WO2015148626A1 - Treatment of fibrotic disorders - Google Patents

Treatment of fibrotic disorders Download PDF

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Publication number
WO2015148626A1
WO2015148626A1 PCT/US2015/022428 US2015022428W WO2015148626A1 WO 2015148626 A1 WO2015148626 A1 WO 2015148626A1 US 2015022428 W US2015022428 W US 2015022428W WO 2015148626 A1 WO2015148626 A1 WO 2015148626A1
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Prior art keywords
fibrosis
disease
fibrotic disorders
treatment
compound
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PCT/US2015/022428
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French (fr)
Inventor
Michael B. Martin
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Millennium Pharmaceuticals, Inc.
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Publication of WO2015148626A1 publication Critical patent/WO2015148626A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to medicinal chemistry, pharmaceutical science, and medicine.
  • fibrotic tissue is part of the normal healing process.
  • fibrosis can be part of a pathological state.
  • excessive fibrous tissue is formed and can obliterate the architecture and function of the underlying organ or tissue.
  • fibrosis can be used to describe the pathological state of excess deposition of fibrous tissue.
  • the need for treatment of fibrotic conditions is a concern for the medical community.
  • the present invention provides for the use of mTOR inhibitors, specifically inhibitors of both mTORCl and mTORC2 mediated activity, such as those found in WO 2010/051043 for the treatment of fibrotic conditions.
  • the present invention provides a method of treating fibrotic disorders, comprising administering to a patient in need thereof an effective amount of a compound of the formula I
  • Ri is selected from the group consisting of hydrogen and methyl
  • R 2 is C alky 1 optionally substituted with one or two hydroxy; or a pharmaceutically acceptable salt thereof.
  • the present invention provides for a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating fibrotic disorders.
  • the present invention provides for the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating fibrotic disorders.
  • Fibrotic disorders can present in a tissue or organ or as a result of a reparative or reactive process.
  • the term "fibrotic disorders” refers to conditions characterized by fibrosis. Specifically, the term “fibrotic disorders” refers to excess scarring; fibrosis resulting from inflammation, including arthrofibrosis; cirrhosis of the liver; endomyocardial fibrosis;
  • fibrosis retroperitoneal fibrosis; progressive mass fibrosis; nephrogenic systemic fibrosis; Crohn's disease; keloid fibrosis; fibrosis related to an old myocardial infarction; atrial fibrosis; and scleroderma or systemic sclerosis.
  • fibrotic disorders includes fibrosis associated with autoimmune and inflammatory disorders including rheumatoid arthritis; systemic lupus erythematosus;
  • inflammatory bowel disease including Crohn's disease and ulcerative colitis
  • spondarthropathy including ankylosing spondylitis, psoriatic arthritis, enteropathic arthritis, and reactive arthritis
  • inflammatory muscle disease including polymositis, dermatomyositis and inclusion body myopathies, whether primary or accompanying malignant disease
  • conjunctivis including polymositis, dermatomyositis and inclusion body myopathies, whether primary or accompanying malignant disease
  • conjunctivis including retinal detachment
  • myasthenia gravis atopic dermatitis and eczema
  • alopecia areata
  • familial Mediterranean fever acute, intercritical, chronic recurring, polyarticular, and tophaceous forms of gout
  • vasculitis including Wegener's granulomatosis, giant cell arteritis, polymyalgia rheumatic, polyarteritis nodosa, and Churg-
  • psoriasis juvenile arthropathies including systemic-onset, polyarticular, pauci-articular and enthesopathic variants, and childhood-onset variants of rheumatoid arthritis and systemic lupus erythematosus; multiple sclerosis, neuromyelitis optica and other demyelinating conditions of the central or peripheral nervous systems; thyroiditis including Hashimoto disease and Grave's ophthalmopathy; autoimmune endocrine glandular dysfunction including Addison disease; automuune bone marrow and hematologic disorders including immune and idiopathic forms of thrombocytopenic purpura and hemolytic anemia, aplastic anemia; psoriasis including psoriasis vulgaris, guttate psoriasis, psoriasis affecting the scalp or nails, and palmo-plantar psoriasis; cervical and lumbar spondylitis or spondylosis;
  • blistering skin and mucosal disease including pemphigus vulgaris, bullous pemphigoid, Stevens- Johnson syndrome, and cutaneous drug reactions; primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis; allergic reactions including to drugs, pollens, animal dander, arthropod or snake bites, and insect feces; celiac disease; sarcoidosis; lichen planus; Behcets disease; idiopathic hearing or visual loss.
