Indolin-2-one derivatives, preparation and their use as...

Details Indolin-2-one derivatives, preparation and their use as... Indolin-2-one derivatives, preparation and their use as...

2002-10-02

2004-01-06

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S144000, C544S373000, C514S339000, C514S417000, C514S414000, C514S254090, C514S323000, C514S217030, C514S235200, C546S277700, C546S201000, C548S486000, C548S467000, C540S602000

Reexamination Certificate

active

06673790

ABSTRACT:

This application is a 371 of PCT/FR01/00980 Apr. 2, 2001.
A subject-matter of the present invention is novel indolin-2-one derivatives, a process for their preparation and the pharmaceutical compositions comprising them. These novel derivatives are powerful and selective ligands of the oxytocin receptors and can thus be used as an active principle in pharmaceutical compositions, in particular in the obstetric or gynaecological field. Oxytocin (OT) is a hormone excreted by the neurohypophysis with a cyclic nonapeptide structure similar to that of arginine vasopressin (AVP). The oxytocin receptors are essentially found on the smooth muscle of the uterus and on the myoedithelial cells of the mammary glands. Thus, oxytocin plays an important role in parturition since it is involved in the contraction of the uterine muscle and in lactation. Furthermore, oxytocin receptors are also located in other peripheral tissues and in the central nervous system; oxytocin can thus have effects in the cardiovascular, renal, endocrinal or behavioural fields.
Indolin-2-one derivatives have been disclosed in some patent applications as ligands of the vasopressin receptors and possibly of the oxytocin receptors; mention may be made of Patent Applications WO 93/15051, EP 636 608, EP 636 609, WO 95/18105, WO 97/15556 and WO 98/25901. To date, no indolin-2-one derivative has been disclosed as a powerful and selective ligand of oxytocin receptors.
It has now been found that certain indolin-2-one derivatives are powerful and selective ligands of oxytocin receptors.
Thus, according to one of its aspects, the present invention relates to novel indolin-2-one derivatives in the form of a pure enantiomer or a mixture of enantiomers of formula:
in which:
R
0
represents a group chosen from:
in which:
Z
1
represents a chlorine, bromine, iodine or fluorine atom or a (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy or trifluoromethyl group;
Z
2
represents a hydrogen, chlorine, bromine, iodine or fluorine atom or a (C
1
-C
4
)alkyl, (C
3
-C
5
)cycloalkyl, (C
1
-C
4
)alkoxy, (C
3
-C
5
) cycloalkoxy or (C
1
-C
4
)polyfluoroalkyl group;
R
5
represents T
1
W in which T
1
represents —(CH
2
)
m
, it being possible for m to be equal to 0 or 1, and W represents a hydrogen atom or a hydroxycarbonyl (or carboxyl), (C
1
-C
4
)alkoxycarbonyl, 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl group,
or else W represents an —NR
6
R
7
group in which R
6
and R
7
represent, independently of one another, a hydrogen atom, a (C
1
-C
4
)alkyl group, a (C
1
-C
4
)alkylsulphonyl group or a phenylsulphonyl group in which the phenyl group can be mono-, di- or trisubstituted by Z
5
; or else R
6
and R
7
form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally substituted by a (C
1
-C
4
)alkyl group or an oxo; or else R
6
and R
7
form, with the nitrogen atom to which they are bonded, a piperazinyl group optionally substituted in the 4-position by a Z
3
substituent; or else R
6
and R
7
form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z
4
;
or else W represents an —NR
8
COR
9
group in which R
8
represents a hydrogen atom or a (C
1
-C
4
)alkyl group and R
9
represents a hydrogen atom or a (C
1
-C
4
)alkyl, benzyl, pyridyl or phenyl group, it being possible for the said phenyl group to be mono-, di- or trisubstituted by Z
5
; or else R
9
represents an —NR
10
R
11
group in which R
10
and R
11
represent, independently of one another, a hydrogen atom or a (C
1
-C
4
)alkyl [lacuna] or else R
10
and R
11
