Cis-imidazolines

Details Cis-imidazolines Cis-imidazolines

2002-12-11

2004-05-11

Rao, Deepak (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S370000, C546S210000, C548S334100

Reexamination Certificate

active

06734302

ABSTRACT:

BACKGROUND OF THE INVENTION
p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation.
The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the p16INK4/p19ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells.
Wells et al.
J. Org. Chem
., 1972, 37, 2158-2161, report synthesis of imidazolines. Hunter et al.,
Can. J. Chem
., 1972, Vol. 50, pgs. 669-77, report the preparation of amarine and isoamarine compounds which had previously been studied for chemiluminescence (McCapra et al.
Photochem. and Photobiol
. 1965, 4, 1111-1121). Zupanc et al.
Bull. Soc. Chem
. &
Tech
. (Yugoslavia) 1980-81, 27/28, 71-80, report the use of triaryl imidazolines as starting materials in the preparation of EDTA derivatives. EP 363 061 to Matsumoto reports imidazoline derivatives useful as immunomodulators. The compounds were indicated to have low toxicity. Treatment and/or prevention of rheumatoid arthritis, multiple sclerosis, systemic lupus, erythemathodes, and rheumatic fever were implicated. WO 00/78725 to Choueiry et al. report a method for making substituted amidine compounds, and indicate that imidazoline-type compounds may be useful in the treatment of diabetes or related diseases involving impaired glucose disposal.
SUMMARY OF THE INVENTION
The present invention provides at least one compound selected from a compound of formula I
and the pharmaceutically acceptable salts and esters thereof, wherein
R is —C═OR1,
wherein R1 is C1-C4 alkyl, —C═CHCOOH, —NHCH
2
CH
2
R2, —N(CH
2
CH
2
OH)CH
2
CH
2
OH, —N(CH
3
)CH
2
CH
2
NCH
3
, —N(CH
3
)CH
2
CH
2
N(CH
3
)CH
3
, saturated 4-, 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group selected from lower alkyl, —C═O—R5, —OH, lower alkyl substituted with hydroxy, lower alkyl substituted with —NH
2
, N-lower alkyl, —SO
2
CH
3
, ═O, —CH
2
C═OCH
3
, and 5- and 6-membered saturated rings containing at least one hetero atom selected from S, N and O,
wherein R5 is selected from H, lower alkyl, —NH
2
, —N-lower alkyl, lower alkyl substituted with hydroxy, and lower alkyl substituted with NH
2
,
wherein R2 is selected from —N(CH
3
)CH
3
, —NHCH
2
CH
2
NH
2
, —NH
2
, morpholinyl and piperazinyl,
X
1
, X
2
and X
3
are independently selected from —OH, C1-C2 alkyl, C1-C5 alkoxy, —Cl, —Br, —F, —CH
2
OCH
3
, and —CH
2
OCH
2
CH
3
,
or one of X
1
, X
2
or X
3
is H and the other two are independently selected from hydroxy, lower alkyl, lower alkoxy, Cl, Br, F, CF
3
—CH
2
OCH
3
, —CH
2
OCH
2
CH
3
—OCH
2
CH
2
R3, —OCH
2
CF
3
, and —O—R4,
or one of X
1
, X
2
or X
3
is H and the other two taken together with the two carbon atoms and the bonds between them from the benzene ring to which they are substituted form a 6-membered saturated ring that contains at least one hetero atom selected from S, N, and O,
wherein R3 is selected from —F, —OCH
3
, —N(CH
3
)CH
3
, unsaturated 5-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O,
wherein R4 is a 3- to 5-membered saturated ring and
Y
1
and Y
2
are each independently selected from —Cl, —Br, —NO
2
, —C≡N and —C≡CH.
The present invention also provides at least one compound selected from a compound of formula II
and the pharmaceutically acceptable salts and esters thereof, wherein
R is —C═OR1,
wherein R1 is selected from C1-C4 alkyl, saturated 5- and 6-membered rings, saturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group selected from C1-C2 alkyl, C1-C3 alcohol, —N(CH
3
)CH
3
, and —C═OCH
3
, and 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N, and O,
X
4
is selected from C1-C2 alkyl, C1-C5 alkoxy, —Cl, —Br, —F, —OCH
2
C═OOQ, —OCH
2
cyclopentyl, —CH
2
OCH
2
-phenyl, saturated and unsaturated 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O,
wherein Q is selected from H and lower alkyl,
Y
1
and Y
2
are independently selected from —Cl, —Br, —NO
2
, —C≡N and —C≡CH,
with the proviso that where Y
1
and Y
2
are both —Cl, and R1 is —CH
3
or phenyl, then X
4
is not —Cl.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides cis-imidazolines which are small molecule inhibitors of the MDM2-p53 interaction. In cell-free and cell-based assays, compounds of the present invention are shown to inhibit the interaction of MDM2 protein with a p53-like peptide with a potency that is approximately 100 fold greater than a p53-derived peptide. In cell-based assays, these compounds demonstrate mechanistic activity. Incubation of cancer cells with wild-type p53 leads to accumulation of p53 protein, induction of p53-regulated p21 gene, and cell cycle arrest in G1 and G2 phase, resulting in potent antiproliferative activity against wild-type p53 cells in vitro. In contrast, these activities were not observed in cancer cells with mutant p53 at comparable compound concentrations. Therefore, the activity of MDM2 antagonists is likely linked to its mechanism of action. These compounds can be potent and selective anticancer agents.
The present invention provides at least one compound selected from a compound of formula I
and the pharmaceutically acceptable salts and esters thereof, wherein
R is —C═OR1,
wherein R1 is C1-C4 alkyl, —C═CHCOOH, —NHCH
2
CH
2
R2, —N(CH
2
CH
2
OH)CH
2
CH
2
OH, —N(CH
3
)CH
2
CH
2
NCH
3
, —N(CH
3
)CH
2
CH
2
N(CH
3
)CH
3
, saturated 4-, 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group selected from lower alkyl, —C═O—R5, —OH, lower alkyl substituted with hydroxy, lower alkyl substituted with —NH
2
, N-lower alkyl, —SO
2
CH
3
, ═O, —CH
2
C═OCH
3
, and 5- and 6-membered saturated rings containing at least one hetero atom selected from S, N and O,
wherein R5 is selected from H, lower alkyl, —NH
2
, —N-lower alkyl, lower alkyl substituted with hydroxy, and lower alkyl substituted with NH
2
,
wherein R2 is selected from —N(CH
3
)CH
3
,

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