  • fibrotic disorders includes primary fibrotic disorders including local and systemic variants of scleroderma; mediastinal, retroperitoneal, and nephrogenic systemic fibrosis; endomyocardial fibrosis; pericarditis; pleuritis; and primary myocardial fibrosis.
  • fibrotic disorders includes secondary fibrosis including fibrosis of the liver following drug or alcohol exposure, non-alcoholic steatohepatosis, metals exposure including iron and copper, viral hepatitis including Hepatitis A, B, C, D or E or other hepatotrophic viruses or bacteria alone or in combination; myocardial and pericardial fibrosis following myocardial infarction, coronary artery bypass, coronary stenting, and other forms of cardiac surgery; and other forms of cardiac damage; myelofibrosis; kidney fibrosis including fibrosis complicating diabetes, drug or heavy metal-related renal injury, or glomerulonephritis; keloid and other forms of excessive scar formation; fibrosis complicating tissue damage from other forms of traumatic, inflammatory, or degenerative disease.
  • fibrotic disorders also includes non-malignant forms of excessive or abnormal tissue proliferation or expansion including polycystic kidney disease,
  • neurofibromatosis uterine fibroids, colonic polyps, meningioma, tuberous sclerosis, and familial and sporadic forms of lymphangioleiomyomatosis; sebaceous cysts; fibrocystic breast disease; nodules of the thyroid gland; granulomas; arteriovenous malformations;
  • fibrotic disorders also includes fibrosis or other connective tissue proliferation or expansion following the implantation of temporary or permanent therapeutic devices including artificial joints, ocular lenses, cardiac valves, pacemakers, and drug-eluting or other implantable drug-delivery systems.
  • fibrotic disorders includes neurodegenerative disease including diabetes
  • Huntington Disease Alzheimer Disease, Niemann-Pick disease, Parkinson's Disease, prion- mediated disease, spinocerebellar ataxia, progressive multifocal encephalopathy, amyotrophic lateral sclerosis, axonal neuropathies, muscular dystrophies, and age-related nervous system degeneration; wet and dry age-related macular degeneration.
  • the present method is carried out using inhibitors of mTOR, which is a
  • mTOR serine/threonine kinase and has been identified as a regulator of protein synthesis as well as cell growth and proliferation. It has been shown that mTOR functions in two distinct complexes (mTORCl and mTORC2). Rapamycin primarily inhibits the mTORCl complex while largely sparing mTORC2 activity.
  • the compounds of the present invention that is, the compounds used in the present method are capable of inhibiting mTORCl and mTORC2 mediated activity.
  • C alkyl optionally substituted with one or two hydroxy refers to a C alkyl optionally having from 1 or 2 hydroxy groups. Included within the scope of the term are methyl, ethyl, propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, 2-hydroxyethyl, 3- hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, and hydroxy-t-butyl.
  • salts refers to salts of pharmaceutically acceptable organic acids and bases or inorganic acids and bases. Such salts are well known in the art and include those described in Journal of Pharmaceutical Science, 66, 2-19 (1977).
  • the compound of the invention may exist as tautomers.
  • tautomer refers to compounds of the invention that can interconvert by way of a migration of one or more hydrogen atoms accompanied by rearrangement in the position of adjacent double bonds.
