Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-04-12
2001-05-22
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S212010, C514S227500, C514S239500, C514S255030, C514S317000, C514S422000, C514S425000, C514S461000, C514S617000, C514S654000, C564S161000, C564S337000, C564S342000, C564S345000
Reexamination Certificate
active
06235791
ABSTRACT:
The present invention relates to a novel use of compounds having good affinity for the receptors to which cis-N-cyclohexyl-N-ethyl [3-(3-chloro-4-cyclo-hexylphenyl) allyl]amine binds, as well as to novel compounds having the same properties.
cis-N-Cyclohexyl-N-ethyl [3-(3-chloro-4-cyclo-hexylphenyl)allyl]amine, also known under the code CM 31747 or SR 31747 and referred to hereinbelow as “SR 31747”, is described in EP 376,850 which also discusses its immunosuppressant activity. It has been found that SR 31747 prevents cancer cells from proliferating and that, consequently, it can exert antitumour activity.
Furthermore, it has been found that SR 31747 has receptor sites on these cells.
Lastly, it has been found that any product capable of displacing tritiated SR 31747 from its receptors on tumour cells prevents cell proliferation. More particularly, it has been observed that compounds capable of displacing tritiated SR 31747 (referred to hereinbelow as “
3
H-SR 31747”) from its receptor sites have activity in preventing cell proliferation.
Thus, according to one of its aspects, the present invention relates to the use of compounds capable of displacing tritiated cis-N-cyclohexyl-N-ethyl [3-(3-chloro-4-cyclohexylphenyl)allyl]amine from its receptors for the preparation of pharmaceutical compositions intended to combat cell proliferation. The capacity of the compounds envisaged for the use according to the present invention of displacing tritiated SR 31747 from its receptors may readily be determined biochemically using
3
H-SR 31747 and binding it to the cells.
This determination may be carried out with tumour cells chosen appropriately, preferably from cell lines which proliferate readily in vitro, for example human myeloma, kidney carcinoma or human lung cells or alternatively on mammary carcinoma cells.
In the context of the present invention, in order to be able to carry out the determinations under standardized conditions making it possible to obtain constant and reproducible results, a human mammary tumour cell line “MCF-7” was chosen arbitrarily.
Also, in the context of the present invention,
3
H-SR 31747 was chosen arbitrarily, in which the tritium is bound to the vinylene bond, but the Sr 31747 may be labelled in any way at all since the labelling serves only to monitor the displacement of the product from its receptors.
Determination of the capacity to displace
3
H-SR 31747 from its receptors present on cells, in particular cells of the MCF-7 cell line, was carried out by performing tests of total binding and of specific binding.
According to the present invention, any product which, when subjected to the above preliminary operation, is capable of displacing
3
H-SR 31747 from its receptors may be used for the preparation of pharmaceutical compositions to combat cell proliferation. SR 31747 is, firstly, capable of displacing
3
H-SR 31747 from its receptors and possesses powerful inhibitory activity on cell proliferation. More particularly, the subject of the present invention is the use of a compound capable of displacing tritiated cis-N-cyclohexyl-N-ethyl[3-(3-chloro-4-cyclohexylphenyl)allyl]amine from its receptors, chosen from the group consisting of:
a) amines of formula
in which
R
1
represents a hydrogen atom or a halogen atom;
R
2
represents a cyclohexyl;
R
3
represents a cycloalkyl containing from 3 to 6 carbon atoms;
R
4
represents a hydrogen atom, an alkyl containing from 1 to 6 carbon atoms or a cycloalkyl containing from 3 to 6 carbon atoms;
A represents a group chosen from: —CO—CH
1
—, —CH(Cl)—CH
2
—, —CH(OH)—CH
2
, —CH
2
, —CH═CH—, —C≡C—;
b) pharmaceutically acceptable addition salts of the amines of formula (I);
c) amines of formula (II)
in which
A
a
is a group chosen from the following: —CO—CH
2
—;
—CH(OH)—CH
2
; —CH═CH—; —C≡C—;
R
1a
represents hydrogen or a halogen;
Rphd
2
a is a cyclohexyl group;
d) the addition salts of a pharmaceutically acceptable acid of the amines of formula (II);
e) amines of formula (III)
in which;
R
1b
represents a hydrogen atom or a halogen atom;
R
2b
represents a cyclohexyl group;
R
3b
represents a hydrogen atom or a C
1
-C
3
alkyl group;
R
4b
represents a C
1
-C
3
alkyl group which may be identical
R
3b
and R
4b
considered together may form, with the nitrogen atom to which they are attached, a 5- to 7-membered heterocyclic group chosen from piperidino, morpholino and pyrrolidino;
A
b
represents a —CH
2
CH
2
— or —CH═CH— group;
f) the pharmaceutically acceptable addition salts with acids of the amines of formula (III).
