Quinoline derivatives as NK-2 and NK-3 receptor ligands

Details Quinoline derivatives as NK-2 and NK-3 receptor ligands Quinoline derivatives as NK-2 and NK-3 receptor ligands

2001-09-28

2003-09-02

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S311000, C514S312000, C514S253040, C514S253060, C546S152000, C546S169000

Reexamination Certificate

active

06613770

ABSTRACT:

This application is a 371 of International Application No. PCT/EP99/09156, filed Nov. 22, 1999.
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 (Myers 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
., 11, 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 novel class of non-peptide compounds having NK-3 antagonist activity 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. Surprisingly however, the present compounds show greater affinity for the NK-2 receptor than for the NK-3 receptor. Thus, although these compounds are 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, they are considered to be of use in those therapeutic areas characterised primarily by overstimulation of the NK-2 receptor, for example the pulmonary area (especially useful in the treatment of the bronchospastic and inflammatory component of asthma, coughing and pulmonary irritation), the gastrointestinal tract area (especially useful in the treatment of intestinal spasms and GI tract disorders including irritable bowel syndrome and gastro-exophageous reflex disease) the inflammatory and tissue repair area (especially useful in the treatment of syndromes associated with bladder disfunctions including urinary incontinence; or inflammatory processes of bladder and ureter associated with cystitis, kidney infections and colics and spasms of the biliary tract; rheumatoid arthritis) (hereinafter referred to as the “NK-2 Conditions”).
These compounds are also useful for treating 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 (hereinafter referred to as the ‘Primary Conditions’). The “Primary Conditions” also include the “NK-2 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 R is linear or branched alkyl;
R
1
represents hydrogen or up to four 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, phthalimido, amino or mono- and di-C
1-6
alkylaamino;
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 alkyl or R
4
and R together with the carbon atom to which they are attached form an optionally substituted C
3-12
cycloalkyl group.
Suitable optionally substituted C
3-12
cycloalkyl groups include C
3-12
cycloalkyl groups, especially C
4-7
cycloalkyl groups, for example a C
5
or C
6
cycloalkyl group, fused to other cycloalkyl groups or fused to C
3-12
cycloalkyl groups fused to aryl.
Suitable C
3-12
cycloalkyl groups fused to other cycloalkyl groups include C
4-12
cycloalkyl groups, especially C
5
and C
6
cycloalkylgroups, fused to other C
3-12
cycloalkyl groups, especially C
5
and C
6
cycloalkylgroups; examples of such groups include 2-adamantyl and bicyclo[2.2.1]heptan-2-yl.
Suitable C
3-12
cycl

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