089 A1 WO 2015004089A1
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Prior art keywords
glomerular disease
nicotinamide
cyclopropylcarbamoyl
dimethylpropyl
fluoro
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PCT/EP2014/064508
Other languages
French (fr)
Inventor
Dennis SPRECHER
Robert Nicholas Willette
Original Assignee
Glaxosmithkline Intellectual Property (No.2) Limited
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Priority to AU2014289296A priority Critical patent/AU2014289296A1/en
Priority to EP14735983.0A priority patent/EP3019168A1/en
Priority to CA2917277A priority patent/CA2917277A1/en
Priority to CN201480038296.4A priority patent/CN105358148A/en
Priority to US14/903,694 priority patent/US9707219B2/en
Priority to KR1020167002417A priority patent/KR20160030206A/en
Priority to JP2016524786A priority patent/JP2016523943A/en
Priority to RU2015156417A priority patent/RU2015156417A/en
Publication of WO2015004089A1 publication Critical patent/WO2015004089A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to a new pharmaceutical use of a compound which is known in the art as a p38 kinase inhibitor. More specifically this invention relates to the use of a nicotinamide derivative in the treatment of one or more glomerular disease(s) or conditions exhibiting glomerular pathology.
  • Glomerular diseases are those in which the glomeruli are no longer fulfilling this function. Damage to the glomeruli affects the kidney's ability to filter fluids and wastes properly. This leads to blood (hematuria) and/or protein (proteinuria) in the urine. Glomerular diseases are often associated with the signs and symptoms of nephrotic syndrome and predispose to acute renal failure, or progressive chronic kidney disease culminating in end-stage renal disease with dialysis or kidney transplantion.
  • Glomerular diseases include many conditions with a variety of differing causes but which can broadly categorised into two major categories namely, glomerulonephritis (inflammation of the tissue in the kidney that serve as a filter) and glomerulosclerosis (hardening or scarring of the blood vessels within the kidney).
  • Diabetic nephropathy one of the leading causes of kidney failure in the USA, is a form of glomerular disease which is considered to be both a systemic disease, since diabetes itself is a systemic disease, and also a sclerotic diseases, because the specific damage done to the kidneys is associated with scarring.
  • FGS Focal segmental glomerulosclerosis
  • Glomerular hypertension is a glomerular disease in which damage to the kidney is associated with chronic high blood pressure.
  • a pharmaceutical formulation comprising the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof for use in the treatment of a glomerular disease.
  • a combination product comprising 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents which are suitable for the treatment of a glomerular disease.
  • a method for treating a glomerular disease in a subject in need thereof which comprises administering to said subject the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof.
  • the glomerular disease is glomerulonephritis.
  • the glomerular disease is glomerulosclerosis.
  • FSGS glomerulosclerosis
  • the glomerular disease is diabetic nephropathy.
  • the glomerular disease is glomerular hypertension.
  • the glomerular disease is selected from the group consisting of systemic lupus erythematosus (SLE), IgA nephropathy, Goodpasture Syndrome, membrous nephropathy, hereditary renal disease, infection related glomerular disease, chronic pyelonephritis, Alport's Syndrome, periarteritis nodosa nephritis associated with amyloidosis, glomerular disease caused by HIV and toxins.
  • SLE systemic lupus erythematosus
  • the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof may be prepared according to procedures described in patent application WO03/068747 (as example 36).
  • compositions of the compound 6-(5-cyclopropylcarbamoyl-3- fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide are non toxic salts and include examples described in patent application WO03/068747, the contents of which is incorporated by reference.
  • suitable pharmaceutically acceptable salts see also Berge eta/., J. Pharm. Sci., 66: 1-19, (1977).
  • the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide is in the form of a free base.
  • 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof Whilst it is possible for the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof to be administered as the raw chemical it would typically be administered in the form of a pharmaceutical composition. 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt may therefore be formulated for administration in any suitable manner that is known to those skilled in the art.
  • Suitable methods for formulating 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt include those described in patent application WO03/068747 and / or the methods that are familiar to those skilled in the art, which are described in Remington: The Science and Practice of Pharmacy, 21 st Edition 2006.
  • a pharmaceutical formulation comprising the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof for use in the treatment of a glomerular disease.
  • a pharmaceutical formulation comprising the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof for use in the treatment of focal segmental glomerulosclerosis (FSGS).
  • FSGS focal segmental glomerulosclerosis
  • the pharmaceutical formulation is adapted for oral administration.
