Heterocyclic retinoid compounds

Details Heterocyclic retinoid compounds Heterocyclic retinoid compounds

2002-10-30

2004-11-16

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S314000, C514S217010, C514S414000, C514S415000, C546S166000, C540S594000, C548S490000

Reexamination Certificate

active

06818652

ABSTRACT:

1. FIELD OF THE INVENTION
The invention relates to novel heterocyclic retinoid compounds and methods of synthesis thereof. The invention also relates to methods of using these heterocyclic retinoid compounds and pharmaceutical compositions thereof.
2. BACKGROUND OF THE INVENTION
2.1. Retinoids
The retinoids are structural analogues of vitamin A and include both natural and synthetic compounds. Retinoid compounds such as all trans retinoic acid (“ATRA”), 9-cis-retinoic acid, trans 3-4 didehydroretinoic acid, 4-oxo retinoic acid, 13-cis-retinoic acid and retinol are pleiotrophic regulatory compounds that influence a large number of inflammatory, immune and structural cells.
For example, retinoids modulate epithelial cell proliferation, morphogenesis in lung and differentiation through a series of hormone nuclear receptors that belong to the steroid/thyroid receptor superfamily. The retinoid receptors are classified into the retinoic acid receptors (RAR) and the retinoid X receptors (RXR) each of which consists of three distinct subtypes (&agr;, &bgr; and &ggr;).
ATRA is the natural ligand for the retinoic acid receptors and binds with similar affinity to the &agr;, &bgr; and &ggr; subtypes. A quantitative structure-activity relationship has been established for a number of synthetic RAR &agr;, &bgr; and &ggr; retinoid agonists, which has elucidated the principal electronic and structural characteristics that provide selective affinity for each RAR subtype (Douget et al.,
Quant. Struct. Act. Relat
., 18, 107, 1999).
ATRA does not bind to RXR, for which 9-cis-retinoic acid is the natural ligand. A number of synthetic RXR and RAR &agr;, &bgr; and &ggr; retinoid agonists have also been described in the art (See, e.g., Billoni et al., U.S. Pat. No. 5,962,508; Belloni et al., WO 01/30326, published May 3, 2001; Klaus et al., U.S. Pat. No. 5,986,131; and Bernardon et al., WO92/06948, published Apr. 30, 1992). Other retinoid patents include Bernadon, U.S. Pat. Nos. 5,716,624 and 6,046,220.
2.2. Therapeutic Uses of Retinoids in Dermatology and Cancer
In tissues other than pulmonary tissues, retinoids typically have anti-inflammatory effects, can alter the progression of epithelial cell differentiation and may inhibit stromal cell matrix production. These biological effects of retinoids have led to the development of many topical agents for dermatological disorders such as psoriasis, acne and hypertrophic cutaneous scars. Retinoids have also been used in the treatment of light and age damaged skin, the healing of wounds caused, for example, by surgery and burns (Mustoe et al.,
Science
237, 1333 1987; Sprugel et al.,
J. Pathol
., 129, 601, 1987; Boyd,
Am. J. Med
., 86, 568, 1989) and as anti-inflammatory agents for treatment of arthritis. Other medicinal applications of retinoids include the control of acute promyelocytic leukemia, adeno and squamous cell carcinoma and hepatic fibrosis. Retinoids have also been used extensively in treatment of premalignant epithelial lesions and malignant tumors (carcinomas) of epithelial origin (Bollag et al., U.S. Pat. No. 5,248,071; Spom et al.,
Fed. Proc
. 1976, 1332; Hong et al., “Retinoids and Human Cancer” in
The Retinoids: Biology, Chemistry and Medicine
, M. B. Sporn, A. B. Roberts and D. S. Goodman (eds.) Raven Press, New York, 1994, 597-630). However, many known retinoids lack selectivity and consequently exert harmful pleiotrophic effects that may cause patient death when used in therapeutically effective amounts. Thus, the therapeutic use of retinoids in diseases other then cancer has been limited by toxic side effects. A general review of retinoids can be found in Goodman & Gilman's “The Pharmacological Basis of Therapeutics”, Chapters 63-64, 9
th
edition, 1996, McGraw-Hill.
2.3. Emphysema
