Compounds which are specific antagonists of the human NK3...

Details Compounds which are specific antagonists of the human NK3... Compounds which are specific antagonists of the human NK3...

1999-05-07

2001-09-25

Kight, John (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S255030, C514S318000, C514S319000, C514S323000, C514S324000, C514S327000, C514S329000

Reexamination Certificate

active

06294537

ABSTRACT:

The subject of the present invention is new compounds which are selective antagonists of the human NK
3
receptor and their use for the preparation of medicinal products useful in the treatment of psychiatric diseases, of diseases of psychosomatic origin, of hypertension and, generally, of any central or peripheral pathology in which neurokinin B and the NK
3
receptor are involved in interneuronal regulation.
During the past few years, many research studies have been carried out on tachykinins and their receptors. Tachykinins are distributed both in the central nervous system and in the peripheral nervous system. The tachykinin receptors have been recognized and are classified into three types: NK
1
, NK
2
, NK
3
. Substance P (SP) is the endogenous ligand for the NK
1
receptors, neurokinin A (NK
A
) that for the NK
2
receptors and neurokinin B (NK
B
) that for the NK
3
receptors.
The NK
1
, NK
2
, NK
3
receptors have been identified in various species. Thus, the NK
3
receptors have been identified in guinea pigs, rats, monkeys (Br. J. Pharmacol., 1990, 99, 767-773; Neurochem. Int., 1991, 18, 149-165); more recently, they were also identified in man (FEBS Letters, 1992, 229 (1), 90-95).
A recent review by C. A. Maggi et al. presents a summary of the findings on the tachykinin receptors and their antagonists and describes the pharmacological studies and the applications on human therapy (J. Autonomic Pharmacol., 1993, 13, 23-93).
Among the specific antagonists of the NK
1
receptor, there may be mentioned the following nonpeptide compounds: CP-96345 (J. Med. Chem., 1992, 35, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88, 10208-10212), SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).
For the NK
2
receptor, a selective nonpeptide antagonist, SR 48968 has been described in detail (Life Sci., 1992, 50, PL101-PL106).
As regards the NK
3
receptor, some nonpeptide compounds, antagonists for Angiotensin II, have been described, up until now, as having affinity for rat and guinea pig brain NK
3
receptor; this affinity is very low and corresponds to an inhibition constant Ki of the order of 10
−5
M (FASEB J., 1993, 7 (4), A 710, 4104). A peptide antagonist [Trp
7
, Ala
8
]NK
A
, weakly specific for rat NK
3
receptor has also been described (J. Autonomic Pharmacol., 1993, 13, 23-93).
In Patent Application EP 512901, it is indicated that 5-[2-(4-hydroxy-4-phenylpiperid-1-yl)ethyl]-5-(3,4-dichlorophenyl)-1-benzylpiperid-2-one hydrochloride, called hereinafter compound A, antagonizes the binding of eledoisin with a Ki of 200 nanomolar, eledoisin being a peptide of batrachian origin equivalent to neurokinin B.
Patent Application EP 474561 describes neurokinin antagonists, more particularly NK
1
or NK
2
receptor antagonists; in particular this application describes N-methyl-N-[2-(3,4-dichlorophenyl)-5-(4-hydroxy-4-phenylpiperid-1-yl)pentyl]benzamide hydrochloride.
None of the peptide or nonpeptide compounds known up until now have a high affinity for the human NK
3
receptor.
Pharmacological studies of the peptide and nonpeptide antagonists of the NK
1
and NK
2
receptors have shown that their affinities for these receptors as well as their pharmacological activities were very highly a function of the species, most probably as a result of small differences in the aminoacid sequences, thereby inducing very fine structural variations in these receptors from one species to another (J. Autonomic Pharmacol., 1993, 13, 23-93). Some experimental data, confirmed by the pharmacological characterization of the compounds which are the subject of the present invention, appear to indicate that a comparable situation exists for the NK
3
receptor. In particular, human NK
3
receptor is different from rat NK
3
receptor.
