阅读说明：本技术 用伊非曲班治疗心脏纤维化的组合物和方法 (Compositions and methods for treating cardiac fibrosis with ifetroban ) 是由 L·巴浦利夫 B·沃斯 J·韦斯特 E·卡里尔 于 2015-05-18 设计创作，主要内容包括：本发明涉及治疗、预防和/或改善纤维化综合征(特别是心脏纤维化)的方法,其通过给药治疗有效量的伊非曲班或其药学上可接受的盐进行。(The present invention relates to a method of treating, preventing and/or ameliorating fibrotic syndromes, in particular cardiac fibrosis, by administering a therapeutically effective amount of ifetroban or a pharmaceutically acceptable salt thereof.)

Use of [1S- (1 α,2 α,3 α,4 α) ] -2- [ [3- [4- [ (pentylamino) carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] methyl ] phenylpropanoic acid (ifetroban), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pulmonary fibrosis in a mammal in need thereof.

2. The use of claim 1, wherein the mammal is a human patient and the medicament is for reducing the rate of formation of fibrotic tissue in the mammal.

3. The use of claim 1, wherein the medicament is administered in an amount of 10 mg/day to 1000 mg/day.

4. The use according to claim 1, wherein the medicament is administered in an amount of 100 mg/day to 500 mg/day.

5. The use according to claim 4, wherein the medicament is for oral, intranasal, rectal, vaginal, sublingual, buccal, parenteral or transdermal administration.

6. The use according to claim 4, wherein the medicament is for oral administration.

7. The use of claim 1, wherein the pharmaceutically acceptable salt of ifetroban is ifetroban sodium.

8. The use of claim 7, wherein the medicament is an oral solid dosage form.

9. The use of claim 1, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

Use of [1S- (1 α,2 α,3 α,4 α) ] -2- [ [3- [4- [ (pentylamino) carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] methyl ] phenylpropanoic acid (ifetroban), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of systemic sclerosis in a mammal in need thereof.

11. The use of claim 10, wherein the mammal is a human patient and the medicament is for reducing the rate of formation of hardened tissue in the mammal.

12. The use of claim 10, wherein the medicament is administered in an amount of 10 mg/day to 1000 mg/day.

13. The use according to claim 10, wherein the medicament is administered in an amount of 100 mg/day to 500 mg/day.

14. The use according to claim 13, wherein the medicament is for oral, intranasal, rectal, vaginal, sublingual, buccal, parenteral or transdermal administration.

15. The use according to claim 13, wherein the medicament is for oral administration.

16. The use of claim 10, wherein the pharmaceutically acceptable salt of ifetroban is ifetroban sodium.

17. The use of claim 16, wherein the medicament is an oral solid dosage form.

Technical Field

The invention relates to thromboxane A₂Use of receptor antagonists (e.g. ifetroban) for the treatment and/or prevention of fibrosis in mammals (e.g. humans), and pharmaceutical compositions for said use comprising thromboxane a in an amount effective for the treatment and/or prevention of these diseases₂Receptor antagonists (e.g., ifetroban). In certain embodiments, the fibrosis is cardiac fibrosis.

Background

Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue during a reparative or reactive process. This can be reactive, benign or pathological and physiologically plays a role in depositing connective tissue, which can eliminate the organ or tissue architecture and function. Fibrosis can be used to describe the pathological state of excessive deposition of fibrous tissue, as well as the process of connective tissue deposition in healing. Although the formation of fibrous tissue is normal and fibrous tissue is a normal component of organs or tissues in the body, scarring caused by fibrotic conditions may eliminate the architecture of organs or tissues.

For example, as fibrotic scar tissue replaces the myocardium damaged by hypertension, the heart becomes less elastic and thus less able to complete its work. Similarly, pulmonary fibrosis causes the lung to become stiff and impair lung function. Fibrotic growth can proliferate and invade healthy surrounding tissue, even after the original lesion heals. In most cases, fibrosis is a reactive process, and several different factors can significantly modulate the pathways leading to tissue fibrosis. Such factors include early inflammatory responses, local increase in fibroblast cell populations, modulation of the synthetic function of fibroblasts, and altered modulation of collagen biosynthesis and degradation. Other factors include inflammation of nearby tissues or generalized inflammatory states with increased circulating mediators.

Fibrosis includes pathological conditions characterized by abnormal and/or excessive accumulation of fibrotic material (e.g., extracellular matrix) following tissue injury. Fibroproliferative disorders are responsible for morbidity and mortality associated with vascular disease (such as heart disease, brain disease and peripheral vascular disease) and with organ failure in a variety of chronic diseases affecting the pulmonary system, renal system, eye, cardiac system, hepatic system, digestive system and skin.

