Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-08-31
2001-11-13
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S265000, C544S277000
Reexamination Certificate
active
06316456
ABSTRACT:
This is a national stage application of PCT/FR96/01905, filed on Nov. 29, 1996, which claims priority of French application 95/14237, filed Dec. 1, 1995.
The invention relates to new purine derivatives having anti-proliferative properties and to their biological uses.
It relates in particular to purine derivatives having an inhibiting effect with respect to cyclin-dependent kinase proteins, or cdk for short.
The study of the molecular mechanisms which control the cell cycle has demonstrated the regulatory role of cdk. These proteins are made up of at least two sub-units, a catalytic sub-unit (of which cdc2 is the prototype) and a regulatory sub-unit (cyclin). Eight cdk have been described, cdk1 (=cdc2), cdk2-cdk8.
With the exception of cdk3, for which no associated cyclin is known, the cdk are regulated by transitory combination with a member of the cyclin family: cyclin A (cdc2, cdk2), cyclin B1-B3 (cdc2), cyclin C (ckd8), cyclin D1-D3 (cdk2-cdk4-cdk5-cdk6), cyclin E (ckd2), cyclin H (cdk7).
Each of these complexes is involved in a phase of the cell cycle. The activity of the cdk is regulated by post-translational modification, by transitory combinations with other proteins and by modification of their intracellular location. Regulators of the cdk include activators (cyclins, cdk7/cyclin H, cdc25 phosphatases), the sub-units p9
CKS
and p15
cdk-BP
and the inhibitory proteins (p16
NK4A
, p15
INK4B
, p21
Cip1
, p18, p27
Kip1
).
In parallel with purely fundamental research into the regulatory mechanisms of cell division, the importance of dysregulations of cyclin-dependent kinases in the development of human tumours has been demonstrated by several studies. Over-expression of cyclins D and E in several tumours, over-expression of cdc2, the oncogenic properties of cyclins D and A, abnormal temporary expression of cyclin-dependent kinases and major dysregulation of protein inhibitors (mutations, deletions) have thus been found.
The regulators of the cell division cycle are the subject of a large number of clinical studies (use as indicating markers for treatment).
These results greatly encourage efforts for detailed comprehension of the regulatory mechanisms of the cell cycle. They also lead to the search, by screening for molecules which inhibit cyclin-dependent kinases.
Several kinase inhibitors have been described, such as butyrolactone, flavopiridol and 2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine, called olomoucine. Works relating to olomoucine are reported by Vesely et al. in the article carrying the reference (1) in the list of bibliographic references given at the end of the description.
This cdc2 inhibitor of high efficacy (its IC
50
is 7 &mgr;M) and high selectivity (more than 35 kinases have been tested) corresponds to the formula:
The works of the inventors in this field have led them to develop new molecules of particular interest which inhibit cdc2 in low doses, while maintaining the enzymatic specificity of olomoucine.
The object of the invention is therefore to provide new purine derivatives having, in particular, anti-proliferative properties.
The invention also relates to a process for obtaining these derivatives by synthesis, which enables them to be prepared on an industrial scale.
It also relates to their therapeutic use and their use as a herbicide.
The purine derivatives of the invention are characterized in that they correspond to the formula I.
in which
R2, R6 and R9, which are identical to or different from one another, represent a halogen atom or an R-NH-, R-NH-NH-, NH
2
-R′-NH- or R-NH-R′-NH- radical, in which R represents a straight- or branched-chain, saturated or unsaturated alkyl radical, an aryl or cycloalkyl radical or a heterocyclic ring and R′ represents a straight- or branched-chain, saturated or unsaturated alkylene group or an arylene or cycloalkylene group, R and R′ each containing 1 to 8 carbon atoms and being substituted, where appropriate, by one or more -OH, halogen, amino or alkyl groups.
R2 can also represent a heterocyclic ring carrying, where appropriate, a straight- or branched-chain, saturated or unsaturated alkyl radical, an aryl or cycloaryl radical or a heterocyclic ring, optionally substituted by one or more -OH, halogen, amino or alkyl groups.
