Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-12
2002-11-12
Sololu, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S023000, C549S355000, C549S407000
Reexamination Certificate
active
06479670
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to new RAR selective retinoid agonists, to the use of such retinoic acid receptor agonists, particularly retinoic acid receptor &ggr; selective agonists (RAR&ggr;-selective) for the treatment of emphysema.
BACKGROUND OF THE INVENTION
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, ranking third and fourth as the leading cause of death in the European Union and North America respectively. COPD is characterized by reduced maximum expiratory flow, which does not change over several months and which persists for 2 or more consecutive years. Patients with the most severe form of COPD generally present with a significant degree of emphysema. Emphysema is defined anatomically by permanent airspace enlargement distal to the terminal bronchioles. It is characterized by gradual loss of lung recoil, alveolar destruction, decreased alveolar surface area and gas exchange, leading to a reduced FEV1. These two features, impaired gas exchange and reduction in expiratory flow, are characteristic physiological abnormalities from which patients with emphysema suffer. The main symptom of patients with severe emphysema is shortness of breath during minimal physical activity.
The most common cause of emphysema is cigarette smoking although other potential environmental toxins may also contribute. These various insulting agents activate destructive processes in the lung including release of active proteases and free radical oxidants in excess of protective mechanisms. The imbalance in protease/anti-protease levels leads to destruction of the elastin matrix, loss of elastic recoil, tissue damage and continuous decline in lung function. Removing the injurious agents (i.e. quit smoking) slows the rate of damage, however, the damaged alveolar structures do not repair and lung function is not regained.
Retinoic acid is a multifunctional modulator of cellular behavior, having the potential to alter both extracellular matrix metabolism and normal epithelial differentiation. In lung, retinoic acid has been shown to modulate various aspects of lung differentiation by interacting with specific retinoic acid receptors (RAR) that are selectively expressed temporally and spatially. Coordinated activation of RAR&bgr; and RAR&ggr; has been associated with lung branching and alveolization/septation. During alveolar septation, retinoic acid storage granules increase in the fibroblastic mesenchyme surrounding alveolar walls and RAR&ggr; expression in the lung peaks. Depletion of these retinyl-ester stores parallels the deposition of new elastin matrix and septation. In support of this concept, Massaro et al., Am. J. Physiol., 1996, 270, L305-L310, demonstrated that postnatal administration of retinoic acid increases the number of alveoli in rats. Furthermore, the capacity of dexamethasone to prevent the expression of CRBP and RAR&bgr; mRNA and subsequent alveolar septation in developing rat lung was abrogated by all-trans retinoic acid.
Recent studies demonstrated that all-trans retinoic acid can induce formation of new alveoli and return elastic recoil to near normal in animal models of emphysema, D. Massaro et el., Nature Medicine, 1997, 3, 675. However, the mechanism by which this occurs remains unclear.
Retinoids are a class of compounds structurally related to vitamin A, comprising natural and synthetic compounds. Several series of retinoids have been found clinically useful in the treatment of dermatological and oncological diseases. Retinoic acid and its other naturally occurring retinoid analogs (9-cis retinoic acid, all-trans 3-4 didehydro retinoic acid, 4-oxo retinoic acid and retinol) are pleiotropic regulatory compounds that modulate the structure and function of a wide variety of inflammatory, immune and structural cells. They are important regulators of epithelial cell proliferation, differentiation and morphogenesis in lung. Retinoids exert their biological effects through a series of hormone nuclear receptors that are ligand inducible transcription factors belonging to the steroid/thyroid receptor superfamily. The retinoid receptors are classified into two families, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), each consisting of three distinct subtypes (&agr;, &bgr;, and &ggr;). Each subtype of the RAR gene family encodes a variable number of isoforms arising from differential splicing of two primary RNA transcripts. All-trans retinoic acid is the physiological hormone for the retinoic acid receptors and binds with approximately equal affinity to all the three RAR subtypes, but does not bind to the RXR receptors for which 9-cis retinoic acid is the natural ligand.
In many non-pulmonary tissues, retinoids have anti-inflammatory effects, alter the progression of epithelial cell differentiation, and inhibit stromal cell matrix production. These properties have led to the development of topical and systemic retinoid therapeutics for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous scars. Other applications include the control of acute promyelocytic leukemia, adeno- and squamous cell carcinoma, and hepatic fibrosis. A limitation in the therapeutic use of retinoids outside of cancer has stemmed from the relative toxicity observed with the naturally occurring retinoids, all-trans retinoic acid and 9-cis retinoic acid. These natural ligands are non-selective and therefore have pleiotropic effects throughout the body, which are often toxic. Recently various retinoids have been described that interact selectively or specifically with the RAR or RXR receptors or with specific subtypes (&agr;, &bgr;, &ggr;) within a class.
SUMMARY OF THE INVENTION
This invention provides new RAR selective retinoid agonists of formula I
wherein
one of R
4
and R
5
is hydrogen and the other is
R
1
is hydrogen, lower alkyl;
R
2
is lower alkyl;
R
3
is lower alkyl or H;
X is oxygen or sulfur;
n is 1 or 2; and
wherein the dotted bond is optional;
and pharmaceutically active salts of carboxylic acids of formula I.
The compounds of formula I contain a chiral carbon (to which R
2
is bound). These compounds may be present as a racemic mixture, i.e. (RS) or in the pure enantiomeric form as (S) or (R) isomer.
Activation of RAR has been associated with lung branching and alveolization. The retinoids according to the invention possess RAR agonist activity in vitro. Therefore such compounds would be useful for the treatment of emphysema and related pulmonary diseases. They may also be useful for the therapy and prophylaxis of dermatological disorders which are accompanied by epithelial lesions, e.g. acne and psoriasis, light- and age-damaged skin; as well as for the promotion of wound healing, for example of incised wounds, such as surgical wounds, wounds caused by burns and other wounds caused by cutaneous trauma; and for the therapy and prophylaxis of malignant and premalignant epithelial lesions, tumours and precancerous changes of the mucous membrane in the mouth, tongue, larynx, oesophagus, bladder, cervix and colon.
DETAILED DESCRIPTION OF THE INVENTION
When the dotted bond is present, a triple bond is meant, when the dotted bond is absent a double bond. Where the “dotted bond” is absent, the double bond may be “E” or “Z” configurated. The terms “E” and “Z” are used herein as defined in Pure and Applied Chem. 1976, 54, 12.
The term “lower alkyl” as used herein denotes straight chain or branched alkyl residues containing 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, amyl and 3-pentyl.
The term “substantially free” of one or another isomer means that the ratio of the desired isomer to the undesired isomer is at least 95:5, more preferably at least 98:2. Resolution of the racemic mixture into either enantiomeric form can be performed in accordance with conventional techniques.
The compounds of formula I, wherein R
1
is hydrogen forms salts with pharmaceutically acceptable bases such as alkali salts, e.g. Na- and K-salts, and ammonium or s
Belloni Paula Nanette
Mohr Peter
Dubberley F. Aaron
Hoffmann-La Roche Inc.
Johnston George W.
Sololu T. A.
Tramaloni Dennis P.
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