Apoptosis inducing adamantyl derivatives and their usage as...

Details Apoptosis inducing adamantyl derivatives and their usage as... Apoptosis inducing adamantyl derivatives and their usage as...

2000-02-04

2002-10-08

Goldberg, Jerome D. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S543000, C514S435000, C514S437000, C514S454000, C514S455000, C514S452000, C514S569000

Reexamination Certificate

active

06462064

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention relates to the discovery that specific adamantyl or adamantyl group derivative containing retinoid related compounds induce apoptosis of cancer cells and therefore may be used for the treatment or prevention of cancer, including advanced cancers and precancers. Also, the present invention relates to novel adamantyl or adamantyl group derivative containing retinoid related compounds and their use for the treatment and/or prevention of cancer, keratinization disorders, dermatological conditions and other therapies. A preferred application of the subject compounds is for the treatment or prevention of cervical cancers and precancers.
BACKGROUND OF THE INVENTION
Solid tumors are the leading cause of death attributable to cancers worldwide. Conventional methods of treating cancer include surgical treatments, the administration of chemotherapeutic agents, and recently immune based treatments which typically involve the administration of an antibody or antibody fragment which may be conjugated to a therapeutic moiety such as a radionuclide. However, to date, such treatments have been of limited success.
Surgical treatments are generally only successful if the cancer is detected at an early stage, i.e., before the cancer has infiltrated major organs and surgery becomes non-feasible. Chemotherapeutic treatments available today are also of limited usefulness because of their non-selective killing and/or toxicity to most cell types. Also, many tumor cells eventually become resistant against the chemotherapeutic agent, thus making treatment of solid tumors and other tumors non-feasible. For example, persons treated with cisplatin often develop tumors which are cisplatin resistant. Immune based treatments are also subject to numerous problems including difficulty in targeting antibodies to desired sites, e.g., solid tumors, and host immune reactions to the administered antibody, attributable to the fact that to date most therapeutic antibodies have been of murine origin.
The usage of retinoids for the prevention of cancer has also been reported. In contrast to most conventional chemotherapeutic agents, retinoids function via specific signal transduction pathways, activating defined receptors in the cell nucleus. These receptors, the RARs, and the RXRs bind to specific DNA sequences, retinoic acid response elements, or RAREs. In addition, retinoids interact with other transcription factors, in particular the activator protein-1 (AP-1).
It is believed that the selective action of certain synthetic retinoids is based on the ability of these molecules to selectively activate subclasses of RARs and/or RXRs in the context of specific DNA sequences and/or proteins. Because of this specificity, not all retinoids possess the same activities. Indeed, thousands of different retinoids have been synthesized with the object being the identification of retinoids having optimal therapeutic activity.
To date, most retinoids have been found to inhibit tumor progression or cell proliferation of certain cancers, but do not directly eliminate cancer cells. Consequently, retinoids have been considered predominantly for the prevention of cancer but not for direct treatment.
One special class of retinoids or retinoid related compounds comprises adamantyl retinoid derivatives. These compounds are aromatic heterocyclic retinoids which contain an adamantyl group or an adamantyl group derivative. In contrast to normal retinoids such as retinoic acid (all-trans, 9-cis or 13-cis) and their synthetic analogs and derivatives, the adamantyl retinoid derivatives exhibit enhanced activity against specific tumor cells both in vitro and in vivo.
Retinoids also comprise known usage in the treatment of keratinization disorders and other dermatological diseases. For example, the use of retinoic acid, vitamin D or analogues thereof for the topical treatment of various dermatological diseases and in the cosmetic field is well known.
However, notwithstanding the large number of retinoids which have been reported, the identification of retinoids or retinoid related compounds having enhanced properties, in particular enhanced therapeutic activity, constitutes a significant need in the art.
BRIEF DESCRIPTION AND OBJECTS OF THE INVENTION
It is an object of the invention to identify specific retinoid or retinoid related compounds having enhanced properties, in particular anti-cancer activity.
It is a more specific object of the invention to identify specific classes of adamantyl or adamantyl derivative containing retinoid related compounds having anti-cancer activity, preferably characterized by the ability to induce apoptosis of cancer cells.
It is an even more specific object of the invention to use adamantyl retinoid related compounds of the following formulae for the treatment of cancer:
with the proviso that such compound is not an RAR-&ggr; receptor-specific agonist ligand (defined infra) and, in which
W is independently —CH
2
—, —O—, —S—, —SO— or —SO
2
—,
X is a radical selected from among those of the following formulae (i)-(iii):
 wherein
Y is a radical —CO—V—, —CH═CH—, —CH
3
C═CH—, —CH═CCH
3
—,
 —CHOH—CH
2
—,
V is an oxygen atom (—O—), an aza radical (—NH—), a radical —CH═CH— or —C≡C—;
Z is a radical —CH— and Z′ is an oxygen atom, or
Z is a nitrogen atom (N) and Z′ is an aza radical (—NH—);
R
1
is a hydrogen atom, a halogen, or a lower alkyl radical;
R′
1
is a hydrogen atom, a halogen, or a lower alkyl radical;
R
2
is a hydroxyl radical, a halogen, an alkyl radical, optionally substituted by one or more hydroxyl or acyl groups, an alkoxyl radical, optionally substituted by one or more hydroxyl, alkoxyl or aminocarbonyl groups, and/or optionally interrupted by one or more oxygen atoms, an acyl radical, an aminocarbonyl radical or a halogen;
R
3
is a hydrogen atom, a halogen, an hydroxyl radical, an alkyl radical, or an alkoxyl radical;
R
2
and R
3
can form together a radical —O—CH
2
—O—;
R
4
is a hydrogen atom, an alkyl radical, an alkoxyl radical or a halogen;
R
5
is a radical —CO—R
10
, an alkyl radical, optionally substituted by one or more hydroxyl groups, or a halogen;
R
6
is a hydrogen atom, a halogen atom, an alkoxyl radical, or hydroxyl group;
R
7
is a hydrogen atom or a halogen;
R
8
is a hydrogen atom, a halogen atom or an alkyl radical;
R
9
is a hydrogen atom, a hydroxyl radical or a halogen atom;
R
10
is a hydroxyl radical, an alkoxy radical, a radical of formula —Nr′r″, wherein r′ and r″ represent a hydrogen atom, an optionally substituted aminoalkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or sugar residue or alternatively, taken together, form a heterocycle;
or a compound having generic formula (III):
wherein R′
1
, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and W are as defined for compounds of formula (I); or
a compound having generic formula:
wherein R′
1
, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and W are as defined for compounds of formula (I). For compounds having formula IV, R
6
is preferably not hydrogen.
It is a further object of the invention to provide novel classes of adamantyl and adamantyl derivative containing retinoids having desirable pharmacological and/or cosmetic properties.
It is a more specific object of the invention to provide novel classes of adamantyl and adamantyl derivative containing retinoids having desirable pharmacological and/or cosmetic properties having the formula set forth below:
wherein
W is independently —CH
2
—, —O—, —S—, —SO— or —SO
2
—,
X is a radical selected from among those of the following formulae (i)-(iii)
 wherein
Y is a radical —CO—V—, —CH═CH—, —CH
3
═CH—, —CH═CCH
3
—,
 —CHOH—CH
2
—O—,
V is an oxygen atom (—O—), an aza radical (—NH—), a radical —CH═CH— or —C≡C—;
Z is a radical —CH— and Z′ is an oxygen atom, or
Z is a nitrogen atom (N) and Z′ is an aza radical (—NH—);
R
1
is a hydrogen atom, a halogen, or

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