  • the tautomeric forms if they exist, are in equilibrium with each other, the position of the equilibrium will depend on the exact nature of the physical state of the compound. It is understood that where tautomeric forms are possible and exist, the present invention includes all possible tautomeric forms.
  • the terms “treat,” “treatment,” and “treating” include improvement of the conditions described herein.
  • the terms “treat,” “treatment,” and “treating” include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition.
  • the terms “treat,” “treatment,” and “treating” are intended to include therapeutic treatment of such disorders.
  • the terms “treat,” “treatment,” and “treating” are intended to include prophylactic treatment of such disorders.
  • patient and “subject” includes humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs.
  • mammals such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs.
  • the term also includes birds, fish, reptiles, amphibians, and the like. It is understood that a more particular patient is a human. Also, more particular patients and subjects are non-human mammals, such as mice, rats, and dogs.
  • the term "effective amount” refers to the amount of compound of the invention which treats, upon single or multiple dose administration, a patient suffering from the mentioned condition.
  • An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • the effective amount a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • An effective amount of the present invention, the treatment dosage is expected to range from 1 mg to 20 mg. Specific amounts can be determined by the skilled person. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient (e.g., an infant) whose mass falls outside of this weight range.
  • Dosages of 1 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7 mg/day, and 8 mg/day are contemplated.
  • the frequency of daily dosing can vary depending on the compound of the invention, the route of administration, and the use of the invention.
  • a compound of the invention in effecting treatment of a patient in need of such treatment, can be administered in any form and route which makes the compound
  • the compounds of the invention can be administered by a variety of routes, including oral and parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally,
  • the method of the invention may be carried out be administering to the patient, for example, a pharmaceutical composition in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, or suspensions.
  • a pharmaceutical composition in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, or suspensions.
  • a particular route of administration for the methods of the invention is oral administration.
  • Another particular route of administration for the methods of the invention is by local administration to the lung.
  • Local administration includes inhalation, topical application, or targeted drug delivery.
  • Administration by inhalation includes liquid instillation, instillation as a pressurized fluid preparation by a metered dose inhaler or equivalent, or inhalation of an aerosolized solution via nebulizer, inhalation of dry powder, and directing soluble or dried material into the air stream during mechanical ventilation.
  • One local administration method is administering to a subject an aerosol suspension of respirable particles comprising a compound of the invention by inhalation.
  • the respirable particles can be liquid or solid, with a particle size sufficiently small to pass through the mouth and larynx upon inhalation; in general, particles ranging from about 5 to 10 microns in size are considered respirable.
  • Suitable pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art and include at least one of the compounds of the invention as the active ingredient.
  • the amount of a compound of the present invention may be varied depending upon its particular form and may conveniently be between 1% to about 70% of the weight of the unit dosage form.
  • pharmaceutically acceptable excipient refers to those typically used in preparing pharmaceutical compositions and should be pharmaceutically pure and non-toxic in the amounts used. They generally are a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient.
  • compositions include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.

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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

The present invention provides methods of treating fibrotic disorders, comprising administering to a patient in need thereof an effective amount of a compound of the formula (I).

Description

TREATMENT OF FIBROTIC DISORDERS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority the United States Serial No. 61/970,485, filed March 26, 2014. The entire contents of the aforementioned application is incorporated herein.
FIELD OF THE INVENTION
[0002] The present invention relates to medicinal chemistry, pharmaceutical science, and medicine.
BACKGROUND OF THE INVENTION
[0003] Formation of fibrotic tissue is part of the normal healing process. However, in fibrotic disorders fibrosis can be part of a pathological state. In such disorders excessive fibrous tissue is formed and can obliterate the architecture and function of the underlying organ or tissue. Thus, fibrosis can be used to describe the pathological state of excess deposition of fibrous tissue.
[0004] The need for treatment of fibrotic conditions is a concern for the medical community. The present invention provides for the use of mTOR inhibitors, specifically inhibitors of both mTORCl and mTORC2 mediated activity, such as those found in WO 2010/051043 for the treatment of fibrotic conditions.
