Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-01
2003-04-22
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S417000, C549S416000, C514S460000
Reexamination Certificate
active
06552073
ABSTRACT:
The invention relates to compounds and their uses, particularly in the pharmaceutical industry. The invention discloses compounds having anti-proliferative activities, as well as methods for treating various diseases associated with abnormal cell proliferation, including cancer, by administering said compounds. It further deals with pharmaceutical compositions comprising said compounds, more particularly useful to treat cancers.
Cancer is still one of the leading causes of death in developed countries, as cancer affects all ages, sexes, racial and ethnic groups. According to the American Association for Cancer Research, one out of five deaths in the US is caused by cancer. Worldwide, the most predominant cancer sites are lung (14%), prostate (13%), breast (11%) and colorectal (11%) (data obtained from the Cancer Statistic Branch, NCI).
Cancer rate is increasing in developed countries in spite of falling incidence of several cancers such as prostate cancer (due to detection programs) or lung cancer in men (due to prevention programs). Among the fastest increasing cancer rates are non-Hodgkin's lymphoma cancer and melanoma (3% annual rise) in the US (The Annual Report to the Nation on the Status of Cancer, 1973-1997).
Unlike cancer incidence, cancer deaths have declined in developed countries. This is due in part to better therapy designs but also to prevention programs and better detection of some cancers at an earlier stage.
However, in spite of higher achievements in treatment and prevention of cancers, several improvements are awaited for:
effective therapies for early stage cancer to reduce relapses,
alternative therapies for curing tumors refractory to standards therapies,
alternative therapies for curing metastatic cancers
less toxic drugs, and
better delivery systems.
Inhibitors of cell signaling pathways could represent such a new alternative therapy by addressing the first three issues, when used alone or in combination with standard chemotoxic drugs.
There are various receptors, enzymes and effector molecules involved in the biochemical pathways necessary for signal processing in a cell. These include small GTPases, which are monomeric guanine nucleotide-binding proteins of 20-25 kDa molecular mass, which function as molecular switches. They are “on” in the GTP-bound state and “off” in the GDP-bound state. Cycling between the active and inactive forms is controlled by several accessory proteins: the guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and GDP dissociation inhibitors (GDIs). The active GTP-bound GTPases interact with a variety of effectors proteins to produce their cellular effects.
Ras, the first GTPase discovered, gave rise to the Ras super family of GTPases. It is a key regulator of cell growth and is found in mutated oncogenic forms in a large number of human tumors. When specific residues in Ras are mutated, this protein becomes constitutively active (insensitive to GAP action) and causes cell transformation. The Ras oncoproteins are among the most potent mitogenic polypeptides known, and activating mutations of Ras are found in nearly one-third of all human cancers.
The Rho subfamily of GTPases is composed of 3 major subtypes, namely Rho, Rac, and Cdc42, which control actin cytoskeleton in distinct ways. Other major roles for the Rho proteins are the regulation of gene transcription (JNK and p38 mitogen-activated protein kinase, serum response factor, NFkB), cell cycle progression, and adhesion. Several Rho GTPases have been shown to play an important role in cell transformation.
U.S. Pat. No. 4,590,201 discloses compound L651582, a cell signaling inhibitor. This compound inhibits proliferation and inflammation by affecting the biochemical pathways necessary for signal processing in the cell. It is an indirect blocker of the effector enzymes which produce the second messengers necessary to induce growth.
The present invention now relates to the identification and characterization of a new class of compounds which present an anti-cell proliferation effect, more particularly on tumor cells. Without being bound by any theory, this effect is believed to be due to an activity on cell signaling, as described above. In particular, as illustrated in the examples, the compounds of this invention inhibit the oncogenic properties of the above family of proteins, potentially by impairing the nucleotide exchange. Advantageously, these compounds will inhibit or reverse malignant cell phenotypes in a wide array of human tissues, have little or no effect on normal cell physiology, will be highly active so that a limited number of treatments will be needed for each patient, and will have excellent bio availability and pharmacokinetic properties.
Accordingly, one aspect of the invention is to provide a compound having a general formula (I):
wherein:
R
1
is CH
2
R
3
or COR
3
;
R
2
represents a hydrogen atom or an alkenyl group containing from 3 to 6 carbon atoms;
R
3
is —OH, —OR
4
, —SR
4
, —NR
5
R
6
, or
R
4
represents a group selected from alkyl containing from 1 to 6 carbon atoms, aryl, aralkyl, alkanoyl from 2 to 6 carbon atoms and arylcarbonyl;
R
5
and R
6
, independently from each other, are selected from a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms, an aryl and an aralkyl;
m is 2 or 3;
n represents an integer between 1 and 10 inclusive;
X represents an oxygen atom, a sulfur atom or a radical —NR
7
—;
Y represents an oxygen atom, a sulfur atom or a radical —NR
7
—;
R
7
, identical or different, is selected in a group consisting of a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms, an aryl and an aralkyl;
A represents either a substituted phenyl group of formula
in which:
R
8
, R
9
, R
10
and R
11
, independently from each other, are selected from a hydrogen atom, a halogen atom (preferably F, Cl, or Br), a hydroxyl group, a (C
1
-C
10
)alkyl group, an (C
1
-C
10
)alkanoyl group, a (C
1
-C
10
)alkoxy group, an aryl group, an aralkyl group, an arylcarbonyl group, a mono- or poly-cyclic hydrocarbon group, —NO
2
, —CN, a —NR
12
R
13
group or a trifluoro(C
1
-C
6
)alkyl group; R
8
, R
9
, R
10
and R
11
, not being simultaneously hydrogen atom,
or alternatively two substituents, R
8
and R
9
, may form together a mono- or poly-cyclic hydrocarbon group with the carbon atoms of the phenyl group they are attached and the two other substituents, R
10
and R
11
, are as defined above;
or A represents a 5- or 6-membered heterocyclic ring which has 1 to 3 hetero-atoms selected from oxygen, sulfur and nitrogen, said ring is bonded directly to X;
R
12
and R
13
, independently from each other, are selected in the group consisting of a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms, an aryl and an aralkyl;
with the provisos that:
when X and Y are oxygen atoms, R
2
is a hydrogen atom, n is 5 and R
8
on the ortho position on the phenyl group vis-à-vis X is n-propyl group, then R
9
, R
10
and R
11
are different from hydrogen;
when X and Y are oxygen atoms, R
2
is a hydrogen atom, n is 5, R
8
on the ortho position on the phenyl group vis-à-vis X is n-propyl group, R
9
on the meta position vis-à-vis X is an hydroxyl group, and R
10
on the para position vis-à-vis X is an acetyl group; then R
11
is different from hydrogen;
when X and Y are oxygen atoms, R
2
is a hydrogen atom, n is 2 or 3, then A is different from a non-substituted naphthalene group;
its tautomers, optical and geometrical isomers, racemates, salts, hydrates and mixtures thereof.
The compounds of the present invention may have one or more asymmetric centers and it is intended that stereoisomers (optical isomers), as separated, pure or partially purified stereoiomers or racemic mixtures thereof are included in the scope of the invention.
The present invention also relates to pharmaceutical compositions comprising at least one compound as defined above in a pharmaceutically acceptable support, optionally in association with another active agent.
The present invention also relates to the use of a compound as de
Leblanc Véronique
Leblond Bertrand
Lopez Rodriguez Maria Luz
Melle-Milovanovic Dominique
Viso Beronda Alma
Coppins Janet L
Exonhit Therapeutics SA
Nixon & Vanderhye PC
Rotman Alan L.
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