  • 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)- N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof is administered orally with a dosage in the range 1 mg twice per day (bid) to 30 mg twice per day (bid), particularly 2.5 mg twice per day (bid) to 15mg twice per day (bid), even more particularly 7.5mg twice per day (bid) or 15mg twice per day (bid).
  • the present invention also provides for a method for treating a glomerular disease in a subject in need thereof which comprises administering the compound 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt.
  • the subject in need thereof is a mammal, particularly a human.
  • a method for treating a glomerular disease in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof.
  • a method for treating focal segmental glomerulosclerosis comprises administering to said subject a therapeutically effective amount of the compound 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof.
  • FSGS focal segmental glomerulosclerosis
  • the term "therapeutically effective amount” means that amount of a 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • 6-(5-cyclopropylcarbamoyl-3- fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of focal segmental glomerulosclerosis (FSGS).
  • FSGS focal segmental glomerulosclerosis
  • 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof may be employed alone or in combination with other therapeutic agents which are suitable for the treatment of a glomerular disease.
  • the present invention further provides a combination product comprising 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents which are suitable for the treatment of a glomerular disease.
  • a combination product comprising 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents which are suitable for the treatment of focal segmental
  • FSGS glomerulosclerosis
  • 6-(5-Cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide and the other therapeutically active agent(s) may be administered together or separately and, when administered separately, this may occur simultaneously or sequentially in any order.
  • the amounts of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient.
  • the therapeutic ingredients may be used in optically pure form.
  • a combination product comprising 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide, or a pharmaceutically acceptable salt thereof, together with an ACE inhibitor, ARB or a statin.
  • a combination product comprising 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide, or a pharmaceutically acceptable salt thereof, together with a corticosteroid or a calcinerun inhibitor (e.g. tacrolimus).
  • a corticosteroid or a calcinerun inhibitor e.g. tacrolimus
  • Losmapimod is orally administered twice daily over a 24-week treatment phase (7.5 mg BID for 2 weeks followed by 15 mg BID for 22 weeks).
  • the primary efficacy endpoint of proteinuria is evaluated by the measurement of the Up/c ratio, assessed from a first morning urine sample, with a responder being a patient with a 50% proteinuria reduction from baseline at the end of treatment.
  • Safety and tolerability is monitored by clinical laboratory evaluations (including liver function tests and serum creatinine), vital signs, ECGs, and adverse events.

Abstract

The use of a compound known in the art as a p38 kinase inhibitor in the treatment of a glomerular disease.

Description

LOSMAPIMOD FOR USE IN TREATING GLOMERULAR DISEASE
Field of the Invention
This invention relates to a new pharmaceutical use of a compound which is known in the art as a p38 kinase inhibitor. More specifically this invention relates to the use of a nicotinamide derivative in the treatment of one or more glomerular disease(s) or conditions exhibiting glomerular pathology.
Background of the Invention
Many diseases affect kidney function by attacking the glomeruli, the clusters of looping blood vessels within the kidney where blood is cleaned/filtered. Glomerular diseases are those in which the glomeruli are no longer fulfilling this function. Damage to the glomeruli affects the kidney's ability to filter fluids and wastes properly. This leads to blood (hematuria) and/or protein (proteinuria) in the urine. Glomerular diseases are often associated with the signs and symptoms of nephrotic syndrome and predispose to acute renal failure, or progressive chronic kidney disease culminating in end-stage renal disease with dialysis or kidney transplantion.
Glomerular diseases include many conditions with a variety of differing causes but which can broadly categorised into two major categories namely, glomerulonephritis (inflammation of the tissue in the kidney that serve as a filter) and glomerulosclerosis (hardening or scarring of the blood vessels within the kidney).
Diabetic nephropathy, one of the leading causes of kidney failure in the USA, is a form of glomerular disease which is considered to be both a systemic disease, since diabetes itself is a systemic disease, and also a sclerotic diseases, because the specific damage done to the kidneys is associated with scarring.
Focal segmental glomerulosclerosis (FSGS) describes scarring in scattered regions of the kidney, typically limited to one part of the glomerulus and to a minority of glomeruli in the affected region. This condition may result from specific genetic mutations, systemic conditions, toxins or may develop as an idiopathic kidney disease.
Glomerular hypertension (or hypertensive renal disease) is a glomerular disease in which damage to the kidney is associated with chronic high blood pressure.
