Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-10
2001-10-02
Solola, Taofiq A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C548S966000, C548S967000, C558S434000
Reexamination Certificate
active
06297230
ABSTRACT:
FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel cyanoaziridines for treatment of cancer. 2. Description of Related Art
This invention is directed towards aziridine-1-carboxamides related to imexon having improved anti-tumor activity.
The search for compounds having anti-tumor activity has included 2-cyanoaziridines with substituents on the nitrogen atom. German patent 2,736,296 (Feb. 22, 1979) claimed 2-cyanoaziridines and its derivatives. German patent 2,727,550 (Jan. 4, 1979) claimed 2-cyanoaziridines with substituted carbonyl, sulfonyl, or phosphoryl groups on nitrogen. East German patent 110 492 (Dec. 20, 1974) claimed 2-cyanoaziridines with alkanoyl and aroyl substituents on nitrogen. It also claimed 2-cyanoaziridine-1-carboxamide. The cyclization of 2-cyanoaziridine-1-carboxamide to imexon, as well as imexon itself, was claimed in U.S. Pat. No. 4,083,987 (Apr. 11, 1978). Two German patents, 2,740,248 (Mar. 15, 1979) and 2,656,323 (Jun. 15, 1978) claimed the preparation of 2-cyano-1-phenoxycarbonylaziridine and its conversion into 2-cyanoaziridine-1-carboxamide. Immunosuppressive activity for imidazolidine derivatives related to imexon was claimed in U.S. Patent 4,996,219.
Imexon (4-imino-1,3-diazabicyclo[3.1.0]hexan-2-one) was developed by Bicker (Immune Modulation and Control of Neoplasia by Adjuvant Therapy, M. A. Ghirigos, Ed., Raven Press, New York, 1978, p. 389) in an investigation of cyanoaziridine derivatives with potential cancerostatic action. It is a cyclic isomer of 2-cyanoaziridine-1-carboxamide, from which it is formed by treatment with a catalytic amount of KOH in methanol as illustrated below (U. Bicker, W. Kampe, and W. Steingross, U.S. Pat. No. 4,083,987, Apr. 11, 1978).
Imexon has both direct cytotoxicity to tumor cells and immunomodulatory effects. It is active against a variety of human tumor cell lines in culture and against fresh human tumor cell lines in clonogenic assay. It is selectively cytotoxic to multiple myeloma in the clonogenic assay (S. E. Salmon and E. M. Hersh, J. Natl. Cancer Inst., 86, 228, 1994). Imexon is active against a variety of transplanted tumors in rodents (U. Bicker and G. Hebold, IRCS Med. Sci.: Cancer; Hematology; Immunology and Allergy; Pharmacology, 5, 428, 1977; U. Bicker and P. Fuhse, Exp. Path. Bd. 10, S. 279-284, 1975) and it is active against human lymphoma, melanoma, and prostate cancer cell lines in SCID mice (Hersh, et al.,
Proc. Am. Assoc. Cancer Res.,
36, 294, 1995). Objective responses were observed in dogs with mast cell tumors after treatment with imexon (R. T. Dorr, J. D. Liddil, M. K. Klein, and E. M. Hersh, Invest. New Drugs, 13, 113, 1995). Despite the presence of an aziridine ring, imexon is not myelosuppressive, which makes it potentially valuable in combination chemotherapy.
SUMMARY OF THE INVENTION
The present invention is directed to novel anti-cancer compounds of the formula:
wherein
X is CN, CO
2
R
1
, or CONR
2
R
3
:
R
1
is lower alkyl, cycloalkyl, alkenyl, or aryl lower alkyl;
R
2
is hydrogen or lower alkyl;
R
3
is hydrogen lower alkyl, lower cycloalkyl, alkenyl, alkynyl, aryl, or heterocyclic ring;
R
2
, R
3
and N taken together form a heterocyclic ring
R
4
is hydrogen or lower alkyl; and
R
5
is lower alkyl, lower cycloalkyl, alkenyl, alkynyl, aryl, monosubstituted aryl, disubstituted aryl, aryl lower alkyl, lower alkoxycarbonyl lower alkyl, or heterocyclic ring, with the proviso that when X is CN, and R
4
is hydrogen, then R
5
is not CH
3
, C
6
H
5
, or, p-nitrophenyl.
R
4
, R
5
and N taken together form a heterocyclic ring.
