Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-09-19
2003-09-16
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C544S224000, C544S326000, C544S336000, C546S309000, C548S110000, C548S195000, C548S233000, C548S309700, C548S331100, C548S372500, C549S004000, C549S069000, C549S480000, C556S419000, C562S455000, C564S155000, C564S180000
Reexamination Certificate
active
06620963
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel compounds having retinoid-like biological activity. More specifically, the present invention relates to tricyclo[6.2.20
2,7
]dodeca-2(7),3,5-trien-4-carbonyl)amino]-phenyl and tricyclo[6.2.20
2,7
]dodeca-2(7),3,5-trien-4-carbonyl)amino]-heteroaryl and related compounds having RAR&agr; receptor selective biological activity.
2. Background Art
Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil
R
, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis. Retinoid compounds have relatively recently been also discovered to be useful for treating type II non-insulin dependent diabetes mellitus (NIDDM).
It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors are respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RAR&agr;, RAR&bgr; and RAR&ggr;, in RXR the subtypes are: RXR&agr;, RXR&bgr; and RXR&ggr;. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, among compounds having agonist-like activity at retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property. Some compounds bind to one or more RAR receptor subtypes, but do not trigger the response which is triggered by agonists of the same receptors. A compound that binds to a biological receptor but does not trigger an agonist-like response is usually termed an antagonist. Accordingly, the “effect” of compounds on retinoid receptors may fall in the range of having no effect at all, (inactive compound, neither agonist nor antagonist) or the compound may elicit an agonist-like response on all receptor subtypes (pan-agonist). As still another alternative a compound may be a partial agonist and/or partial antagonist of certain receptor subtypes if the compound binds to but does not activate certain receptor subtype or subtypes but elicits an agonist-like response in other receptor subtype or subtypes.
Recently, a two-state model for certain receptors, including the above-mentioned retinoid receptors, have emerged. In this model, an equilibrium is postulated to exist between inactive receptors and spontaneously active receptors which are capable of coupling with a G protein in the absence of a ligand (agonist). In this model, so-called “inverse agonists” shift the equilibrium toward inactive receptors, thus bringing about an overall inhibitory effect. Neutral antagonists do not effect the receptor equilibrium but are capable of competing for the receptors with both agonists (ligands) and with inverse agonists. U.S. Pat. No. 5,877,207 titled “Synthesis and Use of Retinoid Compounds Having Negative Hormone and/or Antagonist Activities” describes the foregoing two-state model and the use of retinoid antagonist and negative hormones in detail.
Among the scientific publications Dawson and William H. Okamura,
Chemistry and Biology of Synthetic Retinoids
, published by CRC Press Inc., 1990, pages 334-335, 354 and 324-356 is of special interest as an overview of the prior art on the subject.
The following is a list of United States and foreign patents and publications which disclose compounds having structural similarity to the compounds of the present invention, or disclose compounds having RAR&agr; selective agonist-like activity: U.S. Pat. Nos. 6,235,923; 6,245,786; 6,252,090; 6,342,602; 6,344,561; 6,387,950; 5,965,606; 6,037,488; 6,037,488; 6,187,950; 5,739,338; 5,760,276; 5,037,825; 5,420,145; 5,523,457; 5,559,248; 5,648,385; EPO 0 478 787; EPO 0 617 020; EPO 0 661 259; EPO 0 661 261; Eyrolles et al. J. Med. Chem. 1994 37 pp 1508-1517; Graupner et al. Biochem. Biophys. Res. Commun. 179 1991 pp 1554-1561; Kagechika et al. Biochem. Biophys. Res. Commun. 155 1988 pp 503-508; Kagechika et al. J. Med. Chem. 1988 31 pp 2182-2192; Standeven et al. Toxicology Letters 92 (1997) pp 231-240; Chem. Abstracts 117 (1992) 117:124091j; Teng et al. J. Med. Chem. 1997 40 pp 2445-2451; Teng et al. J. Med. Chem. 1996 39 pp 3035-3038; Nagpal et al. J. of Biol. Chem. 270 (1995) pp 923-927.
SUMMARY OF INVENTION
The present invention relates to compounds of Formula 1
where R
1
is independently H, or alkyl of 1 to 6 carbons;
R
2
is independently H, or alkyl of 1 to 6 carbons;
R
3
is alkyl of 1 to 6 carbons, or halogen;
m is an integer having the values of 0 to 4;
R
4
independently is alkyl of 1 to 6 carbons or halogen;
n is an integer having the values of 0 to 2;
R
5
is H or OH;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyri
Beard Richard
Chandraratna Roshantha A.
Duong Tien T.
Allergan Inc.
Fisher Carlos A.
McKane Joseph K.
Szekeres Gabor L.
Voet Martin A.
LandOfFree
TRICYCLO[6.2.202,7]DODECA-2(7),3,5-TRIEN-4-CARBONY... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with TRICYCLO[6.2.202,7]DODECA-2(7),3,5-TRIEN-4-CARBONY..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and TRICYCLO[6.2.202,7]DODECA-2(7),3,5-TRIEN-4-CARBONY... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3000968