Substituted heterocylic compounds, method of preparing them...

Details Substituted heterocylic compounds, method of preparing them... Substituted heterocylic compounds, method of preparing them...

1998-10-20

2001-06-05

O'Sullivan, Peter (Department: 1621)

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

Organic compounds

Carboxylic acid esters

C514S357000, C514S399000, C514S400000, C514S415000, C514S419000, C514S431000, C514S443000, C514S465000, C514S466000, C514S533000, C514S534000, C514S653000, C546S334000, C546S335000, C548S340100, C548S509000, C548S510000, C549S058000, C549S074000, C549S076000, C549S443000, C549S444000, C560S106000, C560S107000, C560S108000, C564S360000

Reexamination Certificate

active

06242637

ABSTRACT:

The present invention relates to novel substituted heterocyclic compounds, to a method of preparing them and to the pharmaceutical compositions in which they are present as the active principle.
More particularly, the present invention relates to a novel class of substituted heterocyclic compounds for therapeutic use in pathological phenomena involving the tachykinin system, such as: pain (D. Regoli et al., Life Sciences, 1987, 40, 109-117), allergy and inflammation (J. E. Morlay et al., Life Sciences, 1987, 41, 527-544), circulatory insufficiency (J. Losay et al., 1977, Substance P, Von Euler, I. S. and Pernow ed., 287-293, Raven Press, New York), gastrointestinal disorders (D. Regoli et al., Trends Pharmacol. Sci., 1985, 6, 481-484), respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50), neurological disorders and neuropsychiatric disorders (C. A. Maggi et al., J. Autonomic Pharmacol., 1993, 13, 23-93), these examples being neither limiting nor exclusive.
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. 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 therepeutics (J. Autonomic Pharmacol., 1993, 13, 23-93).
The following non-peptide compounds may be mentioned among the antagonists specific for the NK
1
receptor: 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 non-peptide selective antagonist, SR 48968, has been described in detail (Life Sci., 1992, 50, PL101-PL106).
As far as the NK
3
receptor is concerned, some non-peptide compounds have been described as having an affinity for the NK
3
receptor of the rat and guinea-pig brain (FASEB J., 1993, 7 (4), A710-4104); a peptide antagonist, [Trp
7
, &bgr;-Ala
8
]NK
A
, which has a weak specificty for the NK
3
receptor of the rat, has also been described (J. Autonomic Pharmacol., 1993, 13, 23-93).
Patent application EP-A-336230 describes peptide derivatives which are substance P and neurokinin A antagonists useful for the treatment and prevention of asthma.
International patent applications WO 90/05525, WO 90/05729, WO 91/09844 and WO 91/18899 and European patent applications EP-A-0436334, EP-A-0429466 and EP-A-0430771 describe substance P antagonists.
European patent applications EP-A-0474561, EP-A-512901, EP-A-515240, EP-A-559538 and EP-A-591040 also relate to neurokinin receptor antagonists.
Novel substituted heterocyclic compounds have now been found which are neurokinin receptor antagonists.
Thus, according to one of its features, the present invention relates to compounds of the formula
in which:
A is a divalent radical selected from:
A
1
) —O—CO—
A
2
) —CH
2
—O—CO—
A
3
) —O—CH
2
—CO—
A
4
) —O—CH
2
—CH
2
—
A
5
) —N(R
1
)—CO—
A
6
) —N(R
