Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-14
2003-05-27
Rotman, Alan L. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S297000
Reexamination Certificate
active
06569893
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to immunomodulation or anticancer treatment using compounds which are prodrugs of triptolide or its derivatives.
REFERENCES
Gleichmann, E. et al.,
Immunol. Today
5:324 (1984).
Kocienski, P. J.,
PROTECTING GROUPS,
Georg Thieme Verlag, Stuttgart (1994).
Korngold, R. and Sprent, J.,
J. Exp. Med.
148:1687 (1978).
Kupchan, S. M. et al.,
J. Am. Chem. Soc.
94:7194 (1972).
Kupchan, S. M. et al., U.S. Pat. No. 4,005,108 (1977).
Lipsky et al., U.S. Pat. No. 5,294,443 (1994).
Ma et al.,
J. Chin. Pharm. Sci.
1:12 (1992).
Murase, N. et al.,
Transplantation
55:701 (1993).
Ono and Lindsey,
J. Thor. Cardiovasc. Surg.
57(2):225-29 (1969).
Pu, L. et al.,
Zhongguo Yaoli Xuebao
11:76 (1990).
Wang, J. and Morris, R. E.,
Transplantation Proc.
23:699 (1991).
Zheng et al.,
Zhongguo Yixue Kexueyuan Xuebao
13:391 (1991).
Zheng et al.,
Zhongguo Yixue Kexueyuan Xuebao
16:24 (1994).
BACKGROUND OF THE INVENTION
A number of compounds derived from the Chinese medicinal plant
Tripterygium wilfordii
(TW) have been identified as having immunosuppressive activity, e.g. in the treatment of autoimmune disease, and in treating or preventing transplantation rejection, including the treatment of graft-versus-host disease (GVHD), a condition in which transplanted marrow cells attack the recipient's cells. See, for example, co-owned U.S. Pat. No. 6,150,539 (Triptolide prodrugs having high aqueous solubility), U.S. Pat. No. 5,962,516 (Immunosuppressive compounds and methods), U.S. Pat. No. 5,843,452 (Immunotherapy composition and method), U.S. Pat. No. 5,759,550 (Method for suppressing xenograft rejection), U.S. Pat. No. 5,663,335 (Immunosuppressive compounds and methods), and U.S. Pat. No. 5,648,376 (Immunosuppressant diterpene compound), and references cited therein. Such compounds have also been reported to show anticancer activity. See, for example, Kupchan et al., 1972, 1977, as well as copending and co-owned U.S. application Ser. No. 09/766,156.
Triptolide, 16-hydroxy triptolide, triptophenolide, tripdiolide, and celastrol are representative compounds isolated from TW (see e.g. Lipsky et al., 1994; Zheng et al., 1991, 1994; Ma et al., 1992). However, the low water solubility of these compounds has limited their ready administration and therapeutic effectiveness. It would be desirable to have immunosuppressive compounds with improved water solubility and low toxicity. In addition, it would be desirable for such compounds to exhibit immunosuppressive activity in their water-soluble form, or to be convertible to an immunosuppressive form by metabolic processes in vivo.
It would also be desirable to have as part of the xenobiotic compound moieties that are naturally sensitive to metabolic processes. The inclusion of an L-amino acid moiety in the structure of the prodrug is expected to render it more susceptible to certain types of metabolic processes, thereby releasing an active moiety with altered and more rapid kinetics.
Conversely, in some applications it would be desirable to have as part of the xenobiotic compound moieties that are naturally resistant to metabolic processes. The inclusion of a D-amino acid moiety in the structure of the prodrug may render it more resistant to certain types of metabolic processes, thereby releasing an active moiety with altered and possibly slower kinetics.
The inclusion of an amino acid moiety in the structure of the prodrug may also alter absorption into the body when administered by a route other than intravenously. The amino acid moiety may also alter the biodistribution of the agent, giving it better access to organs, tissues, tumors, or areas of the body where therapy is useful or desired, or better access to cells, their outer membranes or cell interiors. The amino acid moiety may also alter the excretion of the prodrug, thereby altering the level in the body and the biodistribution, and/or alter bioavailability, by altering binding to blood components (such as albumin) or other tissues.
