Reverse prenyl compounds as immunosuppressants

Details Reverse prenyl compounds as immunosuppressants Reverse prenyl compounds as immunosuppressants

2000-02-16

2002-03-12

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06355639

ABSTRACT:

FIELD OF THE INVENTION
This invention is in the field of clinical immunology, and relates to compounds having immunosuppressive properties. In particular, the invention relates to a method for treating immune disorders, including autoimmune or inflammatory diseases, and for reducing immunorejection of transplanted organs, said method comprising administering to a subject a therapeutically effective amount of N-acetylardeemin or an analog thereof.
BACKGROUND OF THE INVENTION
The immune system specifically recognizes and selectively eliminates foreign invaders, or other antigenic agents, by a process known as the immune response. Immune rejection is a major problem confronting organ transplantation. The principal approach to mitigate rejection is the pharmacological suppression of the immune system of an organ recipient. Immunosuppressive drugs are an important component in the prevention of organ graft rejection. Such drugs have been used to increase survival times for transplanted organs, including kidney, pancreas, liver, heart, intestines, lung, and bone marrow, allograft or autologous, either as single agents or in combination with other immunosuppresants. They are also useful for treating inflammatory diseases, delayed hypersensitivity, allergic encephalomyelitis and graft vs. host diseases.
Currently used immunosuppressive drugs include antiproliferative agents, such as methotrexate, azathioprine and cyclophosphamide. Since these drugs affect mitosis and cell division, they have severe toxic effects on normal cells with high turn-over rate such as bone marrow cells and the gastrointestinal tract lining. Marrow depression and liver damage are common side effects.
Antiinflammatory compounds used to induce immunosuppression include adrenal corticosteroids such as dexamethasone and prednisolone, and have the advantage of not generating systemic toxic effects. Since they are less specific, they are usually used together with antiproliferative agents. Among the common side effects observed with the use of these compounds are frequent infections, loss of hemodynamic balance and abnormal metabolism.
Other immunosuppresants in use are compounds which inhibit lymphocyte activation. Cyclosporin and its relatives are among the most commonly used immunosuppresants. Cyclosporin A is used for organ rejection in kidney, liver, heart, pancreas, bone-marrow and heart-lung transplants, as well as for the treatment of autoimmune and inflammatory diseases such as Crohn's disease, a plastic anemia, multiple-sclerosis, myasthenai gravis, uveitis, biliary cirrhosis, etc. However, cyclosporins can have severe toxic effects on various tissues, including the liver, kidney and nervous system.
Aside from organ or tissue transplant rejection, examples of immune system conditions or disorders which could benefit from treatment with an immunosuppressant agent include contact dermatitis; graft-vs-host disease in which donor immunological cells present in the graft attack host tissues in the recipient of the graft; diseases with proven or possible autoimmune components, such as rheumatoid arthritis, psoriasis, autoimmune uveitis, multiple sclerosis, allergic encephalomyelitis, systemic lupus erythematosis, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, scleroderma, chronic active hepatitis, myasthenia gravis, Crohn's disease, ulcerative colitis, Graves ophthalmopathy, sarcoidosis, primary biliary cirrhosis, primary juvenile diabetes, uveitis posterior, and interstitial lung fibrosis.
Accordingly, in view of the ineffectiveness or toxicity of current therapeutic agents, an important clinical need exists for new selective, nontoxic immunosuppressive agents for use in organ transplantation, and in the treatment of autoimmune disorders.
SUMMARY OF THE INVENTION
One object of the present invention is to provide a method for suppressing pathogenic immune responses. In particular, an object of the invention is to provide a method for treating a subject in need of immunosuppression, comprising administering to the subject an effective amount of a compound having the structure:
wherein R
1
, R
6
and R
7
are independently hydrogen, OH, NH
2
, SH, halogen, C
1
-C
9
linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylamino, alkoxy, phenyl, alkylphenyl, dialkylphenyl, halophenyl, alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxybenzyl; wherein R
0
, and R
2
are independently hydrogen, OH, C
1
-C
9
linear or branched chain alkyl, —CR
3
R
3
—CH(O)CH
2
, —CR
3
R
3
—CH
2
CH
3
, —CR
3
R
3
—CH
2
CH
2
OH, —CR
3
R
3
—CH(OH)R
4
or —CR
3
R
3
—CH═CHR
4
; wherein R
3
and R
4
are independently hydrogen, halogen, C
1
-C
9
linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, or benzyl; wherein R
5
is hydrogen, C
1
-C
9
linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, alkoxybenzyl, dialkoxybenzyl, indolylmethyl, alkylmercapto, or arylmercapto; and wherein R
8
is hydrogen, C
1
-C
9
linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenzoyl, alkoxybenzoyl, benzyl, or C
1
-C
9
linear or branched chain alkyl.
The invention also provides a method for preventing organ graft rejection in a subject in whom an organ has been transplanted, comprising administering to the subject an effective amount of a compound having the structure:
wherein R
1
, R
6
and R
7
are independently hydrogen, OH, NH
2
, SH, halogen, C
1
-C
9
linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylamino, alkoxy, phenyl, alkylphenyl, dialkylphenyl, halophenyl, alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxybenzyl; wherein R
0
, and R
2
are independently hydrogen, OH, C
1
-C
9
linear or branched chain alkyl, —CR
3
R
3
—CH(O)CH
2
, —CR
3
R
3
—CH
2
CH
3
, —CR
3
R
3
—CH
2
CH
2
OH, —CR
3
R
3
—CH(OH)R
4
or —CR
3
R
3
—CH═CHR
4
; wherein R
3
and R
4
are independently hydrogen, halogen, C
1
-C
9
linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, or benzyl; wherein R
5
is hydrogen, C
1
-C
9
linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, alkoxybenzyl, dialkoxybenzyl, indolylmethyl, alkylmercapto, or arylmercapto; and wherein R
8
is hydrogen, C
1
-C
9
linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenzoyl, alkoxybenzoyl, benzyl, or C
1
-C
9
linear or branched chain alkyl.
A further object of the invention is to provide a method for treating a subject suffering from an autoimmune disease, comprising administering to the subject an effective amount of a compound having the structure:
wherein R
1
, R
6
and R
7
are independently hydrogen, OH, NH
2
, SH, halogen, C
1
-C
9
linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylamino, alkoxy, phenyl, alkylphenyl, dialkylphenyl, halophenyl, alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxybenzyl; wherein R
0
, and R
2
are independently hydrogen, OH, C
1
-C
9
linear or branched chain alkyl, —CR
3
R
3
—CH(O)CH
2
, —CR
3
R
3
—CH
2
CH
3
, —CR
3
R
3
—CH
2
CH
2
OH, —CR
3
R
3
—CH(OH)R
4
or —CR
3
R
3
—CH═CHR
4
; wherein R
3
and R
4
are independently hydrogen, halogen, C
1
-C
9
linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, or benzyl; wherein R
5
is hydrogen, C
1
-C
9
linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, alkoxybenzyl, dialkoxybenzyl, indolylmethyl, alkylmercapto, or arylmercapto; and wherein R
5
is hydrogen, C
1
-C
9
linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenzoyl, alkoxybenzoyl, benzyl, or C
1
-C
9
linear or branched chain alkyl. subject in need of immunosuppression, comprising administering to the subject an effective amount of a compound having the structure:
wherein R
1
is hydrogen, OH, NH
2
, SH, halogen, C
1
-C
9
linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylamino, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl or benzyl; wherein R
0
and R
5
are independently hydrogen, OH, C
1
-C
9
linear or branch

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