Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-03-07
2004-08-03
Russel, Jeffrey E. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S019300, C514S252130, C514S254090, C514S255010, C530S331000, C544S359000, C544S373000, C544S386000, C544S391000
Reexamination Certificate
active
06770627
ABSTRACT:
This invention relates to compounds which inhibit the interaction between MDM2 and the tumour suppressor protein, p53. This invention also relates to processes for the manufacture of MDM2/p53 interaction inhibitors and pharmaceutically acceptable salts, prodrugs or solvates thereof, to novel pharmaceutical compositions containing them and to the use of the compounds as probes of MDM2 and p53 function.
p53 is a transcription factor which plays a pivotal role in the regulation of the balance between cell proliferation and cell growth arrest/apoptosis. Under normal conditions the half life of p53 is very short and consequently the level of p53 in cells is low. However, in response to cellular DNA damage or cellular stress, levels of p53 increase. This increase in p53 levels leads to the activation of the transcription of a number of genes which induces the cell to either growth arrest or to undergo the processes of apoptosis. Thus the function of p53 is to prevent the proliferation of transformed cells and thus protect the organism from the development of cancer (for a review see Levine 1997, Cell 88, 323-331).
MDM2 is a key negative regulator of p53 function, which binds to the amino terminal transactivation domain of p53. MDM2 both inhibits the ability of p53 to activate transcription and targets p53 for proteolytic degradation, thus maintaining the low levels of p53 under normal conditions. MDM2 may also have separate functions in addition to inhibition of p53. For example, MDM2 also binds another tumour suppressor protein, the retinoblastoma gene product, and inhibits its ability to activate transcription. For reviews of MDM2 function see: Piette et al (1997) Oncogene 15, 1001-1010; Lane and Hall (1997) TIBS 22, 372-374; Lozano and de Oca Luna (1998) Biochim Biophys Acta 1377, M55-M59.
MDM2 is a cellular proto-oncogene. Overexpression of MDM2 has been observed in a range of cancers see Momand and Zambetti (1997) J. Cell. Biochem 64, 343-352. The mechanism by which MDM2 amplification promotes tumourigenesis is at least in part related to its interaction with p53. In cells over-expressing MDM2 the protective function of p53 is blocked and thus cells are unable to respond to DNA damage or cellular stress by increasing p53 levels, leading to cell growth arrest and/or apoptosis. Thus after DNA damage and/or cellular stress cells over-expressing MDM2 are free to continue to proliferate and assume a tumourigenic phenotype. Under these conditions disruption of the interaction of p53 and MDM2 would release the p53 and thus allow the normal signals of growth arrest and/or apoptosis to function. Thus disruption of the interaction of MDM2 and p53 offers an approach for therapeutic intervention in cancer.
A few patent applications have been published which describe peptide inhibitors of the interaction of p53 and MDM2, see: International Patent Application, WO9602642, University of Dundee; International Patent Application WO 9801467, Novartis & Cancer Research Campaign Technology Ltd.; and International Patent Application WO 9709343.
We have discovered a novel class of small molecule compounds which inhibit the interaction of MDM2 and p53. These compounds are useful as probes of MDM2 and p53 function and may be useful as agents for the treatment of cancer.
