WO2015148615A1

WO2015148615A1 - Treatment of bronchiolitis obliterans syndrome

Info

Publication number: WO2015148615A1
Application number: PCT/US2015/022409
Authority: WO
Inventors: Michael B. Martin
Original assignee: Millennium Pharmaceuticals, Inc.
Priority date: 2014-03-26
Filing date: 2015-03-25
Publication date: 2015-10-01
Also published as: TW201620520A

Abstract

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

Description

TREATMENT OF BRONCHIOLITIS OBLITERANS SYNDROME

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority the United States Serial No. 61/970,478, filed March 26, 2014. The entire contents of the aforementioned application are incorporated herein.

FIELD OF THE INVENTION

[0002] The present invention relates to medicinal chemistry, pharmaceutical science, and medicine.

BACKGROUND OF THE INVENTION

[0003] Bronchiolitis obliterans syndrome (BOS), also known as obliterative bronchiolitis (OB) and bronchiolitis obliterans (BO), is characterized by fixed airway obstruction.

[0004] Bronchiolitis obliterans syndrome can result from collagen vascular disease, transplant rejection in organ transplant patients, viral infection, Stevens- Johnson Syndrome, Pneumocystis pneumonia, drug reaction, complications of prematurity, and exposure to toxic fumes, including: diacetyl, sulfur dioxide, nitrogen dioxide, ammonia, chlorine, thionyl chloride, methyl isocyanate, hydrogen fluoride, hydrogen bromide, hydrogen chloride, hydrogen sulfide, phosgene, polyamide-amine dyes, mustard gas and ozone. It can also be present in patients with rheumatoid arthritis. Certain orally administrated emergency medications, such as aspiration of activated charcoal. In addition, bronchiolitis obliterans syndrome can be idiopathic.

[0005] Despite treatment with corticosteroids and immunosuppression, improvement in lung function is noted in only 8% to 20% of patients with BOS. Most patients with BOS progress to respiratory failure, and some patients develop bronchiectasis with frequent bacterial exacerbations. The need for treatment of BOS continues to be 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 BOS.

SUMMARY OF THE INVENTION

[0006] The present invention provides a method of treating bronchiolitis obliterans syndrome, comprising administering to a patient in need thereof an effective amount of a compound of the formula I

wherein

Ri is selected from the group consisting of hydrogen and methyl; and

R₂ is C_1-4 alkyl 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 bronchiolitis obliterans syndrome.

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 bronchiolitis obliterans syndrome.

DETAILED DESCRIPTION OF THE INVENTION

[0007] BOS is a serious health concern following both lung transplantation and allogeneic haematopoietic stem cell transplantation (HSCT) with an incidence of 50-60% in patients who survive for 5 years after lung transplantation and up to 48% following HSCT. BOS accounts for more than 30% of all deaths occurring after the third postoperative year for lung transplant patients. The mortality rate in patients with BOS following HSCT varies from 14- 100%, with a median of 65%. Graft versus host disease is an established risk factor for BOS after lung transplantation and HSCT. The histopathologic features of BOS suggest that injury and inflammation of epithelial cells and subepithelial structures of small airways lead to excessive fibroproliferation, seemingly due to ineffective epithelial regeneration and aberrant tissue repair. The respiratory symptoms of BOS include dry cough, dyspnea, and wheezing. Lung biopsies show small airway involvement with fibrinous obliteration of the lumen.

[0008] Diagnosis of BOS can be carried out by the skilled clinician. Imaging tests, such as high resolution chest CT scan, and pulmonary function tests can help detect BOS. Chest x- rays are also used. A surgical lung biopsy can also be carried out to diagnose the BOS. Lung biopsies may show small airway involvement with fibrinous obliteration of the lumen.

Bronchoalveolar lavage (BAL) may show neutrophilic and/or lymphocytic inflammation. [0009] 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.

[0010] The present invention also provides a method of treating graft versus host disease, comprising administering to a patient in need thereof an effective amount of a compound of the formula I. That is, the present invention provides for a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating graft versus host disease. 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 graft versus host disease.

[0011] The present invention also provides a method of treating bronchiectasis, comprising administering to a patient in need thereof an effective amount of a compound of the formula I. That is, the present invention provides for a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating bronchiectasis. 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 bronchiectasis.

[0012] Compounds of formula I, including their preparation, is described in WO

2010/051043. The com ounds below are included in this invention:

[0013] The term "C_1-4 alkyl optionally substituted with one or two hydroxy" refers to a C_1-4 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-hydroxy ethyl, 3- hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, and hydroxy-t-butyl. [0014] In particular, the present invention provides for a method of treating bronchiolitis obliterans syndrome comprising administering to a patient in need thereof an effective amount of 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2- amine or a pharmaceutically acceptable salt thereof. That is the present invention provides for the use of 5-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2- amine or a pharmaceutically acceptable salt thereof for treating bronchiolitis obliterans syndrome.

[0015] In particular, the present invention provides for a method of treating bronchiolitis obliterans syndrome comprising administering to a patient in need thereof an effective amount of 2-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)- 2-methylpropan-l-ol or a pharmaceutically acceptable salt thereof. That is the present invention provides for the use of 2-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)-2-methylpropan-l-ol or a pharmaceutically acceptable salt thereof for treating bronchiolitis obliterans syndrome.

[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-l -ol; or a pharmaceutically acceptable salt of the above-mentioned compounds, in the treatment of bronchiolitis obliterans syndrome.

[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] It is understood that the term "graft versus host disease" includes acute or chronic graft versus host disease and its manifestations including cutaneous, intestinal, respiratory inflammation, and fibrosis and includes solid organ graft rejection such as of the cornea, heart, lung, liver, kidney, bowel, pancreas or pancreatic components including islets and islet cells.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] A particular route of administration for the methods of the invention is oral administration.

[0029] 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.

[0030] 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. [0031] 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.

[0032] The activity of compounds of formula I may be determined by a variety of methods, including in vitro and in vivo methods.

[0033] Example A Tracheal Allografts

[0034] For example, the tracheal allografts (e.g., Koskinen, et al. Am J Respir Crit Care Med 1997, Jan; 155(1): 303-312) can be used to evaluate compounds of formula I along with the evaluation of inflammatory and proliferating cells and cytokine and chemokine profiles.

[0035] Example B Bleomycin-Induced Lung Fibrosis

[0036] The test compound is administered orally to mice or rats, dosages can range, for example, from 10-80 mg/kg. The test compound is given at Day-1 by oral gavage prior to intratracheal instillation of bleomycin (Krishna, et al. Am J Pathol, 2001,158(3): 997-1004) and then daily dosing of test compound until Day 14. At the end of the study period, the animals are sacrificed and one lung is reserved for histopathologic analysis, e.g., H & E and Ashcroft score and the other lung is used for an analysis of hydroxyproline content. In addition, the evaluation of inflammatory and proliferating cells and cytokine and chemokine profiles can be evaluated. Also, the migration of fibroblasts to injured areas can be evaulated. The bleomycin-induced lung fibrosis model can also be carried out using repetitive administration of bleomycin or pre-dosing with bleomycin.

Claims

What is claimed is:

1. A method of treating bronchiolitis obliterans syndrome, comprising administering to a patient in need thereof an effective amount of a com ound of the formula

wherein

Ri is selected from the group consisting of hydrogen and methyl; and

R₂ is C_1-4 alkyl optionally substituted with one or two hydroxy;

or a pharmaceutically acceptable salt thereof.