Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-11-13
2004-12-14
Hui, San-Ming (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S569000
Reexamination Certificate
active
06831101
ABSTRACT:
FIELD OF THE INVENTION
The invention is in the field of therapeutic organic compounds.
BACKGROUND OF THE INVENTION
The recruitment of inflammatory cells into sites of inflammation is a normal physiological response designed to fight infection, remove damaged cells, and stimulate healing. However, the excessive recruitment of such cells often exacerbates tissue damage, slows healing, and in some cases leads to host death. Therefore, inhibition of inflammatory cell recruitment may be an appropriate therapeutic strategy in a number of inflammatory diseases, such as asthma, reperfusion injury, arthritis, and inflammatory bowel disease.
Chemokines constitute a diverse group of small secreted basic cytokine proteins that are shown to regulate the chemotactic migration and activation of a number of different leukocytes, particularly in the context of activation of the immune response during inflammatory conditions.
Examples of cells that have been shown to respond to chemokines, and in some cases become activated by chemokines, are neutrophils, eosinophils, basophils, monocytes, macrophages, B lymphocytes and different types of T lymphocytes, and stem cells as well as cancer cells.
Based on structural similarity, chemokines may be subdivided into four subfamilies, CXC, C—C, C and CX
3
C, depending on the position of their first two cysteine residues. To date, at least 16 chemokine receptors, including nine CC-chemokine receptors and five CXC-chemokine receptors, have been identified and several more might be discovered
The chemokine known as RANTES (an abbreviation of the phrase “raised on activation, normal T-cell derived and secreted”), has a sequence of 68 amino acid residues which identifies it as a beta-chemokine, a member of the C—C chemokine subfamily which includes monocyte chemoattractants such as MIP-1 alpha, MIP-1 beta, MCP-1, MCP-2, and MCP-3. Although RANTES was originally identified in activated T lymphocytes, it has also been found to be inducible in a variety of cell types upon stimulation. Initial studies on RANTES-induced chemotaxis indicated that it elicits migratory responses of monocytes and memory T lymphocytes without showing any effect on neutrophiles. RANTES is reportedly a potent attractor for eosinophils, CD4
+
, CD45RO
+
T-cells and basophiles. A receptor for RANTES has been cloned, which has been shown to bind chemokines in the order of affinity of MIP-1 alpha>RANTES. RANTES chemokine receptor CCR-3 was cloned from a human monocyte or an eosinophil library and subsequently shown to bind eotaxin, RANTES, and MCP-3.
A number of studies have suggested a role for RANTES in rheumatoid arthritis. Both RANTES mRNA and protein appear to be up-regulated in rheumatoid arthritis. Antibodies against RANTES significantly decreased the severity of ongoing clinical disease in a rat adjuvant-induced rheumatoid arthritis model.
It has been established that a number of chemokines including, KC, IP-10, MIP-1 alpha, RANTES, MARC (murine MCP-3), and TCA-3 (murine 1-309) are upregulated during the course of murine experimental allergic encephalitis (EAE), a mouse model of multiple sclerosis (MS). It has also been demonstrated that the chemokines JE (murine MCP-1), RANTES, MIP-1 alpha, IP-10, and KC are upregulated in the spinal cord and brain during the acute stages and chronic relapse of murine EAE. Co-localization studies demonstrated that in EAE MIP-1 alpha and RANTES, are produced exclusively by infiltrating leukocytes.
The principle chemokines that are elevated during acute rejection are thought to be those that interact with the receptors CCR-1 and CCR-5 (i.e., MIP-1 alpha, and RANTES) and recruit monocytes and T-cells. This suggests that antagonists that block these receptors might be beneficial for transplant rejection. Enhanced expression of various chemokines in rejected human allograft tissue has been documented, including RANTES. RANTES has also been shown to be elevated in the bronchoalveolar lavage of lung transplant recipients during rejection, especially in patients diagnosed with cytomegalovirus, a complication associated with accelerated rejection. It has also been reported that RANTES expression in cardiac allograft is linked to rejection in an experimental rat model. In humans, RANTES and MIP-1 alpha have been observed in the arteries of heart-transplant recipients undergoing accelerated atherosclerosis.
