Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-14
2003-06-17
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S543000, C540S581000
Reexamination Certificate
active
06579869
ABSTRACT:
The present invention concerns new cephalotaxanes, their methods of preparation and their use in treatment of cancers, leukemias, parasites including thus resistant to usual chemotherapeutic agents and as reversal agents of harringtonines.
Cephalotaxanes (CTX) are particular alkaloids today only extracted from the Cephalotaxaceae family which exhibiting the structural formula 1.
Several substituents may be encountered on this core: hydroxyl, ether, acyloxy etc. Some double bound or intramolecular bridge achieve to definite cephalotaxanes. Several dozen of cephalotaxanes have been isolated from various cephalotaxus species.
Cephalotaxoids include cephalotaxanes and unnatural analogs of cephalotaxanes.
Cephalotaxines 2 are cephalotaxanes without acyloxy side-chain.
Harringtonines (i.e. harringtonine=HA and homoharringtonine=HHT) are natural esters of cephalotaxines exhibiting generally a strong cytotoxic activity,
Harringtonines are natural esters of cephalotaxines exhibiting generally a strong cytotoxic activity.
Harringtoids include harringtonines and unnatural analogs of harringtonines.
Two harringtonines are very promising drugs in the treatment of certain leukemia such as Chronic Myelogenous Leukemia (CML). Definite activity of HHT was observed in acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), and myelodysplastic syndrome (MDS) (Warrell Jr Rpet al, 3:617-621, 1985; Feldman E et al., Leukemia 6:1185-88, 1992; Feldman E J et al, Leukemia 10:40-42, 1996; Kantarjian H et al., Cancer 63:813-817, 1989; Kantarjian H et al., J Clin Oncol 18:3513-3521,2000). The present applicant have initiated in France compassionate use of HHT in CML patients resistant or not eligible to all existing therapies and several phase II and III clinical trials including in patient with CML and AML are ongoing in France and in the U.S. However, it should be pointed out that harringtonines pertain to the series of natural drugs exhibiting the multiresistance phenomenon which led to relapse of the cancer diseases. This situation is a serious limitation to the use of natural chemotherapeutic agents in the treatment of cancers and leukemia.
Harringtonine inhibit protein synthesis at the level of elongation, however ultimate mechanism of action of harringtonine remain unknown. The final result is the self-destruct of the cell. Clinically, harringtonines have a selective action in leukemia of the myeloid series. In addition, harringtonines interacts with P Glycoprotein (PGP) and Multiresistance Protein (MRP). PGP, MRP and other efflux pumps are complex molecular entities which are ubiquist in nature. Their role is to selectively efflux the environmental natural toxic agents, including agents of chemotherapy (anthracyclines, taxanes, epipodophyllotoxins, harringtonine, etc.) It was pointed out that no common structural feature of this natural cytotoxic may related to molecular recognizing by PGP.
A number of analogs all less active than harringtonines have been synthesized. The more active among these esters are about one magnitude less cytotoxic than harringtonines in vitro (i.e. HA, HHT neoharringtonine, have an activity=IC50 ranged from 10 to 30 ng per mL, whereas analog previously synthesized have an IC50 higher than 100 ng/mL). No relation structure activity relationship had been previously found since the discovering of harringtonines.
Therefore, there is the need of new analogs of harringtonines having the same magnitude of cytotoxicity than harringtonines in vitro.
Surprisingly, the present applicant have synthesized a series of CTX analogs exhibiting stronger in vitro inhibition of leukemic cell lines such as K562, than HHT used as reference.
