9-(3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro-[3&prim...

Details 9-(3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro-[3&prim... 9-(3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro-[3&prim...

2000-10-26

2001-08-28

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S463000, C536S017200, C536S018100, C549S298000

Reexamination Certificate

active

06281198

ABSTRACT:

The present invention relates to new 9-(3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro-[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one compounds.
BACKGROUND OF THE INVENTION
The compounds of the invention are derivatives of podophyllotoxin, a natural extract known for its use in the treatment of cancer. Other synthetic compounds, such as etoposide and teniposide, are currently used as chemotherapeutic agents in the treatment especially of small-cell lung cancer. Those various compounds act by inhibiting the catalytic activity of topoisomerase II.
DESCRIPTION OF THE PRIOR ART
Various modifications have been made to those compounds, such as the modifications described in the Patent Specifications JP 948 782, WO 97/13776 and U.S. Pat. No. 3,634,459.
Nevertheless, anti-cancer therapeutic requirements call for the constant development of new anti-tumour and cytotoxic agents with the aim of obtaining medicaments that are simultaneously more active, more soluble and better tolerated.
In addition to the fact that the compounds of the present invention are new, they have a surprising in vitro and in vivo activity that is superior to that observed hitherto. The compounds discovered by the Applicant accordingly have properties that render them particularly useful in the treatment of cancers.
DETAILED DESCRIPTION OF THE INVENTION
More especially, the present invention relates to the compounds of formula (I):
wherein:
R represents:
a group of formula (i):
wherein:
X and Y, which may be identical or different, each represents a group selected from hydrogen, hydroxy, linear or branched (C
1
-C
6
)alkoxy, amino, linear or branched (C
1
-C
6
)alkylamino and di-(C
1
-C
6
)alkylamino in which each alkyl moiety may be linear or branched,
W represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, aryl or heteroaryl,
or a group of formula (ii):
—A—G  (ii)
wherein:
A represents a single bond or a linear or branched (C
1
-C
6
)alkylene chain optionally substituted by one or more identical or different groups selected from halogen and hydroxy and optionally containing an unsaturation,
G represents a group selected from hydrogen, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OR
2
, —O—T
1
—NR
3
R
4
, —O—T
1
—NR
2
—T′
1
—NR
3
R
4
, —NR
3
R
4
, —NR
2
—T
1
—NR
3
R
4
, —NR
2
—T
1
—OR
5
, —NR
2
—T
1
—CO
2
R
6
, —NR
2
—T
1
—C(O)R
6
, —C(O)NR
3
R
4
, —C(O)—NR
2
—T
2
, —O—C(O)—T
2
, —O—C(S)—T
2
, —NR
2
—C(O)—T
2
, —NR
2
—C(S)—T
2
, —O—C(O)—O—T
2
, —O—C(O)—NR
2
—T
2
, —O—C(S)—O—T
2
, —O—C(S)—NR
2
—T
2
, —NR
2
—C(O)—O—T
2
, —NR
2
—C(O)—NR
6
—T
2
, —NR
2
—C(S)—O—T
2
, —NR
2
—C(S)—NR
6
—T
2
and —NR
2
—SO
2
—T
3
wherein:
R
2
represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, aryl or aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched,
T
1
and T′
1
, which may be identical or different, each represents a linear or branched (C
1
-C
6
)alkylene chain,
R
3
and R
4
, which may be identical or different, each represents independently of the other:
a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group (optionally substituted by one or more hydroxy groups), aryl, aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, cycloalkyl, heteroaryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, heteroaryl, heterocycloalkyl, or heterocycloalkyl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched,
or form together with the nitrogen atom carrying them a saturated or unsaturated, 5- to 7-membered, monocyclic heterocycle optionally containing a second hetero atom selected from oxygen and nitrogen, the said heterocycle being optionally substituted by one or more groups selected from halogen, hydroxy, linear or branched (C