RANTES has been identified in asthmatic patients after allergen challenge.
Ligands for the CCR-1 receptor (MIP-1 alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, including multiple sclerosis and rheumatoid arthritis. CCR-1 has also been found to play a significant role in allograft rejection. Chemokine receptors, CCR-1 and -5 and their natural ligands, MIP-1 alpha, and RANTES are thought to be involved in glomerular and interstitial lesions of human glomerular disease. CCR-1 is also found to be a major contributor to the airway remodeling responses that arise from
Aspergillus fumigatus
-induced allergic airway disease.
The inflammatory diseases known as acute gouty arthritis and acute pseudogout results from the deposition of monosodium urate monohydrate (MSUM) and Calcium pyrophosphate dihydrate (CPPD) [monoclinic (M) and triclinic (T)] crystals in the synovial joints of human. In the synovial fluid (SF) the crystals become coated with numerous proteins, including opsonizing species such as IgG and complement components. The interaction of protein coated crystals with neutrophils results in neutrophil respiratory burst activity, the generation of reactive oxygen species, degranulation and crystal phagocytosis (McCarty; Pathogenesis and treatment of crystal-induced inflammation.
RANTES, along with the natural ligands for the CCR-5 chemokine receptors, MIP-1 alpha, was found to inhibit human immuno-deficiency virus type-1 (HIV-1) infection, leading to the identification of CCR-5 as the major co-receptor for primary isolates of HIV-1, HIV-2 and SIV-1.
Neoabietic acid [8(14), 13(15)-abietadien-18-oic-acid], is a naturally-occurring tricyclic carboxylic acid of the following formula:
Neoabietic acid (98(14), 13(15)-abietadien-18-oic-acid) is a naturally occurring resin acid found with other diterpene acids in rosin oils. Neoabietic acid is reportedly found in a variety of plants such as:
Picea Schrenkiana, Pinus Palustris, Pinus Sylvastris, Pinus Siberica, Pinus massoniana
and
Pinus Panderosa
. Neoabietic acid may be isolated from natural sources in a variety of ways, such as by solvent-solvent extraction, differential chromatographic techniques, column chromatography, gas chromatography and high-pressure liquid chromatography (Volkman, John K. et. al., (1993) J. Chromatogr. 643 (1-2) 209-219
Neoabietic acid has been suggested to have anti pesticidal uses (Kostka, et al., U.S. Pat. No. 6,039,966 issued Mar. 21, 2000).
SUMMARY OF THE INVENTION
In various aspects, the invention provides compounds that bind to one or more RANTES receptors for the treatment of chemokine mediated disease states. In some embodiments, the invention relates to the methods of using a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) or (XV) or a pharmaceutically acceptable salt thereof, to formulate a medicament for the treatment of a chemokine mediated disease state, or to treat such a disease:
(II) e.g., Kaurenolide [13013-56-4] (Hitchison, M. et. al., (1984) J. Chem. Soc., Perkin Trans I, 2363)
(III) e.g., 7-Oxodehydro-abietic acid; or 7-Oxo-8,11,13-abietatrien-18-oic-acid
(IV) e.g., alpha-Pimeric acid or [1R-(1 alpha, 4 beta, 4balpha, 7 alpha, 10a beta)]-7-Etheryl-1,2,3,4,4a,5,6,7,9,10,10a-dodecahydro-1,4a,7-trimethyl-1-phenanthrene carboxylic acid, isolated from American Rosin.
(V) e.g., 1-Phenanthrenemethanamine-1,2,3,4,4a,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methylethyl)-,[1R-(1 alpha,4a beta,10a alpha)]; or Dehydrabietylamine; or Rosin amine D [1446-61-3] (www.chemfinder.com)
(VI) e.g., 12-Sulfo-dehydr
Merzouk Ahmed
Salari Hassan
Saxena Geeta
Tudan Christopher R.
Bozicevic, Field & Francis
Chemokine Therapeutics Corporation
Field Bret E.
Hui San-Ming
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