The present invention provides cephalotaxanes having formula (I)
wherein
W represents O or NH
Q represents an unbranched or branched, saturated or unsaturated or aromatic, cyclic or acyclic or heterocyclic hydrocarboned radical containing 1 to 30 carbon atoms including or not heteroatom(s),
R
1
is H, OH, OMe, O—(C
1
-C
30
)alkyl, O-aryl(C
1
-C
30
)alkyl, O—(C
2
-C
30
)alkenyl, O—(C
3
-C
30
)cycloalkyl or null and R
2
is H or OH, or R
1
, R
2
form together —O—,
R
3
═R
4
=OMe or R
3
and R
4
form together —OCH
2
O—,
R is H, C
1
-C
30
alkyl or O-protecting group and R
6
represents an unbranched or branched, saturated or unsaturated or aromatic, cyclic or acyclic or heterocyclic hydrocarboned radical containing 1 to 30 carbon atoms including or not heteroatom(s), or R and R
6
form together —CMe
2
—,
n is 0 to 8,
R
5
is H, OH, OMe, O—(C
1
-C
30
)alkyl, O-aryl(C
1
-C
30
)alkyl, O—(C
2
-C
30
)alkenyl, O—(C
3
-C
30
)cycloalkyl or O-aryl,
the doted line is null or forms a double bond depending on the meaning of R
1
, except for compounds where
W represents O, the doted line forms a double bond, R
1
is null, R
2
is H, R
3
and R
4
represent —O—CH
2
—O—, R
5
is OMe, Q=CO
2
R
7
and
1.) R=H, R
6
=—(C—OH)Me
2
, n=2 or 3, R
7
=Me or H,
2.) R=H, R
6
=—(C—H)Me
2
, n=2 to 4, R
7
=Me,
3.) R=H, R
6
=—(C—H)Me
2
, n=1 or 2, R
7
=H,
4.) R=H, R
6
=Ph, n=1 to 3, R
7
=Me,
5.) R=H, R
6
=—CH═CH—Ph, n=0, R
7
=Me,
6.) R=H, R
6
=CH
3
, n=4, R
7
=Me,
7.) R and R
6
form together —CMe
2
—, n=2 or 3, R
7
=Me,
W represents O, the doted line forms a double bond, R
1
is null, R
2
is OH, R
3
and R
4
represent —O—CH2—O—, R
5
is OMe and R=H, R
6
=—(C—H)Me
2
, n=2 or 3, R
7
=Me
W represents O, the doted line is null, R
1
and R
2
represent —O—, R
3
and R
4
represent —O—CH
2
—O—, R
5
is OMe and R=H, R
6
=—(C—H)Me
2
, n=2, R
7
=Me.
The term “O-Protecting group” as used in the present invention refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures such as those O-protecting groups disclosed in Greene, “Protective Groups In Organic synthesis”, (John Wiley & Sons, New York (1981)). O-protecting groups comprise substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl) ethoxymethyl, t-butyl, benzyl and triphenylmethyl, tetrahydropyranyl ethers, substituted ethyl ethers, for example, 2,2,2-trichloroethyl, silyl ethers, for example, trimethylsilyl, t-butyidimethylsilyl and t-butyldiphenylsilyl; and esters prepared by reacting the hydroxyl group with a carboxylic acid for example, acetate, propionate, benzoate and the like.
The term “C
1
-C
30
alkyl” as used in the present invention refers to straight or branched chain substituted or unsubstituted alkyl radicals containing from 1 to 30 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl and the like.
The term “C
2
-C
30
alkenyl” as used in the present invention refers to straight or branched chain substituted or unsubstituted alkenyl radicals containing from 1 to 30 carbon atoms including, but not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
The term “aryl” as used in the present invention refers to a monocyclic or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like. Aryl groups can be unsubstituted or substituted with one or more substituents.
The term “aryl(C
1
-C
30
)alkyl” as used in the present invention refers to an aryl group such as defined above appended to a C
1
-C
30
alkyl radical such as defined above, for example, benzyl and the like.
The term “C
3
-C
30
cycloalkyl” as used herein refers to a carbocyclic ring having 3 to 30 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl groups can be unsubstituted or substituted with one or more substituents.
An advantageous embodiment provides compounds of formula (I) wherein
Q=COZ—R
8
,
Z=O, S
Bataille Patricia
Dhal Robert
Drouye Freddy
Marie Jean-Pierre
Radosevic Nina
Burns Doane Swecker & Mathis L.L.P.
Coleman Brenda
Oncopharm Corporation
LandOfFree
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