Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Reexamination Certificate
2001-08-30
2002-08-20
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
C558S070000, C558S166000, C514S114000
Reexamination Certificate
active
06437165
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is related to chemical compounds that have immunoregulatory activity, pharmaceutical compositions containing such compounds and methods of treatment or prevention.
Immunoregulatory abnormalities have been shown to exist in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy and asthma.
Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of autoantibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates. Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce both cellular and humoral responses including antibodies, cytokines and cytotoxic lymphocytes which lead to graft rejection.
One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Anti-inflammatory agents such as NSAID's act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents, such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb to infection as they are to their autoimmune disease.
Cyclosporin A is a drug used to prevent rejection of transplanted organs. FK-506 is another drug approved for the prevention of transplant organ rejection, and in particular, liver transplantation. Cyclosporin A and FK-506 act by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. Cyclosporin A was approved for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis.
Though they are effective in delaying or suppressing transplant rejection, Cyclosporin A and FK-506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort. Therefore, an immunosuppressant without these side effects still remains to be developed and would be highly desirable.
While the main use for immunosuppressants is in treating bone marrow, organ and transplant rejection, other uses for such compounds include the treatment of arthritis, in particular, rheumatoid arthritis, insulin and non-insulin dependent diabetes, multiple sclerosis, psoriasis, inflammatory bowel disease, Crohn's disease, lupus erythematosis and the like.
Thus, the present invention is focused on providing immunosuppressant compounds that are safer and more effective than prior compounds, having a better safety profile. These and other objects will be apparent to those of ordinary skill in the art from the description contained herein.
SUMMARY OF THE INVENTION
The present invention relates to a compound represented by formula 1:
as well as the pharmaceutically acceptable salts and hydrates thereof, wherein:
X is O, S, NR
1
or (CH
2
)
1-2
, optionally substituted with 1-4 halo groups;
R
1
is H, C
1-4
alkyl or haloC
1-4
alkyl;
R
1a
is H, OH, C
1-4
alkyl, or OC
1-4
alkyl, the alkyl and alkyl portions being optionally substituted with 1-3 halo groups;
R
1b
represents H, OH, C
1-4
alkyl or haloC
1-4
alkyl;
each R
2
is H, C
1-4
alkyl or haloC
1-4
alkyl; and
R
3
is H, OH, halo, OC
1-4
alkyl or O-haloC
1-4
alkyl.
The invention also relates to compounds represented by formula A:
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
X is O, S, NR
1
or (CH
2
)
1-2
, optionally substituted with 1-4 halo groups;
R
1
is H, C
1-4
alkyl or haloC
1-4
alkyl;
R
1a
is H, OH, C
1-4
alkyl, or OC
1-4
alkyl, the alkyl and alkyl portions being optionally substituted with 1-3 halo groups;
R
1b
represents H, OH, C
1-4
alkyl or haloC
1-4
alkyl;
R
2
is H, C
1-4
alkyl or haloC
1-4
alkyl,
R
3
is H, OH, halo, C
1-4
alkyl, OC
1-4
alkyl, O-haloC
1-4
alkyl or hydroxyC
1-4
alkyl,
Y is selected from the group consisting of: —CH
2
—, —C(O)—, —CH(OH)—, —C(═NOH)—, O and S, and
R
4
is selected from the group consisting of: C
4-14
alkyl and C
4-14
alkenyl.
Pharmaceutical compositions and methods of treatment are also included.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the following terms are defined as set forth below unless otherwise indicated.
Alkyl includes straight as well as branched alkyl groups containing the indicated number of carbon atoms.
Halo includes F, Cl, I and Br.
Haloalkyl represents a straight or branched alkyl group substituted with at least one halo group, and being optionally substituted with up to the maximum number of halo groups.
The present invention relates to a compound represented by formula 1:
as well as the pharmaceutically acceptable salts and hydrates thereof, wherein:
X is O, S, NR
1
or (CH
2
)
1-2
, optionally substituted with 1-4 halo groups;
R
1
is H, C
1-4
alkyl or haloC
1-4
alkyl;
R
1a
is H, OH, C
1-4
alkyl, or OC
1-4
alkyl, the alkyl and alkyl portions being optionally substituted with 1-3 halo groups;
R
1b
represents H, OH, C
1-4
alkyl or haloC
1-4
alkyl;
each R
2
is H, C
1-4
alkyl or haloC
1-4
alkyl; and
R
3
is H, OH, halo, OC
1-4
alkyl or O-haloC
1-4
alkyl.
In one aspect of the invention that is of particular interest, a compound of formula 1 is provided wherein X is O or (CH
2
)
1-2
, optionally substituted with 1-4 halo groups. Within this subset, all other variables are as originally defined.
More particularly, an aspect of the invention that is of particular interest relates to compounds of formula
1
wherein X is O or CH
2
. Within this subset, all other variables are as originally defined.
Even more particularly, an aspect of the invention that is interest relates to compounds of formula 1 wherein X is O. Within this subset, all other variables are as originally defined.
In another aspect of the invention that is of particular interest, a compound of formula 1 is provided wherein R
1a
is H or OH. Within this subset, all other variables are as originally defined.
In another aspect of the invention that is of particular interest, a compound of formula 1 is provided wherein R
1b
represents H or OH. Within this subset, all other variables are as originally defined.
In another aspect of the invention that is of particular interest, a compound of formula 1 is provided wherein R
3
is H, OH, halo, OC
1-4
alkyl or O-haloC
1-4
alkyl. Within this subset, all other variables are as originally defined.
In another aspect of the invention that is of particular interest, a compound of formula 1 is provided wherein R
2
is H or C
1-4
alkyl. Within this subset, all other variables are as originally defined.
A group of compounds that is of particular interest is described in connection with formula 1 wherein:
X is O or (CH
2
)
1-2
, optionally substituted with 1-4 halo groups;
R
1a
is H or OH;
R
1b
represents H or OH;
R
2
is H, C
1-4
alkyl or haloC
1-4
alkyl, and
R
3
is H, OH, halo, OC
1-4
alkyl or O-haloC
1-4
alkyl.
Preferred compounds of the present invention include the following:
TABLE 1
1a
Cpd
X
R
2
/R
2
R
3
1
O
H/H
OH
2
CH
2
H/H
OH
3
CH
2
CH
2
H/H
OH
4
O
H/CH
3
OH
5
CH
2
H/CH
3
OH
6
CH
2
CH
2
H/CH
3
OH
7
O
CH
3
/CH
3
OH
8
CH
2
CH
3
/CH
3
OH
9
CH
2
CH
2
CH
3
/CH
3
OH
10
O
H/H
H
11
CH
2
H/H
H
12
CH
2
CH
2
H/H
H
13
O
H/CH
3
H
14
CH
2
H/CH
3
H
15
CH
2
CH
2
H/CH
3
H
16
O
CH
3
/CH
3
H
17
CH
2
CH
3
/CH
3
H
18
CH
2
CH
2
CH
Bergstrom James
Card Deborah J.
Hajdu Richard
Kathleen Rupprecht
Maccoss Malcolm
Higel Floyd D.
Merck & Co. , Inc.
Rose David L.
Saeed Kamal
Yuro Raynard
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