To date, there are no commercially available therapies effective in treating or preventing fibrotic diseases (particularly cardiac fibrosis). Conventional treatments for most fibrosis-related disorders often involve corticosteroids (such as prednisone) and/or other drugs that inhibit the body's immune system. The goal of current treatment regimens is to reduce inflammation and subsequent scarring. The response to currently available treatments is variable and the toxicity and side effects associated with these treatments can be severe. In fact, only a few patients respond to corticosteroids alone, and immunosuppressive drugs are often used in combination with corticosteroids.

Right Ventricular (RV) failure is the leading cause of death in Pulmonary Arterial Hypertension (PAH), and is a source of significant morbidity and mortality from other forms of pulmonary hypertension. The production of thromboxane and F2 isoprostane (isprostane), both thromboxane/prostanoid (TP) receptor agonists, is increased in pathological conditions that increase load pressure, such as pulmonary hypertension. The prostacyclin/thromboxane balance has been linked to cardioprotective effects under stress, possibly supported by coronary arteries. Although aspirin treatment can reduce thromboxane and prostaglandin production, it also inhibits beneficial prostacyclin production and has no effect on isoprostane formation.

No therapies are approved for the preservation of RV function. The F-series and E-series isoprostanes are increased in heart failure and PAH, which is associated with the severity of the disease, and can signal through thromboxane/prostanoid (TP) receptors, which has the effect of vasoconstriction to fibrosis. Although treatment reduces pulmonary arterial pressure, loss of RV function can progress. RV responses to chronic pressure overload can be in the form of adaptation and maladaptation, which often determines clinical outcome. Adaptive ventricular hypertrophy with increased protein synthesis maintains function, whereas fibrosis and cardiomyocyte hypertrophy can cause arrhythmias and contractile dysfunction, and maladaptive dilation is associated with RV failure. Thus, therapeutic strategies that promote adaptive hypertrophy in the face of chronic stress load can preserve cardiac function and improve outcomes.

The development of cellular hypertrophy and myocardial fibrosis that occurs with chronic pressure overload is also associated with increased oxidative stress and lipid peroxidation. 15-F_2tIsoprostane (8-isoPGF)_2αOr 8-isoF) is a common biomarker of oxidative stress, and its levels increase with ventricular dilation and correlate with the severity of heart failure. In addition to being a biomarker, it was shown that 8-isoF and other isoprostanes may play a direct role in cardiomyopathy. The F-series and E-series isoprostanes are known to signal via thromboxane/prostanoid (TP) receptors, which have the effect of vasoconstriction to fibrosis. Cyclic endoperoxides (PGH)₂) And thromboxane A₂(TxA₂) Is also a ligand for the TP receptor, and TP receptor activation contributes to cardiac hypertrophy in chronic hypertension models and reduces cardiac function in Gh overexpressing mice. TP receptors are found not only in platelets and blood vessels, but also in the right ventricle, where receptor density is increased in PAH patients.

Summary of The Invention

It is an object of the present invention to provide a novel method for the prevention and/or treatment of fibrosis and/or cirrhosis in a mammal (e.g. a human).

It is an object of the present invention to provide compositions and methods for preventing and/or treating and/or attenuating cardiac fibrosis in a mammal (e.g., a human).

It is another object of the present invention to provide compositions and methods for reducing the effects of cardiac fibrosis in mammals (e.g., humans).

It has now been unexpectedly found that a therapeutically effective amount of thromboxane A₂Treatment of mammals with receptor antagonists (e.g., ifetroban) may prevent or attenuate cardiac fibrosis and associated sequelae. In certain embodiments, a therapeutically effective amount of thromboxane A is administered in the event of an excessive pressure load from inflammation and fibrosis to functional physiological hypertrophy₂Receptor antagonists (e.g., ifetroban) may prevent or attenuate cardiomyopathy and heart failure.

In accordance with the above objects, the present invention provides a method for preventing, reversing, ameliorating or treating fibrosis by administering to a patient in need thereof a therapeutically effective amount of thromboxane A₂A receptor antagonist, such as ifetroban or a pharmaceutically acceptable salt thereof (e.g., ifetroban sodium).

In accordance with the above objects, the present invention provides a method for preventing, reversing, ameliorating or treating cardiac fibrosis by administering to a patient in need thereof a therapeutically effective amount of thromboxane A₂Receptor antagonists (e.g., ifetroban).

In certain embodiments, the present invention relates to methods of treating and/or ameliorating a fibrotic disease or condition (particularly cardiac fibrosis) in a patient comprising administering to a patient in need thereof a therapeutically effective amount of thromboxane a₂A receptor antagonist to provide thromboxane A at about 0.1ng/ml to about 100,000ng/ml₂Desired plasma concentrations of the receptor antagonist (and/or its active metabolite). In certain embodiments, the therapeutically effective amount of the thromboxane a2 receptor antagonist provides a desired plasma concentration of the thromboxane a2 receptor antagonist of about 0.1ng/ml to about 10,000 ng/ml. In some embodiments, the plasma concentration is the plasma concentration at steady state. In some embodiments, the plasma concentration is the maximum plasma concentration (Cmax). In certain preferred embodiments, the thromboxane a2 receptor antagonist is ifetroban or a derivative thereofA pharmaceutically acceptable salt, such as ifetroban sodium.