Nonpeptide compounds have now been found which have a very high affinity for the human NK
3
receptor and a high specificity for said receptor. These compounds can be used for the preparation of medicinal products which are useful in the treatment of psychiatric diseases or of diseases of psychosomatic origin and of all central or peripheral diseases in which neurokinin B and the NK
3
receptor are involved in interneuronal regulation.
Very high affinity for the human NK
3
receptor is understood to mean an affinity characterized by an inhibition constant Ki which is generally less than 5·10
−9
M.
In studies on the binding of a ligand, the inhibition constant Ki is defined by the Cheng-Prusoff equation (in Receptor Binding in Drug Research, eds. R. A. O'BRIEN. Marcel Dekker, New York, 1986):
Ki
=
IC
50
1
+
[
L
]
Kd
[L]: ligand concentration
Kd: dissociation constant of the ligand,
IC
50
: concentration which inhibits 50% of the ligand binding.
By high specificity for the human NK
3
receptor, it is understood that the inhibition constant (Ki) for the human NK
3
receptor is generally at least 100 times lower than the inhibition constant (Ki) for the NK
2
receptor or than that for the NK
1
receptor of different species.
Disease of psychosomatic origin designates diseases having their origin in the central nervous system (CNS) and pathological consequences at the peripheral level.
Thus, according to one of its aspects, the subject of the present invention is compounds of formula:
in which:
Ar represents a pyrid-2-yl or a phenyl which is unsubstituted or substituted by a halogen, a methyl or a (C
1
-C
4
)alkoxy;
R
1
represents the methyl group;
R
11
represents hydrogen;
or R
1
and R
11
together represent a —(CH
2
)
3
— group;
R
2
represents a hydroxyl; a (C
1
-C
7
)alkoxy; a (C
1
-C
7
)acyloxy; a cyano; an —NR
6
R
7
group; an —NR
3
COR
4
group; an —NR
3
COOR
8
group; an —NR
3
SO
2
R
9
group; an —NR
3
CONR
10
R
12
group; a (C
1
-C
7
)acyl group; a (C
1
-C
7
)alkoxycarbonyl; a —CONR
10
R
12
group; a —CH
2
OH group; a (C
1
-C
7
)alkoxymethyl; a (C
1
-C
7
)acyloxymethyl; a (C
1
-C
7
)alkylaminocarbonyloxymethyl; a —CH
2
NR
13
R
14
group; a —CH
2
NR
3
COR
4
group; a —CH
2
NR
3
COOR
8
group; a —CH
2
NR
3
SO
2
R
9
group; a —CH
2
NR
3
CONR
10
R
12
group; or R
2
constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring;
or Ar and R
2
, together with the carbon atom to which they are attached, constitute a group of formula:
R
3
represents a hydrogen or a (C
1
-C
4
)alkyl;
R
4
represents a hydrogen, a (C
1
-C
7
)alkyl, a phenyl, a benzyl, a pyridyl or a (C
3
-C
7
)cycloalkyl which is unsubstituted or substituted by one or more methyls;
or R
3
and R
4
together represent a (CH
2
)
n
group;
n is 3 or 4;
T represents a methylene, a carbonyl, a —COO— group, a —CONR
5
— group;
A represents a direct bond, a methylene, an ethylene, a propylene, a vinylene;
or —T—A— represents the —SO
2
— group
Z represents a phenyl which is unsubstituted or substituted one or several times by a halogen, a (C
1
-C
4
)alkyl, a (C
1
-C
4
)alkoxy, a nitro;
R
5
represents a hydrogen or a (C
1
-C
4
)alkyl;
R
6
and R
7
each represent independently a hydrogen or a (C
1
-C
7
)alkyl; R
7
can furthermore represent a (C
3
-C
7
)cycloalkylmethyl, a benzyl or a phenyl; or R
6
and R
7
, together with the nitrogen atom to which they are attached, constitute a heterocycle chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or perhydroazepine;
R
8
represents a (C
1
-C
7
)alkyl or a phenyl;
R
9
represents a (C
1
-C
7
)alkyl; an amino which is free or substituted by one or two (C
1
-C
7
)alkyls; a phenyl which is unsubstituted or substituted once or several times by a substituent chosen from: a halogen atom, a (C
1
-C
7
)alkyl, a trifluoromethyl, a hydroxyl, a (C
1
-C
7
)alkoxy, a carboxyl, a (C
1
-C
7
)alkoxycarbonyl, a (C
1
-C
7
)alkylcarbonyloxy, a cyano, a nitro, an amino which is free or substituted by one or two (C
1
-C
7
)alkyls, the said substituents being identical or different;
R
10
and R
12
each represent independently a hydrogen or a (C
1
-C
7
)alkyl; R
12
may furthermore represent a (C
3
-C
7
)cycloalkyl, a (C
3
-C
7
)cyclo

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