Quinoline derivatives(2)

Details Quinoline derivatives(2) Quinoline derivatives(2)

1995-05-25

2003-08-19

Mullis, Jeffrey (Department: 1711)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S312000, C514S314000, C514S331000, C546S152000, C546S153000, C546S156000, C546S155000, C546S169000

Reexamination Certificate

active

06608083

ABSTRACT:

The present invention relates to novel quinoline derivatives, processes for their preparation and their use 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.
We have now discovered a novel class of 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 and 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).
According to the present invention there is provided a compound, or a solvate or salt thereof, of formula (I):
in which:
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 heteroatoms 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 —(CH2)
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
2
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.
Examples of Ar are phenyl, optionally substituted by hydroxy, halogen, C
1-6
alkoxy or C
1-6
alkyl. Examples of halogen are chlorine and fluorine, an example of C
1-6
alkoxy is methoxy and an example of C
1-6
alkyl is methyl.
Examples of Ar as a heterocyclic group are thienyl and pyridyl.
Examples of Ar as a C
5-7
cycloalkdienyl group is cyclohexadienyl.
Examples of R are as follows:
C
18
alkyl: methyl, ethyl, n-propyl, iso-propyl, n-butyl, heptyl;
phenyl C
1-6
alkyl: benzyl;
hydroxy C
1-6
alkyl: —CH
2
OH, —CH
2
CH
2
OH, CH(Me)OH;
amino C
1-6
alkyl: —CH
2
NH
2
;
di C
1-6
alkylaminoalkyl: —CH
2
NMe
2
;
C
1-6
alkoxylalkyl: CH
2
OMe;
C
1-6
alkylcarbonyl: COMe;
C
1-6
alkoxycarbonyl: COOMe;
C
1-6
alkoxycarbonyl C
1-6
alkyl: CH
2
COOMe;
C
1-6
alkylaminocarbonyl: CONHMe;
di C
1-6
alkylaminocarbonyl: CONMe
2
, CO(l-pyrrolidinyl);
halogen C
1-6
alkyl: trifluoromethyl;
—(CH
2
)
p
— when cyclized onto Ar:
Example of R
1
and R
2
as C
1-6
alkyl is methyl; example of R
1
together with R forming a group-(CH2)q- is spirocyclopentane.
Examples of R
3
and R
4
are methyl, ethyl, n-propyl, n-butyl, methoxy, hydroxy, amino, chlorine, fluorine, bromine, acetyloxy, 2-(dimetylamino)ethoxy, 2-(1-phthaloyl)ethoxy, aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, phthaloyl, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino, dimethylaminomethyl and phenyl.
Examples of R
5
are cyclohexyl, phenyl optionally substituted as defmed for Ar above; examples of R
5
as a heterocyclic group are furyl, thienyl, pyrryl, thiazolyl, benzofuryl and pyridyl.
A preferred group of compounds of formula (I) are those in which:
Ar is phenyl, optionally substituted by C
1-6
alkyl or halogen; thienyl or a C
5-7
cycloalkdienyl group;
R is C
1-6
alkyl, C
1-6
alkoxycarbonyl, C
1-6
alkylcarbonyl, hydroxy C
1-6
alkyl;
R
1
and R
2
are each hydrogen or C
1-6
alkyl;
R
3
is hydrogen, hydroxy, halogen, C
1-6
alkoxy, C
1-6
alkyl;
R
4
is hydrogen, C
1-6
alkyl, C
1-6
alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl, phthaloylalkoxy, mono- or di-alkylaminoacylamino and acylamino;
R
5
is phenyl, thienyl, furyl, pyrryl and thiazolyl.
A further preferred group of compounds of formula (I) are those in which:
Ar is phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl;
R is methyl, ethyl, n-propyl, -COOMe, -COMe;
R
1
and R
2
are each hydrogen or methyl;
R
3
is hydrogen, methoxy, or hydroxy;
R
4
is hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine, bromine, dimethylaminoethoxy, 2-(1-phthaloyl)ethoxy, aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino, and dimethylaminomethyl.
R
5
is phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-thiazolyl and 3-thienyl; and
X is oxygen.
A preferred sub-group of compounds within the scope of formula (I) above is of formula (Ia):
in which:
R, R
2
, R
3
and R
4
are as defined in formula (I), and Y and Z, which may be the same or different, are each Ar as defined in formula (I).
A particularly preferred group of compounds of formula (Ia) are those of formula (Ib) in which the group R is oriented downward and H upward.
The compo

Affiliated with

Also associated with

Rating

Quinoline derivatives(2) does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Quinoline derivatives(2), we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Quinoline derivatives(2) will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3128498