Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-12
2004-04-27
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S329000, C514S423000, C540S485000, C540S531000, C544S229000, C544S333000, C544S334000, C548S566000
Reexamination Certificate
active
06727241
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to pharmaceutical compositions containing active compounds and their pharmaceutically acceptable salts, which inhibit the binding of various chemokines, such as MIP-1&agr; and RANTES, to the CCR1 receptor. It also is directed to methods of treating inflammatory and immunoregulatory disorders and diseases using these pharnmaceutical compositions.
Human health depends on the body's ability to detect and destroy foreign pathogens that might otherwise usurp valuable resources from the individual and/or induce illness. The immune system, which comprises leukocytes (white blood cells (WBCs): T and B lymphocytes, monocytes, eosinophils, basophils, and neutrophils), lymphoid tissues and lymphoid vessels, is the body's system of defense. To combat infection, B and T lymphocytes circulate throughout the body, interact with antigen-presenting cells and detect pathogens. Once an invader is detected, cytotoxic T cells are recruited to the infection site to destroy the pathogen. Chemokines act as molecular beacons for the recruitment and activation of T lymphocytes, neutrophils and macrophages, flagging pathogen battlegrounds.
While defending the individual from pathogens, the immune system can also mutiny. Inappropriate chemokine signaling has been attributed to engendering inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis and others. In rheumatoid arthritis, unregulated chemokine accumulation in bone joints attracts and activates infiltrating macrophages and T-cells. The activities of these cells induce synovial cell proliferation that leads to inflammation and eventual bone and cartilage loss (DeVries, Ran et al. 1999). A hallmark of some demyelinating diseases such as multiple sclerosis is the chemokine-mediated macrophage and T cell recruitment to the central nervous system (Kennedy and Karpus 1999). Chemokine recruitment of destructive WBCs to transplants.has been implicated in their subsequent rejection (DeVries, Ran et al. 1999). Because chemokines play pivotal roles in inflammation and lymphocyte development, the ability to specifically manipulate their activity will have enormous impact on ameliorating and halting diseases that currently have no satisfactory treatment. In addition, transplant rejection may be minimized without the generalized and complicating effects of costly immunosuppressive pharmaceuticals.
Chemokines, a group of greater than 40 small peptides (7-10 kD), ligate receptors expressed on WBCs that signal through G-protein-coupled signaling cascades to mediate their chemotractant and chemostimulant functions. Receptors may bind more than one ligand; for example, the receptor CCR1 ligates RANTES (regulated on activation normal T cell expressed), MIP-1&agr; (macrophage inflammatory protein) and MIP-1&bgr; chemokines. To date, 24 chemokine receptors are known. The sheer number of chemokines, multiple ligand binding receptors, and different receptor profiles on WBCs allow for tightly controlled and specific immune responses (Rossi and Zlotnik 2000). Chemokine activity can be controlled through the modulation of their corresponding receptors, treating related inflammatory and immunological diseases and enabling organ and tissue transplants.
The receptor CCR1 and its chemokine ligands, including, for example MIP-1&agr; MIP-1&bgr;, and RANTES, represent promising therapeutic targets since they have been implicated in rheumatoid arthritis, transplant rejection (both reviewed in (DeVries, Ran et al. 1999)), and multiple sclerosis (Fischer, Santambrogio et al. 2000; Izikson, Klein et al. 2000; Rottman, Slavin et al. 2000). In fact, function-blocking antibodies, modified chemokine receptor ligands and small organic compounds have been discovered, some of which have been successfully demonstrated to prevent or treat some chemokine-mediated diseases (reviewed in (Rossi and Zlotnik 2000)). Notably, in an experimental model of rheumatoid arthritis, disease development is diminished when a signaling-blocking, modified-RANTES ligand is administered (Plater-Zyberk, Hoogewerf et al. 1997). While function-blocking antibody and small peptide therapies are promising, they suffer from the perils of degradation, extremely short half-lives once administered, and prohibitive expense to develop and manufacture characteristic of most proteins. Small organic compounds are preferable since they often have longer half lives in vivo, require fewer doses to be effective, can often be administered orally, and are consequently less expensive. Some organic antagonists of CCR1 have been previously described (Hesselgesser, Ng et al. 1998; Ng, May et al. 1999; Liang, Mallari et al. 2000; Liang, Rosser et al. 2000). Because such compounds have been shown to be effective in treating disease in some animal models (Liang, Mallari et al. 2000), it is desirable to have more compounds in the pharmaceutical arsenal in the art. The applicants have identified effective organic antagonists to CCR1 that promise to be important tools in this arsenal.
Piperazine derivatives of the type disclosed herein are known anti-inflammatory agents (See for example, WO98/56771, WO97/44329, WO99/37651, WO99/37619, WO00/53600). The specific piperazine derivatives disclosed herein have not previously been identified as antagonists to CCR1.
BRIEF SUMMARY OF THE INVENTION
In one embodiment, this invention provides compositions comprising a pharmaceutically acceptable carrier and an active compound that inhibits the binding of various chemokines, including for example MIP-1&agr; and RANTES, to the CCR1 receptor.
In another embodiment, this invention provides methods for blocking the CCR1 receptor by administering an active compound that inhibits the activity of various chemokines, including for example MIP-1&agr; and RANTES.
In another embodiment, this invention provides methods for treating inflammatory and immunoregulatory disorders and diseases by administering the compositions of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compositions that comprise a pharmaceutically acceptable carrier and an active compound inhibits the binding of various chemokines, including for example the major ligands MIP-1&agr;, MIP-1&bgr;, MIP-1&dgr;, myeloid progenitor inhibitory factor-1 (MPIF-1), hemofiltrate C-C-1 (HCC-1), leukotactin and RANTES, to the CCR1 receptor.
The compositions of the present invention are useful for treating inflammatory disorders.
Definitions
“Alkyl” refers to a saturated aliphatic group, including a straight-chain alkyl group, branched-chain alkyl group, or cycloalkyl group. In preferred embodiments, a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone, and more preferably 6 or fewer and most preferred 4 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, iso-butyl, tert-butyl, sec-butyl, cyclobutyl, pentyl, hexyl, cyclohexyl and the like. Methyl and ethyl are preferred.
“Alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
“Aryl” refers to any monovalent aromatic carbocyclic group of 5 to 10 carbon atoms. The aryl group can be bicyclic (i.e. phenyl (or Ph)) or polycyclic (i.e. naphthyl) and can be unsubstituted or substituted. Preferred aryl groups include phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, quinolinyl or isoquinolinyl.
“Haloalkyl” refers to an alkyl group, as defined above, substituted by one or more halogen atoms. Exemplary haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, chloroethyl, bromobutyl, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,
Brinks Hofer Gilson & Lione
Chemocentryx
Jones Dwayne C.
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