The inclusion of multiple amino acid moieties as an oligopeptide may be used to target the prodrug to cancer or immune regulatory cells. Targeted prodrugs that bind to specific molecular sites near, on, or in cancer cells, or are selectively transported within these cells, have the potential to significantly decrease side effects associated with anti-tumor drug administration. In addition, prodrugs that are selectively converted by tumor-specific enzymes (as determined e.g. by screening extent of conversion by preparations of such enzymes) can also reduce such side effects, in that they are converted to their active form only in the proximity of the tumor target.
Likewise, targeted prodrugs that bind to immune regulatory cells, such as T-cells, B-cells or lymphocytes, or are selectively transported into these cells, have the potential to significantly decrease side effects associated with immunosuppressant drug administration. Thus, conjugation of olipeptides to triptolide or triptolide related molecules may result in enhanced drug localization, showing an improved efficacy and toxicity profile compared to that of the triptolide alone.
SUMMARY OF THE INVENTION
The present invention includes, in one aspect, a compound having the structure:
where
X
1
is OH or OR
1
, and X
2
and X
3
are independently OH, OR
1
or H, with the proviso that at least one of X
1
, X
2
and X
3
is OR
1
, and at least one of X
2
and X
3
is H; and
R
1
is selected from the group consisting of:
(b): C(═O)CHY—NHP
1
and
(e): [C(═O)CHY—NH]
Z
—C(═O)CHY—NHP
1
;
where:
Y is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof;
P
1
is selected from the group consisting of H, C(═O)OR
2
, and C(═O)R
3
, wherein each of R
2
and R
3
is independently H, alkyl, alkenyl, aryl, or aralkyl;
m is an integer from 0-5;
n is an integer from 0-5; and
z is an integer from 2-10.
P
2
is selected from the group consisting of H, alkyl, alkenyl, aryl, and aralkyl.
In one embodiment, P
1
and P
2
are non-hydrogen. In further embodiments of this category, R
2
and R
3
are also non-hydrogen; i.e. selected from alkyl, alkenyl, aryl, and aralkyl.
In selected embodiments, “alkyl” and “alkenyl” are lower alkyl and alkenyl, containing one to six carbon atoms; in other embodiments, “alkyl” and “alkenyl” are fatty alkyl and alkenyl, containing about 10 to 24, preferably about 12 to 18, carbon atoms.
The chiral &agr;-carbon bearing the nitrogen atom, in each of groups (a)-(d), is of the L (naturally occurring) configuration, the D configuration, or a mixture thereof. In selected embodiments, this carbon is of the L configuration. In other embodiments, this carbon is of the D configuration.
In preferred embodiments, Y is a side chain of a naturally occurring amino acid.
In selected embodiments, X
2
=X
3
=H. In further embodiments of this class, R
1
is selected from
In other aspects, the invention provides methods of anticancer treatment and of effecting immunosuppression. In accordance with these methods, a compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in need of such treatment. In selected embodiments, the anticancer treatment is treatment of colon cancer, breast cancer, lung cancer, or prostate cancer. Immunosuppressive treatments include inhibition of transplant rejection, inhibition of graft-versus-host disease, and treatment of autoimmune disease, such as rheumatoid arthritis.
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
The terms below have the following meanings unless indicated otherwise.
A “naturally occurring amino acid” is one of the following, referred to by full name or by standard single-letter or three-letter notation: A, Ala, alanine; C, Cys, cysteine; D, Asp, aspartic acid; E, Glu, glutamic a
Dai Dongcheng
Fidler John M.
Musser John H.
Gorthey LeeAnn
Perkins Coie LLP
Pharmagenesis, Inc.
Rotman Alan L.
Shameem Golam M. M.
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