Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2000-09-22
2002-09-03
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S492000, C540S553000, C544S171000, C544S055000, C544S058200, C544S058600, C544S096000, C544S098000, C544S316000, C544S129000, C544S130000, C544S361000, C544S171000, C544S187000, C544S209000, C544S210000, C546S174000, C546S175000, C546S193000, C546S201000, C546S202000
Reexamination Certificate
active
06444809
ABSTRACT:
This invention concerns novel therapeutic heterocycles, and, more particularly, novel 4-substituted piperidine derivatives which antagonize the pharmacological actions of one of the endogenous neuropeptide tachykinins known as neurokinins, particularly at the neurokinin 2 (NK2) receptor. The novel therapeutic heterocycles are useful whenever such antagonism is desired. Thus, such compounds may be of value in the treatment of those diseases in which an NK2 receptor is implicated, for example, in the treatment of asthma and related conditions. The invention also provides pharmaceutical compositions containing the novel therapeutic heterocycles for use in such treatment, methods for their use, and processes and intermediates for the manufacture of the novel therapeutic heterocycles.
The mammalian neurokinins comprise a class of peptide neurotransmitters which are found in the peripheral and central nervous systems. The three principal neurokinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB). There are also N-terminally extended forms of at least NKA. At least three receptor types are known for the three principal neurokinins. Based upon their relative selectivities favoring the neurokinin agonists SP, NKA and NKB, respectively, the receptors are classifed as neurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3) receptors, respectively. In the periphery, SP and NKA are localized in C-afferent sensory neurons, which neurons are characterized by non-myelinated nerve endings known as C-fibers, and are released by selective depolarization of these neurons, or selective stimulation of the C-fibers. C-Fibers are located in the airway epithelium, and the tachykinins are known to cause profound effects which clearly parallel many of the symptoms observed in asthmatics. The effects of release or introduction of tachykinins in mammalian airways include bronchoconstriction, increased microvascular permeability, vasodilation and activation of mast cells. Thus, the tachykinins are implicated in the pathophysiology and the airway hyperresponsiveness observed in asthmatics; and blockade of the action of released tachykinins may be useful in the treatment of asthma and related conditions.
Peptidic NK2 antagonists have been reported. For example, a cyclic hexapeptide known as L-659,877 has been reported as a selective NK2 antagonist. Nonpeptidic NK2 antagonists also have been reported, for example, certain piperidines are disclosed in European Patent Applications, Publication Numbers 428434, 474561, 512901, 512902, 515240, and 559538. A series of piperidine NK2 antagonists has also been reported in International Application, Publication Number WO 94/10146.
We have discovered a series of novel nonpeptidic NK2 antagonists and this is the basis for our invention. One aspect of the discovery includes 4-substituted piperidino derivatives in which the 4-substituent is an N-linked heterocycle (as defined below). For example, we discovered the 4-(2-oxo-1,3-oxazolidin-3-yl)piperidino compound disclosed below at Example 1 to be a potent NK2 antagonist in the in vitro screen described below as Test A and in the functional assay described below as Test B.
According to the invention, there is provided a Compound of the invention; which is a compound of formula I (formula set out hereinbelow following the Examples, together with other formulae denoted by Roman numerals) wherein
m is 2 or 3;
D is a residue of formula Ia or formula Ib wherein
Q is phenyl which may bear one or two substituents independently selected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyl and methylenedioxy; or Q is thienyl, imidazolyl, benzo[b]thiophenyl or naphthyl any of which may bear a halo substituent; or Q is biphenylyl; or Q is carbon-linked indolyl which may bear a benzyl substituent at the 1-position;
