Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-15
2003-12-16
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S304000, C514S330000, C546S124000, C546S212000, C546S225000, C546S226000, C546S227000
Reexamination Certificate
active
06664271
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to agents useful for stimulating the immune system of a host animal, and more particularly, to agents and methods for providing selective stimulation to the immune system of a host animal.
A primary function of the immune system is to protect the animal against the deleterious effects of invading pathogens. One type of immune system response to such invasion, known as cell-mediated immune response, protects the animal against invasion by microorganisms, such as bacteria, protozoa and viruses, and also against invasion by abnormal and malignant cells. Cell-mediated immune response is controlled by the T-lymphocytes, or T-cells. When the body recognizes the presence of an invading pathogen, two types of T-cells are produced, namely cytotoxic, or killer, T-cells that can destroy the invading pathogen, and helper T-cells that enhance the body's defenses against the invader.
The immune system of an animal may become compromised due to such factors as disease, exposure to etiologic agents, allergic reactions, autoimmune system disorders and advanced age. When the animal becomes immunocompromised in this manner, the ability of the T-cells to destroy invading pathogens is reduced, and in severe cases, may be lost altogether. In addition, even when an animal has a functional immune system, the ability of the T-cells to resist infection by certain pathogens may be insufficient.
When the invading pathogen is a microorganism, such as a bacterium, it is common to administer antibiotics to the animal suffering from such invasion. The purpose of the antibiotics is to control the spread of the bacteria within the body, and preferably, to destroy it altogether. Many effective antibiotics have been developed to treat both humans and non-human animals against diseases caused by invading etiologic agents. The effectiveness of these antibiotics has contributed to their widespread usage. However, this widespread usage of antibiotics has caused increased concern in recent years that antibiotic-resistant strains of bacteria may develop and spread. As a consequence, regulatory authorities have begun to more closely scrutinize and monitor the use of certain antimicrobial agents. In some cases, certain uses of these agents have been banned. In order to minimize the possibility that resistant bacterial strains may develop, it would be desirable to reduce the use of these antimicrobial agents. However, any such reduction would necessitate the development of new treatments to counter the harmful effects on the body that may be caused by an etiologic agent if left untreated.
It is believed that the class of drugs known as immunopotentiators acts on the immune system by priming the function of leukocytes, thereby enabling the leukocytes to respond with increased bactericidal activity upon stimulation by a pathogen. The inventors postulate that the mechanism of action of the immunopotentiators in the present application is a blastogenic effect on the T-cells, which is mediated by cytokines. The cytokines then prime the function of bactericidal leukocytes, such as macrophages, killer T-cells and polymorphonuclear leukocytes (PMNs). In the presence of pathogenic bacteria, the leukocytes phagocytize and kill the bacteria.
It is well known that certain bacterial agents are the source of numerous diseases afflicting animals. An example of an agent affecting both human and non-human animals is the bacterium
Escherichia coli
. Outbreaks caused by various strains of
E. coli
have been widely documented. Such outbreaks in humans are known to result from, among others, the consumption of undercooked and/or unwashed food. These outbreaks have been known to cause severe intestinal distress and, in some instances, death. The exposure to
E. coli
is also known to cause severe problems in many animal species. For example, the syndrome avian colibacillosis is caused in poultry by
E. coli
. Manifestations of colibacillosis in poultry may include acute septicemia, airsacculitis, pericarditis, perihepatitis and peritonitis. The control of this disease is economically important to poultry producers, because it causes morbidity, mortality, lack of uniformity, decreased performance and increased condemnations.
Etiologic agents such as
E. coli
are often secondary pathogens to a primary viral insult. However, some virulent bacterial isolates are known to cause disease even in the absence of a primary insult.
E. coli
causes airsacculitis in poultry by colonizing in the air sac following a reduction in respiratory host defenses, which is often a sequelae to stressors or viral infections, such as infectious bronchitis virus and Newcastle's disease virus. Presently, colibacillosis in poultry is prevented by the early administration of antimicrobial agents such as cephalosporin, quinolone, and aminoglycoside antibiotic to one-day old chicks. However, in view of the concern that use of these antimicrobial agents may contribute to the development of antibiotic-resistant bacteria, it is desirable to reduce such use.
