Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-13
2004-05-11
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06734208
ABSTRACT:
BACKGROUND OF THE INVENTION
TGF-beta dynamically regulates the differentiation of smooth muscle cells, and has been postulated to maintain vessel wall structure. TGF-beta also appears to possess immunosuppressive properties which protect the vascular endothelium against local inflammation and damage. Moreover, TGF-beta may inhibit the proliferation and migration of smooth muscle cells after vascular injury.
TGF-beta is synthesized as a latent peptide (FIG.
1
). Latent TGF-beta refers to any of several complexes that include the 25 kD TGF-beta dimer in association with the latency associated peptide (LAP) or any of several additional TGF-beta binding proteins (LTBPs). Latent TGF-beta has no biological activity, i.e., it does not bind to the TGF-beta receptors.
The 25 kD TGF-beta dimer is also found associated with matrix components or other plasma proteins (FIG.
1
). TGF-beta that is associated with matrix components or other plasma proteins is termed mature TGF-beta. This association also prevents the binding of TGF-beta to the TGF-beta receptors.
In addition to latent and mature forms of TGF-beta, which cannot bind to the TGF-beta receptors and which possess no known biological activity, TGF-beta also exists in forms which are capable of binding to the TGF-beta receptors and which elicit biological effects (FIG.
1
). These forms of TGF-beta are termed “active TGF-beta.” One example of a form of active TGF-beta is the 25 kD TGF-beta dimer which is free from association with LAP/LTBPs, or matrix or plasma components. The process(es) by which the latent form of TGF-beta is converted to the active form is termed “activation.” The process(es) by which the mature form of TGF-beta is converted to the active form is termed “release.”
Decreased levels of TGF-beta have been implicated in the development of atherosclerosis. Atherosclerosis is a disease of the major arteries, typified by changes in the vessel wall architecture. At lesion-prone sites where the endothelium becomes damaged or dysfunctional, smooth muscle cells from the media of the vessel migrate into the intima. At these sites, leukocytes, and in particular, monocytes and macrophages invade the expanded intima. As the lesion develops, lipid from the circulation is deposited into the intima (reviewed in Ross,
Nature,
362 801 (1993); Grainger et al.
Biol. Rev. Camb. Philos. Soc.,
70, 571 (1995)).
Agents which elevate TGF-beta activity, such as tamoxifen (TMX) (Grainger et al.,
Biochem. J.,
294, 109 (1993)) and aspirin (Grainger et al.,
Nat. Med.,
1, 74 (1995)), can exhibit cardioprotective effects. However, the positive cardioprotective effects of these agents may be counterindicated by their potential side effects. TMX can cause liver carcinogenicity in rats, has been correlated with an increased risk of endometrial cancer in women and may increase the risk of certain gut cancers. Aspirin may result in ulcerogenesis and increased bleeding.
Agents which elevate TGF-beta levels may also be useful to prevent or treat diseases or conditions including cancer, Marfan's syndrome, Parkinson's disease, fibrosis, Alzheimer's disease, senile dementia, osteoporosis, diseases associated with inflammation, such as rheumatoid arthritis, multiple sclerosis and lupus erythematosus, and other auto-immune disorders. Such agents may also be useful to promote wound healing and to lower serum cholesterol levels.
Thus, there is a need for improved therapeutic methods and agents useful to maintain or elevate TGF-beta levels in mammals.
SUMMARY OF THE INVENTION
The present invention provides a method to maintain or elevate TGF-beta levels in a mammal, such as a human, in need of such therapy. The method comprises administering an effective amount of an aspirinate as defined herein. The method can also be carried out by administering an amount of a first therapeutic agent effective to elevate the level of latent TGF-beta and an amount of a second therapeutic agent effective to increase the level of TGF-beta which is capable of binding to the TGF-beta receptors, wherein said amounts are effective to maintain or elevate the level of TGF-beta in said mammal.
