TW201620520A - Treatment of bronchiolitis obliterans syndrome - Google Patents

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 occlusive bronchiolitis

The present invention relates to medical chemistry, medical science, and pharmaceuticals.

The atresia bronchiolitis syndrome (BOS) (also known as bronchiolitis obliterans (OB) and atrection bronchiolitis (BO)) is characterized by fixed airway obstruction.

Autistic bronchiolitis syndrome can be derived from collagen vascular disease, transplant rejection in organ transplant patients, viral infection, Stevens-Johnson Syndrome, Pneumocystis pneumonia, drug reactions, complications of preterm infants and Exposure to toxic fumes including: diethyl sulfonium, sulfur dioxide, nitrogen dioxide, ammonia, chlorine, sulfoxide, methyl isocyanate, hydrogen fluoride, hydrogen bromide, hydrogen chloride, hydrogen sulfide, phosgene, polyfluorene Amine-amine dyes, mustard gas and ozone. It can also be present in patients with rheumatoid arthritis. Some oral administration of emergency agents, such as pumping activated carbon. In addition, the occlusive bronchiolitis syndrome may be idiopathic.

Despite treatment with corticosteroids and immunosuppression, improvement in lung function was observed in only 8% to 20% of patients with BOS. Most patients with BOS progress to respiratory failure, and some patients suffer from bronchiectasis with frequent bacterial exacerbations. The need for treatment with BOS remains a problem for the medical community. The present invention provides inhibitors of mTOR inhibitors, particularly those mediated by both mTORC1 and mTORC2, such as those found in WO 2010/051043, for use in the treatment of BOS.

The present invention provides a method of treating a occlusive bronchiolitis inflammatory group comprising administering an effective amount of a compound of formula I to a patient in need thereof

Wherein R _{1 is} selected from the group consisting of hydrogen and methyl; and R ₂ is a C _1-4 alkyl group optionally substituted with one or two hydroxyl groups; or a pharmaceutically acceptable salt thereof.

That is, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a occlusive bronchiolitis syndrome.

In other words, the invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a occlusive bronchiolitis syndrome.

BOS is a serious health problem after lung transplantation and allogeneic hematopoietic stem cell transplantation (HSCT). Among them, the incidence rate is 50%-60% in patients who survived for 5 years after lung transplantation and 48% after HSCT. BOS accounts for more than 30% of all deaths occurring after the third year after surgery in a lung transplant patient. The mortality of patients with BOS after HSCT varied from 14% to 100% with a median of 65%. Graft-versus-host disease is a risk factor for BOS that has been established after lung transplantation and HSCT. The histopathological features of BOS suggest that lesions and inflammation of the epithelial cells and subepithelial structures of the small airways lead to excessive fibrosis, which appears to be due to ineffective epithelial regeneration and abnormal tissue repair. Breathing symptoms of BOS include dry cough, difficulty breathing, and wheezing. Lung biopsy Show small airway involvement with fibrous occlusion.

The diagnosis of BOS can be performed by a skilled clinician. Imaging tests (such as high-resolution chest CT scans) and lung function tests can help detect BOS. Chest x-rays are also used. Surgical lung biopsy can also be performed to diagnose BOS. Lung biopsy can demonstrate small airway involvement with fibrous occlusion. Bronchoalveolar lavage (BAL) can show neutrophilic and/or lymphocytic inflammation.

The methods of the invention are practiced using inhibitors of the serine/threonine kinase mTOR and have been identified as modulators of protein synthesis and cell growth and proliferation. The function of mTOR in two different complexes (mTORC1 and mTORC2) has been demonstrated. Rapamycin primarily inhibits the mTORC1 complex while greatly retaining mTORC2 activity. The compounds of the invention (i.e., the compounds used in the methods of the invention) are capable of inhibiting mTORC1 and mTORC2-mediated activities.

The 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 formula I. That is, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of graft versus host disease. In other words, the invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of graft versus host disease.

The invention also provides a method of treating bronchiectasis comprising administering to a patient in need thereof an effective amount of a compound of formula I. That is, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of bronchiectasis. In other words, the invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of bronchiectasis.