In particular, the invention is also directed to compound of the formula 1:
wherein X is CN, CO
2
R
1
or CONR
2
R
3
where R
1
is an alkyl of 1-6 carbons, a cycloalkyl of 4-7 carbons, alkenyl of 3-6 carbons or a lower alkyl substituted aryl of 7-12 carbons;
R
2
is hydrogen or lower alkyl of 1-4 carbons, and
R
3
is lower alkyl of 1-4 carbons, lower cycloalkyl of 4-7 carbons, alkenyl of 3-6 carbons, an aryl of 4-10 carbons, a substituted aryl of 4-12 carbons or heterocyclic ring of 4-16 ring members;
wherein R
4
is hydrogen or lower alkyl of 1-4 carbons; and,
wherein R
5
is an alkyl of 1-8 carbons, lower cycloalkyl of 4-7 carbons, alkenyl of 3-6 carbons, an aryl of 4-10 carbons, a substituted aryl of 4-12 carbons, a heterocyclic group of 4-16 members and where R
4
R
5
and N taken together form a heterocyclic ring of between 4 and 16 members.
The invention further includes compound of the formula 1:
wherein X is CN, CO
2
R
1
or CONR
2
R
3
where R
1
is an alkyl of 1-6 carbons, a cycloaklyl of 4-7 carbons, alkenyl of 3-6 carbons or an lower alkyl substituted aryl of 7-12 carbons;
where R
2
is hydrogen or lower alkyl of 1-4 carbons, and
where R
3
is a lower alkyl of 1-4 carbons, a lower cycloalkyl of 4-7 carbons, an alkenyl, an aryl of 4-10 carbons, a heterocyclic ring of 4-16 members or a substituted aryl or substituted heterocyclic ring where said substitutents are 1 or 2 and independently selected from the group consisting of lower alkyl of 1-4 carbons, nitro, halo substituted lower alkyls of 1-4 carbons, a lower alkyl substituted acyloxy of 1-5 carbons, a lower alkyl substituted acyl of 1-5 carbons;
wherein R
4
is hydrogen or lower alkyl of 1-4 carbons; and,
wherein R
5
is an alkyl of 1-8 carbons, lower cycloalkyl of 4-7 carbons, alkenyl of 3-6 carbons, an aryl of 4-10 carbons, a substituted aryl of 4-12 carbons having 1-2 substitutents wherein the substituents are independently selected from the group consisting of lower alkyl of 1-4 carbons, nitro, halo substituted lower alkyls of 1-4 carbons, a lower alkyl substituted acyloxy of 1-5 carbons, a lower alkyl substituted acyl of 1-5 carbons, a heterocyclic group of 4-16 members. Substituents R
4
and R
5
may join to form a heterocyclic ring of 4-16 members.
Preferred compounds include those wherein X is CN. Additional preferred compounds are those where X is CN and R
4
is hydrogen; and R
5
is a straight chain alkyl of 1 to 8 carbons, an unsubstituted aryl, a mono-substituted or disubstituted aryl wherein the aryl is independently substituted with halo, lower alkyl, halo substituted lower alkyl, lower alkyl-substituted acyloxy or lower alkyl-substituted acyloxy.
Also preferred are those compounds wherein X is CN and R
4
is hydrogen; and R
5
is a heterocyclic group or an unsubstituted aryl. Particularly preferred are those compounds where X is CN and R
4
is hydrogen; and R
5
is a pyridyl, a phenyl or a naphthyl.
This invention also includes the use of the above identified compounds to treat a variety of cancers by administering to a patient in need of treatment a unit dose of the compounds described above wherein said unit dose is effective to reduce at least one of the symptoms of the cancer. Preferred dose ranges are unit doses of 0.25 to 2 grams. The preferred route of administration is parental.
Specific cancers include multiple myeloma, a B-lymphocyte plasmacytoma including advanced disease refractory to alkylating agent and glucocorticosteroids, advanced stage ovarian epithelial cell cancer, including patients previously treated with alkylating agents, taxanes or platinum-containing anticancer agents, surgically unresectable (metastatic) melanoma in combination with myelosuppressive anticancer agents, multidrug-resistant leukemias of lymphoid and nonlymphoid origin including multidrug-resistant lymphomas and those lymphomas occurring in patients infected with human immunodeficiency virus-1 (AIDS), advanced stage and especially metastatic colon cancer, including those refractory to fluoropyrimidines such as 5-fluorouracil, prostate cancer, advanced stage breast cancers previously treated with alkylating agents, or natural products which induce multidrug resistance (such as doxorubicin, paclitaxel and vincristine) and metastatic lung cancers of small cell and non-small cell types which are not responsive to local radiotherapy or systemic chemotherapy with cytotoxic drugs.
In addition
Dorr Robert T.
Hersh Evan M.
Iyengar Bhashyam
Remers William A.
Amplimed, Inc.
Solola Taofiq A.
Townsend and Townsend / and Crew LLP
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