Chronic Obstructive Pulmonary Disease (“COPD”) refers to a large group of lung diseases which prevent normal respiration. Approximately 11% of the population of the United States has COPD and available data suggests that the incidence of COPD is increasing. Currently, COPD is the fourth leading cause of mortality in the United States.
COPD is a disease in which the lungs are obstructed due to the presence of at least one disease selected from asthma, emphysema and chronic bronchitis. The term COPD was introduced because these conditions often co-exist and in individual cases it may be difficult to ascertain which disease is responsible for causing the lung obstruction (1987 Merck Manual). Clinically, COPD is diagnosed by reduced expiratory flow from the lungs that is constant over several months and in the case of chronic bronchitis persists for two or more consecutive years. The most severe manifestations of COPD typically include symptoms characteristic of emphysema.
Emphysema is a disease where the gas-exchange structures (e.g., alveoli) of the lung are destroyed, which causes inadequate oxygenation that may lead to disability and death. Anatomically, emphysema is defined by permanent airspace enlargement distal to terminal bronchioles (e.g., breathing tubes) which is characterized by reduced lung elasticity, decreased alveolar surface area and gas exchange and alveolar destruction that results in decreased respiration. Thus, the characteristic physiological abnormalities of emphysema are reduced gas exchange and expiratory gas flow.
Cigarette smoking is the most common cause of emphysema although other environmental toxins may also contribute to alveoli destruction. The injurious compounds present in these harmful agents can activate destructive processes that include, for example, the release of excessive amounts of proteases that overwhelm normal protective mechanisms, such as protease inhibitors present in the lung. The imbalance between proteases and protease inhibitors present in the lung may lead to elastin matrix destruction, elastic recoil loss, tissue damage, and continuous lung function decline. The rate of lung damage may be decreased by reducing the amounts of toxins in the lung (i.e., by quitting smoking). However, the damaged alveolar structures are not repaired and lung function is not regained. At least four different types of emphysema have been described according to their locations in the secondary lobule: panlobar emphysema, centrilobular emphysema, distal lobular emphysema and paracicatrical emphysema.
The major symptom of emphysema is chronic shortness of breath. Other important symptoms of emphysema include, but are not limited to, chronic cough, coloration of the skin caused by lack of oxygen, shortness of breath with minimal physical activity and wheezing. Additional symptoms that may be associated with emphysema include but are not limited to vision abnormalities, dizziness, temporary cessation of respiration, anxiety, swelling, fatigue, insomnia and memory loss. Emphysema is typically diagnosed by a physical examination that shows decreased and abnormal breathing sounds, wheezing and prolonged exhalation. Pulmonary function tests, reduced oxygen levels in the blood and a chest X-ray may be used to confirm a diagnosis of emphysema.
No effective methods for reversing the clinical indications of emphysema currently exist in the art. In some instances, medications such as bronchodilators, &bgr;-agonists, theophylline, anticholinergics, diuretics and corticosteroids delivered to the lung by an inhaler or nebulizer may improve respiration impaired by emphysema. Oxygen treatment is frequently used in situations where lung function has been so severely impaired that sufficient oxygen cannot be absorbed from the air. Lung reduction surgery may be used to treat patients with severe emphysema. Here, damaged portions of the lung are removed, which allows the normal portions of the lung to expand more fully and benefit from increased aeration. Finally, lung transplantation is another surgical alternative available to individuals with emphysema, which may increase quality of life but does not significantly improve life expectancy.
2.4. Lung Development, Alveolar Septation and Use of Retinoids in Treating Emphysema
Alveoli are

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