SUMMARY OF THE INVENTION
[0005] The present invention provides a method of treating fibrotic disorders, comprising administering to a patient in need thereof an effective amount of a compound of the formula I
Figure imgf000002_0001
wherein
Ri is selected from the group consisting of hydrogen and methyl; and
R2 is C alky 1 optionally substituted with one or two hydroxy; or a pharmaceutically acceptable salt thereof.
That is, the present invention provides for a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating fibrotic disorders.
Said another way, the present invention provides for the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating fibrotic disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0006] Fibrotic disorders can present in a tissue or organ or as a result of a reparative or reactive process. The term "fibrotic disorders" refers to conditions characterized by fibrosis. Specifically, the term "fibrotic disorders" refers to excess scarring; fibrosis resulting from inflammation, including arthrofibrosis; cirrhosis of the liver; endomyocardial fibrosis;
mediastinal fibrosis; Peyronie's disease; Dupuytren's contracture; myelofibrosis;
retroperitoneal fibrosis; progressive mass fibrosis; nephrogenic systemic fibrosis; Crohn's disease; keloid fibrosis; fibrosis related to an old myocardial infarction; atrial fibrosis; and scleroderma or systemic sclerosis.
[0007] The term "fibrotic disorders" includes fibrosis associated with autoimmune and inflammatory disorders including rheumatoid arthritis; systemic lupus erythematosus;
primary and secondary Sjogren syndrome; inflammatory bowel disease, including Crohn's disease and ulcerative colitis; spondarthropathy including ankylosing spondylitis, psoriatic arthritis, enteropathic arthritis, and reactive arthritis; inflammatory muscle disease including polymositis, dermatomyositis and inclusion body myopathies, whether primary or accompanying malignant disease; conjunctivis, iritis, keratitis, keratoconjunctivitis, scleritis, and uveitis; retinopathies including retinal detachment; myasthenia gravis; atopic dermatitis and eczema; alopecia areata; familial Mediterranean fever; acute, intercritical, chronic recurring, polyarticular, and tophaceous forms of gout; vasculitis including Wegener's granulomatosis, giant cell arteritis, polymyalgia rheumatic, polyarteritis nodosa, and Churg- Strauss syndrome; polychondritis; calcium pyrophosphate tissue deposition disease, both acute and chronic variants; primary and secondary osteoarthritis; adhesive capsulitis;
psoriasis; juvenile arthropathies including systemic-onset, polyarticular, pauci-articular and enthesopathic variants, and childhood-onset variants of rheumatoid arthritis and systemic lupus erythematosus; multiple sclerosis, neuromyelitis optica and other demyelinating conditions of the central or peripheral nervous systems; thyroiditis including Hashimoto disease and Grave's ophthalmopathy; autoimmune endocrine glandular dysfunction including Addison disease; automuune bone marrow and hematologic disorders including immune and idiopathic forms of thrombocytopenic purpura and hemolytic anemia, aplastic anemia; psoriasis including psoriasis vulgaris, guttate psoriasis, psoriasis affecting the scalp or nails, and palmo-plantar psoriasis; cervical and lumbar spondylitis or spondylosis;
blistering skin and mucosal disease including pemphigus vulgaris, bullous pemphigoid, Stevens- Johnson syndrome, and cutaneous drug reactions; primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis; allergic reactions including to drugs, pollens, animal dander, arthropod or snake bites, and insect feces; celiac disease; sarcoidosis; lichen planus; Behcets disease; idiopathic hearing or visual loss.
[0008] The term "fibrotic disorders" includes primary fibrotic disorders including local and systemic variants of scleroderma; mediastinal, retroperitoneal, and nephrogenic systemic fibrosis; endomyocardial fibrosis; pericarditis; pleuritis; and primary myocardial fibrosis.