According to the invention there is provided a compound of formula (1):
wherein:
L
1
is hydrogen or methyl;
R
1
and R
2
and R
3
are each independently hydrogen, halo, nitro, cyano, carbamoyl, N-(C
1-4
alkyl)carbamoyl, NN-(diC
1-4
alkyl)carbamoyl or C
1-4
alkoxycarbonyl;
R
4
is indole, N-(C
1-4
alkyl) indole, C
5-7
carbocyclic ring or aryl, any of which can be optionally substituted on ring carbon atoms with up to three substituents each independently selected from halo, C
1-4
alkyl, or C
1-4
alkoxy;
R
5
is hydrogen, C
1-4
alkyl, R
6
CH
2
— or R
6
C(O)—;
R
6
is aryl, heteroaryl, heterocyclyl, aminoC
3-6
alkyl, N(C
1-4
alkyl)aminoC
3-6
alkyl, NN-(diC
1-4
alkyl)aminoC
3-6
alkyl, or R
7
; wherein the aryl, heteroaryl or heterocyclyl rings may be optionally substituted with up to three substituents independently selected from nitro, C
1-4
alkyl, C
1-4
alkoxy, halo, (C
1-4
alkyl)sulfanyl, C
1-4
alkoxycarbonyl, N-(C
1-4
alkyl)carbamoyl, NN-(diC
1-4
alkyl)carbamoyl, N-(C
1-4
alkyl)amino or NN-(diC
1-4
alkyl)amino;
wherein R
7
is either a group of formula (2) of formula (3):
wherein:
L
2
, L
3
and L
4
are each independently hydrogen or methyl;
R
8
is amino, guanadino, imidazolo, any of which can be mono or di-N-substituted with C
1-4
alkyl;
A
1
is oxygen or a direct bond;
R
9
is a C
5-8
membered mono-carbocyclic ring, a C
6-10
membered bi-carbocyclic ring, C
8-12
membered tri-carbocyclic ring, C
5-7
alkyl or aryl, any of which can be optionally mono, bi or tri substituted by C
1-4
alkyl,
R
10
is C
1-6
alkyl or a C
3-8
mono-carbocyclic ring;
R
11
is hydrogen, halo, C
1-4
alkyl, or C
1-4
alkoxy;
R
12
is hydrogen or methyl or ethyl or R
12
together with L
2
forms a C
5-7
nitrogen-containing heterocyclic ring;
R
13
is hydrogen or methyl ethyl or R
13
together with L
4
forms a C
5-7
nitrogen-containing heterocyclic ring;
n is 0, 1 or 2;
p is 0, 1 or 2;
q is an integer from 1 to 6
r is 0, 1 or 2;
s is 0, 1 or 2;
provided that when R
6
is aryl, heteroaryl, heterocyclyl aminoC
3-6
alkyl, N-(C
1-4
alkyl)aminoC
3-6
alkyl or NN-(diC
1-4
alkyl)aminoC
3-6
alkyl then R
6
is other than R
6
CH
2
—; and when R
1
is hydrogen, R
2
is hydrogen, R
3
is hydrogen, L
1
is hydrogen, n is 1, R
4
is phenyl, R
5
is R
6
C(O)—, then R
6
cannot be 2-methyl-4-amino-butyl,
or a pharmaceutically acceptable salt, prodrug or solvate thereof.
In this specification the generic term “alkyl” includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only. An analogous convention applies to other generic terms.
The term “aryl” refers to phenyl or naphthyl.
The term “heteroaryl” refers to a 5-10 membered aromatic mono or bicyclic ring containing up to 5 heteroatoms selected from nitrogen, oxygen or sulphur. Examples of 5- or 6-membered heteroaryl ring systems include imidazole, triazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, furan, pyrazole, 1,2,3-thiadiazole and thiophene. A 9 or 10 membered bicyclic heteroaryl ring system is an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring. Examples of 5/6 and 6/6 bicyclic ring systems include benzofuran, benzimidazole, benzthiophene, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, 4-oxo-4H-1-benzopyran and naphthyridine.
The term “heterocyclyl” refers to a 5-10 membered non-aromatic mono or bicyclic ring containing up to 5 heteroatoms selected from nitrogen, oxygen or sulphur. Examples of ‘heterocyclyl’ include pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl and dihydropyrimidinyl
The term “carbocyclic ring” refers to a totally saturated or partially saturated mono, bi or tri cyclic carbon ring. Examples of carbocyclic rings are cyclopentyl, cyclohexyl, cyclopentyl, bicyclo-octane or adamantyl.
The term “halo” refers to fluorine, chlorine, bromine or iodine.
The term carbamoyl refers to —C(O)NH
2
.
The term “warm-blooded animal” includes human.
Examples of C
1-4
alkyl include methyl, ethyl, propyl, isopropyl, sec-butyl and tert-butyl; examples of C
1-4
alkoxy include methoxy, ethoxy and propoxy; examples of C
1-4
alkanoyl include formyl, acetyl and propionyl; examples of C
1-4
alkylamino include methylamino, ethylamino, propylamino, isopropylamino, sec-butylamino and tert-butylamino; examples of di-(C
1-4
alkyl)amino include di-methylamino, di-ethylamino and N-ethyl-N-methylamino; examples of N-(C
1-4
Cotton Ronald
Jewsbury Philip J.
Luke Richard Wa
AstraZeneca AB
Ropes & Gray LLP
Russel Jeffrey E.
LandOfFree
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