In addition, due to the crowded pens and unsanitary structures that are often used to house non-human animals, these animals are at a high risk of infection and re-infection, and of immune system disorders occurring as a result of such conditions. In many cases, an infected and/or immunocompromised animal must be treated with antibiotics in order to prevent and/or attempt to control the disease.
Accordingly, it is desired to provide a class of compounds that stimulates the natural immune system of a host animal, thereby enabling the host animal to increase its resistance to infection. In addition, it is desired to provide a class of compounds that provides an alternative to the use of antibiotics.
SUMMARY OF THE INVENTION
A class of drugs, known as immunopotentiators, is provided. These drugs, when introduced into the body of a host animal, selectively stimulate the natural immune system of the host, thereby reducing or eliminating altogether the necessity to introduce antibiotics into the host's body in order to fight certain infectious agents. As a result of this selective stimulation, i.e., T-cell blastogenesis and production of cytokines, the natural immune system of the host animal achieves an enhanced ability to control the bacteria.
In one aspect of the present invention, there is provided an immunopotentiating composition comprising a physiologically acceptable carrier and an effective immunopotentiating amount of a compound defined by the following Formula I:
wherein:
R
1
is H, C
1
-C
4
alkyl or (═O);
R
2
is C(O)R
8
, CH
2
C(O)R
8
, CN, CH
2
OH, OH, OC(O)R
9
or OS(O)
2
R
9
R
3
, R
4
and R
5
are each independently H or C
1
-C
4
alkyl;
R
6
is C(O)OCH
2
Ar
3
, C(O)NHCH
2
Ar
3
, C(O)Ar
1
, C(O)CH(R
3
)Ar
2
, C(O)CH(R
3
)CH
2
Ar
2
, C(O)CH(R
3
)CH
2
CH
2
Ar
4
or C(O)NHR
9
;
R
7
is H or CH
2
C(O)R
8
;
R
8
is H, C
1
-C
4
alkyl, OR
10
, NHR
11
or OH (when R
6
is C(O)Ar, or C(O)CH(R
3
)Ar
2
);
R
9
is C
1
-C
4
alkyl;
R
10
is C
2
-C
8
alkyl, CH
2
CH
2
N(CH
3
)
2
or CH
3
(when R
6
is C(O)Ar
1
and Ar
1
is phenyl);
R
11
is C
2
-C
6
alkyl, CH
2
CH
2
N(CH
3
)
2
or C
7
-C
9
alkyl (when R
6
is C(O)Ar
1
);
Ar
1
is phenyl, 4-fluorophenyl, 2-thienyl, 3-thienyl or 1,4-biphenyl;
Ar
2
is phenyl or 2-thienyl;
Ar
3
is phenyl;
Ar
4
is 2-thienyl;
Ar
5
is phenyl or 2-halo-phenyl;
halo is Cl, Br or F; and
Ar
6
is plienyl or 4-fluorophenyl;
with the proviso that when R
7
is CH
2
C(O)R
8
, then R
2
and R
3
are H, R
4
and R
5
are H or C
1
-C
4
alkyl; R
6
is C(O)CH(R
3
)Ar
4
; R
8
is H, C
1
-C
4
alkyl, OR
9
or NHR
10
; R
9
is C
1
-C
8
alkyl and R
10
is C
2
-C
8
alkyl; and with the further proviso that when R
1
is (═O), then R
2
is C(O)R
8
or CH
2
C(O)R
8
; R
3
, R
4
and R
5
are H or C
1
-C
4
alkyl; R
6
is C(O)OCH
2
Ar
3
, C(O)Ar
6
or C(O)NHR
9
; R
7
is H or, together with R
5
, CH
2
CH
2
: R
8
is H, C
1
-C
4
alkyl, OR
10
or NHR
11
; R
9
is C
1
-C
4
alkyl; R
10
is C
1
-C
8
alkyl and R
11
Creemer Lawrence Camillo
Herring Janice Rhea
McGruder Edward Deorsey
Chang Ceila
Demeter John C.
Eli Lilly and Company
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