[0009] The term "fibrotic disorders" includes secondary fibrosis including fibrosis of the liver following drug or alcohol exposure, non-alcoholic steatohepatosis, metals exposure including iron and copper, viral hepatitis including Hepatitis A, B, C, D or E or other hepatotrophic viruses or bacteria alone or in combination; myocardial and pericardial fibrosis following myocardial infarction, coronary artery bypass, coronary stenting, and other forms of cardiac surgery; and other forms of cardiac damage; myelofibrosis; kidney fibrosis including fibrosis complicating diabetes, drug or heavy metal-related renal injury, or glomerulonephritis; keloid and other forms of excessive scar formation; fibrosis complicating tissue damage from other forms of traumatic, inflammatory, or degenerative disease.
[0010] The term "fibrotic disorders" also includes non-malignant forms of excessive or abnormal tissue proliferation or expansion including polycystic kidney disease,
neurofibromatosis, uterine fibroids, colonic polyps, meningioma, tuberous sclerosis, and familial and sporadic forms of lymphangioleiomyomatosis; sebaceous cysts; fibrocystic breast disease; nodules of the thyroid gland; granulomas; arteriovenous malformations;
syndesmophyte and osteophyte formation; and disseminated idiopathic skeletal hyperostosis.
[0011] The term "fibrotic disorders" also includes fibrosis or other connective tissue proliferation or expansion following the implantation of temporary or permanent therapeutic devices including artificial joints, ocular lenses, cardiac valves, pacemakers, and drug-eluting or other implantable drug-delivery systems.
[0012] The term "fibrotic disorders includes neurodegenerative disease including
Huntington Disease, Alzheimer Disease, Niemann-Pick disease, Parkinson's Disease, prion- mediated disease, spinocerebellar ataxia, progressive multifocal encephalopathy, amyotrophic lateral sclerosis, axonal neuropathies, muscular dystrophies, and age-related nervous system degeneration; wet and dry age-related macular degeneration.
[0013] The present method is carried out using inhibitors of mTOR, which is a
serine/threonine kinase and has been identified as a regulator of protein synthesis as well as cell growth and proliferation. It has been shown that mTOR functions in two distinct complexes (mTORCl and mTORC2). Rapamycin primarily inhibits the mTORCl complex while largely sparing mTORC2 activity. The compounds of the present invention, that is, the compounds used in the present method are capable of inhibiting mTORCl and mTORC2 mediated activity.
[0014] Compounds of formula I, including their preparation, is described in WO
2010/051043. The com ounds below are included in this invention:
Figure imgf000005_0001
[0015] The term "C alkyl optionally substituted with one or two hydroxy" refers to a C alkyl optionally having from 1 or 2 hydroxy groups. Included within the scope of the term are methyl, ethyl, propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, 2-hydroxyethyl, 3- hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, and hydroxy-t-butyl.
[0016] The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable organic acids and bases or inorganic acids and bases. Such salts are well known in the art and include those described in Journal of Pharmaceutical Science, 66, 2-19 (1977).
[0017] The terms "compounds of the invention" and "a compound of the invention" and the like include the use of the embodiment of formula I and 5-(4-amino-l-isopropyl-lH- pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine, 5-(4-amino-l-isopropyl-6-methyl- lH-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine, 2-(4-amino-3-(2- aminobenzo[d]oxazol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)propan-l-ol, or 2-(4-amino-3- (2-aminobenzo [d]oxazol-5-yl)- 1 H-pyrazolo [3 ,4-d]pyrimidin- 1 -yl)-2-methylpropan- 1 -ol; and the pharmaceutically acceptable salts of the above-mentioned compounds, in the treatment of fibrotic disorders. [0018] The compound of the invention may exist as tautomers. The term "tautomer" refers to compounds of the invention that can interconvert by way of a migration of one or more hydrogen atoms accompanied by rearrangement in the position of adjacent double bonds. The tautomeric forms, if they exist, are in equilibrium with each other, the position of the equilibrium will depend on the exact nature of the physical state of the compound. It is understood that where tautomeric forms are possible and exist, the present invention includes all possible tautomeric forms.
