Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-03-05
2004-08-31
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S317000
Reexamination Certificate
active
06784156
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel semisynthetic cyclosporin analogs for the treatment of asthma and other diseases characterized by airflow obstruction, their use as pharmaceuticals and pharmaceutical compositions comprising them, as well as the processes for their production.
BACKGROUND OF THE INVENTION
Respiratory diseases are a global problem: millions of people worldwide, both children and adults, suffer from these medical conditions. These diseases, which include asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, as well as chronic sinusitis, reduce quality of life, impair the ability of sufferers to perform everyday tasks and, in some cases, cause death.
Asthma is a disease of unknown etiology in which the bronchi are inflamed and, as a consequence, obstructed. This narrowing results from a combination of bronchial smooth muscle contraction, mucosal oedema, inflammatory cell infiltrate and partial or total occlusion of the lumen with mucus, cells and cell debris. Bronchial obstruction is either partially or totally reversible, and this important feature distinguishes asthma from chronic bronchitis. Asthma is an extremely common disease with a worldwide prevalence of between 5% and 8%. In the developed world it is the most common chronic illness and, for reasons that are unclear, the disease is on the increase. It is now accepted that asthma is a chronic inflammatory disorder of the airways in which many cells play a role, in particular mast cells, eosinophils and T-lymphocytes. In susceptible individuals this inflammation causes symptoms which are usually associated with widespread but variable airflow obstruction. This is often reversible, either spontaneously or with treatment, and causes an associated increase in airway responsiveness to a variety of stimuli.
Current drugs for the treatment for asthma are corticosteroids, beta agonists non steroidal anti-inflammatory drugs (NSAIDS), leukotriene antagonists, Xanthines and anticholinergics.
The illness has a wide clinical spectrum ranging from mild episodic bronchospasm (easily controlled by the occasional use of a bronchodilator) to a very severe, intractable asthma that sometimes is resistant to treatment with high doses of oral corticosteroids. Steroid resistance occurs in fewer than 5% of people with asthma. However, these patients with severe chronic disease may have been dependent on corticosteroids, and their disease is often so severe that full reversibility can be difficult or impossible to demonstrate.
Chronic obstructive airways disease, chronic obstructive lung disease and ‘smoker's chest’ have all been used to describe what is now known as COPD. COPD is characterized by progressive, irreversible airway obstruction. It can lead to death from respiratory or cardiorespiratory failure. COPD consists of two subsets: chronic bronchitis and emphysema. In practice, it is very difficult to define the contribution of each of these two conditions to the obstruction of the airway, and this has led to the displacement of these labels by the non-specific term COPD. The pathology of COPD is not fully elucidated, but features include hypertrophy of mucus-secreting glands, inflammation (including infiltration with lymphocytes) and goblet cell hyperplasia.
The treatment of COPD consists of bronchodilators, intermittent courses of antibiotics and, in some patients, inhaled and/or oral corticosteroids. The latter are claimed to reduce the decline in lung function in COPD.
Cystic fibrosis is an inherited condition. Excess viscid mucus is produced. This leads to recurrent chest infections and progressive bronchiectasis. Approximately 50% of cystic fibrosis sufferers have bronchial hyperresponsiveness and there is an increased incidence of atopy. There is widespread airway narrowing and wheezing. Most cystic fibrosis sufferers take bronchodilators; some take inhaled corticosteroids. At least one study has reported benefit with oral corticosteroids.
Corticosteroids are the mainstay of treatment of chronic respiratory diseases since their introduction in the 1950′s. Oral corticosteroids have today been largely replaced by inhaled corticosteroids, although severe asthmatics still require medication by mouth. Inhaled corticosteroids are relatively safe and extremely effective in most patients, and have improved the quality of life for millions of asthma sufferers. For those with severe asthma, however, oral therapy with corticosteroids is required. When taken for more than a few days, oral corticosteroids have a number of serious side effects. These include growth retardation in children, severe osteoporosis (especially in old age), decreased responsiveness of the pituitary adrenal axis to stress, fluid retention, diabetes and precipitation of psychosis.
Furthermore, an appreciable number of patients have apparent corticosteroid resistance or unresponsiveness. Patients considered successfully treated with inhaled or oral steroids often have to be content with 60% of their predicted lung function. Further increase in the dose of oral corticosteroids runs the risk of concomitant side effects.
Although corticosteroids are effective, for the reasons stated above, they are not ideal drugs. Over the years doctors have occasionally used immunosuppressive agents as adjuncts to corticosteroids in patients with extremely severe disease. Examples of immunosuppressive drugs include azathioprine, methotrexate, mycophenolic acid and prodrug, leflunamide, cyclosporin A, ascomycin, FK-506 and rapamycin.
There is increasing evidence that chronic inflammation in asthma is mediated via a network of cytokines emanating from inflammatory and structural cells in the airways. The prominent eosinophilic inflammation that characterizes asthma appears to be orchestrated by cytokines derived from type 2 T-helper (Th2)-like lymphocytes, suggesting that immunosuppressants such as cyclosporin A might be beneficial in the control of asthma.
The cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-methylated undecapeptides, commonly possessing pharmacological, in particular immunosuppressive, anti-inflammatory or antiparasitic activity. The first of the cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclosporin, also known as cyclosporin A.
Since the original discovery of Ciclosporin, a wide variety of naturally occurring cyclosporins have been isolated and identified, and many further non-natural cyclosporins have been prepared by total- or semi-synthetic means or by the application of modified culture techniques. The class comprised by the cyclosporins is thus now substantial and includes, for example, the naturally occurring cyclosporins A through Z [cf., Traber et al.;
1, Helv. Chim. Acta, 60, 1247-1255 (1977); Traber et al.; 2, Helv. Chim. Acta, 65, 1655-1667 (1982); Kobel et al.; Europ. J. Applied Microbiology and Biotechnology, 14, 273-240 1982); and von Wartburg et al.; Progress in Allergy, 38, 28-45, 1986)], as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporin derivatives and artificial or synthetic cyclosporins including dihydrocyclosporins [in which the the—MeBmt-residue is saturated by hydrogenation]; derivatized cyclosporins (e.g., in which the 3′-O-atom of the—MeBmt-residue is acylated or a further substituent is introduced at the—carbon atom of the sarcosyl residue at the 3-position); and cyclosporins in which variant amino acids are incorporated at specific positions within the peptide sequence, e.g. employing the total synthetic method for the production of cyclosporins developed by R. Wenger—see e.g. Traber et al., 1; Traber et al., 2; and Kobel et al., loc cit. U.S. Pat. Nos. 4,108,985, 4,220,641, 4,288,431, 4,554,351, 4,396,542 and 4,798,823; European Patent Publication Nos. 34,567A, 56,782A, 300,784A and 300,785; International Patent Publication No. WO 86/02080 and UK Patent Publication Nos. 2,206,119 and 2,207,678; Wenger 1, Transpl. Proc., 15 Suppl. 1:2230
Lazarova Tsvetelina
Or Yat Sun
Carlson Karen Cochrane
Enanta Pharmaceuticals, Inc.
Ferrone Jason D.
Gaetano Maccarone
Liu Samuel W.
LandOfFree
Cyclosporins for the treatment of respiratory diseases does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cyclosporins for the treatment of respiratory diseases, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclosporins for the treatment of respiratory diseases will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3361314