Phenyl substituted pyridine and benzene derivatives

Details Phenyl substituted pyridine and benzene derivatives Phenyl substituted pyridine and benzene derivatives

2000-02-16

2002-06-18

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S253010, C544S131000

Reexamination Certificate

active

06407111

ABSTRACT:

BACKGROUND OF THE INVENTION
The neuropeptide receptor for Neurokinin 1 (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. 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 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, in
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.
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.
SUMMARY OF THE INVENTION
In accordance with the present invention, the compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Objects of the present invention are the compounds of formula I 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 illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments. The most preferred indications for treatment in accordance with the present invention are those which include disorders of the central nervous system or emesis, for example the treatment or prevention of certain depressive disorders by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of the general formula
wherein
R is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;
R
1
is hydrogen or halogen; or
R and R
1
may be together —CH═CH—CH═CH—;
R
2
is hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;
R
3
is, independently from each other, hydrogen, lower alkyl or form a cycloalkyl group;
R
4
is hydrogen, halogen, lower alkyl, lower alkoxy, —N(R
5
)
2
, —N(R
5
)S(O)
2
-lower alkyl, —N(R
5
)C(O)R
5
or a cyclic tertiary amine of the group
R
5
is, independently from each other, hydrogen, C
3-6
-cycloalkyl, benzyl or lower alkyl;
R
6
is hydrogen, hydroxy, lower alkyl, —N(R
5
)CO-lower alkyl, hydroxy-lower alkyl, cyano, —CHO or a 5- or 6 membered heterocyclic group, optionally bonded via an alkylene group,
X is —C(O)N(R
5
)—, —(CH
2
)
m
O—, —(CH
2
)
m
N(R
5
)—, —N(R
5
)C(O)—, —C(O)O— or —N(R
5
)(CH
2
)
m
—;
Y is —(CH
2
)
n
—, —O—, —S—, —SO
2
—, —C(O)— or —N(R
5
)—;
Z is ═N—, —CH═ or —C(O)═;
n is 0-4; and
m is 1 or 2;
and to pharmaceutically acceptable acid addition salts thereof.
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, containing 3-6 carbon atoms.
The term “cyclic tertiary amine” denotes, for example, 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.
The term “5 or 6 membered heterocyclic group” denotes, for example pyridinyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, piperazinyl or piperidyl.
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.
Exemplary preferred are compounds, in which Y is —C(O)— and R
4
is 4-methylpiperazinyl, for example the following compounds:
N-[2-Benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2-(3,5-bis-trifluoromethyl-phenyl)isobutyramide,
4-Benzoyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl) nicotinamide and
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-benzoyl)-N-methyl-6-(4-methyl-piperazin-1-yl)nicotinamide.
Further preferred are compounds, in which Y is —O— and R
4
is hydrogen, morpholinyl or 4-methylpiperazinyl. Examples of such compounds are:
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-phenoxy-phenyl)-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-o-tolyloxy-phenyl)-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[2-(2,4-dichloro-phenoxy)-phenyl]-N-methyl-isobutyramide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-morpholin-4-yl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide and
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyloxy-nicotinamide.
Further preferred are compounds, in which Y is —N(CH
3
)— and R
4
is hydrogen, for example the following compounds:
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-propionamide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(me

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