The invention also relates to a method for providing a cardioprotective effect to a human patient experiencing pulmonary hypertension by administering thromboxane A as described herein₂Receptor antagonists.

The invention further relates to a method for improving the adaptation of the right heart to stress load in a human patient by administering thromboxane A as described herein₂Receptor antagonists.

In certain embodiments, the thromboxane A is₂The receptor antagonist comprises a therapeutically effective amount of [1S- (1 α,2 α,3 α,4 α)]-2- [ [3- [4- [ (pentylamino) carbonyl ] amino group]-2-oxazolyl]-7-oxabicyclo [2.2.1]Hept-2-yl]Methyl radical]Phenylpropionic acid (ifetroban) and pharmaceutically acceptable salts thereof.

The invention further relates to a method of treating cardiac fibrosis in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of [1S- (1 α,2 α,3 α,4 α)]-2- [ [3- [4- [ (pentylamino) carbonyl ] amino group]-2-oxazolyl]-7-oxabicyclo [2.2.1]Hept-2-yl]Methyl radical]Phenylpropionic acid (ifetroban) or a pharmaceutically acceptable salt thereof. In certain embodiments, the thromboxane A is₂The receptor antagonist comprises a therapeutically effective amount of [1S- (1 α,2 α,3 α,4 α)]-2- [ [3- [4- [ (pentylamino) carbonyl ] amino group]-2-oxazolyl]-7-oxabicyclo [2.2.1]Hept-2-yl]Methyl radical]Mono-sodium salt of phenylpropanoic acid (ifetroban sodium). In certain preferred embodiments, the therapeutically effective amount of ifetroban reduces the rate of formation of fibrotic tissue in the mammal. In certain preferred embodiments, the mammal is a human patient. In certain preferred embodiments, the therapeutically effective amount of ifetroban slows the progression of myocardial fibrosis in a human patient, and/or improves exercise capacity in a human patient, and/or reduces RV fibrosis in a human patient, and/or reduces cardiomyocyte hypertrophy in a human patient, and/or provides an increased E/a ratio in a human patient, and/or increases cardiomyocyte diameter in a human patient, and/or improves or maintains a function selected from the group consisting of: right Ventricular Ejection Fraction (RVEF), Left Ventricular Ejection Fraction (LVEF), pulmonary dynamics, Right Ventricular Systolic Pressure (RVSP), left ventricular ejection fraction (RVSP)Systolic Function (LVSF), Right Ventricular Diastolic Function (RVDF), and Left Ventricular Diastolic Function (LVDF).

In certain preferred embodiments, the therapeutically effective amount of ifetroban is cardioprotective against pressure overload by progressing the right heart towards fibrosis, inflammation and cellular hypertrophy as accommodation rather than maladaptation.

In certain preferred embodiments, the therapeutically effective amount of ifetroban attenuates left heart failure in a human patient.

In any of the above methods and other methods described herein, ifetroban is preferably administered in an amount effective to provide a plasma concentration of ifetroban (and/or an active metabolite of ifetroban) of from about 1ng/ml to about 100,000ng/ml, or ifetroban itself of from about 1ng/ml to about 10,000ng/ml, and in some embodiments, from about 1ng/ml to about 1,000 ng/ml. In some embodiments, the plasma concentration is the plasma concentration at steady state. In some embodiments, the plasma concentration is the maximum plasma concentration (Cmax). In certain preferred embodiments wherein the mammal is a human patient, the therapeutically effective amount is from about 100 mg/day to about 2000 mg/day, alternatively from about 10 mg/day or from about 100 mg/day to about 1000 mg/day, and in certain embodiments more preferably from about 100 mg/day to about 500 mg/day. The daily dose may be administered in divided doses, or in one bolus or unit dose or in multiple doses administered in parallel. In this regard, ifetroban may be administered orally, intranasally, rectally, vaginally, sublingually, buccally, parenterally or transdermally.

The invention also relates to pharmaceutical compositions comprising thromboxane A₂A receptor antagonist (e.g., ifetroban or a pharmaceutically acceptable salt thereof), the thromboxane A₂The receptor antagonist is in an amount effective to improve or maintain a function selected from the group consisting of: right Ventricular Ejection Fraction (RVEF), Left Ventricular Ejection Fraction (LVEF), lung dynamics, Right Ventricular Systolic Pressure (RVSP), Left Ventricular Systolic Function (LVSF), Right Ventricular Diastolic Function (RVDF), and Left Ventricular Diastolic Function (LVDF). In certain preferred embodimentsWherein the ifetroban salt is ifetroban sodium.

In certain preferred embodiments, in the above pharmaceutical composition, the therapeutically effective amount is about 10mg to about 1000mg ifetroban (or a pharmaceutically acceptable salt thereof) per day. In certain preferred embodiments, the therapeutically effective amount is from about 100 mg/day to about 500 mg/day.

