Colloid systems and wetting agents; subcombinations thereof; pro – Continuous liquid or supercritical phase: colloid systems;... – Aqueous continuous liquid phase and discontinuous phase...
Reexamination Certificate
2001-01-05
2002-03-12
Qazi, Sabiha (Department: 1616)
Colloid systems and wetting agents; subcombinations thereof; pro
Continuous liquid or supercritical phase: colloid systems;...
Aqueous continuous liquid phase and discontinuous phase...
C514S272000, C514S315000, C514S316000, C514S317000, C546S184000, C546S186000, C546S187000
Reexamination Certificate
active
06355695
ABSTRACT:
This invention concerns novel heterocyclic compounds which antagonize the pharmacological actions of one of the endogenous neuropeptide tachykinins known as neurokinins, particularly at the neurokinin 2 (NK2) receptor. The novel heterocyclic compounds 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 heterocyclic compounds for use in such treatment, methods for their use, and processes and intermediates for the manufacture of the novel heterocyclic compounds.
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 tachykinin antagonists have been reported, for example in European Patent Application, Publication Number (EPA) 428434, EPA 474561, EPA 512901, EPA 512902, EPA 515240 and EPA 559538, as well as in WO 94/10146, EPA 0625509, EPA 0630887, WO 95/05377, WO 95/12577, WO 95/15961, EPA 680962, and WO 95/16682.
We have discovered a series of nonpeptidic NK2 antagonists, and this is the basis for our invention.
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
Q
1
is a radical (attached at Z) selected from the group of radicals of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij, Ik and Im, wherein
for a radical of formula Ia, Z
a
is nitrogen or a group CR
ad
in which R
ad
is hydrogen or R
ad
together with R
ac
and the existing carbon to carbon bond forms a double bond; R
aa
is Ar or Het; R
ab
is hydrogen and R
ac
is hydrogen or hydroxy or R
ac
together with R
ad
and the existing carbon to carbon bond forms a double bond, or R
ac
and R
ad
together form a diradical —(CH
2
)
j
— in which j is an integer from 1 to 5; or R
ab
and R
ac
together form a diradical —(CH
2
)
k
— in which k is an integer from 2 to 6, or R
ab
and R
ac
together are oxo or dialkylaminoalkyloxyimino of formula ═N—O—(CH
2
)
q
—NR
ae
R
af
in which q is the integer 2 or 3 and R
ae
and R
af
are independently hydrogen or (1-4C)alkyl, or the radical NR
ae
R
af
is pyrrolidino, piperidino or morpholino;
for a radical of formula Ib, Z
b
is a substituted imino group R
ba
N or R
ba
CH
2
N in which R
ba
is (3-7C)cycloakyl, Ar or Het; or Z
b
is a disubstituted methylene group R
bb
(CH
2
)
p
—C—R
bc
in which R
bb
is Ar or Het; p is the integer 0 or 1; and R
bc
is hydrogen, hydroxy, (1-4C)alkoxy, (1-4C)alkanoyloxy, COOR
bd
(wherein R
bd
is hydrogen or (1-3C)alkyl), cyano, NR
be
R
bf
or SR
bg
in which R
be
and R
bf
are independently hydrogen, (1-4C)alkyl, (1-4C)hydroxyalkyl or (1-4C)alkanoyl, or the radical NR
be
R
bf
is pyrrolidino, piperidino or morpholino; and R
bg
is hydrogen or (1-4C)alkyl; or R
bc
forms a double bond with the carbon atom to which it is bonded and with the adjacent carbon atom in the piperidine ring;
for a radical of formula Ic, R
ca
is Ar or Het; and Z
c
is oxo, thio, sulfinyl, sulfonyl or imino of formula —NR
cb
— in which R
cb
is (1-3C)alkyl or R
cc
R
cd
N—(CH
2
)
q
— in which q is the integer 2 or 3 and in which R
cc
and R
cd
are independently hydrogen or (1-3C)alkyl or the radical R
cc
R
cd
N is pyrrolidino, piperidino or morpholino;
for a radical of formula Id, R
da
is hydrogen, (1-6C)alkyl, Ar, Het, &agr;-hydroxybenzyl, styryl, or R
db
—(1-3C)alkyl in which R
db
is aryl, pyridyl, pyridylthio or 1-methyl-2-imidazolylthio in which an aromatic group or portion of R
da
may bear one or more halo, hydroxy, (1-4C)alkyl or (1-4C)alkoxy substituents; X
d
is oxy or —CHR
dc
—; R
dc
is hydrogen, hydroxy, (1-3C)alkoxy, (1-4C)alkanoyloxy, NR
dd
R
de
or (1-4C)alkanoylamino; R
dd
and R
de
are independently hydrogen or (1-4C)alkyl or the radical NR
dd
R
de
is pyrrolidino, piperidino or morpholino; p is the integer 0 or 1; and Z
d
is a single bond (except when R
da
is hydrogen or p is 1), methylene or carbonyl;
for a radical of formula Ie, J
e
is oxygen, sulfur or NR
ea
in which R
ea
is hydrogen or (1-3C)alkyl; R
eb
is hydrogen, (1-6C)alkyl which may bear a hydroxy substituent and/or one to three fluoro substituents, (3-6C)alkenyl (in which a vinyl carbon is not bound to nitrogen), 2-hydroxyethyl, (3-7C)cyloalkyl, Ar or Het; R
ec
is hydrogen, (1-6C)alkyl which may bear a hydroxy substituent and/or one to three fluoro substituents, (3-6C)cycloalkyl, (1-5C)alkoxy (only when J
e
is oxygen), (3-6C)cycloalkoxy (only when J
e
is oxygen), or an amino group of formula NR
ed
R
ee
containing zero to seven carbon atoms in which each of R
ed
and R
ee
is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or the radical NR
ed
R
ee
is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl group may bear a (1-3C)alkyl substituent at the 4-position);
for a radical of formula If, J
f
is oxygen, sulfur or NR
fa
in which R
fa
is hydrogen or (1-3C)alkyl; L
f
is a divalent hydrocarbon group in which the 1-position is bound to the carbon bearing the group J
f
, the divalent group L
f
being selected from trimethylene, cis-propenylene, tetramethylene, cis-butenylene, cis-but-3-enylene, cis,cis-butadienylene, pentamethylene and cis-pentenylene which divalent group L
f
itself may bear one or two methyl substituents;
for a radical of formula Ig, Z
g
is (1-8C)alkyl or (3-8C)cycloalkyl which may bear one or more substituents selected from the group consisting of halo, (3-6C)cycloalkyl, cyano, nitro, hydroxy, (1-4C)alkoxy, (1-5C)alkanoyloxy, aroyl, heteroaroyl, oxo, imino (which may bear a (1-6C)alkyl, (3-6C)cycloalkyl, (1-5C)alkanoyl or aroyl substituent), hydroxyimino (which hydroxyimino may bear a (1-4C)alkyl or a phenyl substituent on the oxygen), an amino group of formula NR
ga
R
gb
, an amino group of formula NR
gc
R
gd
, an amidino group of formula C(═NR
gg
)NR
ge
R
gf
, and a carbamoyl group of formula CON(OR
gh
)R
gi
, but excluding any radical wherein a hydroxy and an oxo substituent together form a carboxy group, wherein an amino group of formula NR
ga
R
gb
contains zero to seven carbon atoms and each of R
ga
and R
gb
is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or the radical NR
ga
R
gb
is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent group at the 4-position); a
Jacobs Robert T.
Miller Scott C.
Shenvi Ashokkumar B.
Person Richard V.
Qazi Sabiha
Zeneca Limited
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