Substituted diarylureas as stimulators for Fas-mediated...

Details Substituted diarylureas as stimulators for Fas-mediated... Substituted diarylureas as stimulators for Fas-mediated...

2002-02-22

2003-02-25

O'Sullivan, Peter (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S518000, C514S522000, C514S597000, C514S598000, C558S024000, C558S037000, C558S413000, C564S049000, C564S050000, C564S051000

Reexamination Certificate

active

06525091

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to substituted diarylureas, to pharmaceutical compositions containing them, and to their use for stimulating Fas-mediated apoptosis.
2. Description of the Related Art
The Fas receptor, also known as APO-1 or CD95, is thought to be a key initiator of apoptotic programmed cell death in a variety of cell types. Activation of the Fas receptor by Fas ligands (FasL) or agonist antibodies leads to aggregation of the Fas receptor and recruitment of the intracellular death-inducing signal complex (DISC). See, for example, Kischkel et al.,
EMBO J.
14:5579-5588 (1995). Recruitment of other molecules, such as caspases, and in some cells, bcl-2, may also occur. It has been suggested that the main function of the Fas signaling complex is to activate caspase-8 protease. See, for example, Siegel et al.,
J. Allergy Clin. Immunol.
103:729 (1999). CD4
+
T cells are unique in their ability to commit suicide by stimulating their own Fas receptors. T cells can also trigger apoptosis in B cells, macrophages, and other cell types through FasL. These interactions negatively regulate the immune system but can also contribute to immunopathology, such as in Fas-mediated damage of target tissues in hepatitis and other organ-specific autoimmune diseases. Fas plays a significant role in regulation of the human immune response, and the details of its clinical importance is being actively investigated. Altered Fas receptor or altered FasL are thought to contribute to autoimmune, infectious, and malignancies including autoimmune lymphoproliferative syndrome, autoimmune thyroid disease, hypereosinophilia, viral hepatitis, colon carcinomas, breast carcinomas, prostate cancers, neuroblastomas, gliomas, and other cancers and disease conditions. See, for example, Houghton,
J. Curr. Opin. Oncol.
11:475 (1999) and Siegel et al.,
J. Allergy Clin. Immunol.
103:729 (1999).
There are large numbers of diarylureas cited in the literature, however there are only a limited number of diarylureas substituted with halogens. Certain diarylureas have been reported are to be useful as p38 kinase inhibitors (WO 99/32463, WO 99/00357), raf kinase inhibitors (WO 99/32436), and 5-HT receptor antagonists (WO 98/50346).
The documents cited here and elsewhere in this application are incorporated into this application by reference.
SUMMARY OF THE INVENTION
In a first aspect, this invention is compounds of the formula:
where:
X
1
and X
2
are independently selected from —F, —Cl, —Br, and —OSO
2
R
1
;
Y
1
and Y
2
are independently selected from —CN, —NO
2
, —COR
1
, —CONR
1
R
2
, —SO
2
R
1
, and —SO
2
R
1
R
2
; and
each R
1
is independently selected from optionally substituted alkyl, optionally substituted aryl, and optionally substituted aralkyl;
each R
2
is independently selected from H, optionally substituted alkyl, optionally substituted aryl, and optionally substituted aralkyl,
and the pharmaceutically acceptable salts thereof.
In a second aspect, this invention is pharmaceutical compositions comprising a compound of the first aspect of the invention and a pharmaceutically acceptable excipient.
In a third aspect, this invention is methods of treating diseases in mammals treatable by administration of a stimulator of Fas-mediated apoptosis, by administering to the mammal a therapeutically effective amount of a compound of the first aspect of this invention or a composition of the second aspect of this invention. The compounds of the first aspect of this invention stimulate Fas-mediated apoptosis, leading to cell death in cells containing the Fas receptor, and are useful in the regulation of the immune system and immune responses, cell proliferation, and malignancy. Suitable diseases for such treatment are autoimmune diseases, infectious diseases, and malignancies, including autoimmune lymphoproliferative syndrome, autoimmune thyroid disease, hypereosinophilia, viral hepatitis, colon carcinomas, breast carcinomas, prostate cancers, neuroblastomas, gliomas, and other cancers and diseases. This aspect also includes the use of compounds of the first aspect of this invention in the preparation of medicaments for the treatment of diseases in mammals treatable by administration of a stimulator of Fas-mediated apoptosis.
