Thiophene derivatives

Details Thiophene derivatives Thiophene derivatives

2001-06-15

2002-06-11

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S448000, C514S438000

Reexamination Certificate

active

06403810

ABSTRACT:

SUMMARY OF THE INVENTION
The present invention relates to retinoic acid receptor (“RAR”) selective retinoid agonists, pharmaceutical compositions containing such RAR agonists, to the use of such retinoic acid receptor agonists, particularly retinoic acid receptor &ggr; (RAR&ggr;) selective agonists, for the treatment of emphysema and related pulmonary diseases. More specifically, the invention is directed to retinoic acid receptor agonists of formula I
wherein X, R, R
1
and m are as defined below, and pharmaceutical compositions containing such compounds.
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 to the disease. 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. Avoiding injurious agents (i.e. cessation of smoking) slows the rate of damage. However, the damaged alveolar structures do not regenerate and to the extent lung function is lost, it 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. It has been demonstrated that postnatal administration of retinoic acid increases the number of alveoli in rats. See Massaro et al., Am. J. Physiol., 1996, 270, L305-L3 10. Furthermore, the capacity of dexamethasone to prevent the expression of CRBP and RAR&bgr; mRNA and subsequent alveolar septation in developing rat lungs was abrogated by all-trans retinoic acid.
Recent studies have shown 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 al. 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 lungs. 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.
Thus, in addition to their use in the treatment of emphysema and other pulmonary diseases, the retinoids of the invention are useful in the therapy, amelioration, 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 premaligant epithelial lesions, tumors and precancerous changes of the mucous membrane in the mouth, tongue, larynx, oesophagus, bladder, cervix and colon.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention is directed toward new RAR selective retinoid agonists of formula
wherein
R is selected from the group consisting of hydrogen, alkyl, alkoxy, benzyl and phenethyl;
R
1
is hydrogen or alkyl;
X is C(R
2
R
3
) and m is an integer 1, 2 or 3, or alternatively, X is oxygen, sulfur or NH and m is 1; and
R
2
, and R
3
are each independently selected from hydrogen and lower alkyl; and pharmaceutically acceptable salts of the carboxylic acids of compounds of formula I.
The term “alkyl” as used herein denotes straight chain or branched alkyl residues containing 1 to 10, preferably 1 to 7, carbon atoms, such as methyl, ethyl, isobutyl, pentyl, amyl, 3-pentyl, hexyl, heptyl and the like. The term “lower alkyl” as used herein denotes alkyl residues as defined above, but having 1 to 5 carbon atoms.
As used herein, the term “alkoxy” refers to a straight or branched chain hydrocarbonoxy group wherein the “alkyl” portion is an alkyl group as defined above. Examples include methoxy, ethoxy, n-propyloxy and the like.
The term “pharmaceutically acceptable” such as pharmaceutically acceptable carrier, excipient, salt, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
The compounds of formula I whe

Affiliated with

Also associated with

Rating

Thiophene derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Thiophene derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Thiophene derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2967280