Human NK3 receptor-selective antagonist compounds, method...

Details Human NK3 receptor-selective antagonist compounds, method... Human NK3 receptor-selective antagonist compounds, method...

2001-09-18

2004-03-23

Aulakh, C. S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S597000, C540S598000

Reexamination Certificate

active

06710042

ABSTRACT:

The present invention relates to novel selective human NK
3
receptor antagonist compounds for the preparation of drugs useful in the treatment of psychiatric diseases, diseases of psychosomatic origin, hypertension and, in general, any central or peripheral pathological condition in which neurokinin B and the NK
3
receptor are involved in the interneuronal regulatory processes, to a method of obtaining said compounds and to the pharmaceutical compositions in which they are present as the active principle.
Diseases of psychosomatic origin are understood as meaning diseases which originate in the central nervous system (CNS) and have pathological consequences on the peripheral nervous system.
In recent years, numerous research studies have been carried out on tachykinins and their receptors. Tachykinins are distributed throughout both the central nervous system and 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 of the NK
1
receptors, neurokinin A (NK
A
) that of the NK
2
receptors and neurokinin B (NK
B
) that of the NK
3
receptors.
The NK
1
, NK
2
and NK
3
receptors have been identified in different species. Thus the NK
3
receptors have been identified in the guinea-pig, the rat and the monkey (Br. J. Pharmacol., 1990, 99, 767-773); Neurochem. Int., 1991, 18 149-165); they have also been identified in man (FEBS Letters, 1992, 299 (1), 90-95).
A review by C. A. Maggi et al. looks at the tachykinin receptors and their antagonists and gives an account of the pharmacological studies and the applications in human therapeutics (J. Autonomic Pharmacol., 1993, 13, 23-93).
The following non-peptide compounds may be mentioned among the specific NK
1
receptor antagonists: CP-96345 (J. Med. Chem., 1992, 35, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88, 10208-10212) and SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).
In the case of the NK
2
receptor, the non-peptide selective antagonist SR 48968 has been described in detail (Life Sci., 1992, 50, PL101-PL106).
As far as the human NK
3
receptor is concerned, the non-peptide selective antagonist (+)-N-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperid-3-yl]propyl]-4-phenylpiperid-4-yl]-N-methylacetamide hydrochloride, or SR 142801, has been described (EP-A-0 673 928; Peptides and their antagonists in tissue injury, Montreal, Canada, Jul. 31, 1994-Aug. 3, 1994. Canadian J. Physiol. Pharmacol., 1994, 72 (suppl. 2), 25, Abst. III. 0.9; Life Sci., 1994, 56 (1), 27-32; British Pharmacol. Society, Canterbury, Apr. 6-8, 1995; Eur. J. Pharmacol., 1995, 278 (1), 17-25; 1st Eur. Congress Pharmacol., Milan, Jun. 16-19, 1995).
Patent applications EP 474 561 and EP 512 901 describe neurokinin antagonists, more particularly NK
1
or NK
2
receptor antagonists. Pharmacological studies of peptide and non-peptide NK
1
and NK
2
receptor antagonists have shown that their affinities for these receptors, and their pharmacological activities, are very dependent on the species; this is very probably the result of small differences in the amino acid sequences, inducing very slight structural variations in these receptors from one species to another (J. Autonomic Pharmacol., 1993, 13 23-93). Some experimental data, confirmed by pharmacological characterization of the compounds forming the subject of the present invention, seem to indicate that a comparable situation exists for the NK
3
receptor. In particular, the human NK
3
receptor differs from the NK
3
receptor of the rat.
Non-peptide compounds have now been found which have a very strong affinity for the human NK
3
