Substituted 1-phenyl-3-pyrazolecarboxamides active on...

Details Substituted 1-phenyl-3-pyrazolecarboxamides active on... Substituted 1-phenyl-3-pyrazolecarboxamides active on...

1999-08-16

2001-01-09

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S335500, C548S338100, C548S341500, C548S346100, C548S347100, C548S354100, C548S356100, C548S376100, C548S377100, C548S518000, C548S521000, C548S523000, C548S950000, C548S962000, C560S019000, C560S038000, C560S042000, C560S043000, C560S048000, C560S055000, C560S059000, C560S061000, C560S064000, C562S452000, C562S457000, C562S458000, C562S469000, C562S471000

Reexamination Certificate

active

06172239

ABSTRACT:

The present invention relates to new substituted 1-phenyl-3-pyrazolecarboxamides having a great affinity for human neurotensin receptors, to a process for preparing them and to pharmaceutical compositions containing them as active principles.
The first synthetic non-peptide potential medicinal products capable of binding to neutotensin receptors have been described in EP-0,477,049. They are amides of 3-pyrazolecarboxylic acid, variously substituted with amino acids, which displace iodinated neurotensin from its receptor, at doses of less than one micromole, on guinea pig brain membranes. This series led to the development of a compound, 2-[(1-(7-chloro-4-quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl)carbonylamino]-2-adamantanecarboxylic acid, SR 48692, endowed with potent and selective neurotensin-antagonist activity (D. Gully et al., Proc. Natl. Acad. Sci. USA, 1993, 90, 65-69).
The feature of the series of products described in EP-0,477,049 is the presence at position 1 of the pyrazole ring of, in particular, a phenyl, naphthyl or 4-quinolyl group, substituted or unsubstituted. More especially, SR 48692 possesses a 7-chloro-4-quinolyl group in position 1 of the pyrazole. The products described in this document having a 1-naphthyl or 4-chloro-1-naphthyl group in position 1 of the pyrazole ring have an extremely high affinity for the guinea pig neurotensin receptor, since their IC
50
is of the order of 1 to 10 nanomoles, whereas their affinity for the human receptor is lower since their IC
50
is from 10 to 100 nmol.
It has now been found that, by substituting the phenyl group of 1-phenyl-3-pyrazolecarboxamide compounds with particular groups, the affinity for neurotensin receptors is increased, and more especially the affinity for human neurotensin receptors is increased.
In addition, the compounds according to the present invention show in vivo a broader spectrum of activity than the compounds described in EP-0,477,049 as antagonists of the neurotensin receptors.
Thus, the present invention relates, according to one of its aspects, to new substituted 1-phenyl-3-pyrazolecarboxamides of formula:
in which:
R
1
represents a group chosen from:
—T—CN;
—C(NH
2
)═NOH;
—C(═NOH)NH(CH
2
)
r
NR
5
R
6
;
—T—C(NR
12
R
13
)═NR
14
;
—C(NH
2
)═NO(CH
2
)
r
NR
5
R
6
;
—T—CONR
a
R
b
;
—T—CONR
7
R
c
;
—Y—CO
2
R
7
;
—OR
d
;
—T—NR
5
R
6
, on condition that R
5
and R
6
do not simultaneously represent hydrogen when T represents a direct bond;
—T—N(R
7
)COR
e
;
—SO
2
NR
a
R
b
;
—T—N(R
7
)SO
2
R′
7
;
—T—NR
27
R
28
;
—NR
a
R
b
represents a group chosen from:
—NR
5
R
6
; —NR
9
(CH
2
)
s
CR
7
R
8
(CH
2
)
t
NR
5
R
6
;
—NR
7
(CH
2
)
q
CN; —NR
7
(CH
2
)
q
C(NR
12
R
13
)═NR
14
; —NR
7
(CH
2
)
q
CONH
2
; —NR
7
(CH
2
)
q
CO
2
R
7
; —NR
21
(CH
2
)
s
CR
7
R
8
(CH
2
)
t
NR
25
R
26
;
R
c
represents a group chosen from:
—X—OR
7
; —CHR
20
CO
2
R
7
; —(CH
2
)
4
CH(NH
2
)CO
2
R
7
;
R
d
represents a group chosen from:
—X—NR
5
R
6
; —Y—CONR
5
R
6
; —Y—CO
2
R
7
; —Y—SO
2
NR
5
R
6
;
R
e
represents a group chosen from:
—R
16
; —Y—NR
5
R
6
; —Y—NHCOR
16
; —CH(R
17
)NR
5
R
6
;
—(CH
2
)
q
CN; —(CH
2
)
q
C(NR
12
R
13
)═NR
14
; —NR
18
R
19
;
R
2
and R
3
each independently represent hydrogen, a (C
1
-C
6
)alkyl, a (C
3
-C
8
)cycloalkylmethyl, a (C
3
-C
8
)-cycloalkyl, a halogen, a nitro, a trifluoromethyl, a group —OR
4
, a group —NR
5
R
6
, a 1-pyrrolyl, a cyano, a carbamoyl;
or R
2
and R
3
together constitute a trimethylene, tetramethylene or pentamethylene group;
R
4
represents hydrogen; a (C
1
-C
6
)alkyl; a (C
3
-C
4
)-alkenyl; a (C
3
-C
8
)cycloalkyl; a (C
3
-C
8
)cycloalkylmethyl; a (C
1
-C
4
)alkoxy(C
l
-C
4
