Barbituric acid derivatives with antimetastatic and...

Details Barbituric acid derivatives with antimetastatic and... Barbituric acid derivatives with antimetastatic and...

2000-04-03

2002-01-01

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S270000, C544S060000, C544S299000, C544S300000, C544S301000

Reexamination Certificate

active

06335332

ABSTRACT:

The present invention relates to new derivatives of the barbituric acid 5,5-bis-substituted. These compounds showed a marked antimetastatic and antitumor activity.
BACKGROUND OF THE INVENTION
In the past the therapy of the tumors has been achieved by surgical intervention, radiation treatment and chemotherapy. The drawbacks of this latter are mainly due to the toxicity of the cytotoxic drugs, which is usually not restricted to the cancer cells, and to the acquired resistance of the cancer cells to some of the most widely used drugs, which varifies the final result of the therapy.
On the other hand, the elimination of the primary tumor by surgery is not always possible and in any case does not prevent the most metastasizing tumors, such as for example breast cancer or melanoma, to invade other target organs, which develop further secondary tumors after months or years from the surgical treatment. These secondary tumors are usually the main cause of death in the patient.
In the years it has become apparent that the therapy of the metastasizing tumors is unlikely to bring the complete cure of the patient: therefore, the treatment with cytotoxic drugs is now seen as a palliative and life-prolonging method rather than a curative method. A croncial treatment with a drug having low toxicity would be preferable while targeted to the control of the progression of the disease. An example of such therapy is the treatment of invasive breast cancer with tamoxifen.
The efforts of many researchers have been focused recently to the development of drugs able to inhibit the invasive process of the tumor which brings to metastases formation. Among the targets that have been evaluated up to now to give rise to a possible antimetastatic activity, the inhibition of the matrix metalloproteinases seems to be one of the most promising.
The matrix metalloproteinases (or metalloproteases), which are upregulated in the cancer cells, degrade the extracellular matrix and bring to the propagation of the tumor cells into the blood stream to reach the target organs where the metastasis develop. Moreover, they are associated with tumor growth and angiogenesis. Nevertheless, since different types of such proteases exist in the organism and are implicated in the regulation of vital functions, selected inhibition of certain combination of MMPs is desired, in order to avoid toxic side effects, especially in a chronical treatment.
A number of compounds are known in the literature [see review article: Beckett et al., DDT 1, 16 (1996)] or are described in the patent literature [WO-A-92/09563 by Glycomed, EP-A-497 192 by Hoffmann-LaRoche, WO-A-90/05719 by British Biotechnology, EP-A-489 577 by Celltech, EP-A-320 118 by Beecham, U.S. Pat. No. 4,595,700 by Searle]. In particular, batimastat and marimastat have been developed by British Biotechnology and the latter is now under investigation in clinical trials. However, such compounds are broad inhibitors of matrix metalloproteinases, therefore therapy with these molecules might be associated to undesirable toxicity.
It is therefore evident that there is still a high need of new compounds, which must have a low toxicity and a marketed activity in inhibiting both the tumor growth and the metastasis process, as candidates for a chronical antitumor therapy.
We have now found a new class of compounds that possesses a marked inhibitory activity against the matrix metalloproteinases and showed antimetastatic and antitumor activity.
DESCRIPTION OF THE INVENTION
The present invention relates to compounds of the general formula (I):
wherein:
R is a W-V group, in which W is a bond or a linear or branched (C
1
-C
8
)alkyl or a (C
2
-C
8
)alkenyl; V is a monocycle to bicycle, saturated or unsaturated, which can optionally contain from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur and which can be optionally substituted by a (C
1
-C
4
)alkoxy, phenoxy or phenyl group: or W-V is a (C