The compounds of formula I, including their preparation, are described in WO 2010/051043. The following compounds are included in the present invention:

The term "optionally substituted with one or two of hydroxy C _1-4 alkyl" means optionally having C 1 or 2 hydroxyl groups _1-4 alkyl. Methyl, ethyl, propyl, n-butyl, t-butyl, isobutyl, tert-butyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4- Hydroxybutyl and hydroxy-tert-butyl are included within the scope of this term.

In particular, the invention provides a method of treating a occlusive bronchiolitis inflammatory disorder comprising administering to a patient in need thereof an effective amount of 5-(4-amino-1-isopropyl-1H-pyrazolo[3 , 4-d]pyrimidin-3-yl)benzo[d]oxazole-2-amine or a pharmaceutically acceptable salt thereof. That is, the present invention provides 5-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine or The use of a pharmaceutically acceptable salt for the treatment of a occlusive bronchiolitis syndrome.

In particular, the present invention provides a method of treating a occlusive bronchiolitis inflammatory group comprising administering an effective amount of 2-(4-amino-3-(2-aminobenzo[d]) to a patient in need thereof Zol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpropan-1-ol or a pharmaceutically acceptable salt thereof. Namely, the present invention provides 2-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl The use of 2-methylpropan-1-ol or a pharmaceutically acceptable salt thereof for the treatment of a occlusive bronchiolitis syndrome.

The term "pharmaceutically acceptable salt" means a pharmaceutically acceptable organic acid and a salt of an alkali or inorganic acid and a base. Such salts are well known in the art and include those described in Journal of Pharmaceutical Science, 66, 2-19 (1977).

The terms "compounds of the invention" and "compounds of the invention" and the like include the use of the formula I and 5-(4-amino-1-isopropyl-1H-pyrazolo[3,4] -d] Pyrimidin-3-yl)benzo[d]oxazole-2-amine, 5-(4-amino-1-isopropyl-6-methyl-1H-pyrazolo[3,4-d]pyrimidine 3-yl)benzo[d]oxazole-2-amine, 2-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl)propan-1-ol or 2-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyridyl Zoxao[3,4-d]pyrimidin-1-yl)-2-methylpropan-1-ol; or a pharmaceutically acceptable salt of a compound as mentioned above for the treatment of atresia bronchiolitis Syndrome.

The compounds of the invention may exist in tautomeric forms. The term "tautomer" refers to a compound of the invention which can be converted into one another by the migration of one or more hydrogen atoms, accompanied by a positional rearrangement of adjacent double bonds. The tautomeric forms, if present, are in equilibrium with one another, and the equilibrium position will depend on the exact nature of the physical state of the compound. It is to be understood that tautomeric forms are possible and exist, and that the invention encompasses all possible tautomeric forms.

Those skilled in the art will appreciate that certain of the compounds of the invention exist as isomers. All stereoisomers (including mirror image isomers and non-image isomers) of the compounds of the invention in any ratio are encompassed within the scope of the invention.

The terms "method of the invention" and "use of the invention" include all methods and uses described herein.

It should be understood that the term "graft versus host disease" includes acute or chronic graft-versus-host disease and its manifestations, including skin, intestines, respiratory inflammation, and fibrosis, and includes, for example, the cornea, heart, lung, liver, kidney, intestine, Solid organ transplant rejection of the pancreas or pancreas components, including islets and islet cells.

The terms "treat", "treatment" and "treating" include modifications to the conditions described herein. The terms "treat", "treatment" and "treating" include all procedures that provide for the mitigation, interruption, prevention, control or termination of the condition or progression of the conditions described herein, but do not necessarily indicate complete elimination. All symptoms or cures of the condition. The terms "treat", "treatment" and "treating" are intended to include therapeutic treatment of such conditions. The term "treat", "Treatment" and "treating" are intended to include prophylactic treatment of such conditions.

As used herein, the terms "patient" and "individual" include human and non-human animals, such as mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. Terms also include birds, fish, reptiles, amphibians, and the like. It should be understood that more specific patients are humans. Moreover, more specific patients and systems are non-human mammals such as mice, rats and dogs.