[0019] The skilled artisan will appreciate that certain of the compounds of the present invention exist as isomers. All stereoisomers of the compounds of the invention, including enantiomers and diastereomers, in any ratio, are contemplated to be within the scope of the present invention.
[0020] The terms "method of the invention" and "use of the invention" include all the methods and uses described herein.
[0021] The terms "treat," "treatment," and "treating" include improvement of the conditions described herein. The terms "treat," "treatment," and "treating" include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition. The terms "treat," "treatment," and "treating" are intended to include therapeutic treatment of such disorders. The terms "treat," "treatment," and "treating" are intended to include prophylactic treatment of such disorders.
[0022] As used herein the terms "patient" and "subject" includes humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. The term also includes birds, fish, reptiles, amphibians, and the like. It is understood that a more particular patient is a human. Also, more particular patients and subjects are non-human mammals, such as mice, rats, and dogs.
[0023] As used herein, the term "effective amount" refers to the amount of compound of the invention which treats, upon single or multiple dose administration, a patient suffering from the mentioned condition. An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount, the daily dosage, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. An effective amount of the present invention, the treatment dosage, is expected to range from 1 mg to 20 mg. Specific amounts can be determined by the skilled person. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient (e.g., an infant) whose mass falls outside of this weight range.
[0024] Dosages of 1 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7 mg/day, and 8 mg/day are contemplated. The frequency of daily dosing can vary depending on the compound of the invention, the route of administration, and the use of the invention.
[0025] In effecting treatment of a patient in need of such treatment, a compound of the invention can be administered in any form and route which makes the compound
bioavailable. The compounds of the invention can be administered by a variety of routes, including oral and parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally,
intraadiposally, intrathecally and via local delivery for example by catheter or stent.
[0026] One skilled in the art can readily select the form and route of administration depending upon the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant
circumstances. The method of the invention may be carried out be administering to the patient, for example, a pharmaceutical composition in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, or suspensions.
[0027] A particular route of administration for the methods of the invention is oral administration.
[0028] Another particular route of administration for the methods of the invention is by local administration to the lung. Local administration includes inhalation, topical application, or targeted drug delivery. Administration by inhalation includes liquid instillation, instillation as a pressurized fluid preparation by a metered dose inhaler or equivalent, or inhalation of an aerosolized solution via nebulizer, inhalation of dry powder, and directing soluble or dried material into the air stream during mechanical ventilation.
[0029] One local administration method is administering to a subject an aerosol suspension of respirable particles comprising a compound of the invention by inhalation. The respirable particles can be liquid or solid, with a particle size sufficiently small to pass through the mouth and larynx upon inhalation; in general, particles ranging from about 5 to 10 microns in size are considered respirable.
[0030] Suitable pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art and include at least one of the compounds of the invention as the active ingredient. The amount of a compound of the present invention may be varied depending upon its particular form and may conveniently be between 1% to about 70% of the weight of the unit dosage form. The term "pharmaceutically acceptable excipient" refers to those typically used in preparing pharmaceutical compositions and should be pharmaceutically pure and non-toxic in the amounts used. They generally are a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Some examples of pharmaceutically acceptable excipients are found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.

Claims

What is claimed is:
1. A method of treating fibrotic disorders, comprising administering to a patient in need thereof an effective amount of a com ound of the formula
Figure imgf000009_0001
wherein
Ri is selected from the group consisting of hydrogen and methyl; and
R2 is C alkyl optionally substituted with one or two hydroxy;
or a pharmaceutically acceptable salt thereof.
PCT/US2015/022428 2014-03-26 2015-03-25 Treatment of fibrotic disorders WO2015148626A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010051043A1 (en) * 2008-11-03 2010-05-06 Intellikine, Inc. Benzoxazole kinase inhibitors and methods of use
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