Salts of quinoline derivatives as NK3 antagonists

Details Salts of quinoline derivatives as NK3 antagonists Salts of quinoline derivatives as NK3 antagonists

1998-05-21

2002-03-12

Seaman, D. Margaret (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S153000

Reexamination Certificate

active

06355654

ABSTRACT:

The present invention relates to novel compounds, in particular to salts of quinoline derivatives, to a process for the preparation of such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions 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.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).
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.
International Patent Application Number PCT/EP95/02000 describes certain quinoline derivatives and describes inter alia 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 salts of the quinoline derivatives of the compounds of PCT/EP95/02000. The new salts are selective, 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 in treating pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough), skin disorders and itch (for example, atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety, psychosis). These disorders are referred to hereinafter as the Primary Disorders.
The novel NK
3
antagonists of the present invention are also of potential therapeutic utility in treating convulsive disorders (for example epilepsy), renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating, disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (for example Alzheimer's disease), psoriasis, Huntington's disease, and depression (hereinafter referred to as the Secondary Disorders).
The compounds of the present invention are also useful in the prevention and treatment of 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 (hereinafter referred to as the ‘Further Disorders’).
According to the present invention there is provided a salted form of a compound of formula (I) (hereinafter also referred to as ‘a Salt of the invention’):
or a solvate 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-alkylaninoalkyl, 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; characterised in that the salt comprises a compound of formula (I) in anionic form and a salting cation.
Suitably, the salt is a compound of formula (A):
S
t−
M
t+
  (A)
or a solvate thereof, wherein;
t is an integer 1, 2 or 3;
M
t+
is a salting cation; and
S
t−
is an anion provided by an appropriate compound of the above defined formula (I).
Suitable salting cations M
t+
include metal ions and organic cations, in particular pharmaceutically acceptable metal ions and organic cations.
Suitable pharmaceutically acceptable metal ions include those ions provided by aluminium, alkali metals such as lithium, sodium or potassium, alkaline earth metals such as cal

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