g) amines of formula (IV)
in which
A
c1
represents a phenyl, naphthyl, substituted phenyl or substituted naphthyl group,
n represents an integer between 1 and 4 inclusive,
RB represents an alkyl group and, in this case, A
c
represents a single bond and RA and RC, which may be identical or different, represent, independently of each other, a hydrogen atom or a group chosen from halogen, alkyl, alkyl substituted with one or more halogens, and alkoxy,
or RB and RC together form a bridge —(CH
2
) p- with p representing 0, 1 or 2 and, in this case, RA represents a hydroxyl or alkoxy group in position 5 on the aromatic ring which bears it or RA represents a hydrogen or halogen atom in any position on the aromatic ring,
or RB and RC together form a —CH═ bridge, and the bond with links it to the aromatic ring is a single bond and, in this case, A
c
represents a CH
2
group and RA represents a hydrogen atom or a hydroxyl or alkoxy group in position 5 on the aromatic ring which bears it,
or RB and RC together form a bond and A
c
then represents a group
the carbonyl being linked to the oxygen and the bond connecting A
c
to the carbon bearing the side chain is a double bond, and, in this case, RA represents a hydrogen atom or a hydroxyl or alkoxy group,
when RB represents an alkyl group, X and Y each represent two hydrogen atoms or form, together with the carbon atom which bears them, a C═O group, and RD represents a hydrogen atom or an alkyl group,
when RB and RC form a bridge, X and Y each representing two hydrogen atoms and RD, which exists only when all the bonds of the carbon which bears it are single bonds, represents a hydrogen atom, it being understood that
the terms “alkyl” and “alkoxy” denote linear or branched saturated groups containing from 1 to 6 carbon atoms.
the term “substituted” relating to the phenyl and naphthyl substituents means that these may be substituted with 1 to 3 groups chosen from hydroxyl, alkyl, alkyl substituted with one or more halogens, alkoxy and halogen,
the pharmaceutically acceptable salts and solvates of the amines of formula (IV);
i) amines of formula (V)
in which:
A
r2
and A
r3
, which may be identical or different, represent, independently of each other, a phenyl group, or a naphthyl or phenyl group substituted with 1 to 3 groups chosen from hydroxyl, (C
1
-C
6
) alkyl, alkoxy, halogen and alkyl, and alkyl substituted with one or more halogens;
X′ and Y′ each represent two hydrogen atoms or together form an oxo group,
RE represents a (C
1
-C
6
) alkyl group, their isomers in pure form or in the form of a mixture.
j) the pharmaceutically acceptable salts and solvates of the amines of formula (V)
k) amines of formula (VI)
in which:
R
3c
is H or (C
1
-C
3
) alkyl;
R
1c
and R
1c
, which may be identical or different, are chosen from H, OH, (C
1
-C
3
) alkyl, (C
1
-C
3
) alkoxy, halogen and cyano; V
1
and V
2
together form a double bond linked to an oxygen atom or alternatively a hydroxyimino radical N—OH, or alternatively are connected as an ethylenedioxy chain —O—CH
2
—CH
2
—O—;
A
d
represents a valency bond, an oxygen atom, a methylene group or an ethylene group; m′ is equal to zero, 1 or 2;
n′ is an integer from 1 to 5;
l) the pharmaceutically acceptable addition salts with acids of the amines of formula (VI)
m) amines of formula (VII)
in which
m″ and n″ represent 1 or 2,
Cy represents a (C
3
-C
7
) cycloalkyl,
Ar
4
represents an a
Breliere Jean Claude
Broeck Didier Van
Ferrara Pascual
Lebouteiller Christine
Paul Raymond
Alexander Michael D.
Chang Ceila
Sanofi-Synthelabo
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