R9 can also represent a straight- or branched-chain, saturated or unsaturated alkyl radical or an aryl or cycloalkyl radical,
R2 and R9 can also represent a hydrogen atom, with the exception of the derivatives in which the said substituents have, respectively, the following meanings:
R6 and R9 - a benzylamino and methyl group,
R2 and R6 - a hydroxyethylamino and benzylamino group,
R2, R6 and R9 - an amino, benzylamino and methyl, or chloro, amino and methyl, or chloro, benzylamino and methyl, or chloro, 3-hydroxybenzylamino and methyl, or chloro, 5-hydroxypentylamino and methyl, or 2-hydroxyethylamino, benzylamino and isopropyl, or 2-hydroxyethylamino, amino and methyl, or 2-hydroxyethylamino, isopentenyl and methyl, or 2-hydroxyethylamino, isopentenylamino and methyl, or 2-hydroxyethylamino, benzylamino and methyl, or 2-hydroxyethylamino, benzylamino and 2-hydroxyethyl, or 2-hydroxyethylamino, benzylamino and isopropyl, or 2-hydroxyethylamino, (3-hydroxybenzyl)amino and methyl, or 2-hydroxyethylamino, (3-hydroxybenzyl)amino and isopropyl, or 2-hydroxyisobutylamino, 6-benzylamino and methyl, or 2-hydroxyethylamino, isopentenylamino and isopropyl, or (2-hydroxyethyl)amino, (4-methoxybenzyl)amino and isopropylamino group.
and the purine derivatives of the invention are furthermore characterized in that they have an IC
50
less than or equal to about 5 &mgr;M for cdc2/cyclin B.
The abovementioned derivatives which are excluded from the invention are described in reference (1).
In general, the derivatives of the invention are kinase protein inhibitors of great interest.
Preferably, the halogen atom is chosen from chlorine, bromine or fluorine, the alkyl radical is chosen from the methyl, ethyl, propyl, isopropyl, butyl and isobutyl, pentyl, hexyl and heptyl radicals the alkylene radical is chosen from the methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentene or isopentene radicals, the aryl radical is a benzyl group, the cycloalkyl radical is a cyclohexyl group, the arylene radical is a benzylene group, the cycloalkylene radical is a cyclohexylene group and the heterocyclic ring is a nitrogen-containing and or oxygen-containing heterocyclic ring, such as an imidazole, an oxadiazole, a pyridine, a pyridazine or a pyrimidine, or also a pyrrolidine.
According to one embodiment of the invention, R2 is chosen from the radicals which are capable of bonding in a cdk2/ATP complex to a region of the bonding domain of ATP occupied by ribose. These are advantageously radicals chosen from a chlorine atom, and amino, methylamino, ethylamino, n-heptylamino, aminoethylamino, aminopropylamino, dimethyleminoethylamino, hydroxyethylamino, hydroxy-propylamino, hydroxyisobutylamino, hydroxypentylamino, dimethylhydrazino or hydroxymethylpropylamino. [(2R)-2-hydroxymethyl-pyrrolidin-1yl], N-benzyl-aminoethanol, (R,S)-amino-hexanol, (S)-amino-2-phenylethanol, (R)-amino-2-phenylethanol, (R)-amino-3-phenylpropanol, (R,S)-amino-pentanol, (R)-amino-propanol, (S)-amino-propanol and (R)-N-pyrrolidine-methanol radical.
Particularly preferred radicals contain a hydroxypropylamino radical as the group R2.
According to another embodiment of the invention, R6 is chosen from an amino, isopentenylamino, hydroxypentylamino, 4-hydroxy-3-methyl-trans-2-butenylamino, benzylamino, hydroxybenzylamino, hydroxyethylbenzylamino, cyclohexylmethylamino, isopentene, benzylamino or (3-iodo)-benzylamino group.
R6 preferably comprises a hydrophobic radical, such as benzyl, hydroxybenzyl or isopentenyl.
Preferably, R2 is chosen from the group consisting of [1-D,L-hydroxymethylpropylamino], [(2R)-2-hydroxymethyl-pyrrolidin-1-yl] and [(R)-N-pyrrolidine-methanol] and R6 is benzylamino.
According to yet another embodiment of the invention, t
Bisagni Emile
Legraverend Michel
Meijer Laurent
Berch Mark L.
Centre National de la Recherche Scientifique
Foley & Lardner
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