The invention also relates to methods and compositions for treating fibrosis, particularly cardiac fibrosis, in a subject or patient in need thereof, comprising administering to the subject or patient in need thereof a therapeutically effective amount of thromboxane A₂A receptor antagonist. In particular, it relates to a method of treating or preventing a condition resulting in fibrosis or cirrhosis in an individual or patient in need of such treatment comprising administering a composition comprising administering to a patient in need thereof a therapeutically effective amount of thromboxane A₂A receptor antagonist in an amount effective to reduce the rate of fibrosis or cirrhosis. The invention also provides a method of preventing fibrosis or cirrhosis in a subject or patient in need of such treatment comprising administering an amount of a composition comprising thromboxane A effective to reduce the formation of fibrotic or sclerotic tissue that would occur in the absence of such treatment₂Compositions of receptor antagonists.

In certain embodiments, the fibrosis is associated with a fibroproliferative disease selected from cardiac fibrosis, renal fibrosis, liver fibrosis, lung fibrosis, and systemic sclerosis.

Detailed Description

In accordance with the above objectives, it is believed that a therapeutically effective amount of thromboxane A is administered to an individual or patient in need thereof₂Receptor antagonists can prevent and/or treat fibrosis (fibrotic diseases or conditions, and in particular cardiac fibrosis).

Failure of the right ventricle to accommodate stress load is a direct cause of mortality in pulmonary hypertension. Thromboxane production is increased in pathological states that increase stress load (such as pulmonary hypertension) and the prostacyclin/thromboxane balance has been linked to cardioprotective effects under stress, possibly supported by the coronary arteries. Although aspirin treatment may reduce the production of thromboxane and prostaglandins, it may also inhibit beneficial prostacyclin production, and a more targeted approach may be desirable.

Fibrosis can occur in many tissues in the body, often as a result of inflammation or injury, and examples include: pulmonary fibrosis (lung); idiopathic pulmonary fibrosis (in which the cause is unknown); cystic fibrosis; liver fibrosis or cirrhosis (liver); cardiac fibrosis, including endocardial myocardial fibrosis (heart), old myocardial infarction (heart), atrial fibrosis (heart); and other fibrotic conditions including, but not limited to mediastinal fibrosis (parenchyma of mediastinum), myelofibrosis (bone marrow), retroperitoneal fibrosis (parenchyma of retroperitoneal cavity), progressive massive fibrosis (lung); complications of coal workers 'pneumoconiosis, nephrogenic systemic fibrosis (skin), crohn's disease (intestine), keloids (skin), scleroderma/systemic sclerosis (skin, lung), joint fibrosis (knee, shoulder, other joints) and some forms of adhesive capsulitis (shoulder). Other names of the various types of pulmonary fibrosis used in the past include chronic interstitial pneumonia, interstitial idiopathic pulmonary fibrosis syndrome, common interstitial pneumonia (UIP), and diffuse fibrotic alveolitis.

Symptoms of pulmonary fibrosis include shortness of breath, cough, and reduced exercise tolerance. The severity of symptoms and the worsening of symptoms over time may vary and depend, at least in part, on the cause of fibrosis.

Cirrhosis is extensive scarring (fibrosis) in the liver caused by long-term injury. The injury is caused by inflammation, which is a normal response to some injuries (such as chronic viral infection or chronic alcoholism). The liver repairs the damaged area by: in a similar manner to scar tissue formation during the healing process when an individual suffers an incision on their body, the injured area is replaced with scar tissue. Fibrosis in the liver is different from that of the surrounding healthy liver tissue. Unfortunately, since scar tissue does not function in the form of normal liver cells, too much scar tissue interferes with basic liver function. Cirrhosis has many causes, but the most common causes are alcoholism and chronic hepatitis. Some other causes of cirrhosis are blocked bile ducts in the liver and gallbladder, autoimmune hepatitis, and genetic diseases (such as hepatolenticular degeneration or hemochromatosis).

Liver fibrosis is a scarring process that is initiated in response to Chronic Liver Disease (CLD) caused by continuous and repeated liver injury. The late stage of CLD is characterized by extensive remodeling of the liver architecture and chronic organ failure, whatever the underlying disease (e.g., cirrhosis, nonalcoholic steatohepatitis (NASH), Primary Sclerosing Cholangitis (PSC)).

Idiopathic Pulmonary Fibrosis (IPF) is the predominant form of pulmonary fibrosis. IPF is a debilitating and life-threatening lung disease characterized by progressive scarring of the lung that impedes oxygen uptake.

Systemic sclerosis is a degenerative disorder in which excessive fibrosis occurs in multiple organ systems, including skin, blood vessels, heart, lung, and kidney. Several forms of fibrotic disease cause death in scleroderma patients, including pulmonary fibrosis, congestive heart failure, and renal fibrosis; each of which occurs in about half of patients with systemic sclerosis.

