Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-07
2002-12-03
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S563000, C546S175000, C562S439000
Reexamination Certificate
active
06489339
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel C3A receptor ligands, pharmaceutical compositions containing these compounds and methods of using the present compounds to treat inflammation.
BACKGROUND OF THE INVENTION
Anaphylatoxins are 74-77 amino acid bioactive fragments of C5, C3 and C4 that are generated in vivo during complement activation. Binding of the anaphylatoxins to specific cell surface receptors initiates and maintains the inflammatory process. The fragments are believed to elicit mast cell and basophil degranulation with release of histamine, cytokines and other inflammatory mediators and induce smooth muscle cell contraction. They are potent inflammatory mediators, inducing cellular degranulation, smooth muscle contraction, arachidonic acid metabolism, cytokine release, cellular chemotaxis. See Gerard, C., and Gerard, N. P. (1994)
Annu. Rev. Immunol
. 12, 775-808; Hugli, T. E. (1984)
Springer Semin. Immunopathol
. 7, 193-219; Bitter-Suermann, D. (1988) in
The Complement System
, Ed. by K. Rother & G. Till, Springer Verlag, Heidelberg 367-395.
The present fragments have been implicated in the pathogenesis of a number of inflammatory diseases. See Vogt, W. (1986)
Complement
3, 177-188; Morgan, B. P. (1994)
European J Clin Investigation
24, 219-228. Studies have demonstrated the presence of a C3A receptor (C3A-R) on guinea pig platelets, rat mast cells, human neutrophils, eosinophils and platelets (Bitter-Suermann, D. (1988) in The Complement System, Ed. by K. Rother & G. Till, Springer Verlag, Heidelberg 367-395). A single class of high affinity C3A binding sites has been characterized on human neutrophils and differentiated U937 cells (KIos, A., Bank, S., Gietz, C., Bautsch, W., Köhl, J., Burg, M., and Kretzschmar, T (1992)
Biochemistry
31, 112741-1282). Competition binding and functional desensitization studies are consistent with the presence of a receptor for C3A which is distinct from the C5A-R (Bitter-Suernann, D. (1988) in The Complement System, Ed. by K. Rother & G. Till, Springer Verlag, Heidelberg 367-395; Klos, A., Bank, S., Gietz, C., Bautsch, W., Köhl, J., Burg, M., and Kretzschmar, T. (1992)
Biochemistry
31, 11274-11282). However, there is evidence that C3A and C4A may bind to the same receptor as the two anaphylatoxins cross desensitize guinea pig ileal tissue (Hugli, T. E. (1984)
Springer Semin. Immunopathol
. 7, 193-219; Bitter-Suermann, D. (1988) in
The Complement System
, Ed. by K Rother & G. Till, Springer Verlag, Heidelberg 367-395), although other investigators using guinea pig macrophages indicate that there may be separate receptors (Murakami, Y., Yamamoto, T., Imamichi, T., Nagasawa, S. (1993)
Immunol. Lett
. 36, 301-304). Functional activity of the C 3A-R is sensitive to pertussis toxin, consistent with the binding site being composed of a GPCR (Klos, A., Bank, S., Gietz, C., Bautsch, W., köhl, J., Burg, M., and Kretzschmar, T. (1992)
Biochemistry
31, 11274-11282).
A complete understanding of the role of C3A in the pathogenesis of the inflammatory response has been hampered by the lack of the cloned receptor. The present invention provides methods of using and functional characterization of human C3A receptor. This same receptor was recently independently cloned from an HL-60 library by low-stringency screening with a fMetLeuPhe receptor probe and, lacking functional data, claimed to be an orphan receptor (AZ3B,8). Mouse L cells expressing AZ3B failed to bind and respond to the agonists examined, although C3A was not tested (Roglic, A., Prossnitz, E. R., Cavanagh, S. L., Pan, Z, Zou, A. & Ye, R. D. (1996)
Biochimica et Biophysica Acta
1305, 39-43). The present invention discloses compounds that antagonize C3A receptor function.
