Quinoline derivatives

Details Quinoline derivatives Quinoline derivatives

1998-05-22

2001-08-21

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S312000, C514S313000, C514S314000, C546S153000, C546S159000, C546S169000

Reexamination Certificate

active

06277862

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,
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.
We have now discovered a 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 a inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; opthalmic 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 and urinary incontinence; renal disorders and disorders of the bladder function, (hereinafter referred to as the ‘Primary Conditions’).
In addition, certain of the present compounds are indicated to be particularly selective for the periphery rather than the central nervous system. These compounds are therefore considered to be especially useful in the treatment of those components of the ‘Primary Conditions’ which require a peripheral-selectivity.
Certain compounds of this invention 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’).
Certain of these compounds are selective antagonists of the NK-3 receptor relative to the NK-2 receptor.
In an alternative aspect, certain of these compounds are combined NK-2/NK-3 antagonists and hence are considered to be particularly suitable for the treatment and/or prophylaxis of respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity and cough.
The compounds are also considered to be useful as diagnostic tools for assessing the degree to which neurokinin-3 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms.
According to the present invention there is provided a compound of formula (I):
or a solvate thereof, or a salt thereof, wherein, Ar is an optionally substituted aryl or a C
5-7
cycloalkdienyl group, or an optionally substituted single or fused ring aromatic heterocyclic group;
R is C
1-6
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylalkyl, optionally substituted phenyl or phenyl C
1-6
alkyl, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatoms selected from O and N, hydroxy C
1-6
alkyl, amino C
1-6
alkyl, C
1-6
alkylaminoalkyl, di C
1-6
alkylaminoalkyl, C
1-6
acylaminoalkyl, C
1-6
alkoxyalkyl, C
1-6
alkylcarbonyl, carboxy, C
1-6
alkoxyxcarbonyl, C
1-6
alkoxycarbonyl C
1-6
alkyl, aminocarbonyl, C
1-6
alkylaminocarbonyl, di C
1-6
alkylaminocarbonyl, halogeno C
1-6
alkyl; or R is a group —(CH
2
)
p
- wherein p is 2 or 3 which group forms a ring with a carbon atom of Ar;
R
1
represents hydrogen or up to four optional subtitutents 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
alkylamino;
R
2
represents a moiety —O—(CH
2
)
n
-X wherein X is alkyl optionally substituted with one or two groups selected from hydroxy and amino; carboxy, cyano, C
1-6
alkoxycarbonyl, aminocarbonyl, mono- or di-C
1-6
alkylaminocarbonyl, amino-C
1-6
-alkylaminocarbonyl or mono- or di-C
1-6
-alkylamino-C
1-6
-alkylaminocarbonyl; or X is a group —NX
1
X
2
wherein X
1
and X
2
each independently represent hydrogen, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl-C
1-6
-alkylcarbonyl, heteroaryl C
1-6
-alkylcarbonyl, aminocarbonyl, mono- or bis-C
1-6
alkylaminocarbonyl, amino C
1-6
alkylcarbonyl, mono-or bis-C
1-6
alkylamino C
1-6
alkylcarbonyl, a moiety of formula —CO—T—CO—T
1
or a 5 to 9 membered single or fused ring cycloalkyl group optionally comprising 1 or 2 nitrogen atoms and optionally 1 or 2 additional heteroatoms selected from O or N and wherein one or two ring atoms are optionally substituted with C
1-6
alkyl, said ring being optionally fused to a benzene ring; wherein the above mentioned aryl and heteroaryl groups are optionally substituted with up to two groups selected from: hydroxy, C
1-6
alkoxy, hydroxy-C
1-6
alkyl, amino-C
1-6
-alkyl, mono- or bis-C
1-6
-alkylamino, mono- or bis-C
1-6
-alkylamino-C
1-6
-alkyl, amino-C
1-6
-alkoxy, mono- or bis-C
1-6
-alkylamino-C
1-6
-alkoxy, carboxy, C-
1-6
-alkylcarbonyl, C-
1-6
-alkoxycarbonyl, carboxy-C
1-6
alkyl, carboxy-C
1-6
alkoxy and C-
1-6
-alkylcarbonyl C
1-6
alkoxy; and wherein the alkyl moiety of any heteroaryl-C
1-6
-alkyl or aryl-C
1-6
-alkyl group is optionally substituted wit

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