Fibrosis is also a major cause of organ transplant rejection.

The phrase "therapeutically effective amount" refers to an amount of a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. The effective amount of such a substance will vary depending on the individual and disease condition being treated, the weight and age of the individual, the severity of the disease condition, the mode of administration, and the like, which can be readily determined by one of ordinary skill in the art.

The term "thromboxane A" as used herein₂A receptor antagonist "refers to a compound that inhibits the expression or activity of a thromboxane receptor by at least or at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% in a standard bioassay or in vivo or when used at a therapeutically effective dose. In certain embodiments, thromboxane A₂Receptor antagonists inhibiting thromboxane A₂Binding to a receptor. Thromboxane A₂Receptor antagonists include competitive antagonists (i.e., antagonists that compete with agonists for the receptor) and non-competitive antagonists. Thromboxane A₂Receptor antagonists include antibodies to the receptor. The antibody may be monoclonal. They may be human or humanized antibodies. Thromboxane A₂The receptor antagonists also include thromboxane synthase inhibitors, and compounds having thromboxane A₂Compounds having receptor antagonist activity and thromboxane synthase inhibitor activity.

₂Thromboxane A receptor antagonists

Thromboxane A for about 30 years₂The discovery and development of receptor antagonists has been the subject of many pharmaceutical companies (see Dogne J-M et al, exp. Opin. Ther. patents 11:1663-1675 (2001)). Some of the individual compounds identified by these companies (with or without the accompanying thromboxane A)₂Synthase inhibitory activity) include ifetroban (BMS), ridogrel (Janssen), terbogrel (BI), UK-147535(Pfizer), GR 32191(Glaxo), and S-18886 (Servier). Preclinical pharmacology has established that such compounds have potent antithrombotic activity through inhibition of the thromboxane pathway. These compounds also prevent the formation of thromboxane A₂And other prostaglandins (which act on thromboxane A in the vascular bed)₂Receptor) and thus can be advantageously used for the prevention and/or treatment of hepatorenal syndrome and/or hepatic encephalopathy.

Thromboxane A suitable for use in the present invention₂Receptor antagonists may include, for example, but are not limited to, small molecules such as ifetroban (BMS; [1S- (1 α,2 α,3 α,4 α)]-2- [ [3- [4- [ (pentylamino) carbonyl ] amino group]-2-oxazolyl]-7-oxabicyclo [2.2.1]Hept-2-yl]Methyl radical]Phenylpropionic acid), and others described in U.S. patent application publication No. 2009/0012115 (the disclosure of which is hereby incorporated by reference in its entirety).

Other thromboxanes A suitable for use herein₂Receptor antagonists are also at 4,839,384 (ogletere); 5,066,480(Ogletree et al); 5,100,889(Misra et al); 5,312,818(Rubin et al); 5,399,725(Poss et al) and 6,509,348(Ogletree) U.S. patent application Ser. No. 4The disclosures of which are hereby incorporated by reference in their entirety. These may include, but are not limited to, interrupted phenylene (interphenylene) 7-oxabicyclo-heptyl substituted heterocycloamide prostaglandin analogs as disclosed in U.S. patent No. 5,100,889, which include:

[1S- (1 α,2 α,3 α,4 α) ] -2- [ [3- [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] methyl ] phenylpropanoic acid (SQ 33,961) or an ester or salt thereof;

[1S- (1 α,2 α,3 α,4 α) ] -2- [ [3- [4- [ [ [ (4-chlorophenyl) butyl ] amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] methyl ] phenylpropionic acid or an ester or salt thereof;

[1S- (1 α,2 α,3 α,4 α) ] -3- [ [3- [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] phenylacetic acid or an ester or salt thereof;

[1S- (1 α,2 α,3 α,4 α) ] - [2- [ [3- [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] methyl ] phenoxy ] acetic acid or an ester or salt thereof;

[1S- (1 α,2 α,3 α,4 α ] -2- [ [3- [4- [ [ (7, 7-dimethyloctyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] methyl ] phenylpropionic acid or an ester or salt thereof.

7-oxabicycloheptyl substituted heterocycloamide prostaglandin analogs, as disclosed in U.S. Pat. No. 5,100,889 (issued 3.31.1992), which include [1S- [1 α,2 α (Z),3 α,4 α) ] -6- [3- [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or esters or salts thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -2-thiazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ [ (4-cyclohexylbutyl) methylamino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ (1-pyrrolidinyl) carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ (cyclohexylamino) carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl-4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ [ (2-cyclohexylethyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ [ [2- (4-chlorophenyl) ethyl ] amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] -6- [3- [4- [ [ (4-chlorophenyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ [ [4- (4-chlorophenyl) butyl ] amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [11 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4 α - [ [ - (6-cyclohexyl-hexyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ [ (6-cyclohexyl-hexyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α ] ] -6- [3- [4- [ (propylamino) carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ [ (4-butylphenyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ (2, 3-dihydro-1H-indol-1-yl) carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -N- (benzenesulfonyl) -4-hexenamide;

