Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-16
2002-11-12
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000, C514S313000, C546S105000, C546S159000, C546S160000
Reexamination Certificate
active
06479504
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of immunology. More particularly, it concerns preventative and therapeutic compositions and methods that inhibit stimulation of the immune system.
2. Description of Related Art
While stimulation of the immune systems prevents and controls infection, it can have an adverse physiological effect, as is the case with autoimmune diseases and phenomena, with rejection of cells and tissues during adoptive immunotherapy and transplants, and with invasions by pathogens. Inhibition of this stimulation can have beneficial therapeutic results. However, new and more effective treatments to effect inhibition of immunostimulation are still needed.
Autoimmunity is generally caused by aberrations in lymphocyte activities. While the precise cause of autoimmunity is not known, it most likely involves a mechanistic failure in at least one of the steps of maintaining self-tolerance to the body's own antigens. Several factors are thought to play a part in the development of autoimmunity, including the host's genetic makeup. Autoimmune diseases afflict approximately 1% to 2% of the human population. Autoimmune phenomena, are the result of a disease, for example myocardial infarcation, that may cause damage to tissue, which consequently effects the release of immunogenic tissue antigens; this condition, unlike autoimmune disease, is unrelated to the pathogenesis of the disease that caused it.
There are a wide variety of autoimmune diseases. They are classified as either organ-specific based on the primary site of injury or systemic (see Table 1). There are three ways in which damage or injury to tissue is caused by autoimmune disease: cell-mediated immunity, cell lysis and autoantibody-induced release of inflammatory mediators, and immune complex disease.
Cell-mediated immunity occurs when sensitized T cells directly damage cells or release lymphokines that augment the inflammatory reaction. An association of an autoantibody with its antigen in intercellular fluid causes cell lysis and autoantibody-induced release of inflammatory mediators. This interaction results in release of inflammatory mediators, induction of the complement pathway, or activation of cytotoxic cells, which can trigger cell lysis. The third mechanism, immune complex disease, involves a reaction between circulating autoantibodies and antigens on the cell surface. This complex becomes deposited in tissue such as the joints, blood vessels, and glomeruli, causing complement to be fixed and subsequent inflammation and tissue damage.
Rejection of cells and tissue can involve rejection of the graft by the host. The body's own cells are identified as self because of a complex series of cell surface molecules known as major histocompatibility molecules (MHC). Rejection of cells and tissues can occur following transplantation of cells or organs or after adoptive immunotherapy has been implemented. In graft-versus host disease (GVHD), the grafted immune system attacks the host cells. One example in which GVHD becomes particularly significant is bone marrow transplantation (BMT), which is frequently used for the treatment of a variety of bone marrow-related disorders and in cancer therapy to replace bone marrow cells lost to chemotherapy and radiation treatment. In severe cases of GVHD, a patient's compromised immune system gives rise to many complications including those in the liver, causing jaundice, in the skin causing rash, and in the gastrointestinal tract, including diarrhea, anorexia, nausea and vomiting, malabsorption, abdominal pain ileus, and ascites formation.
Sepsis is the primary cause of death in the intensive care unit with more than 400,000 cases in the United States annually. It can be caused by infection by a pathogen, such as viruses, bacteria, fungi, and parasites, which triggers host defenses. This may result in activation of innate immunity, particularly, an inflammatory response, which consequently promotes deleterious effects (collectively termed “sepsis”) including shock, respiratory distress, capillary leaks, renal failure, jaundice, bleeding, coma and death.
Despite this information, preventative and therapeutic treatment to inhibit stimulation of the immune system is still needed. Oligodeoxynucleotides (ODN), bacterial DNA, and phosphorothioate oligodeoxynucleotides with unmethylated CpG-motifs are immunostimulatory and may contribute to autoimmunity. Thus, they can serve as a model system to identify compounds and methods that effect inhibition of immunostimulation. Using CpG-ODN, a number of compounds have been identified as possessing this property. For example, a number of quinoline derivatives that are active against stimulation by CpG-ODN have been shown to induce remission of rheumatoid arthritis and lupus erythematosus (Fox, 1993; Wallace, 1994). Chloroquine and a number of structural analogs specifically and powerfully inhibit this effect at nanomolar concentration. Therefore, inhibition of CpG-ODN immunostimulation can be effected generally in the treatment of autoimmune diseases and phenomena, sepsis, and transplantation rejection, including graft-versus-host disease.
SUMMARY OF THE INVENTION
The inhibition of immune stimulation in cases such as autoimmune diseases, tissue transplantation and the like would be therapeutically beneficial. Currently, methods to inhibit stimulation of the immune system are limited. Therefore, it is a goal of the present invention to provide methods and compositions for inhibiting immunostimulation in a subject.
In one embodiment of the invention, a method of inhibiting immunostimulation in a subject by administering an effective amount of a substituted 4-quinolinamine composition to the subject comprising a compound having the structural formula A is provided.
A substituted 4-quinolinamine composition of formula A, comprises groups R
A
, R
B
, R
2
, R
3
, R
5
, R
6
, R
7
and R8, wherein R
A
is hydrogen atom or a lower alkyl group, R
B
is a substituted or unsubstituted alkyl, alkenyl or alkynyl secondary or tertiary amine, R
2
is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, an substituted or unsubstituted anthracyl group, a substituted or unsubstituted phenanthryl group or a substituted or unsubstituted styryl group, R
3
is a hydrogen atom, R
5
is a hydrogen atom, R
6
is a hydrogen atom or a halogen atom, R
7
is a hydrogen atom or a halogen atom, R
8
is a hydrogen atom and pharmaceutically acceptable salts thereof. In preferred embodiments, the R
2
phenyl, naphthyl, anthracyl, styryl or phenanthryl group substitution further comprise one or more substitutions selected from the group consisting of an alkyl group, an alkoxy group, an alkoxyalkyl group, an ester group, an alkylamino group, a dialkylamino group, a cyclic amino group, a halogen atom, and any combination thereof. In some aspects of the invention, the R
2
substitution is an N-substituted aminomethyl group, a cyclic aminomethyl group, or an aminomethyl group, additionally substituted at the nitrogen atom with a cyclic aminoalkyl group. In particularly preferred embodiments, a cyclic amino group is a piperazino group, a piperidino group, a pyrrolidino group, an imidazolyl group, a pyridyl, or a morpholino group. In another embodiment, the R
B
substituted alkyl is selected from the group consisting of a cyclic amino group, furyl, thienyl, phenyl, alkylamino group, dialkylamino group, and any combination thereof. It is contemplated that phenyl includes a substituted phenyl. In preferred embodiments, a cyclic amino group is a piperazino group, a piperidino group, a pyrrolidino group, an imidazolyl group, a pyridyl group, or a morpholino group. The cyclic amino groups in R
B
or R
2
may be further substituted with an alkyl group, for example, an N-methylpiperazino or an N-pyrrolidinoalkyl. It is further contemplated that there is a covalent bond formed between R
A
and R
B
, for example, to form an N-methylpiperazino.
In another embo
Barlin Gordon B.
Ismail Fyaz M. D.
Macfarlane Donald E.
Manzel Lori
Strekowski Lucjan
Fulbright & Jaworski LLP
Seaman D. Margaret
The University of Iowa Research Foundation
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