4-phenyl-pyridine derivatives

Details 4-phenyl-pyridine derivatives 4-phenyl-pyridine derivatives

2001-07-10

2002-11-12

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S365000, C544S058200, C544S058600, C514S253130, C514S355000, C546S316000

Reexamination Certificate

active

06479483

ABSTRACT:

BACKGROUND OF THE INVENTION
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
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 are 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 reviewed in “Tachykinin Receptor and Tachykinin Receptor Antagonists”, J. Auton. Pharmnacol., 13, 23-93, 1993.
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. The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. 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.
SUMMARY OF THE INVENTION
This invention relates to compounds of the general formula
wherein
R is lower alkyl, lower alkoxy, halogen or trifluoromethyl;
R
1
is halogen or hydrogen; and when p is 1, R
1
may in addition to the above substituents be taken together with R to form —CH═CH—CH═CH—
R
2
and R
2′
are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;
and when n is 1, R
2
and R
2′
may in addition to the above substituents form —CH═CH—CH═CH—, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy,
R
3
and R
3′
are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group;
R
4
is hydrogen, —N(R
5
)
2
, —N(R
5
)(CH
2
)
n
OH, —N(R
5
)S(O)
2
-lower alkyl, —N(R
5
)S(O)
2
-phenyl, —N═CH—N(R
5
)
2
, —N(R
5
)C(O)R
5
,
R
5
is hydrogen, C
3-6
-cycloalkyl, benzyl or lower alkyl;
R
6
is hydrogen, hydroxy, lower alkyl, —(CH
2
)
n
COO—(R
5
), —N(R
5
)CO—lower alkyl, hydroxy-lower alkyl, —(CH
2
)
n
CN, —(CH
2
)
n
O(CH
2
)
n
OH, —CHO or a 5-or 6 membered heterocyclic ring containing from 1 to 4 heteroatoms, selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which hetercyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule;
 is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker —(CH
2
)
n
N(R
5
)—;
X is —C(O)N(R
5
)—, —(CH
2
)
m
O—, —(CH
2
)
m
N(R
5
)—, —N(R
5
)C(O)—, or —N(R
5
)(CH
2
)
m
—;
n, p and q are 1 to 4; and
m is 1 or 2;
and pharmaceutically acceptable acid addition salts thereof, which are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
This invention includes compounds and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of symptoms associated with certain conditions and diseases.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term “lower alkyl” denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term “lower alkoxy” denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
The term “halogen” denotes chlorine, iodine, fluorine and bromine.
The term “cycloalkyl” denotes a saturated carbocyclic group (e.g. a nonaromatic ring), preferably containing 3-6 carbon atoms (i.e. C
3
-C
6
cycloalkyl).
A “cyclic tertiary amine” denotes a ring system which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine, which ring is directly attached via the ring nitrogen to the remainder of the molecule or is attached through the linker —(CH
2
)
n
N(R
5
)—.
The cyclic tertiary amine may contain three to five carbon atoms. When the ring is substituted it is preferably substituted at the heteroatom, for example N-alkyl-piperazine. Examples of such rings include pyrrol-1-yl, imidazol-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, 1-oxo-thiomorpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl.
When R
4
is substituted (as in for example “substituted piperazinyl”), the substituent is R
6
, as defined above.
The term a “5-or 6 membered hetercyclic ring” is a ring system, which contains from 1 to 4 heteroatoms, selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group. Examples of such rings are pyrimidine, oxadiazole, triazole, tetrazole, pyridine, thiazole, thiene, furane, pyrane, pyrrole, imidazole, pyrazole, isothiazole, piperazine or piperidine.
When R
6
is R
6′
(a 5 or 6 membered heterocyclic ring) is bonded via an alkylene group to the remainder of the molecule, this phrase designates the substituent R
6′
linked to a CH
2
(for example) linked to the
ring, e.g.
The term “alkylene” denotes a lower alkyl linker which is bound to a group at either end.
The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
Compounds of this invention are NK-1 receptor antagonists and, as such, are particularly useful for treating depression and pain, especially that resulting from inflammatory conditions such as migraine, rheumatoid arthritis, asthma, and infl

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