[1S- [11 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -2-oxazolyl ] -N- (methylsulfonyl) -7-oxabicyclo [2-.2.1] hept-2-yl ] -4-hexenamide;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -7- [3- [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo (2.2.1] hept-2-yl ] -5-heptenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -1H-imidazol-2-yl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α,3 α,4 α) ] -6- [3- [4- [ [ (7, 7-dimethyloctyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

[1S- [1 α,2 α (E),3 α,4 α) ] ] -6- [3- [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid;

[1S- [1 α,2 α,3 α,4 α) ] -3- [4- [ [ (4- (cyclohexylbutyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] heptane-2-hexanoic acid or an ester or salt thereof;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -2-oxazolyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or an ester or salt thereof;

7-oxabicycloheptane and 7-oxabicycloheptene compounds, such as [1S- (1 α,2 α (Z),3 α (1E,3S, 4R), 4 α) ] ] -7- [3- (3-hydroxy-4-phenyl-1-pentenyl) -7-oxabicyclo [2.2.1] hept-2-yl ] -5-heptenoic acid (SQ 29,548), as disclosed in U.S. Pat. No. 4,537,981 to Snitman et al, the disclosure of which is incorporated herein by reference in its entirety; 7-oxabicycloheptane substituted aminoprostane analogs such as [1S- [1 α,2 α (Z),3 α,4 α) ] ] -7- [3- [ [2- (phenylamino) carbonyl ] hydrazino ] methyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -5-heptenoic acid as disclosed in Nakane et al, U.S. patent No. 4,416,896, the disclosure of which is incorporated herein by reference in its entirety; 7-oxabicycloheptane substituted diamide prostaglandin analogs such as disclosed in U.S. patent No. 4,663,336 to Nakane et al, the disclosure of which is hereby incorporated by reference in its entirety, such as [1S- [1 α,2 α (Z),3 α,4 α) ] ] -7- [3- [ [ [ [ (1-oxoheptyl) amino ] acetyl ] amino ] methyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -5-heptenoic acid and the corresponding tetrazoles, and [1S- [1 α,2 α (Z),3 α,4 α) ] ] -7- [3- [ [ [ [ (4-cyclohexyl-1-oxobutyl) amino ] acetyl ] amino ] methyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -5-heptenoic acid;

7-oxabicycloheptane imidazole prostaglandin analogs such as [1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [ [4- (4-cyclohexyl-1-hydroxybutyl) -1H-imidazol-1-yl ] methyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or its methyl ester, as disclosed in U.S. patent No. 4,977,174, the disclosure of which is incorporated herein by reference in its entirety;

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [ [4- (3-cyclohexylpropyl) -1H-imidazol-1-yl ] methyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or its methyl ester;

[1S- [1 α,2 α (X (Z),3 α,4 α) ] ] -6- [3- [ [4- (4-cyclohexyl-1-oxobutyl) -1H-imidazol-1-yl ] methyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or its methyl ester;

[1S- [1 α,2 α (Z),3 α,4 α ] ] -6- [3- (1H-imidazol-1-ylmethyl) -7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or its methyl ester; or

[1S- [1 α,2 α (Z),3 α,4 α) ] ] -6- [3- [ [4- [ [ (4-cyclohexylbutyl) amino ] carbonyl ] -1H-imidazol-1-yl ] methyl-7-oxabicyclo [2.2.1] hept-2-yl ] -4-hexenoic acid or its methyl ester;

phenoxyalkylcarboxylic acids disclosed in U.S. patent No. 4,258,058 to Witte et al, the disclosure of which is incorporated herein by reference in its entirety, include 4- [2- (benzenesulfonylamino) ethyl ] phenoxyacetic acid (BM 13,177-Boehringer Mannheim), sulfonylaminophenylcarboxylic acids disclosed in U.S. patent No. 4,443,477 to Witte et al, the disclosure of which is incorporated herein by reference in its entirety, include 4- [2- (4-chlorobenzenesulfonylamino) ethyl ] phenylacetic acid (BM 13,505, Boehringer 35nheim), arylthioalkylphenylparboxylic acids disclosed in U.S. patent No. 4,752,616, the disclosure of which is incorporated herein by reference in its entirety, include 4- (3- ((4-chlorophenyl) sulfonyl) propyl) phenylacetic acid.