The invention also provides a method of preventing or treating a mammal, such as a human, having, or at risk of, a vascular indication which is associated with a TGF-beta deficiency. The method comprises the administration of an amount of an aspirinate that elevates the level of TGF-beta in said mammal so as to inhibit or reduce diminution in vessel lumen diameter. Preferably, the levels of active TGF-beta are elevated after administration of the aspirinate.
Preferred agents useful in the practice of the invention are copper aspirinates. Preferably, the effective amount of aspirinate inhibits lipid accumulation, increases plaque stability, decreases lesion formation or development, promotes lesion regression, or any combination thereof. Agents useful in the practice of the method include aspirinate salts such as copper salts of aspirinates, including copper aspirinate itself (copper 2-acetylsalicylate or copper 2-acetoxybenzoate), salicylate salts such as copper salts of salicylates, including copper salicylate (copper 2-hydroxybenzoate), or a compound of formula (I) (see below) including a pharmaceutically acceptable salt thereof, or a combination thereof.
An aspirinate useful in the present invention is a compound of formula (I):
wherein
R
1
is hydrogen, halo, nitro, cyano, hydroxy, CF
3
, —NR
c
R
d
, —C(═O)OR
e
, —C(═N)OR
e
—OC(═O)OR
e
, (C
1
-C
6
)alkyl or (C
1
-C
6
)alkoxy;
R
2
is hydrogen or —XR
a
;
R
3
is —C(═O)YR
b
, or —N(R
f
)C(═O)R
g
—;
R
4
is (═O)
n
; or R
4
is (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl or (C
2
-C
6
)alkanoyloxy;
R
5
is hydrogen, —C(═O)OR
h
or —C(═O)SR
h
;
n is 0, 1 or 2;
X is oxygen, —N(R
i
)—, or sulfur;
Y is oxygen or sulfur;
R
a
is (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkyl, or hydrogen;
R
b
is hydrogen or (C
1
-C
3
)alkyl;
R
c
and R
d
are each independently hydrogen, (C
1
-C
4
)alkyl, phenyl, C(═O)OH, C(═O)O(C
1
-C
4
)alkyl CH
2
C(═O)OH, CH
2
C(═O)O(C
1
-C
4
)alkyl, or (C
1
-C
4
)alkoxy; or R
c
and R
d
together with the nitrogen to which they are attached are a 3, 4, 5, or 6 membered heterocyclic ring; and
R
e
-R
i
are independently hydrogen or (C
1
-C
6
)alkyl;
a pharmaceutically acceptable salt thereof; or a combination thereof;
provided that R
2
and R
3
are on adjacent positions of the ring to which they are attached, or are on the 2- and 5-positions of the ring; and further provided that when R
2
is hydrogen; R
3
is on the 2-or 5-position of the ring to which it is attached and R
4
is (C
1
-C
4
)alkanoyloxy. Preferably, the compound of formula (I) is not 3-acetoxy-2-carboxythiophene.
Also provided is a method of preventing or treating a mammal having, or at risk of, a vascular indication by administering there to an amount of a first therapeutic agent and an amount of a second therapeutic agent which together are effective to elevate the level of TGF-beta, preferably the level of active TGF-beta, in said mammal. Preferably, the administration inhibits or reduces diminution in vessel lumen diameter. The inhibition or reduction in diminution in vessel lumen diameter preferentially occurs at a site in a vessel where the vascular indication is, or is likely to be, manifested. The invention thus provides for combination therapy, e.g., the administration of one agent that can elevate the level of latent TGF-beta, and another agent that can elevate the level of TGF-beta which is available to bind to, or is capable of binding to, the TGF-beta receptor. This combination therapy can yield a significantly greater cardiovascular efficacy than would be expected from the administration of either agent singly. The therapeutic agents can act in a synergistic, rather than in an additive, manner to elevate TGF-beta levels. The therapeutic agents can be administered simultaneously in a single dosage form simultaneously in individual doses, or sequentially.
A first therapeutic agent u
Grainger David J.
Kasina Sudhakar
Metcalfe James C.
Baker & Botts LLP
Lambkin Deborah C.
NeoRx Corporation
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