Current treatments for such diseases include medications that seek to control blood pressure and blood cholesterol e.g. angiotension converting enzyme inhibitors (ACE inhibitors), angiotension receptor blockers (ARBs) or statins. Despite current treatment, there still exists a need for novel therapies to halt progression of chronic kidney disease and/or treat the signs and symptoms of nephritic syndrome. Patent application WO03/068747 (SmithKline Beecham Corporation) discloses a series of nicotinamide derivatives that are useful as p38 inhibitors. The compound 6- (5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide is specifically described therein. The statement of non-proprietary name adopted by the USAN Council for this compound is losmapimod.
Summary of the Invention
In a first aspect there is provided the compound 6-(5-cyclopropylcarbamoyl- 3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof for use in the treatment of a glomerular disease.
In a second aspect there is provided a pharmaceutical formulation comprising the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof for use in the treatment of a glomerular disease.
In a third aspect there is provided a combination product comprising 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents which are suitable for the treatment of a glomerular disease.
In a fourth aspect there is provided a method for treating a glomerular disease in a subject in need thereof which comprises administering to said subject the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof.
In a fifth aspect there is provided the use of 6-(5-cyclopropylcarbamoyl-3- fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a glomerular disease.
Detailed Description of the Invention
According to the present invention there is provided the compound 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide, that is to say, the compound having the formula (I)
Figure imgf000003_0001
(I) or a pharmaceutically acceptable salt thereof for use in the treatment of a glomerular disease.
In one embodiment the glomerular disease is glomerulonephritis.
In one embodiment the glomerular disease is glomerulosclerosis.
In a particular embodiment the glomerular disease is focal segmental
glomerulosclerosis (FSGS).
In a particular embodiment the glomerular disease is diabetic nephropathy.
In a particular embodiment the glomerular disease is glomerular hypertension.
In a further particular embodiment the glomerular disease is selected from the group consisting of systemic lupus erythematosus (SLE), IgA nephropathy, Goodpasture Syndrome, membrous nephropathy, hereditary renal disease, infection related glomerular disease, chronic pyelonephritis, Alport's Syndrome, periarteritis nodosa nephritis associated with amyloidosis, glomerular disease caused by HIV and toxins.
The compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof may be prepared according to procedures described in patent application WO03/068747 (as example 36).
Pharmaceutically acceptable salts of the compound 6-(5-cyclopropylcarbamoyl-3- fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide are non toxic salts and include examples described in patent application WO03/068747, the contents of which is incorporated by reference. For a review of suitable pharmaceutically acceptable salts see also Berge eta/., J. Pharm. Sci., 66: 1-19, (1977).
In one embodiment the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide is in the form of a free base.
Whilst it is possible for the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof to be administered as the raw chemical it would typically be administered in the form of a pharmaceutical composition. 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt may therefore be formulated for administration in any suitable manner that is known to those skilled in the art. It may, for example, be formulated for topical administration, transdermal administration, administration by inhalation, oral administration or parenteral administration (e.g. intravenously, intravascularly or subcutaneously). Suitable methods for formulating 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt include those described in patent application WO03/068747 and / or the methods that are familiar to those skilled in the art, which are described in Remington: The Science and Practice of Pharmacy, 21st Edition 2006.
In a further aspect there is provided a pharmaceutical formulation comprising the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof for use in the treatment of a glomerular disease.
In one embodiment there is provided a pharmaceutical formulation comprising the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof for use in the treatment of focal segmental glomerulosclerosis (FSGS).
In one embodiment the pharmaceutical formulation is adapted for oral administration.
In a particular embodiment 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)- N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof is administered orally with a dosage in the range 1 mg twice per day (bid) to 30 mg twice per day (bid), particularly 2.5 mg twice per day (bid) to 15mg twice per day (bid), even more particularly 7.5mg twice per day (bid) or 15mg twice per day (bid).
The present invention also provides for a method for treating a glomerular disease in a subject in need thereof which comprises administering the compound 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt.
Suitably the subject in need thereof is a mammal, particularly a human.
In one embodiment there is provided a method for treating a glomerular disease in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof.
In a particular embodiment there is provided a method for treating focal segmental glomerulosclerosis (FSGS) in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of the compound 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof.
As used herein, the term "therapeutically effective amount" means that amount of a 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
Also provided is the use of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)- N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a glomerular disease.