Thromboxane A suitable for use herein₂Other examples of receptor antagonists include, but are not limited to, vapreoprost (which is a preferred example), (E) -5- [ [ [ (pyridyl)]3- (trifluoromethyl) phenyl]Methylene group]Amino group]Oxy radical]Pentanoic acid (also known as R68,070-Janssen Research Laboratories), 3- [1- (4-chlorophenylmethyl) -5-fluoro-3-methylindol-2-yl]-2, 2-Dimethylpropanoic acid [ (L-655240 Merck-Frost) Eur.J.Pharmacol.135(2):193, 3.17.87 years]5(Z) -7- ([2,4, 5-cis)]-4- (2-hydroxyphenyl) -2-trifluoromethyl-1, 3-dioxan-5-yl) heptenoic acid (ICI 185282, Brit.J. Pharmacol.90(Proc. Suppl):228P-Abs, 3.87 years), 5(Z) -7- [2, 2-dimethyl-4-phenyl-1, 3-dioxan-cis-5-yl]Heptenoic acid (ICI 159995, Brit.J.Pharmacol.86(Proc.Suppl):808P-abs., 12 months 85 years), N' -bis [7- (3-chloroanilino-sulfonyl) -1,2,3, 4-tetrahydro-isoquinolinyl]Disulfonyl imide (SKF 88046, Pharmacologist 25(3):116Abs.,117Abs,8 months 83), (1 α (Z) -2 β,5 α)]- (+) -7- [5- [ [ (1,1' -biphenyl) -4-yl]-methoxy radical]-2- (4-morpholinyl) -3-oxocyclopentyl]-4-heptenoic acid (AH 23848-Glaxo, Circulation 72(6):1208, 12 months 85), levorphanol allyl bromide (CM 32,191 Sanofi, Life Sci.31(20-21):2261,82, 11 months 15 days), (Z, 2-endo-3-oxo) -7- (3-acetyl-2-bicyclo [ 2.2.1)]heptyl-5-hept-3Z-enoic acid, 4-phenyl-thiosemicarbazone (EP092-Univ. Edinburgh, Brit. J. Pharmacol.84(3):595, 3 months 85), GR 32,191 (Varapantel) - [1R- [1 α (Z),2 β,3 β,5 α]]- (+) -7- [5- ([1,1' -biphenyl)]-4-ylmethoxy) -3-hydroxy-2- (1-piperidinyl) cyclopentyl]-4-heptenoic acid; ICI 192,605-4(Z) -6- [ (2,4, 5-cis) 2- (2-chlorophenyl) -4- (2-hydroxyphenyl) -1, 3-dioxan-5-yl]Hexenoic acid; BAY u 3405 (ramatroban) -3- [ [ (4-fluorophenyl) -sulfonyl group]Amino group]-1,2,3, 4-tetrahydro-9H-carbazole-9-propionic acid, or ONO 3708-7- [2 α,4 α - (dimethylendomethylene) -6 β - (2-cyclopentyl-2 β -hydroxyacetamido) -1 α -cyclohexyl]-5(Z) -heptenoic acid; (±) (5Z) -7- [ 3-internal- ((phenylsulfonyl) amino]-bicyclo [2.2.1]Hept-2-exo-yl]Heptenoic acid (S-1452, Shionogi domitroban,) (ii) a (-)6, 8-difluoro-9-p-methylsulfonylbenzyl-1, 2,3, 4-tetrahydrocarbazol-1-yl-acetic acid (L670596)Merck) and (3- [ l- (4-chlorobenzyl) -5-fluoro-3-methylindol-2-yl]2, 2-Dimethylpropanoic acid (L655240, Merck).

Preferred thromboxanes A according to the invention₂The receptor antagonist is ifetroban or any pharmaceutically acceptable salt thereof.

In certain preferred embodiments, preferred thromboxane A₂The receptor antagonist is ifetroban sodium (chemically defined as [1S- (1 α,2 α,3 α,4 α)]-2- [ [3- [4- [ (pentylamino) carbonyl ] amino group]-2-oxazolyl]-7-oxabicyclo [2.2.1]Hept-2-yl]Methyl radical]Phenylpropionic acid, monosodium salt.

Method of treatment

In certain embodiments of the invention, methods are provided for preventing and/or treating and/or ameliorating fibrosis in one or more organs or tissues of a patient or patient population by administering to a patient in need thereof a therapeutically effective amount of thromboxane A₂Receptor antagonists.

Therapeutically effective amount of thromboxane A₂Administration of the receptor antagonist can be accomplished by any therapeutically useful route of administration, including, but not limited to, oral, intranasal, rectal, vaginal, sublingual, buccal, parenteral, or transdermal. In certain preferred embodiments, the thromboxane A is₂The receptor antagonist is administered parenterally. In certain other embodiments, the thromboxane A is₂The receptor antagonist is administered by intra-articular injection. In certain other embodiments, the thromboxane A is₂The receptor antagonist is administered directly to the affected anatomical site. In another embodiment, the thromboxane A is₂The receptor antagonist is administered via the hepatic artery.