Q
a
is hydrogen, (1-4C)alkyl, or a radical of formula —(CH
2
)
q
—NR
5
R
6
in which q is 2 or 3 and R
5
and R
6
are independently (1-4C)alkyl or NR
5
R
6
is piperidino or 4-benzylpiperidino;
R
1
is hydrogen, methyl or (2-6C)n-alkyl which may bear a terminal amino radical;
R
2
is —C(═O)R
3
, —C(=O)OR
3
or —C(═J
1
)NHR
3
in which J
1
is oxygen or sulfur and R
3
is hydrogen, (1-6C)alkyl, phenyl(1-3C)alkyl (in which the phenyl may bear one or more halo, hydroxy, (1-4C)alkoxy or (1-4C)alkyl substituents), pyridyl(1-3C)alkyl, naphthyl(1-3C)alkyl, pyridylthio(1-3C)alkyl, styryl, 1-methylimidazol-2-ylthio(1-3C)alkyl, aryl (which may bear one or more halo, hydroxy, (1-4C)alkoxy or (1-4C)alkyl substituents), heteroaryl (which may bear one or more halo, hydroxy, (1-4C)alkoxy or (1-4C)alkyl substituents), or (when R
2
is —COR
3
) &agr;-hydroxybenzyl;
n is 0, 1, 2 or 3;
p is 1 or 2, and when p is 2, n is 1 and J
2
is two hydrogens;
J
2
is oxygen or two hydrogens;
L is carbonyl or methylene;
r is 0, 1, 2, or 3; and
R
4
is phenyl which may bear one or more halo, trifluoromethyl, (1-4C)alkyl, hydroxy or (1-4C)alkoxy substituents (and particularly one or more chloro or fluoro substituents); naphthyl which may bear one or more halo, trifluoromethyl, (1-4C)alkyl or hydroxy substituents; pyridyl; thienyl; indolyl; quinolinyl; benzothienyl or imidazolyl; or when L
6
is carbonyl, the group —(CH
2
)
r
—R
4
may represent aryl, heteroaryl or a benzyl group bearing an &agr;-substituent selected from hydroxy, (1-4C)alkoxy and (1-4)alkyl, and further wherein the aryl, heteroaryl or phenyl portion of the benzyl group may bear one or more substituents selected independently from halo, trifluoromethyl, (1-4C)alkyl, hydroxy and (1-4C)alkyl, hydroxy and (1-4C)alkoxy (and particularly one or more chloro or,fluoro substituents);
G denotes a single bond, a double bond or a divalent hydrocarbon radical;
J denotes a radical joined to the ring by a single bond if G denotes a double bond or, otherwise, a radical joined by a double bond;
M denotes a heteroatom or substituted heteroatom; and
L denotes a hydrocarbon radical in which the 1-position is attached to M; wherein
the values of G, J, M and L are selected from
(a) G is a single bond; J is oxo or thioxo; M is oxy, thio or NR
12
; and L is L
1
;
(b) C is a single bond; J is NR
8
; M is NR
7
; and L is L
1
;
(c) G is a double bond, J is OR
7
, SR
7
or NR
9
R
10
; M is nitrogen; and L is L
1
;
(d) G is methylene which may bear one or two methyl substituents; J is oxo, thio or NR
11
; M is oxy, thio, sulfinyl, sulfonyl or NR
7
; and L is L
2
;
(e) G is a single bond; J is oxo, thioxo or NR
11
; M is nitrogen; and L is L
3
;
(f) G is methine, which may bear a (1-3C)alkyl substituent; J is oxo, thioxo or NR
11
; M is nitrogen; and L is L
4
; and
(g) G is cis-vinylene, which may bear one or two methyl substituents; J is oxo, thioxo, or NR
11
; M is nitrogen; and L is L
5
; wherein
R is hydrogen or (1-3C)alkyl;
R
8
is hydrogen, (1-3C)alkyl, cyano, (1-3C)alkylsulfonyl or nitro;
R
9
and R
10
are independently hydrogen or (1-3C)alkyl or the radical NR
9
R
10
is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazino (which may bear a (1-3C)alkyl substituent at the 4-position);
R
11
is hydrogen or (1-3C)alkyl;
R
12
is hydrogen, (1-3C)alkyl, RaOC(═O)CH
2
— or RbRcNC(═O)CH
2
—.
R
a
is hydrogen or (1-3C)alkyl;
R
b
and Rc are independently hydrogen, (1-3C)alkyl, phenyl or benzyl;
L
1
is ethylene, cis-vinylene, trimethylene or tetramethylene which radical L
1
itself may bear one or two methyl substituents;
L
2
is ethylene or trimethylene which radical L
2
itself may bear one or two methyl substituents;
L
3
is prop-2-en-1-yliden-3-yl, which radical L
3
itself may bear one or two methyl substituents;
L
4
is cis-vinylene, which radical L
4
itself may bear one or two methyl substituents; and
L
5
is methine, which radical L
5
itself may bear a (1-3C)alkyl substituent;
or the N-oxide of said compound of formula I at the piperidino nitrogen indicated by &Dgr;;
or a pharmaceutically acceptable salt of said compound of formula I or said N-oxide;
or a quaternary ammonium salt of said compound of formula
Mitchell Kenneth F.
Raymond Richard L.
Zeneca Limited
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