Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-16
2002-07-16
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S328000
Reexamination Certificate
active
06420367
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel pyrimidine derivative having an antitumor activity, a cytostatic activity, and an inhibitory activity against a signal derived from Ras oncogene products.
BACKGROUND ART
The oncogene “ras” such as H-ras, K-ras, and N-ras is mutated and activated in many of neoplasms. The “Ras”, the products of ras oncogene, strongly concerns tumorigenesis caused by acceleration of cell cycle and induction of expression of many of genes associated with a malignant conversion such as a vascular endothelial growth factor and type-IV coliagenase. Especially, it is found that there is highly frequent ras mutation in solid tumor such as pancreatic cancer (>80%), colon cancer (>40%), and lung cancer (>20%) which are difficult to be cured by using existing chemotherapeutics. Therefore, it is considered that Ras is one of the most important target molecules in the development of the chemotherapeutics against them.
A farnesyl-protein-transferase (FPT) inhibitor (FPTI) is known as chemotherapeutics of which target are Ras (WO95/13059, WO95/25086, WO95/25092, W095134535, U.S. Pat. No. 5,608,067, and JP-A-7-112930).
In the cells expressing activated Ras, the excess signals reach cell nucleus through some signaling pathways and some signal transmitter molecules such as MAPK (Mitogen Activated Protein Kinase) and P13K (Phosphatidylinositol-3-Kinase). The signals activate the transcription factors such as AP1 (Activator Protein-1) and ETS (E26 transformation specific) in the cell nucleus and then they induce the expression of many genes related to malignant features through transcription activation element such as Ras Responsive Element (RRE). Therefore, it is possible to repress the malignant conversion of the cancer cells, when the signal transmission (a signal derived from ras oncogene products) is inhibited.
DISCLOSURE OF INVENTION
In the above situation, the inventors of the present invention have studied on the antitumor agent having an inhibitory activity against a signal derived from Ras oncogene products.
The activation of gene expression through RRE is in proportion to a signal derived from Ras and the signal can be measured by the amount of its expression. The inventors of the present invention artificially made cells having activated Ras wherein expression of firefly luciferase gene, reporter gene, is regulated by RRE and carried out a screening of the inhibitors taking luciferase activity shown by the cells as an index of signals through Ras. As a result, the inventors of the present invention found that a series of pyrimidine derivatives have a strong inhibitory activity against a signal derived from Ras oncogene products.
The present invention relates to I) a compound represented by the formula (I):
wherein R
1
, R
2
, R
3
, and R
4
are each independently hydrogen atom, optionally substituted alky, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, an optionally substituted non-aromatic heterocyclic group, or acyl; or
R
1
and R
2
, R
3
and R
4
, and R
2
and R
3
each taken together with the adjacent nitrogen atom form the same or different 3- to 6-membered ring optionally containing O, S, or N, provided that R
1
and R
2
and R
3
and R
4
do not form a ring when R
2
and R
3
taken together form a ring;
R
5
and R
6
are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkyloxy, alkylthio, optionally substituted alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, hydroxy, mercapto, optionally substituted amino, carboxy, cyano, or nitro;
X is —N(R
7
)—, —NH—NH—, —O—, or —S— wherein R
7
is hydrogen atom or optionally substituted alkyl;
Y is optionally substituted 5-membered non-aromatic heterocycle-diyl or optionally substituted 5-membered heteroaryl-diyl;
Z is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl alkenyl, or optionally substituted alkenyl; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.
In more detail, the present invention relates to:
II) a compound represented by the formula (II):
wherein R
8
, R
9
, R
10
, and R
11
are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, a non-aromatic heterocyclic group, or acyl;
W is —O—, —S—, or —N(R
A
)— wherein R
A
is hydrogen atom or optionally substituted alkyl;
R
5
, R
6
, X, and Z are as defined above, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates,
III) a compound represented by the formula (III):
wherein R
5
, R
6
, R
8
, R
9
, R
10
, R
11
, and Z are as defined above, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates,
IV) a compound represented by the formula (IV):
wherein R
12
is hydrogen atom or alkyl;
V is optionally substituted aryl;
R
8
, R
9
, R
10
, and R
11
are as defined above, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates,
V) a compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in above I), wherein R
1
, R
2
, R
3
, and R
4
are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, or acyl,
VI) a compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in any one of the above II) to IV), wherein R
8
, R
9
, R
10
, and R
11
are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, or acyl,
VII) a pharmaceutical composition which contains as active ingredient a compound as described in any one of I) to VI),
VIII) a pharmaceutical composition for use as an antitumor agent which contains as active ingredient a compound as described in any one of I) to VI)s,
IX) a pharmaceutical composition for use as a cytostatic agent which contains as described in any one of I) to VI),
X) a pharmaceutical composition for use as an inhibitor against a signal derived from Ras oncogene products which contains as active ingredient a compound as described in any one of I) to VI),
XI) use of a compound of any one of I) to VI) for the preparation of a pharmaceutical composition for treating cancer, and
XII) a method of treating a mammal, including a human, to alleviate the pathological effects of cancer; which comprises administration to the mammal of a compound as described in any one of I) to VI).
The term “alkyl” employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 1 to 8 carbon atoms. Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. Preferably, C1 to C6 alkyl is exemplified. More preferably, C1 to C3 alkyl is exemplified.
The term “alkenyl” employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more double bonds. An example of the alkenyl includes vinyl, allyl, propenyl, crotonyl, prenyl, a variety of butenyl isomers and the like. Preferably, C2 to C6 alkenyl is exemplified. More preferably, C2 to C3 alkenyl is exemplified.
The term “alkynyl” employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more triple bonds. The alkynyl may contain (a) double bond(s). An example of the alkenyl includes ethynyl, propynyl, 6-heptynyl, 7-octynyl, and the like. Preferably, C2 to C6 alkynyl is exemplified. More preferably, C2 to C3 alkynyl is exemplified.
The te
Takenaka Hideyuki
Tanaka Hidekazu
Ueda Kazuo
Birch & Stewart Kolasch & Birch, LLP
Shah Mukund J.
Shionogo & Co., Ltd.
Truong Tamthom N.
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