form, with the nitrogen atom to which they are bonded, a pyrrolidinyl, piperidyl or morpholinyl group optionally substituted by a (C
1
-C
4
)alkyl group; or else R
9
represents a pyrrolidin-2-yl or -3-yl or piperid-2-yl, -3,-yl or -4-yl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z
7
; or else R
9
represents a —T
2
—R
12
or —T
2
—COR
12
group in which T
2
represents —(CH
2
)
n
—, it being possible for n to be equal to 1, 2, 3 and 4, and R
12
represents a (C
1
-C
4
)alkoxy or —NR
10
R
11
group, R
10
and R
11
being as defined above;
or else W represents a —CONR
13
R
14
group in which R
13
represents a hydrogen atom or a (C
1
-C
4
) alkyl, (C
3
-C
7
) cycloalkyl, monofluoro(C
1
-C
4
)alkyl or polyfluoro(C
1
-C
4
)alkyl group and R
14
represents a hydrogen atom, a (C
1
-C
4
)alkyl group, a phenyl group optionally substituted by Z
5
, a —T
4
—R
15
group in which T
4
represents —(CH
2
)
q
, with q equal to 1, 2, 3 or 4, and R
15
represents a hydroxyl group, a (C
1
-C
4
)alkoxy group, a (C
1
-C
4
)alkoxycarbonyl group, a (C
1
-C
4
)alkoxycarbonylamino group, a phenyl group optionally mono- or disubstituted by Z
5
, a pyrid-2-yl, -3-yl or -4-yl, or an —NR
16
R
17
group in which R
16
and R
17
represent, independently of one another, a hydrogen atom or a (C
1
-C
4
)alkyl [lacuna] or else R
16
and R
17
form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C
1
-C
4
)alkyl group or else R
16
and R
17
form, with the nitrogen atom to which they are bonded, a piperazinyl group optionally substituted in the 4-position by a Z
3
substituent or else R
16
and R
17
form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z
5
, it being understood that, when q=1, R
15
is other than hydroxyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkoxycarbonylamino or —NR
16
R
17
; or else R
13
and R
14
form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C
1
-C
4
)alkyl group or a piperazinyl group optionally substituted in the 4-position by a Z
3
substituent; or else R
13
and R
14
form, with the nitrogen atom to which they are bonded, an azetidinyl, pyrrolidinyl, piperidyl or hexahydroazepinyl group, the said pyrrolidinyl, piperidyl and hexahydroazepinyl groups optionally being mono- or disubstituted by Z
8
;
or else W represents an OR
18
group in which R
18
represents a hydrogen atom or a (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy(C
1
-C
4
)alkyl or —T
3
—R
19
group in which T
3
represents —(CH
2
)
p
—, it being possible for p to be equal to 2 or 3, and R
19
is chosen from the hydroxyl, triphenylmethoxy or —NR
20
R
21
groups in which R
20
represents a hydrogen atom or a (C
1
-C
4
)alkyl group and R
21
represents a hydrogen atom or a (C
1
-C
4
)alkyl, tetrahydrofuranylmethyl or tetrahydropyranylmethyl group, or else R
20
and R
21
form,,with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C
1
-C
4
)alkyl group or a piperazinyl group optionally substituted in the 4-position by a Z
3
substituent, or else R
20
and R
21
form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z
5
;
Z
3
represents a (C
1
-C
4
)alkyl, pyridyl, phenyl, (C
1
-C
4
)alkylcarbonyl or (C
1
-C
4
)alkoxycarbonyl group;
Z
4
represents an oxo, a fluorine atom, a hydroxyl, a (C
1
-C
4
)alkyl, a benzyl, an amino, a (C
1
-C
4
)alkylamino, a di(C
1
-C
4
)alkylamino, a (C
1
-C
4
)alkoxy, a (C
1
-C
4
)alkoxycarbonyl or a (C
1
-C
4
)alkoxycarbonylamino;
Z
5
represents a chlorine, bromine, iodine or fluorine atom, a hydroxyl group, a (C
1
-C
4
)alkyl group or a (C
1
-C
4
)alkoxy group;
Z7 represents a fluorine atom, a hydroxyl group, a hydroxy(C
1
-C
4
)alkyl group, a (C
1
-C
4
)alkyl [lacuna], a (C
1
-C
4
)alkoxy [lacuna] or a (C
1
-C
4
)alkylcarbonyl [lacuna];
Z
8
represents a fluorine atom or a hydroxyl, (C
1
-C
4
)alkyl, (C
3
-C
6
)cycloalkyl, benzyl, amino, (C
1
-C
4
)alkylamino, di(C
1
-C
4
)alkylamino, (C
1
-C
4
)alkoxycarbonyl, (C
1
-C
4
)alkoxycarbonylamino, (C
3
-C
6
)cycloalkoxy, hydroxycarbonyl, hydroxy(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy (C
1
-C
4
)alkyl, (C
1

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