1
-C
6
)alkyl and heterocyclic groups,
R
5
represents a linear or branched (C
1
-C
6
)alkyl group, aryl or aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched,
R
6
represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, aryl or aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, T
2
represents a group selected from hydrogen, linear or branched (C
1
-C
6
)alkyl (optionally substituted by one or more halogen atoms), aryl, aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, cycloalkyl, cycloalkyl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, heterocycloalkyl and heterocycloalkyl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, or T
2
represents a linear or branched (C
1
-C
6
)alkylene chain, the said chain being substituted by one or more identical or different groups selected from —NR
3
R
4
, —OR
2
, —CO
2
R
6
, —NR
2
-C(O)R
6
, —NR
2
—CO
2
R
6
, —C(O)R
6
, —C(O)NR
3
R
4
, —NR
2
—T
1
—NR
3
R
4
, —NR
2
—T
1
—OR6 and —O—T
1
—NR
3
R
4
wherein R
2
, R
4
, R
6
and T
1
are as defined hereinbefore,
T
3
represents a group selected from linear or branched (C
1
-C
20
)alkyl (optionally substituted by one or more groups selected from halogen, —OR
2
, —NR
2
R
6
, nitro, cyano and azide), aryl, aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, cycloalkyl, cycloalkyl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, heterocycloalkyl, heterocycloalkyl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, heteroaryl and heteroaryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched,
R
1
represents a group selected from hydrogen, linear or branched (C
1
-C
6
)alkyl, aryl, aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, heteroaryl, to heteroaryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, linear or branched (C
1
-C
6
)alkylcarbonyl, arylcarbonyl, aryl-(C
1
-C
6
)alkylcarbonyl in which the alkyl moiety may be linear or branched, heterocycloalkylcarbonyl, linear or branched (C
1
-C
6
)alkylsulphonyl, arylsulphonyl, aryl-(C
1
-C
6
)alkylsulphonyl in which the alkyl moiety may be linear or branched, phosphono, linear or branched (C
1
-C
6
)alkoxycarbonyl, aryloxycarbonyl and aryl-(C
1
-C
6
)alkoxycarbonyl in which the alkoxy moiety may be linear or branched,
to their isomers, and also to addition salts thereof with a pharmaceutically acceptable acid or base,
wherein:
aryl denotes a phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or indanyl group, each of those groups optionally having one or more identical or different substituents selected from halogen, hydroxy, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, cyano, nitro, amino, linear or branched (C
1
-C
6
)alkylamino, di-(C
1
-C
6
)alkylamino in which each alkyl moiety may be linear or branched, linear or branched (C
1
-C
6
)alkylsulphonyl, linear or branched (C
1
-C
6
)alkylsulphonylamino, carboxy, linear or branched (C
1
-C
6
)alkoxycarbonyl, aryloxycarbonyl, aryl-(C
1
-C
6
)alkoxycarbonyl in which the alkoxy moiety may be linear or branched, linear or branched (C
1
-C
6
)hydroxyalkyl, linear or branched (C
1
-C
6
)trihaloalkyl, methylenedioxy, ethylenedioxy, morpholinyl, piperidyl, piperazinyl, linear or branched (C
1
-C
6
)alkylcarbonyloxy and linear or branched (C
1
-C
6
)alkylcarbonyl,
heteroaryl denotes an aromatic monocyclic group, an aromatic bicyclic group, or a bicyclic group in which one of the rings is aromatic and the other ring is partially hydrogenated, each of which groups has from 5 to 12 ring members and contains in the ring system one, two or three identical or different hetero atoms selected from oxygen, nitrogen and sulphur, it being possible for the said heteroaryl optionally to be substituted by the same substituents as those decribed in the case of the aryl group,
cycloalkyl denotes a monocyclic or bicyclic group that is saturated or unsaturated, but not of aromatic character, that contains from 3 to 10 carbon atoms and is optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C
1
-C
6
)alkyl, line

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