receptor and a high specificity for said receptor. These compounds can be used for the preparation of drugs useful in the treatment of psychiatric diseases, diseases of psychosomatic origin and any central or peripheral diseases in which neurokinin B and the NK
3
receptor are involved in the interneuronal regulatory processes.
Very strong affinity for the human NK
3
receptor is understood as meaning an affinity characterized by an inhibition constant Ki which is generally less than 5.10
−9
M.
In ligand binding studies, the inhibition constant Ki is defined by the Cheng-Prusoff relationship (in Receptor Binding in Drug Research, eds. R. A. O'BRIEN. Marcel Dekker, New York, 1986):
Ki
=
IC
50
1
+
[
L
]
Kd
[L]: concentration of the ligand,
Kd: dissociation constant of the ligand,
IC
50
: concentration which inhibits ligand binding by 50%.
High specificity for the human NK
3
receptor is understood as meaning 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 the inhibition constant for the NK
1
receptor of different species.
Thus, according to one of its aspects, the present invention relates to compounds of the formula
in which:
R
1
is hydrogen;
R
2
is the methyl group;
or R
1
and R
2
together form a group —(CH
2
)
3
— or —(CH
2
)
4
—;
Ar
1
is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C
1
-C
4
)alkoxy, a (C
1
-C
4
)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; a thienyl which is unsubstituted or substituted by a halogen atom; a benzothienyl which is unsubstituted or substituted by a halogen atom; a naphthyl which is unsubstituted or substituted by a halogen atom; an indolyl which is unsubstituted or N-substituted by a (C
1
-C
4
)alkyl or a benzyl; an imidazolyl which is unsubstituted or substituted by a halogen atom; a pyridyl which is unsubstituted or substituted by a halogen atom; or a biphenyl;
T is a group —CH
2
—; a group —CO—; a group —COO—; or a group —CONR
3
— in which R
3
is a hydrogen or a (C
1
-C
4
)alkyl;
A is a direct bond; a group —(CH
2
)
t
—, in which t is one, two or three; or a vinylene group;
or —T—A— is the group —SO
2
—;
Z is an optionally substituted, mono-, di- or tri-cyclic aromatic or heteroaromatic group; and
B is:
i—either a group B
1
of the formula
in which J
1
is:
i
1
either a group
in which:
x is zero or one;
Ar
2
is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a nitro, a hydroxyl, a trifluoromethyl, a (C
1
-C
4
)alkyl, a (C
1
-C
4
)alkoxy and a methylenedioxy, said substituents being identical or different; a pyridyl; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstituted or substituted by a (C
1
-C
4
)alkyl; and
X
1
is a group selected from:
(1) hydrogen;
(2) (C
1
-C
7
)alkyl;
(3) formyl;
(4) (C
1
-C
7
)alkylcarbonyl;
(5) —(CH
2
)
m
—OR
4
;
(6) —(CH
2
)
m
—OCOR
5
;
(7) —(CH
2
)
m
—OCONH—(C
1
-C
7
)alkyl;
(8) —O—CH
2
CH
2
—OR
6
;
(9) —(CH
2
)
n
—SR
7
;
(10) —CH
2
—S(O)
j
—(C
1
-C
7
)alkyl;
(11) —NR
8
R
9
;
(12) —(CH
2
)
p
—NR
10
R
11
;
(13) —NR
12
COR
13
;
(14) —NR
4
COCOR
15
;
(15) —(CH
2
)
p
—NR
14
C(═W
1
)R
16
;
(16) —(CH
2
)
m
—NR
14
COOR
17
;
(17) —(CH
2
)
m
—NR
14
SO
2
R
18
;
(18) —(CH
2
)
m
—NR
14
C(═W
1
)NR
19
R
20
;
(19) —(CH
2
)
n
—COOR
21
;
(20) —(CH
2
)
n
—C(═W
1
)NR
19
R
20
;
(21) —CO—NR
22
—NR
23
R
24
;
(22) —CN;
 or X
1
forms a double bond between the carbon atom to which it is bonded and the adjacent carbon atom of the piperidine ring;
in which groups:
m is zero, one or two;
n is zero or one;
p is one or two;
j is one or two;
W
1
is an oxygen atom or a sulfur atom;
R
4
is a hydrogen or a (C
1
-C
7
)alkyl;
R
5
is a hydrogen; a (C
1
-C
7
)alkyl; a (C
3
-C
7
)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
R
6
is a hydrogen; a (C
1
-C
7
)alkyl; a formyl; or a (C
1
-C
7
)alkylcarbonyl;
R
7
is a hydrogen or a (C
1
-C
7
)alkyl;
R
8
and R
9
are each independently a hydrogen or a (C
1
-C
7
)alkyl; R
9
can also be a (C
3
-C
7
)cycloalkylmethyl, a benzyl or a phenyl;
or R
8
and R
9
, together with the nitrogen atom to which they are b

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