1
)—CO—CO—
A
7
) —N(R
1
)—CH
2
—CH
2
—
A
8
) —O—CH
2
—
in which R
1
is a hydrogen or a (C
1
-C
4
)-alkyl;
m is 2 or 3;
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 selected from CH
2
—Z, —CH(C
6
H
5
)
2
and —C(C
6
H
5
)
3
; T can also be the group —CO—B—Z if A is a divalent radical selected from —O—CH
2
—CH
2
—, —N(R
1
)— CH
2
—CH
2
— and —O—CH
2
—;
B is a direct bond or a methylene;
Z is an optionally substituted mono-, di- or tri- cyclic aromatic or heteroaromatic group; and
Am is:
i—either a group Am
1
of the formula
in which J
1
is:
i
1
—either a group
in which:
Ar
2
is a pyridyl; 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, a nitro and a methylendioxy, said substituents being identical or different; a thienyl; a pyrimidyl; or an imidazoyl which is unsubstituted or substituted by a (C
1
-C
4
)-alkyl; and
R
2
is a hydrogen; a (C
1
-C
7
)-alkyl; a benzyl; a formyl; or a (C
1
-C
7
)-alkylcarbonyl;
i
2
—or a group
in which:
Ar
2
is as defined above;
n is 0 is 1; and
R
3
is a group selected from:
(1) hydrogen;
(2) (C
1
-C
7
)-alkyl;
(3) formyl;
(4) (C
1
-C
7
)-alkylcarbonyl;
(5) cyano;
(6) —(CH
2
)
q
—OH;
(7) —(CH
2
)
q
—O—(C
1
-C
7
)-alkyl;
(8) —(CH
2
)
q
—OCHO;
(9) —(CH
2
)
q
—OCOR
17
;
(10) —(CH
2
)
q
—OCONH—(C
1
-C
7
)-alkyl;
(11) —NR
4
R
5
;
(12) —(CH
2
)
q
—NR
6
C(═W
1
)R
7
;
(13) —(CH
2
)
q
—NR
6
COOR
8
;
(14) —(CH
2
)
q
—NR
6
SO
2
R
9
;
(15) —(CH
2
)
q
—NR
6
C(═W
1
)NR
10
R
11
;
(16) —CH
2
—NR
12
R
13
;
(17) —CH
2
—CH
2
—NR
12
R
13
;
(18) —COOH;
(19) (C
1
-C
7
)-alkoxycarbonyl;
(20) —C(═W
1
)NR
10
R
11
;
(21) —CH
2
—COOH;
(22) (C
1
-C
7
)-alkoxycarbonylmethyl;
(23) —CH
2
—C(═W
1
)NR
10
R
11
;
(24) —O—CH
2
CH
2
—OR
18
;
(25) —NR
6
COCOR
19
;
(26) —CO—NR
20
—NR
21
R
22
;
or R
3
constitutes a double bond between the carbon atom to which it is bonded and the adjacent carbon atom of the piperidine ring;
q is 0, 1 or 2;
W
1
is an oxygen atom or a sulfur atom;
R
4
and R
5
are each independently a hydrogen or a (C
1
-C
7
)-alkyl; R
5
can also be a (C
3
-C
7
)-cycloalkylmethyl, a benzyl or a phenyl; or R
4
and R
5
, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C
1
-C
4
)-alkyl;
R
6
is a hydrogen or a (C
1
-C
7
)-alkyl;
R
7
is a hydrogen; a (C
1
-C
7
)-alkyl; a vinyl; a phenyl; a benzyl; a pyridyl; a (C
3
-C
7
)-cycloalkyl which is unsubstituted or substituted by one or more methyls; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
or R
6
and R
7
together are a group —(CH
2
)
p
—;
p is 3 or 4;
R
8
is a (C
1
-C
7
)-alkyl or a phenyl;
R
9
is a (C
1
-C
7
)-alkyl; an amino which is free or substituted by one or two (C
1
-C
7
)-alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected 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 and an amino which is free or substituted by one or two (C
1
-C
7
)-alkyls, said substituents being identical or different;
R
10
and R
11
are each independently a hydrogen or a (C
1
-C
7
)-alkyl; R
11
can also be a (C
3
-C
7
)-cycloalkyl, a (C
3
-C
7
)-cycloalkylmethyl, a hydroxyl, a (C
1
-C
4
)-alkoxy, a benzyl or a phenyl; or R
10
and R
11
, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine and perhydroazepine;
R
12
and R
13
are each independently a hydrogen or a (C
1
-C
7
)-alkyl; R
13
can also be a (C
3
-C
7
)-cycloalkylmethyl or a benzyl;
R
17
is a (C
1
-C
7
)-alkyl; a (C
3
-C
7
)-cycloalkyl which is unsubstituted or substituted

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