In a fourth aspect, this invention provides a method of stimulating Fas-mediated apoptosis in a cell that has a Fas receptor, by contacting the cell with a compound of the first aspect of this invention in an amount sufficient to stimulate Fas-mediated apoptosis. In vivo, the step of contacting the cell with the compound may be effected by administering to an animal containing the cell an effective amount of the compound. In vitro, the step of contacting the cell with a compound of the formula may be effected by administering to the cell or to a solution bathing the cell an effective amount of the compound.
In a fifth aspect, this invention is methods of making the compounds of the first aspect of this invention.
DETAILED DESCRIPTION OF THE INVENTION
(a) Definitions and General Parameters
“Alkyl” means a C
1
-C
10
monovalent hydrocarbyl that may be linear, branched, or cyclic, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclopropylmethyl, cyclohexyl, and cyclohexylmethyl. C
12
-C
6
alkyls are preferred.
A “substituted alkyl” is an alkyl substituted with up to three halogen atoms and/or a substituent selected from —CN, —NO
2
, —OR, —SR, —COR, —OC(O)R, —C(O)OR, —NR
2
, —SO
2
OR, —OSO
2
R, —SO
2
NR
2
, —NRSO
2
R, —CONR
2
, or —NRCOR, where each R is, independently, hydrogen, optionally R′-substituted alkyl, optionally R′-substituted aryl, heteroaryl, optionally R′-substituted aralkyl, or heteroaralkyl and each R′ is, independently, halo, —CN, —NO
2
, —OH, C
1-3
alkyl, C
1-3
alkoxy, —SH, or —NH
2
. Preferred substituted alkyls are substituted with up to three halogen atoms and/or one of the substituents selected from the group consisting of —CN, —NO
2
, —OH, C
1-3
alkoxy, —SH, and —NH
2
; and a particularly preferred substituted alkyl is —CF
3
.
“Aryl” means an aromatic hydrocarbyl containing 6 to 20 ring carbon atoms, which is monocyclic (phenyl), condensed polycyclic, preferably condensed bicyclic (e.g., naphthyl), or linked polycyclic, preferably linked bicyclic (e.g., biphenylyl). The aryl is preferably C
6
-C
16
and even more preferably, C
6
-C
14
. A particularly preferred aryl is phenyl.
A “substituted aryl” is an aryl substituted with up to three substituents selected from halo, —CN, —NO
2
, —OR, optionally halo-substituted C
1-3
alkyl, optionally halo-substituted C
1-3
alkoxy, —SR, —COR, —OC(O)R, —C(O)OR, —NR
2
, —SO
2
OR, —OSO
2
R, —SO
2
NR
2
, —NRSO
2
R, —CONR
2
, or —NRCOR, where each R is, independently, hydrogen or optionally R′-substituted alkyl and each R′ is, independently, halo, —CN, —NO
2
, —OH, C
1-3
alkyl, C
1-3
alkoxy, —SH, or —NH
2
. Preferred substituted aryls are substituted with up to three substituents selected from the group consisting of halo, —CN, —NO
2
, —OH, optionally halo-substituted C
1-3
alkyl, optionally halo-substituted C
1-3
alkoxy, —SH, and —NH
2
; and particularly preferred substituted aryls are substituted phenyls.
“Aralkyl” means an alkyl substituted with an aryl. Preferred aralkyls are benzyl and phenethyl.
A “substituted aralkyl” is an aralkyl in which the aryl or the alkyl, or both, are substituted in the manner described above for substituted aryl and substituted alkyl.
“Halogen” or “halo” means F, Cl, or Br.
“Heteroaryl” means a monocyclic or condensed bicyclic aromatic hydrocarbyl containing 6 to 20 ring atoms in which 1 to 3 of the ring carbon atoms are replaced by O, S, N, or NR (where R is H or C
1-3
alkyl). Preferred heteroaryls are monocyclic containing 5 or 6 ring atoms and include furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and the like.
“Pharmaceutically acceptable salts” are described in the sect

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