Clearly, there is a need for factors that mediate inflammation and their roles in dysfunction and disease. There is a need, therefore, for identification and characterization of compounds which antagonize C3A receptor function, and which can play a role in preventing, ameliorating or correcting dysfunctions or diseases.
Thus, C3A ligands offer a unique approach towards the pharmacotherapy of immune and inflammatory diseases such as rheumatoid arthritis, Alzheimer's disease, psoriasis, gout, multiple sclerosis, systemic lupus erythematosus, glomerulonephritis and adult respiratory distress syndrome.
SUMMARY OF THE INVENTION
The present invention involves compounds represented by Formula (I) hereinbelow and their use as C3A receptor ligands which are useful in the treatment of a variety of diseases associated with complement activation and or increased levels of anaphylatoxins, including but not limited to rheumatoid arthritis, Alzheimer's disease, psoriasis, gout, multiple sclerosis, systemic lupus erythematosus, glomerulonephritis and adult respiratory distress syndrome.
The present invention further provides methods for antagonizing C3A receptors in an animal, including humans, which comprises administering to an animal in need of treatment an effective amount of a compound of Formula (1), indicated hereinbelow.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are selected from Formula (I) hereinbelow:
wherein:
A represents C
1-4
alkylene, unsubstituted or optionally substituted by C
1-4
alkyl or aryl; or
A forms a 5-8 membered fused aliphatic ring with the adjacent phenyl ring;
m is an integer from 1 to 3;
each R
1
is independently selected from the group consisting of halo, C
1-4
alkyl, methanesulfonyl, alkoxy, nitrile, dimethylamine, methylenedioxy and CF
3
; and
R
2
is hydrogen or methyl.
Preferably, A represents phenethyl.
Preferably m is 0.
Preferably, R
1
represents hydrogen.
Preferably, R
2
represents hydrogen.
As used herein, “alkyl” refers to an optionally substituted hydrocarbon group joined together by single carbon-carbon bonds. The alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Preferably, the group is linear. Preferably, the group is unsubstituted. Preferably, the group is saturated.
As used herein “cycloalkyl” refers to 3-7 membered carbocyclic rings.
As used herein “heterocycloalkyl” refers to 4-7 membered heterocyclic rings containing 1 to 2 heteroatoms selected from N, O and S.
As used herein, “aryl” refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems. “Aryl” includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. A preferred aryl group is phenyl.
As used herein “acyl” refers to alkylcarbonyl.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
Preferred compounds in the present invention include:
1-Naphthyloxyacetylarginine;
1-[7-(4-hydroxyphenylmethyl)naphthyloxy]acetylarginine;
(2,2-Diphenylethoxy)acetylarginine;
(2,2-Diphenylethoxy)acetyl-N&agr;-methylarginine;
(3-Chlorobenzyloxy)acetylarginine;
2-Naphthyloxyacetylarginine;
(2,3-Dimethylphenoxy)acetylarginine;
8-(Quinolinyloxy)acetylarginine;
6-(Quinolinyloxy)acetylarginine;
2-(1-Bromonaphthyloxy)acetylarginine;
(4-Benzyloxyphenoxy)acetylarginine; and
2-(6-Methoxynaphthyloxy)acetylarginine.
More preferred compounds of the present invention include:
1-Naphthyloxyacetylarginine;
1-[7-(4-hydroxyphenylmethyl)naphthyloxy]acetylarginine;
(2,2-Diphenylethoxy)acetylarginine; and
2-Naphthyloxyacetylarginine.
The most preferred compounds of the present invention include:
1-Naphthyloxyacetylarginine; and
(2,2-Diphenylethoxy)acetylarginine.
An especially preferred compound of the present invention is (2,2-Diphenylethoxy)acetylarginine.
The present compounds can also be formulated as pharmaceutically acceptable salts and complexes thereof. Pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations at which they are administered.
Phar
Bondinell William E.
Jurewicz Anthony J.
Lee Dennis
McCarthy Mary E.
Ramsuer Robert W.
Simon Soma G.
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