)alkylene; a benzyl;
R
5
and R
6
each independently represent a hydrogen, a (C
1
-C
6
)alkyl; a (C
3
-C
8
)alkenyl; a (C
3
-C
8
)cycloalkylmethyl; a benzyl; or R
5
and R
6
, together with the nitrogen atom to which they are attached, represent a heterocycle chosen from: pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine substituted at position 4 with R
9
, aziridine, azetidine and perhydroazepine;
R′
5
and R′
6
each independently represent a hydrogen or a (C
1
-C
6
)alkyl; or alternatively, R′
5
and R′
6
, together with the nitrogen atom to which they are attached, represent a heterocycle chosen from: pyrrolidine, piperidine, morpholine, thiomorpholine and piperazine which is unsubstituted or substituted at position 4 with a (C
1
-C
6
)alkyl;
R′
7
represents a (C
1
-C
4
)alkyl; a phenyl which is unsubstituted or substituted one or more times with a (C
1
-C
4
)alkyl; a group —X—NR
5
R
6
;
R
7
represents a hydrogen, a (C
1
-C
4
)alkyl or a benzyl;
R
8
represents a hydrogen, a (C
1
-C
4
)alkyl, a hydroxyl, or R
7
and R
8
, together with the carbon atom to which they are attached, constitute a (C
3
-C
5
)cycloalkane;
R
9
represents hydrogen, a (C
1
-C
4
)alkyl, a benzyl, a group —X—OH or a group —X—NR′
5
R′
6
, a (C
3
-C
8
)alkenyl;
R
10
represents a hydrogen, a (C
1
-C
4
)alkyl, a benzyl, a carbamoyl, a cyano;
R
11
represents a hydrogen, a (C
1
-C
4
)alkyl, a group —X—OH, a group —X—NR′
5
R′
6
;
R
12
and R
13
each independently represent a hydrogen or a (C
1
-C
4
)alkyl;
R
14
represents hydrogen, R
14
can, in addition, represent a (C
1
-C
4
)alkyl when R
12
represents hydrogen and R
13
represents a (C
1
-C
4
)alkyl;
or R
13
and R
14
together represent a group Z;
R
15
represents hydrogen, a (C
1
-C
4
)alkyl, a group —(CH
2
)
s
NR
5
R
6
;
R
16
represents hydrogen, a (C
1
-C
8
)alkyl, a (C
3
-C
8
)-cycloalkyl, a phenyl, a 2-piperidyl, a 3-piperidyl, a 4-piperidyl;
R
17
represents a (C
1
-C
6
)alkyl, a phenyl, a benzyl, a hydroxy(C
1
-C
4
)alkyl, an amino(C
1
-C
4
)alkyl;
R
18
and R
19
each independently represent a hydrogen, a (C
1
-C
4
)alkyl; R
18
can, in addition, represent a group —(CH
2
)
q
—NR
5
R
6
;
or R
18
and R
19
, together with the nitrogen atom to which they are attached, represent a heterocycle chosen from: pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine substituted at position 4 with R
9
;
R
20
represents hydrogen, a (C
1
-C
4
)alkyl, a benzyl, a hydroxyphenylmethyl, preferably a 4-hydroxyphenylmethyl, a hydroxy(C
1
-C
4
)alkyl, a mercapto(C
1
-C
4
) alkyl; a —(CH
2
)
3
—NH—C(═NH)NH
2
group, a —(CH
2
)
4
NH
2
group, a group —CH
2
—Im in which Im represents a 4-imidazolyl;
R
21
represents a (C
1
-C
4
)alkyl, an allyl or a benzyl;
R
22
and R
23
each independently represent a (C
1
-C
6
)-alkyl; or alternatively R
22
and R
23
, together with the nitrogen atom to which they are attached, represent a heterocycle chosen from: pyrrolidine, piperidine, morpholine and perhydroazepine;
R
24
represents a (C
1
-C
4
)alkyl, a benzyl, an allyl, a hydroxy(C
1
-C
4
)alkyl, a (C
1
-C
4
)alkoxy(C
1
-C
4
)alkyl;
Q
⊖
represents an anion;
R
25
represents hydrogen or a (C
1
-C
6
)alkyl;
R
26
represents a (C
1
-C
4
)alkoxycarbonyl, a benzyloxycarbonyl; a (C
1
-C
4
)alkylcarbonyl;
R
27
represents a hydrogen; a (C
1
-C
4
)alkyl, a (C
1
-C
4
)alkylcarbonyl; a group —CO—(CH
2
)
r
—OH; a group SO
2
R′
7
;
R
28
represents a group —X—NR
5
R
6
;
s=0 to 3;
t=0 to 3, on the condition that (s+t), in a same group, is greater than or equal to 1;
r=2 to 5;
q=1 to 5;
T represents a direct bond or (C
1
-C
7
)alkylene;
X represents a (C
2
-C
7
)alkylene;
Y represents a (C
1
-C
7
)alkylene;
Z represents a (C
2
-C
6
)alkylene;
the bivalent radicals A and E, together with the carbon atom and the nitrogen atom to which they are attached, constitute a saturated 4- to 7-membered heterocycle which can, in addition, be substituted with one or more (C
1
-C
4
)alkyls;
the bivalent radicals G and L, together with the nitrogen atoms to which they are attached, constitute a piperazine or imidazolidine or imidazoline ring, the said rings being optionally substituted on the carbon atoms with one or more (C
1
-C
4
)alkyls;
the group —NH—AA(OH) represents the residue of an amino acid:
 where X
a
is hydrogen and X′
a

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