Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-27
2004-04-13
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S375000, C548S163000
Reexamination Certificate
active
06720344
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds and their use for the treatment of nuclear hormone receptor (NHR) family associated disorders. More specifically, the present invention relates to compounds having a particular 3-dimensional spatial orientation that are capable of binding to and thus altering the function of NHRs. Such compounds would be useful as therapeutic agents for disorders associated with NHRs such as the retinoid x receptor (RXR). The invention also relates to compositions and methods for the treatment or prophylaxis of osteoporosis, bone loss, arthritis, inflammation, cancer and skin conditions.
BACKGROUND OF THE INVENTION AND DESCRIPTION OF THE PRIOR ART
Modern day methods for the discovery of therapeutic agents for the amelioration of major diseases center on the interdisciplinary approaches of molecular biology, enzymology, crystallography, drug synthesis, molecular modeling and pharmacology. The typical approach involves: identification, isolation, purification, and crystallization of a target protein associated with the disease(s) of interest; modeling the protein binding and active sites; and modeling, synthesizing and evaluating compounds to optimize their pharmacological activity. Even with the advanced state of the art, drug discovery and, in particular, prediction of structure-activity relationships continue to require significant effort on the part of the pharmaceutical industry. Thus, the need to develop efficient and cost effective methods for the identification of pharmacologically active compounds for the treatment specific diseases still remains.
Osteoporosis is a condition characterized by a decrease in bone mass with decreased density and enlargement of bone spaces, producing porosity and fragility. This condition afflicts both men and women, particularly menopausal women, with advancing age. This condition is primarily a disorder in the formation of bone matrix. Osteoblasts, the bone-forming population of cells, are typically reduced in number. Osteoblasts are derived from adjacent mesenchymal precursors in a process regulated by local bone-derived factors. Osteoclasts, a population of cells that break down bone and that are associated with bone resorption, are not reduced in number. Osteoclasts are large, usually multinuclear cells found on the resorbing surfaces of mineralized bone. Osteoclasts are formed by fusion of mononuclear precursors, originating from extraskeletal blood-born precursors.
All known and local stimulators of osteoclastic bone resorption, including parathyroid hormone, 1, 25D, IL-2, and TNF, modulate their stimulatory effects on the osteoclast through an initial effect on osteoblasts. Osteoblasts are therefor believed to play a major role in regulating bone turnover by controlling the rate of new bone formation, as well as by serving to generate signals that stimulate osteoclastic bone resorption.
NHR families are associated with the modulation of mammalian cell proliferation and differentiation. These cellular processes are controlled by signal molecules that regulate gene expression. NHRs such as retinoid receptors are associated with many diseases and disorders such as osteoporosis, cancer, acne, AIDS, arthritis, psoriasis, lupus erythematosus and the like. The retinoid x receptor (RXR) serves to modulate cellular transcriptional activity thereby controlling cellular proliferation.
It is recognized in the art that osteoblasts play a very complex role in the formation of bone. It is generally thought that osteoclasts serve to dissolve (resorb) bone so that osteoblasts can then deposit more bone. It is reasonable then that compounds which can either inhibit the excessive resorption of bone or stimulate the proliferation of osteoblasts will be useful for the prevention of bone loss or the stimulation of bone growth.
Takashi et al. (Jpn. Kokai Tokyo Koho JP03130216 A2, Jun. 4, 1994) discloses diphenyl compounds having the following general structure
where X is —CH
2
— or —C(═O)—, for the treatment and prophylaxis of osteoporosis.
Labroo (U.S. Pat. No. 5,389,646 issued Feb. 14, 1995) discloses compounds having the following general structure
where R
1
is H, OH, C1-C17 alkoxy, (C1-C17)alkylcarbonyloxy, (C1-C17)alkylcarbonylamino or (C1-C17)alkylcarbonyl; R
2
is —(CH
2
)
(1-6)
—CH
2
-heterocycle; and R
3
is H, OH, C1-C17 alkoxy, (C1-C17)alkylcarbonyloxy, (C1-C17)alkylcarbonylamino or (C1-C17)alkylcarbonyl, for the treatment and prevention of bone loss.
Other compounds such as the one below
have been proposed for the treatment of osteoporosis. Even so, those compounds have not found general use due to their limited efficacy. Thus, the need for more efficacious compounds for the treatment of osteoporosis still remains.
Kamala et al. (
Indian J. Chem.
(1983), 22B, 1194-96) and Waisser et al. (Collect. Czech.
Chem. Commun.
(1991), 56, 2978-2985) disclose the synthesis of
and its uses as a synthetic intermediate and anti-tuberculotic agent, respectively.
Bis-aromatic compounds are widely known for their use in the treatment of cancer and tumors. Such compounds generally effectively inhibit DNA replication thereby exerting their cytotoxic effect upon mammalian cells. Here too, no compound has been found to be generally applicable for the treatment of a broad spectrum of cancers and tumors. Thus, the need for more efficacious broader spectrum anticancer and tumoricidal compounds still remains.
It is an object of the present invention to overcome the limitations inherent in the art of modeling pharmaceutical agents by providing a method for selecting candidate chemical agents using defined 3-dimensional spatial characteristics. These spatially defined chemical compounds in some aspects further overcome limitations associated with available osteogenic agents by providing agents that stimulate production of bone morphogenic proteins, and thus provide compositions useful for stimulating osteoblast proliferation and in diseases which result in bone loss.
A further object of the invention is to provide agents that bind other receptors in the nuclear hormone receptor (NHR) family that are associated with diseases.
It is another object of the present invention to provide a method of using particular pharmacologically active compounds for the treatment or prophylaxis of physiological disorders or diseases associated with NHRs such as osteoporosis, arthritis, cancer, tumors and the like.
It is another object of the invention to provide a method for the selection of pharmacologically active compounds which are capable of stimulating osteoblast proliferation and differentiation and are useful for the treatment of physiological disorders associated with NHRs and in particular diseases associated with bone loss.
Another object of the present invention is to provide methods for selecting and screening for pharmacologically active compositions which are capable of stimulating osteoblast proliferation and differentiation activity. Such selected composition would be used for the treatment or prophylaxis of osteoporosis and other physiological disorders associated with NHRS.
SUMMARY OF THE INVENTION
The present invention provides methods of stimulating osteoblast proliferation, as well as methods for selecting pharmacologically active compounds. In one embodiment, the method for stimulating osteoblast proliferation comprises selecting substances of the general formula I
X—L—Z,
wherein:
X is selected from the group consisting of:
L is selected from the group consisting of:
Z is selected from the group consisting of:
wherein R
1
is selected from the group consisting of:
H, OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, halo and (C1-C12)alkyl-carbonyloxy;
R
2
is selected from the group consisting of:
H, OH, halo, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy and (C1-C12)alkyl-carbonyloxy;
R
3
is selected from the group consisting of:
H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl and (C1-C12)alkyl-carbonyloxy;
R
4
is selected from the group consisting of:
H, OH, halo, C1-C6 alkyl, C1-C6 alkoxy and (C1-C
DeLuca Mark R.
Hurley Laurence H.
Kerwin Sean M.
Moore, III Bob M.
Mundy Gregory R.
McKane Joseph K.
Morrison & Foerster / LLP
Saeed Kamal
The Board of Regents of the University of Texas System
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