1
-C
20
)alkyl group which can be optionally interrupted or terminated by one or more heteroatoms selected from oxygen or sulfur or by a —N(R
5
)— group, in which R
5
is selected from hydrogen, (C
1
-C
4
)alkyl or (C
1
-C
4
)acyl.
n is an integer from 1 to 3;
A is selected from the following groups: R
1
, —N(R
2
)—(CH
2
)
m
—N(R
9
)—T—R
10
, —N(R
2
)—CHR
6
—CO—R
7
, —N(R
2
)—T—NR
3
R
4
, in which
T is a —CO— or —SO
2
— group;
m is an integer from 2 to 6;
R
1
is selected from —OH, (C
1
-C
4
)alkoxy,—NH
2
, mono- or di-(C
1
-C
4
)alkylamino, benzylamino, phenoxy or benzyloxy groups, these two latter being optionally substituted with one or more groups selected from (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, halogen, —OH, —NH
2
, mono- or di-(C
1
-C
4
)alkylamino, nitro, (C
1
-C
4
)alkylsulphonyl, (C
1
-C
4
)alkylsulphonamido; or is a group of formula —N(R
9
)—CO—R
10
in which R
9
and R
10
, taken together with the N—CO group to which they are linked, form a 5- to 7-membered lactam, which can optionally be benzocondensed and/or substituted with a group selected from (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, halogen, —OH, —NH
2
, mono- or di-(C
1
-C
4
)alkylamino, nitro, (C
1
-C
4
)alkylsulphonyl, (C
1
-C
4
)alkylsulphonamido,
R
2
is selected from hydrogen, (C
1
-C
4
)alkyl, (C
3
-C
7
)cycloalkyl, (C
3
-C
7
)cycloalkyl-(C
1
-C
4
)alkyl, phenyl or benzyl groups, these two latters being optionally substituted with one or more groups selected from (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, halogen, —OH,—NH
2
, mono- or di-(C
1
-C
4
)alkylamino, nitro, (C
1
-C
4
)alkylsulphonyl, (C
1
-C
4
)alkylsulphonamido; or R
2
is a Het-(C
1
-C
2
)alkyl group, in which Het is a 5- or 6-membered heterocycle having from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, which can be optionally benzocondensed;
R
3
is selected from hydrogen, (C
1
-C
4
)alkyl, (C
3
-C
7
)cycloalkyl, phenyl, benzyl or phenetyl, which can be optionally substituted by a group selected from (C
1
-C
4
)alkoxy, —SO
2
NH
2
.
R
4
is a —(CH
2
)
p
—B group, wherein p is 0, 1 or 2 and B is selected from (C
1
-C
4
)alkyl; benzyldryl; monocycle or bicycle, saturated or unsaturated, which can optionally be benzocondensed and/or substituted with a group selected from (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, halogen, —OH,—NH
2
, mono- or di-(C
1
-C
4
)alkylamino, nitro, (C
1
-C
4
)alkylsulphonyl, (C
1
-C
4
)alkylsulphonamido; 5- or 6-membered heterocycle having from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, which can be optionally benzocondensed and/or substituted with a group selected from (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, halogen, —OH, —NH
2
mono- or di-(C
1
-C
4
)alkylamino, nitro, (C
1
-C
4
)alkylsulphonyl, (C
1
-C
4
)alkylsulphonamido; or R
3
and R
4
, taken together with the nitrogen atom to which they are linked, form a 5- or 6-membered heterocycle having from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, which can be optionally benzocondensed and/or substituted with a group selected from (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, halogen, —OH, —NH
2
, mono- or di-(C
1
-C
4
)alkylamino, nitro, (C
1
-C
4
)alkylsulphonyl, (C
1
-C
4
)alkylsulphonamido;
R
6
is a —(CH
2
)
q
-D group in which q is 0, 1 or 2 and D is selected from hydrogen; (C
1
-C
4
)alkyl; a monocycle or bicycle, saturated or unsaturated, which can optionally be benzocondensed and/or substituted with a group selected from (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, halogen, —OH, —NH
2
, mono- or di-(C
1
-C
4
)alkylamino, nitro, (C
1
-C
4
)alkylsulphonyl, (C
1
-C
4
)alkylsulphonamido; 5- or 6-membered heterocycle having from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, which can be optionally benzocondensed and/or substituted with a group selected from (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, halogen, —OH, —NH
2
, mono- or di-(C
1
-C
4
)alkylamino, nitro, (C
1
-C
4
)alkylsulphonyl, (C
1
-C
4
)alkylsulphonamido;
R
7
is selected from —OH, (C
1
-C
8
)alkoxy, —NHR
3
, —NH—CH(R
6
)—COR
8
, in which R
8
on its turn is selected from —OH, (C
1
-C
8
)alkoxy or —NHR
3
and R
3
is as above defined;
R
9
and R
10
have the same meanin

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