In a particular embodiment there is provided the use of 6-(5-cyclopropylcarbamoyl-3- fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of focal segmental glomerulosclerosis (FSGS). It will be appreciated that 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof may be employed alone or in combination with other therapeutic agents which are suitable for the treatment of a glomerular disease.
Therefore, the present invention further provides a combination product comprising 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents which are suitable for the treatment of a glomerular disease.
In a particular embodiment there is provided a combination product comprising 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents which are suitable for the treatment of focal segmental
glomerulosclerosis (FSGS).
6-(5-Cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide and the other therapeutically active agent(s) may be administered together or separately and, when administered separately, this may occur simultaneously or sequentially in any order. The amounts of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient. It will be clear also that where appropriate, the therapeutic ingredients may be used in optically pure form.
In one embodiment there is provided a combination product comprising 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide, or a pharmaceutically acceptable salt thereof, together with an ACE inhibitor, ARB or a statin.
In a further embodiment there is provided a combination product comprising 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide, or a pharmaceutically acceptable salt thereof, together with a corticosteroid or a calcinerun inhibitor (e.g. tacrolimus).
The following example illustrates the invention.
Example 1
A pharmaceutical formulation of 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide (losmapimod) suitable for oral administration
A representative formulation for use in this invention is shown in the table below.
Figure imgf000007_0001
Example 2
An efficacy, safety and tolerability study relating to losmapimod in the treatment of primary (idiopathic) focal segmental glomerulosclerosis (FSGS)
This evaluation may be carried out by treatment of FSGS patients having nephrotic range proteinuria (urinary protein/creatinine [Up/c] ratio > 3) and a history of steroid resistance, including relapse of proteinuria after steroid treatment (n = approximately 20). Losmapimod is orally administered twice daily over a 24-week treatment phase (7.5 mg BID for 2 weeks followed by 15 mg BID for 22 weeks). The primary efficacy endpoint of proteinuria is evaluated by the measurement of the Up/c ratio, assessed from a first morning urine sample, with a responder being a patient with a 50% proteinuria reduction from baseline at the end of treatment. Safety and tolerability is monitored by clinical laboratory evaluations (including liver function tests and serum creatinine), vital signs, ECGs, and adverse events.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

Claims

Claims:
I. The compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof for use in the treatment of a glomerular disease.
2. The compound according to claim 1 in which the glomerular disease is focal segmental glomerulosclerosis (FSGS).
3. The compound according to claim 1 in which the glomerular disease is diabetic nephropathy.
4. The compound according to claim 1 in which the glomerular disease is glomerular hypertension.
5. The compound according to claim 1 in which the glomerular disease is selected from the group consisting of systemic lupus erythematosus (SLE), IgA nephropathy, Goodpasture Syndrome, membrous nephropathy, hereditary renal disease, infection related glomerular disease, chronic pyelonephritis, Alport's Syndrome, periarteritis nodosa nephritis associated with amyloidosis, glomerular disease caused by HIV and toxins.
6. The compound according to any one of claims 1 - 5 which is in the form of a free base.
7. A pharmaceutical formulation comprising the compound 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof for use in the treatment of a glomerular disease.
8. A pharmaceutical formulation according to claim 7 which is adapted for oral administration.
9. A combination product comprising 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents which are suitable for the treatment of a glomerular disease.
10. A method for treating a glomerular disease in a subject in need thereof which comprises administering to said subject the compound 6-(5-cyclopropylcarbamoyl-3- fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof.
II. The use of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a glomerular disease.
PCT/EP2014/064508 2013-07-10 2014-07-08 Losmapimod for use in treating glomerular disease WO2015004089A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
AU2014289296A AU2014289296A1 (en) 2013-07-10 2014-07-08 Losmapimod for use in treating glomerular disease
EP14735983.0A EP3019168A1 (en) 2013-07-10 2014-07-08 Losmapimod for use in treating glomerular disease
CA2917277A CA2917277A1 (en) 2013-07-10 2014-07-08 Losmapimod for use in treating glomerular disease
CN201480038296.4A CN105358148A (en) 2013-07-10 2014-07-08 LOSMAPIMOD for use in treating glomerular disease
US14/903,694 US9707219B2 (en) 2013-07-10 2014-07-08 Losmapimod for use in treating glomerular disease
KR1020167002417A KR20160030206A (en) 2013-07-10 2014-07-08 Losmapimod for use in treating glomerular disease
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