Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-08-09
2003-02-04
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06514949
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods and compositions for treating the inflammatory response in mammalian tissue.
2. Discussion of the Background
The release of inflammatory cytokines such as tumor necrosis factor-alpha (TNF&agr;) by leukocytes is a means by which the immune system combats pathogenic invasions, including infections. Cytokines stimulate neutrophils to enhance oxidative (e.g., superoxide and secondary products) and nonoxidative (e.g., myeloperoxidase and other enzymes) inflammatory activity. Inappropriate and over-release of cytokines can produce counterproductive exaggerated pathogenic effects through the release of tissue-damaging oxidative and nonoxidative products (Tracey, K. G. et al.,
J. Exp. Med
., 167, 1211-1227 (1988); and Männel, D. N. et al.,
Rev. Infect. Dis
., 9 (suppl 5), S602-S606 (1987)).
For example, inflammatory cytokines have been shown to be pathogenic in: arthritis (Dinarello, C. A.,
Semin. Immunol
., 4, 133-45 (1992)); ischemia (Seekamp, A. et al.,
Agents
-
Actions
-
Supp
., 41, 137-52 (1993)); septic shock (Männel, D. N. et al.,
Rev. Infect. Dis
., 9 (suppl 5), S602-S606 (1987)); asthma (Cembrzynska Nowak M. et al.,
Am. Rev. Respir. Dis
., 147, 291-5 (1993)); organ transplant rejection (Imagawa, D. K. et al.,
Transplantation
, 51, 57-62 (1991)); multiple sclerosis (Hartung, H. P.,
Ann. Neurol
., 33, 591-6 (1993)); and AIDS (Matsuyama, T. et al.,
AIDS
, 5, 1405-1417 (1991)). In addition, superoxide formation in leukocytes has been implicated in promoting replication of the human immunodeficiency virus (HIV) (Legrand-Poels, S. et al.,
AIDS Res. Hum. Retroviruses
, 6, 1389-1397 (1990)).
It is well known that adenosine and some adenosine analogs that nonselectively activate adenosine receptor subtypes decrease neutrophil production of inflammatory oxidative products (Cronstein, B. N. et al.,
Ann. N.Y. Acad. Sci
., 451, 291-314 (1985); Roberts, P. A. et al.,
Biochem. J
., 22, 669-674 (1985); Schrier, D. J. et al.,
J. Immunol
., 137, 3284-3289 (1986); Cronstein, B. N. et al.,
Clinical Immunol. and Immunopath
., 42, 76-85 (1987); Iannone, M. A. et al., in
Topics and Perspectives in Adenosine Research
, E. Gerlach et al., eds., Springer-Verlag, Berlin, 286-298 (1987); McGarrity, S. T. et al.,
J. Leukocyte Biol
., 44, 411-421 (1988); De La Harpe, J. et al.,
J. Immunol
., 143, 596-602 (1989); McGarrity, S. T. et al.,
J. Immunol
., 142, 1986-1994 (1989); and Nielson, C. P. et al.,
Br. J. Pharmacol
., 97, 882-888 (1989)). For example, adenosine has been shown to inhibit superoxide release from neutrophils stimulated by chemoattractants such as the synthetic mimic of bacterial peptides, f-met-leu-phe (fMLP), and the complement component C
5
a (Cronstein, B. N. et al.,
J. immunol
., 135, 1366-1371 (1985)). Adenosine can decrease the greatly enhanced oxidative burst of PMNs (neutrophils) first primed with TNF&agr; (an inflammatory cytokine) and then exposed to a second stimulus such as f-met-leu-phe (Sullivan, G. W. et al.,
Clin. Res
, 41, 172A (1993)). There is evidence that in vivo adenosine has anti-inflammatory activity (Firestein, G. S. et al.,
Clin. Res
., 41, 170A (1993); and Cronstein, B. N. et al.,
Clin. Res
., 41, 244A (1993)). Additionally, it has been reported that adenosine can decrease the rate of HIV replication in a T-cell line (Sipka, S. et al.,
Acta. Biochim, Biopys. Hung
., 23, 75-82 (1988)).
It has been suggested that there is more than one subtype of adenosine receptor on neutrophils that have opposite effects on superoxide release (Cronstein, B. N. et al.,
J. Clin. Invest
., 85, 1150-1157 (1990)). The existence of the A
2A
receptor on neutrophils was originally demonstrated by Van Calker et al. (Van Calker, D. et al.,
Eur. J. Pharmacology
, 206, 285-290 (1991)).
