Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-29
2003-09-23
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S340000, C514S341000, C514S349000, C514S228800, C546S309000, C546S194000, C546S275400, C546S272400, C546S274100, C544S098000
Reexamination Certificate
active
06624176
ABSTRACT:
FIELD OF INVENTION
The present invention is generally related to novel heteroaromatic substituted amide compounds and more particularly to heteroaromatic substituted amide compounds showing antagonist activity To neurokinin 1 (NK-1, substance P) receptors.
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 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).
“Tachykinin Receptor and Tachykinin Receptor Antagonists”, J. Auton. Pharmacol., 13, 23-93, 1993 reviews 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. The neurokinin-1 receptor antagonists are also known to be useful for the treatment of motion sickness and for treatment of induced vomiting.
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).
In addition, a paper published in 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.
U.S. Pat. No. 5,972,938 discloses 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 also have been reported to have a beneficial effect in the therapy of traumatic brain injury in a paper presented by Professor 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 relates to compounds having the formulae
wherein
R
1
is
—NH(CH
2
)
2
OH or —NR
3
C(O)R
4
;
R
2
is methyl or chloro;
R
3
is hydrogen or methyl;
R
4
is lower alkyl or lower cycloalkyl;
R is hydrogen or —(CH
2
)
2
OH; and
n is 1 or 2
or a pharmaceutically acceptable acid addition salt thereof.
A 4-phenyl-pyridine compound, related to compounds disclosed in the present application, is disclosed in U.S. App. Ser. No. 09/507,456.
The compounds of formulae IA and IB can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compound's advantages in adsorption, pharmacokinetics in distribution and transport to the brain.
The compounds of formulae IA and IB 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. 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 therefore, the compounds of the invention can be used to treat diseases 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.
DETAILED DESCRIPTION
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. Particularly preferred are methyl groups. The term “cycloalkyl” denotes a saturated carbocyclic group, containing 3-6 carbon atoms. A preferred cycloalkyl group is cyclopropyl.
Exemplary preferred are compounds of formula IA, in which R
2
is methyl, for example the following compounds:
N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-6-[1,2,4]triazol-1-yl-nicotinamide,
N-(3,5-bis-trifluoromethyl-benzyl)-6-(2-hydroxy-ethylamino)-N-methyl-4-o-tolyl-nicotinamide,
4-hydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,
4-(2-hydroxy-ethoxy)-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide or
(R)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(3-hydroxy-pyrrolidin-1-yl)-N-methyl-4-o-tolyl-nicotinamide.
Further preferred are compounds of formula IA, in which R
2
is chloro.
An example of such compound is:
4′-(2-chloro-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide
Exemplary preferred are compounds of formula IB, in which R
2
is methyl, for example the following compounds:
2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-ethylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2,3-dihydro-[1,4]oxazin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,
N-(6-acetylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,
N-[6-(acetyl-methyl-amino)-4-o-tolyl-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,
cyclopropanecarboxylic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino }-4-o-tolyl-pyridin-2-yl)-amide,
cyclopropanecarboxylic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-methyl-amide or
2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-imidazol-1-yl-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide.
Further preferred are compounds of formula IB, in which R
2
is chloro, for example the following compound:
2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide.
Also preferred are compounds of formula 1B, in which R
1
is —NH(CH)
2
OH. Also for formula 1B, R
1
is preferred as —N R
3
C(O) R
4
, R
3
is methyl and R
4
is lower alkyl. R
4
being methyl is particularly preferred. Additionally, R
4
is preferred as cycloalkyl, particularly cyclopropyl. Additi
Hoffmann Torsten
Schnider Patrick
Stadler Heinz
Fan Jane
Hoffmann-La Roche Inc.
Johnston George W.
Rocha-Tramaloni Patricia S.
Smith Lyman H.
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