Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-02-05
2004-08-24
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S169000, C546S020000, C544S128000, C544S333000, C544S363000, C514S235200, C514S253030, C514S278000, C514S311000
Reexamination Certificate
active
06780875
ABSTRACT:
The present invention relates to novel compounds, in particular to novel quinoline derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds in medicine.
The mammalian peptide Neurokinin B (NKB) belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA). Pharmacological and molecular biological evidence has shown the existence of three subtypes of TK receptor (NK
1
, NK
2
and NK
3
) and NKB binds preferentially to the NK
3
receptor although it also recognises the other two receptors with lower affinity (Maggi et al, 1993,
J. Auton. Pharmacol.,
13, 23-93).
Selective peptidic NK
3
receptor antagonists are known (Drapeau, 1990
Regul. Pept.,
31, 125-135), and findings with peptidic NK
3
receptor agonists suggest that NKB, by activating the NK
3
receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Mycrs and Undem, 1993
J. Physiol.,
470, 665-679; Counture et al., 1993,
Regul. Peptides,
46, 426-429, Mccarson and Krause, 1994,
J. Neurosci.,
14 (2), 712-720; Arenas et al. 1991,
J. Neurosci
18, 2332-8). However, the peptide-like nature of the known antagonists makes them likely to be too labile from a metabolic point of view to serve as practical therapeutic agents.
Copending International Patent Application number PCT/EP98/03014 discloses certain compounds stated to be non-peptide NK-3 antagonists and also to have NK-2 antagonist activity. These compounds are therefore considered to be of potential use in the prevention and treatment of a wide variety of clinical conditions which are characterized by overstimulation of the tachykinin receptors, in particular NK-3 and NK-2.
We have now discovered a further novel class of non-peptide NK-3 antagonists which are far more stable from a metabolic point of view than the known peptidic NK-3 receptor antagonists and are of potential therapeutic utility. These compounds also have NK-2 antagonist activity and are therefore considered to be of potential use in the prevention and treatment of a wide variety of clinical conditions which are characterized by overstimulation of the tachykinin receptors, in particular NK-3 and NK-2.
These conditions include respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systhemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), gastro-exophageous reflex disease (GERD); urinary incontinence and disorders of the bladder function; renal disorders (hereinafter referred to as the ‘Primary Conditions’).
Certain of these compounds also show CNS activity and hence are considered to be of particular use in the treatment of disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, Huntington's disease, Parkinson's disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease and pain or nociception, for example, that is attributable to or associated with any of the foregoing conditions especially the transmission of pain in migraine, (hereinafter referred to as the ‘Secondary Conditions’).
The compounds of formula (I) are also considered to be useful as diagnostic tools for assessing the degree to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms.
According to the present invention there is provided a compound, or a solvate or a salt thereof, of formula (I):
wherein, Ar is an optionally substituted aryl or a C
5-7
cycloalkdienyl group, or an optionally substituted C
5-7
cycloalkyl group, or an optionally substituted single or fused ring aromatic heterocyclic group;
R is hydrogen, linear or branched C
1-6
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylalkyl;
R
1
represents hydrogen or up to three optional substituents selected from the list consisting of: C
1-6
alkyl, C
1-6
alkenyl, aryl, C
1-6
alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C
1-6
alkoxycarbonyl, trifluoromethyl, acyloxy, amino or mono- and di-C
1-6
alkylamino;
R
2
represents a moiety —(CH
2
)
n
—NY
1
Y
2
wherein n is an integer in the range of from 1 to 9, Y
1
and Y
2
are independently selected from C
1-6
-alkyl; C
1-6
alkyl substituted with hydroxy, alkoxy, C
1-6
alkylamino or bis (C
1-6
alkyl) amino; C3-6 cycloalkyl; C4-6 azacycloalkyl; C
1-6
-alkenyl; aryl or aryl-C
1-6
-alkyl or Y
1
and Y
2
together with the nitrogen atom to which they are attached represent an optionally substituted N-linked single or fused ring heterocyclic group;
R
3
is branched or linear C
1-6
alkyl, C
3-7
cycloalkyl, C
4-7
cycloalkylalkyl, optionally substituted aryl, or an optionally substituted single or fused ring aromatic heterocyclic group; and
R
4
represents hydrogen or C
1-6
alkyl.
R
5
represents hydrogen or halogen.
Preferably R
5
represents hydrogen. In another preferred aspect R5 is chloro or bromo.
Suitably, Ar represents optionally substituted phenyl,unsubstituted phenyl or cyclohexyl.
Suitably, Ar represents cyclohexyl.
Preferably Ar is phenyl or cyclohexyl.
Suitably, R represents C
1-6
alkyl, for example methyl or ethyl or iso-propyl.
In one preferred aspect, R is ethyl. In another preferred aspect, R is methyl or isopropyl.
Suitably R
1
represents hydrogen, C
1-6
alkoxy, for example methoxy, or hydroxy.
Preferably, R
1
represents hydrogen. In another preferred aspect, R1 is methoxy or hydroxy.
Suitably, NY
1
Y
2
represents an optionally substituted N-linked single or fused ring heterocyclic group.
Suitable N-linked single or fused heterocyclic groups, include groups in which any single or fused ring is saturated or unsaturated and consists of 5- or 6-ring atoms, said ring atoms optionally comprising 1 or 2 additional heteroatoms selected from O or N and wherein one or two ring atoms are optionally substituted with one or two oxo groups or one or two of hydroxy, carboxy, carboxy C1-6 alkyl, C
1-6
alkoxycarbonyl, aminocarbonyl, C1-6 alkylcarbonyl optionally substituted with an aromatic heterocyclic group, arylcarbonyl, aryl C1-6 alkylcarbonyl, carboxy C1-6 alklycarbonyl, carboxyarylcarbonyl, amino, C1-6 alkylcarbonylamino, C
1-6
alkyl, C
1-6
hydroxyalkyl, aryl, aryl, C1-6 alkyl, C
3-7
cycloalkyl, optionally substituted C4-7 cycloalkenyl, optionally substituted C4-7 azacycloalkyl, optionally substituted C4-7 dia
Farina Carlo
Giardina Giuseppe
Grugni Mario
Morvan Marcel
Nadler Guy Marguerite Marie Gerard
Aulakh Charanjit S.
Furman Theodore R.
SmithKline Beecham S.p.A.
Stein-Fernandez Nora
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