In any of the above methods and other methods described herein, it is preferred to effectively provide thromboxane A at from about 1ng/ml to about 100,000ng/ml or about 0.1ng/ml₂Plasma concentrations of the receptor antagonist (and/or its active metabolites), or plasma concentrations of ifetroban itself from 1ng/ml to about 10,000ng/ml, and in some embodiments from about 1ng/ml to about 1,000ng/ml or more (e.g., in some embodiments, up to about 10,000ng/ml, andin other embodiments, up to about 100,000ng/ml) of the thromboxane A) is administered₂Receptor antagonists (e.g., ifetroban). In some embodiments, the plasma concentration is the plasma concentration at steady state. In some embodiments, the plasma concentration is the maximum plasma concentration (Cmax). In certain preferred embodiments, where the mammal is a human patient, the therapeutically effective amount is from about 100 mg/day to about 2000 mg/day, alternatively from about 10 mg/day or from about 100 mg/day to about 1000 mg/day, and in certain embodiments more preferably from about 100 mg/day to about 500 mg/day. The daily dose may be administered in divided doses, or in one bolus or unit dose or in multiple doses administered in parallel. In this regard, ifetroban may be administered orally, intranasally, rectally, vaginally, sublingually, buccally, parenterally or transdermally.

The dosage administered should be adjusted according to the age, weight and condition of the patient, as well as the route, dosage form and regimen of administration and the desired result.

To obtain thromboxane A₂Desired plasma concentrations of receptor antagonists for the treatment or prevention of fibrosis, thromboxane A₂The daily dosage of the receptor antagonist is preferably from about 0.1mg to about 5000 mg. In certain preferred embodiments, thromboxane A for the treatment or prevention of fibrosis₂The daily dose of receptor antagonist may be from about 1 mg/day to about 2000 mg/day; about 10 mg/day to about 1000 mg/day; about 100 mg/day to about 1000 mg/day; about 50 mg/day to about 500 mg/day; about 100 mg/day to about 500 mg/day; about 200 mg/day to about 500 mg/day; about 300 mg/day to about 500 mg/day; or from about 400 mg/day to about 500 mg/day.

In certain preferred embodiments, a daily dose of ifetroban sodium of about 10mg to about 250mg (amount of ifetroban free acid) will result in a therapeutically effective plasma level of ifetroban free acid for the treatment or prevention of fibrosis.

When the thromboxane A is present₂When the receptor antagonist is ifetroban, for providing A₂Inhibitory effects of prostaglandin endoperoxide receptor (TPr) activation and thereby provide reduction of brain microvascular activationShould be greater than about 10ng/mL (ifetroban free acid). Thromboxane A is visible at concentrations greater than about 1ng/mL₂Some inhibitory effects of receptor antagonists (e.g., ifetroban).

The dosage administered must be carefully adjusted according to the age, weight and condition of the patient, as well as the route, dosage form and regimen of administration and the desired result.

In which the thromboxane A₂In certain preferred embodiments where the receptor antagonist is ifetroban or a pharmaceutically acceptable salt thereof, a daily dose of ifetroban sodium of about 10mg to about 500mg, preferably about 10mg to about 300mg (amount of ifetroban free acid) will result in an effective plasma level of ifetroban free acid.

Pharmaceutical composition

The thromboxane A of the present invention₂The receptor antagonist is administered by any pharmaceutically effective route. For example, the thromboxane A may be formulated in such a way that they can be administered orally, intranasally, rectally, vaginally, sublingually, buccally, parenterally or transdermally₂Receptor antagonists and are therefore formulated accordingly.

In certain embodiments, the thromboxane A can be₂The receptor antagonist is formulated into a pharmaceutically acceptable oral dosage form. Oral dosage forms may include, but are not limited to, oral solid dosage forms and oral liquid dosage forms.

Oral solid dosage forms may include, but are not limited to, tablets, capsules, caplets, powders, pills, multiparticulates, beads, spheres, and any combination thereof. These oral solid dosage forms may be formulated as immediate release formulations, controlled release formulations, sustained (extended) release formulations, or modified release formulations.

The oral solid dosage forms of the present invention may also contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersants, suspending agents, disintegrants, viscosity increasing agents, film forming agents, granulation aids, flavoring agents, sweeteners, coating agents, solubilizing agents and combinations thereof.

The oral solid dosage form of the present invention may contain suitable amounts of controlled release agents, extended release agents, modified release agents depending on the desired release profile.

Oral liquid dosage forms include, but are not limited to, solutions, emulsions, suspensions, and syrups. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those skilled in the art for the preparation of liquid dosage forms. Such as water, glycerin, simple syrup, alcohol, and combinations thereof.

In certain embodiments of the invention, the thromboxane A may be₂The receptor antagonist is formulated in a dosage form suitable for parenteral use. For example, the dosage form may be a lyophilized powder, a solution, a suspension (e.g., a depot suspension).

In other embodiments, the thromboxane A can be₂The receptor antagonist is formulated into topical dosage forms such as, but not limited to, patches, gels, pastes, creams, emulsions, liniments, balms, lotions, and ointments.

Description of The Preferred Embodiment

The following examples are not intended to be limiting and represent certain embodiments of the present invention.