Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-05-22
2003-05-20
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
Reexamination Certificate
active
06566395
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to methods and compositions for treating proliferative disorders, such as cancers, blood vessel disorders and fibrotic disorders, using N-(3-methyl-4-trifluoromethylphenyl) 2-cyano-2-(cycloalkylcarbonyl)acetamide compounds or pharmaceutical compositions comprising such compounds.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1 U.S. Pat. No. 4,284,786, issued Aug. 18, 1981, to Kammerer et al.
2 U.S. Pat. No. 4,351,841, issued Sep. 28, 1982, to Kammerer et al.
3 U.S. Pat. No. 5,700,822, issued Dec. 23, 1997, to Hirth et al.
4 U.S. Pat. No. 5,700,823, issued Dec. 23, 1997, to Hirth et al.
5 U.S. Pat. No. 5,721,277, issued Feb. 24, 1998, to Tang.
6 International Publication No. WO 95/19169, published Jul. 20, 1995.
7 U.S. Pat. No. 5,240,960, issued Aug. 31, 1993, to Hambleton et al.
8 U.S. Pat. No. 5,384,423, issued Jan. 24, 1995, to Hambleton et al.
Each of the publications, patents and patent applications referred to in this application, including those listed above, are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
Proliferative growth of cells, tissues and organs occurs in various mammalian disorders, such as cancers, blood vessel disorders and fibrotic disorders. The compounds leflunomide (also known as 5-methylisoxazole-4-carboxylic acid-(4-trifluromethyl)-anilide) and N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide have been reported to be useful in inhibiting hyper-proliferative cell growth. Leflunomide reportedly acts as a pro-drug for the in vivo formation of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide. See, for example, U.S. Pat. No. 4,284,786
1
and U.S. Pat. No. 4,351,841.
2
Other compounds reportedly useful for the treatment of cell proliferation disorders are disclosed in U.S. Pat. No. 5,700,822;
3
U.S. Pat. No. 5,700,823;
4
U.S. Pat. No. 5,721,277;
5
and International Publication No. WO 95/19169.
6
U.S. Pat. No. 5,240,960
7
and U.S. Pat. No. 5,384,423
8
disclose various N-(substituted phenyl) 2-cyano-2-(cycloalkylcarbonyl)acetamide compounds and methods for treating inflammation in warm-blooded animals using such compounds.
Surprisingly, it has now been discovered that certain N-(substituted phenyl) 2-cyano-2-(cycloalkylcarbonyl)acetamide compounds, i.e., those having a 3-methyl-4-trifluoromethylphenyl group, are also useful for the treatment of proliferative disorders, such as cancers, blood vessel disorders, fibrotic disorders and the rejection of transplanted organs, tissues and cells.
SUMMARY OF THE INVENTION
The present invention is directed to methods and compositions for treating proliferative disorders using N-(3-methyl-4-trifluoromethylphenyl) 2-cyano-2-(cycloalkylcarbonyl)acetamide compounds or pharmaceutical compositions comprising such compounds.
Accordingly, in one of its method aspects, the present invention provides a method of treating a cell, tissue or organ with a proliferative disorder comprising administering to said cell, tissue or organ a proliferation-inhibiting amount of a compound of formula I or a tautomeric isomer thereof:
wherein
R
1
is hydrogen or alkyl of from 1 to 3 carbon atoms;
R
2
is cycloalkyl or substituted cycloalkyl having from 3 to 6 carbon atoms in the cycloalkyl ring; or a pharmaceutically-acceptable salt or pro-drug thereof; and
further wherein the proliferation-inhibiting amount provides a concentration of the compound of formula I in the cell, tissue or organ which inhibits the proliferative disorder.
Preferably, in the methods of this invention, R
1
in formula I is hydrogen or methyl. More preferably, R
1
is hydrogen.
R
2
in formula I is preferably cyclopropyl, cyclobutyl or cyclopentyl. More preferably, R
2
is cyclopropyl. In a particularly preferred embodiment, R
1
is hydrogen and R
2
is cyclopropyl.
Preferably, the proliferation-inhibiting amount employed in the above method provides a concentration of the compound of formula I in the cell, tissue or organ from about 0.1 &mgr;g/mL to about 1000 &mgr;g/mL.
In another of its method aspects, the present invention provides a method of treating a mammal having a proliferative disorder comprising administering to said mammal a proliferation-inhibiting amount of a compound of formula I or a tautomeric isomer thereof:
wherein
R
1
is hydrogen or alkyl of from 1 to 3 carbon atoms; and
R
2
is cycloalkyl or substituted cycloalkyl having from 3 to 6 carbon atoms in the cycloalkyl ring; or a pharmaceutically-acceptable salt or pro-drug thereof.
Preferably, the proliferation-inhibiting amount of the compound of formula I ranges from about 0.001 mg/kg/day to about 2000 mg/kg/day; more preferably, from about 0.01 mg/kg/day to about 1000 mg/kg/day, and still more preferably, from about 1 mg/kg/day to about 1000 mg/kg/day.
In a preferred embodiment of the methods of this invention, the proliferative disorder being treated by the compounds of formula I is a cancer; preferably, a solid tumor cancer, a bone marrow cell cancer or lymphatic or lymph node-related cancer; more preferably, a solid tumor cancer, or lymphatic or lymph node-related cancer.
In other preferred embodiments of this invention, the proliferative disorder being treated is a blood vessel proliferative disorder or a fibrotic disorder.
In yet another preferred embodiment of this invention, the proliferative disorder being treated is the acute or chronic rejection of a transplanted organ, tissue or cell.
In the methods of this invention, the compound of formula I is preferably administered orally, intravenously, parenterally or transdermally.
In one embodiment of this invention, the compounds of formula I are administered in a manner to establish an adequate plasma level of the compound of formula I in the mammal being treated. In this embodiment, a compound of formula I is administered to said mammal in a dosing cycle comprising the steps of:
(a) administering to the mammal a first proliferation-inhibiting amount for a period of 1 to 21 days; and then
(b) administering to the mammal a second proliferation-inhibiting amount for a period of 1 to 21 days,
wherein said second proliferation-inhibiting amount is the same or different from said first proliferation-inhibiting amount.
If desired, this dosing cycle can optionally further comprise a non-dosing period of from 1 to 21 days between step(a) and step (b).
Preferably, the ratio of the second proliferation-inhibiting amount to the first proliferation-inhibiting amount ranges from about 1:1 to about 1:6, and if a reduction in ratio below 1:1 is required, then more preferably, from about 2:6 to about 4:6. This treatment regime may be repeated any number of times to establish and/or maintain an adequate plasma level of the compound of formula I in the mammal being treated, i.e., a plurality of such dosing cycles can be administered to the mammal.
The compounds of formula I may be administered to a mammal with a proliferative disorder before, after or in conjunction with other chemotherapeutic agents or with other therapy intended to modulate, to suppress or to stimulate the mammal's immune system. Additionally, the compounds of formula I can be administered before, in conjunction with, or after other conventional methods for treating proliferative disorders, such as radiation therapy, ablative or partially ablative surgical procedures or a bone marrow transplant, which themselves may be employed in conjunction with chemotherapeutic agents or with other therapy intended to modulate, suppress or stimulate the mammal's immune system.
When administered with another chemotherapeutic agent or agents, each chemotherapeutic agent is preferably independently selected from the group consisting of androgens, asparaginase, azathioprine, 5-azacitidine, BCG, bleomycin, busulfan, carbetim
BioMedicines, Inc.
Burns Doane , Swecker, Mathis LLP
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