As used herein, the term "effective amount" refers to an amount of a compound of the invention that is administered to a patient suffering from the mentioned condition after single or multiple dose administration. The effective amount can be readily determined by the attending physician skilled in the art using conventional techniques and by observing the results obtained under similar circumstances. In determining the effective amount, the attending physician considers a number of factors including, but not limited to, the patient's species; its size, age, and overall health; the particular condition, disorder, or disease involved; the condition, condition, or condition of the disease Or involvement or severity; individual patient response; specific compound administered; mode of administration; bioavailability characteristics of the formulation administered; selected dosage regimen; concomitant use of the agent; and other relevant circumstances. It is contemplated that an effective amount (therapeutic dose) of the invention will range from 1 mg to 20 mg. Specific amounts can be determined by those skilled in the art. Although the dosages are based on an average human individual having a mass of from about 60 kg to about 70 kg, the physician will be able to determine the dosage for a patient (eg, an infant) whose mass is not within 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 administration can vary depending on the compound of the invention, the route of administration, and the use of the invention.

In the treatment of a patient in need of such treatment, the compounds of the invention may be administered in any form or pathway in which the compound is bioavailable. The compounds of the invention may be administered by a variety of routes including oral and parenteral routes, more specifically by inhalation, subcutaneous, intramuscular, intravenous, transdermal, intranasal, rectal, vaginal, Eye, bureau , sublingual and buccal, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, intrahepatic, intrathecal and via local delivery, for example by catheter or stent .

The form and route of administration can be readily selected by those skilled in the art, depending on the particular characteristics of the selected compound, the condition or condition to be treated, the period of the condition or condition, and other relevant circumstances. The method of the present invention can be carried out by administering to a patient, for example, a pharmaceutical composition in the form of a tablet, a capsule, a pack, a paper, a lozenge, a tablet, an elixir, an ointment, a transdermal patch, an aerosol, Inhalation, suppository, solution or suspension.

The specific route of administration of the methods of the invention is oral administration.

Another specific route of administration of the methods of the invention is by topical administration to the lungs. Topical administration includes inhalation, topical administration, or targeted drug delivery. By inhalation, including liquid instillation, instillation of a pressurized fluid preparation by metered dose inhaler or equivalent, or inhalation of an aerosolized solution via a nebulizer, inhalation of dry powder, and directing of soluble or dry material during mechanical ventilation To the air stream.

One method of topical administration is by inhalation administering to the subject an aerosol suspension of respirable particles comprising a compound of the invention. The respirable particles can be liquid or solid and the particles are small enough to pass through the mouth and throat after inhalation; typically, particles having a size ranging from about 5 microns to 10 microns are considered breathable.

Suitable pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art and include at least one compound of the invention as the active ingredient. The amount of the compound of the present invention may vary depending on its particular form, and may conveniently be between 1% and about 70% by weight of the unit dosage form. The term "pharmaceutically acceptable excipient" means the one which is normally used in the preparation of pharmaceutical compositions and which is pharmaceutically pharmaceutically acceptable and non-toxic. It is typically a solid, semi-solid or liquid material that can be used 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, Adhesives, disintegrants, lubricants, glidants, sweeteners, flavoring agents, gel bases, sustained release matrices, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants , coating agents and other excipients.

The activity of the compounds of formula I can be determined by a variety of methods, including in vitro and in vivo methods.

Example A Tracheal allograft

For example, tracheal allografts (e.g., Koskinen et al, Am J Respir Crit Care Med 1997, Jan; 155(1): 303-312) can be used to assess compounds of formula I and to assess inflammatory and proliferating cells and interleukins. And chemokine characteristics.

Example B Bleomycin-induced pulmonary fibrosis

The test compound is administered orally to mice or rats at a dose ranging, for example, from 10 to 80 mg/kg. The test compound was administered by oral gavage on day 1, followed by intratracheal instillation of bleomycin (Krishna et al, Am J Pathol, 2001, 158(3): 997-1004), and then administered daily. The compounds were tested until day 14. At the end of the study period, the animals were sacrificed and one lung was reserved for histopathological analysis (eg, H & E and Ashcroft scores) and the other lung was used to analyze the hydroxyproline content. In addition, assessment of inflammatory and proliferative cells as well as interleukin and chemokine characteristics can be assessed. Moreover, migration of fibroblasts to damaged areas can be assessed. The bleomycin-induced pulmonary fibrosis model can also be performed using repeated administration of bleomycin or pre-administration of bleomycin.

Claims (1)

A use of a compound of the formula or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a occlusive bronchiolitis syndrome, In which R ₁ is selected from the group consisting of hydrogen and the group consisting of methyl; and R ₂ is optionally substituted with one line or two of hydroxy substituted C _1-4 alkyl.