Substituted phenyl-piperidine methanone compounds

Details Substituted phenyl-piperidine methanone compounds Substituted phenyl-piperidine methanone compounds

2002-01-25

2003-11-04

Morris, Patricia L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S231500, C514S235500, C514S255030, C514S256000, C514S317000, C514S318000, C514S330000, C514S331000, C544S060000, C546S194000, C546S208000

Reexamination Certificate

active

06642226

ABSTRACT:

BACKGROUND
The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and is involved in regulating a number of diverse biological processes.
The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson's disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281,1640-1645).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases is reviewed in “Tachykinin Receptor and Tachykinin Receptor Antagonists”, J. Auton. Pharmacol., 13, 23-93, 1993.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 describes the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in “Neuropeptides, 32(1), 1-49, (1998)” and “Eur. J. Pharmacol., 383(3), 297-303, (1999)”.
NK1 receptor antagonists have been reported to have also a beneficial effect in the therapy of traumatic brain injury (oral disclosure by Prof. Nimmo at the International Tachykinin Conference 2000 in La Grande Motte, France, Oct. 17-20, 2000 with the title “Neurokinin 1 (NK-1) Receptor Antagonists Improve the Neurological Outcome Following Traumatic Brain Injury” (Authors: A. J. Nimmo, C. J. Bennett, X. Hu, I. Cernak, R. Vink).”
SUMMARY
The present invention is a compound of formula
wherein
R
1
a) is unsubstituted phenyl or phenyl substituted by at least one substituent selected from the group R
1′
consisting of
halogen,
trifluoromethyl,
unsubstituted piperazinyl or piperazinyl substituted by lower alkyl,
morpholinyl,
NH-phenyl,
pyrrolidinyl,
NH(CH
2
)
n
—O-lower alkyl,
NR
a
R
b
NH(CH
2
)
n
-cycloalkyl and
NH(CH
2
)
n
—NR
c
R
d
, or is
b) unsubstituted morpholinyl, or morpholinyl substituted by one or two lower alkyl groups, or is
c) unsubstituted piperazinyl, or piperazinyl substituted in the 4-position by the group R
1″
which is selected from the group consisting of
lower alkyl,
cycloalkyl,
phenyl,
benzoxazolyl,
pyridinyl,
pyrimidinyl
pyrazinyl,
(CH
2
)
n
-cycloalkyl,
(CH
2
)
n
-phenyl,
(CH
2
)
n
-hydroxy,
(CH
2
)
n
—CF
3
,
(CH
2
)
n
—C(O)-morpholinyl,
(CH
2
)
n
—C(O)—N(R
e
)-phenyl, wherein the phenyl ring is unsubstituted or substituted by a substitutent selected from the group consisting of
lower alkyl, halogen and
(CH
2
)
n
—C(O)—NR
f
R
g
,
C(O)-phenyl, wherein the phenyl ring is unsubstituted or substituted by a substitutent selected from the group consisting of trifluoromethyl,
C(O)—(CH
2
)
n
-phenyl,
C(O)—NR
h
R
i
,
C(O)—NR
j
—(CHR
k
)
n
-phenyl,
C(O)-lower alkyl,
C(O)—CF
3
,
C(O)-cycloalkyl,
C(O)-morpholinyl,
C(O)O-lower alkyl,
C(O)—O—(CH
2
)
n
—NR
l
R
m
, and
S(O)
2
-lower alkyl,
or is
d) unsubstituted pyrrolidinyl, or pyrrolidinyl substituted by at least one group R
1′″
, selected from the group consisting of
halogen,
hydroxy,
═O,
NR
n
R
o
,
N(cycloalkyl)
2
,
N[(CH
2
)
n
cycloalkyl]
2
,
NR
p
—C(O)-cycloalkyl, and
O—(CH
2
)
n
-cycloalkyl, or is
