Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-07
2004-06-01
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S314000, C514S912000
Reexamination Certificate
active
06743804
ABSTRACT:
The present invention relates to a novel use, in particular a novel pharmaceutical use for a series of quinoline derivatives.
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 Undern, 1993
, J. Phisiol
., 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).
International Patent Application Number PCT/EP95/02000 describes certain quinoline derivatives, the preparation of the quinolines and their use in medicine. The disclosures of PCT/EP95/02000 are relevant to the present application only by virtue of Article 54(3) of the European Patent Convention.
We have now discovered certain novel uses for the compounds of PCT/EP95/02000 in particular use in the prevention and treatment of certain conditions characterized by overstimulation of the thachykinin receptors, in particular NK-3 receptors. Such conditions include disorders of the central nervous system, such as schizophrenia; neurodegenerative disorders, such as aids related dementia, senile dementia of the Alzheimer type and Down's syndrome; demyelinating diseases such as multiple sclerosis and other neuropathological disorders such as diabetic or peripheral neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; respiratory diseases such as, bronchopneumonia and bronchospasm; inflammatory diseases such as inflammatory bowel disease, fibrositis, osteoarthritis, rheumatoid arthritis; allergies such as eczema and rhinitis; hypersensivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases such as contact dermatitis, urticaria and other eczematoid dermatitis; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancment 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; disorders of the bladder function; 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; pain or nociception, for example, that is attributable to or associated with any of the foregoing conditions especially the transmission of pain in migraine, (herein also referred to as the ‘Conditions of the invention’). It will be appreciated that the Conditions of the invention do not include the conditions disclosed in WO PCT/EP95/02000.
Accordingly, the present invention provides a method for the treatment and or prophylaxis of conditions characterized by overstimulation of the thachykinin receptors, in particular NK-3 receptors, which method comprises the administration to a mammal in need thereof, of an effective, non-toxic, pharmaceutically acceptable amount of a compound of formula (I):
or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
Ar is an optionally substituted phenyl, naphthyl or C
5-7
cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
R is linear or branched C
1-8
alkyl, C
3-7
cycloalkyl, C
4-7
cycloalkylalkyl, optionally substituted phenyl or phenyl C
1-6
alkyl, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatom 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 is a group —(CH
2
)
p
— when cyclized onto Ar, where p is 2 or 3.
R
1
and R
2
, which may be the same or different, are independently hydrogen or C
1-6
linear or branched alkyl, or together form a —(CH
2
)n-group in which n represents 3, 4, or 5; or R
1
together with R forms a group —(CH
2
)
q
—, in which q is 2, 3, 4 or 5;
R
3
and R
4
, which may be the same or different, are independently hydrogen, C
1-6
linear or branched 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, mono- and di-C
1-6
alkylamino, —O(CH
2
)
r
—NT
2
, in which r is 2, 3, or 4 and T is hydrogen or C
1-6
alkyl or it forms with the adjacent nitrogen a group
in which V and V
1
are independently hydrogen or oxygen and u is 0, 1 or 2;
—O(CH
2
)
s
—OW in which s is 2, 3, or 4 and W is hydrogen or C
1-6
alkyl;
hydroxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; with
up to four R
3
substituents being present in the quinoline nucleus;
or R
4
is a group —(CH
2
)
t
— when cyclized onto R
5
as aryl, in which t is 1, 2, or 3;
R
5
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 heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
X is O, S, or N—C≡N.
Suitable mammals are humans.
Suitable conditions for prevention and treatment characterized by overstimulation of the thachykinin receptors, in particular NK-3 receptors are the Conditions of the Invention described above.
Favoured conditions for prevention and treatment are disorders of the central nervous system, such as schizophrenia; neuropathological disorders such as diabetic or peripheral neuropathy; respiratory diseases such as, bronchopneumonia and bronchospasm; inflammatory diseases such as inflammatory bowel disease, fibrositis, osteoarthritis, rheumatoid arthritis allergies such as eczema and rhinitis; ophthalmic diseases such as conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases such as contact dermatitis, urticaria and other eczematoid dermatitis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronai control or viscera such as ulcerative colitis, Crohn's disease; disorders of the bladder function; pain or nociception, for example, that is attributable to or associated with any of the foregoing conditions especially the transmission of pain in migraine.
A suitable inflamatory disease for prevention and treatment is inflammatory bowel disease.
A suitable ophthalmic disease for prevention and treatment is conjunctivitis.
Suitable disorders and diseases of the GI tract for prevention and treatment are disorders associated with the neuronal control of viscera such as ulcerative colitis.
Preferred conditions for prevention and treatment are respiratory diseases such as, bronchopneumonia and bronchospasm; in
Farina Carlo
Giardina Giuseppe Arnaldo Maria
Grugni Mario
Raveglia Luca Francesco
Fay Zohreh
Furman Theodore R.
SmithKline Beecham S p.A.
Stein-Fernandez Nora
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