There has been progressive development of compounds that are more and more potent and selective as agonists of A
2A
adenosine receptors based on radioligand binding assays and physiological responses. Initially, compounds with little or no selectivity for A
2A
receptors were used, such as adenosine itself or 5′-carboxamides of adenosine, such as 5′-N-ethylcarboxamidoadenosine (NECA) (Cronstein, B. N. et al.,
J. Immunol
. 135, 1366-1371 (1985)). Later it was shown that addition of 2-alkylamino substituents increased potency and selectivity, e.g., CV1808 and CGS21680 (Jarvis, M. F. et al.,
J. Pharmacol. Exp. Ther
., 251, 888-893 (1989)). 2-Alkoxy-substituted adenosine derivatives such as WRC-0090 are even more potent and selective as agonists on the coronary artery A
2A
receptor (Ukena, M. et al.,
J. Med. Chem
., 34, 1334-1339 (1991)). The 2-alkylhydrazino adenosine derivatives, e.g., SHA 211 (also called WRC-0474) have also been evaluated as agonists at the coronary artery A
2A
receptor (Niiya, K. et al.,
J. Med. Chem
., 35, 4557-4561 (1992)).
There is one report of the combination of relatively nonspecific adenosine analogs, R-phenylisopropyladenosine (R-PIA) and 2-chloroadenosine (Cl-Ado) with a phosphodiesterase (PDE) inhibitor resulting in a lowering of neutrophil oxidative activity (Iannone, M. A. et al., in
Topics and Perspectives in Adenosine Research
, E. Gerlach et al., Eds., Springer-Verlag, Berlin, 286-298 (1987)). However, R-PIA and Cl-Ado analogs are actually more potent activators of A
1
adenosine receptors than of A
2A
adenosine receptors and, thus, are likely to cause side effects due to activation of A
1
receptors on cardiac muscle and other tissues causing effects such as “heart block”.
Linden et al. (U.S. Pat. No. 5,877,180) is based on the discovery that inflammatory diseases may be effectively treated by the administration of drugs which are selective agonists of A
2A
adenosine receptors, preferably in combination with a phosphodiesterase inhibitor. An embodiment of the Linden et al. invention provides a method for treating inflammatory diseases by administering an effective amount of an A
2A
adenosine receptor of the following formula:
wherein X is a group selected from the group consisting of —OR
1
, —NR
2
R
3
, and —NH—N═R
4
;
wherein R
1
is C
1-4
-alkyl; C
1-4
-alkyl substituted with one or more C
1-4
-alkoxy groups, halogens (fluorine, chlorine, or bromine), hydroxy groups, amino groups, mono(C
1-4
-alkyl)amino groups, di(C
1-4
-alkyl)amino groups, or C
6-10
-aryl groups (wherein the aryl groups may be substituted with one or more halogens (fluorine, chlorine, or bromine), C
1-4
-alkyl groups, hydroxy groups, amino groups, mono (C
1-4
-alkyl)amino groups, or di(C
1-4
alkyl)amino groups); C
6-10
-aryl; or C
6-10
-aryl substituted with one or more halogens (fluorine, chlorine, or bromine), hydroxy groups, amino groups, mono(C
1-4
-alkyl)amino groups, or di(C
1-4
-alkyl)amino groups, or C
1-4
-alkyl groups;
one of R
2
and R
3
has the same meaning as R
1
and the other is hydrogen;
R
4
is a group having the formula:
wherein each of R
5
and R
6
independently may be hydrogen, C
3-7
-cycloalkyl, or any of the meanings of R
1
, provided that R
5
and R
6
are not both hydrogen; and
R is —CH
2
OH, —CH
2
H, —CO
2
R
7
, or —C(═O)NR
8
R
9
; wherein R
7
has the same meaning as R
1
and wherein R
8
and R
9
have the same meanings as R
5
and R
6
and R
8
and R
9
may both be hydrogen.
In a preferred embodiment, the Linden et al. invention involves the administration of a Type IV phosphodiesterase (PDE) inhibitor in combination with the A
2A
adenosine receptor agonist. The Type IV phosphodiesterase (PDE) inhibitor can be racemic and optically active 4-(polyalkoxyphenyl)-2-pyrrolidones of the following formula:
(disclosed and described in U.S. Pat. No. 4,193,926) wherein R
18
and R
19
each are alike or different and are hydrocarbon radicals having up to 18 carbon atoms with at least one being other than methyl, a heterocyclic ring, or alkyl of 1-5 carbon atoms which is substituted by one or more of halogen atoms, hydroxy, carboxy, alkoxy, alkoxycarbonyl or an amino group; amino; R
1
is a hydrogen atom, alkyl, aryl or acyl;
Linden Joel M.
Scheld W. Michael
Sullivan Gail W.
Jarvis William R. A.
University of Virginia Patent Foundation
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