e) unsubstituted piperidinyl or piperidinyl substituted by at least one group R
1″″
in the 3 or 4-position, selected from the group consisting of
hydroxy,
═O,
halogen,
morpholinyl,
NR
s
-cycloalkyl,
NR
t
—C(O)-cycloalkyl,
NR
u
—C(O)-phenyl,
NR
v
—C(O)—(CH
2
)
n
-phenyl, and
O—(CH
2
)
n
-cycloalkyl,
or is
f) thiomorpholinyl, 1-oxo-thiomorpholinyl or 1,1-dioxothiomorpholinyl;
R
2
is independently selected from the group consisting of hydrogen, halogen, lower alkyl, —NH—(CH
2
)
n
—O-lower alkyl, pyrrolidinyl and morpholinyl;
R
3
/R
4
are independently from each other trifluoromethyl or halogen;
R
a-v
are independently selected from the group consisting of hydrogen and lower alkyl;
n is 1, 2, 3 or 4;
m is 0, 1 or 2;
or a pharmaceutically acceptable acid addition salt thereof
In more detail, the compounds of the present invention relate to the following formulae
wherein m is 0, 1 or 2 and R
1′
, R
2
, R
3
and R
4
are described above, or to
wherein R is lower alkyl, m is 0, 1 or 2, R
2
, R
3
and R
4
have the significances given above, or to
wherein m is 0, 1 or 2, R
1″
, R
2
, R
3
and R
4
have the significances given above, or to
wherein m is 0, 1 or 2, R
1′″
, R
2
, R
3
and R
4
have the significances given above, or to
wherein m is 0, 1 or 2, R
1″″
, R
2
, R
3
and R
4
have the significances given above, or to
wherein R
2
, R
3
and R
4
are described above and m is 0, 1 or 2.
Further encompassed by the present invention is a compound having the formula
wherein
R
1
is unsubstituted phenyl, or phenyl substituted by one or two substituents, selected from the group R
1′
, consisting of
halogen,
trifluoromethyl,
unsubstituted piperazinyl or piperazinyl substituted by lower alkyl,
morpholinyl,
NH-phenyl,
pyrrolidinyl,
NH(CH
2
)
n
—O-lower alkyl,
NR
a
R
b
,
NH(CH
2
)
n
-cycloalkyl, and —NH(CH
2
)
n
—NR
c
R
d
, or is
morpholinyl, or is
unsubstituted piperazinyl, or piperazinyl substituted by the group R
1″
, which is selected from the group consisting of
lower alkyl,
cycloalkyl,
C(O)-phenyl, wherein the phenyl ring is optionally substituted by trifluoromethyl,
(CH
2
)
n
—C(O)—NR
f
R
g
,
(CH
2
)
n
-cycloalkyl,
(CH
2
)
n
-phenyl,
C(O)-lower alkyl,
C(O)—CF
3
,
C(O)-cycloalkyl,
C(O)-morpholinyl,
C(O)—O—(CH
2
)
n
—NR
l
R
m
, and
(CH
2
)
n
—C(O)—N(R
e
)-(unsubstituted) phenyl or —(CH
2
)
n
—C(O)—N(R
e
)-phenyl substituted by
lower alkyl, or is
pyrazinyl, or is
unsubstituted pyrrolidinyl, or pyrrolidinyl substituted by the group R
1′″
, which is selected from the group consisting of
hydroxy,
═O and
O—(CH
2
)
n
-cycloalkyl, or is
unsubsituted piperidinyl, or piperidinyl substituted by the group R
1″″
, which is selected from the group consisting of
hydroxy,
O—(CH
2
)
n
-cycloalkyl,
═O and
halogen, or is
thiomorpholinyl, 1-oxo-thiomorpholinyl or 1,1-dioxothiomorpholinyl;
R
2
is selected from the group consisting of hydrogen, halogen, lower alkyl, —NH—(CH
2
)
n
—O-lower alkyl, pyrrolidinyl and morpholinyl;
R
a,b,c,d,e,f,g,l,m
is independently hydrogen or lower alkyl and
n is 1, 2, 3 or 4;
or a pharmaceutically acceptable acid addition salt thereof.
The compound of formula I and pharmaceutically acceptable salts thereof are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention ar

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