Tetrahydroquinoline derivatives as glycine antagonists

Details Tetrahydroquinoline derivatives as glycine antagonists Tetrahydroquinoline derivatives as glycine antagonists

2001-02-15

2002-03-26

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...

C514S253010, C514S255050, C544S363000, C544S405000, C546S165000, C546S167000

Reexamination Certificate

active

06362199

ABSTRACT:

This invention relates to 1, 2, 3, 4 tetrahydroquinoline derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. In particular, it relates to 1, 2, 3, 4 tetrahydroquinoline derivatives which are potent and specific antagonists of excitatory amino acids.
Carling et al., Bioorganic and Medicinal Chemistry Letters, Vol. 13 pp. 65-70, 1993, teaches 4-substituted-2-carboxy tetrahydroquinolines having good in vitro affinity for the glycine modulatory site of the NMDA receptor complex but at best only weak in vivo activity. More particularly, it teaches that such derivatives substituted at the 4 position by the group CH
2
CO
2
H or CH
2
CONHPh have little or no in vivo activity when administered systemically (ip).
WO 97112870 and WO 98/107704 describe novel 4-substituted-2-carboxy-tetrahydroquinoline derivatives which not only have a good in vitro affinity for the strychnine insensitive glycine binding site associated with the NMDA receptor complex but also have good in vivo activity when administered intravenously (iv).
We have now discovered a novel group of 4-substituted-2-carboxy tetrahydroquinoline having a particularly useful profile of activity as selective antagonists for the strychnine insensitive glycine binding site associated with the NMDA receptor complex.
Thus the present invention provides a compound of formula (I)
or a salt or a non toxic metabolically labile esters thereof, wherein
Y represents a carbon atom;
Z is the group CH which is linked to the group Y via a double bond and
X is CH or Z is methylene or NR
11
and X is a carbon atom linked to the group Y via a double bond;
A represents a C
1-2
alkylene chain and which chain may be substituted by one or two groups selected from C
1-6
alkyl optionally substituted by hydroxy, amino, C
1-4
alkyl amino or C
1-4
dialkyl amino or which chain may be substituted by the group ═O;
R represents a halogen atom or C
1-4
alkyl group;
R
1
represents a hydrogen, a halogen atom or C
1-4
alkyl group;
R
2
represents phenyl which may be substituted with up to 3 groups selected from halogen, hydrogen, or (CH
2
)
n
R
3
wherein R
3
is COR
4
, NR
6
R
5
, NHCOR
7
, NHCONR
9
R
8
or NH SO
2
R
10
group or R
2
is a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen; or 6 membered heteroaryl group containing 1 to 3 nitrogen atoms
R
4
represents an amino, a hydroxyl or C
1-4
alkoxy group;
R
5
and R
6
each independently represents hydrogen or C
1-4
alkyl group or
R
5
and R
6
together with the nitrogen atom to which they are attached represent a saturated 5-7 membered heterocyclic group optionally containing an additional heroatom selected from oxygen,sulphur or nitrogen
R
7
represents a hydrogen atom or C
1-4
alkyl, C
1-4
alkoxy, or phenyl;
R
8
represents hydrogen or C
1-8
alkyl group;
R
9
represents hydrogen, optionally substituted C
1-4
alkyl (optionally substituted by one or more hydroxy carboxyl and amino group), phenyl;
R
11
represents hydrogen or C
1-4
alkyl group;
R
10
represents hydrogen, C
1-4
alkyl or a nitrogen protecting group. n is zero or an integer from 1 to 2;
A further embodiment of the invention provides compounds of formula(I) or a salt or a non toxic metabolically labile esters thereof, wherein
Y represents a carbon atom;
Z is the group CH which is linked to the group Y via a double bond and
X is CH or Z is methylene or NR
11
and X is a carbon atom linked to the group Y via a double bond;
A represents a C
1-2
alkylene chain and which chain may be substituted by one or two groups selected from C
1-6
alkyl optionally substituted by hydroxy, amino, C
1-4
alkyl amino or C
1-4
dialkyl amino or which chain may be substituted by the group ═O;
R represents a halogen atom;
R
1
represents a hydrogen or a halogen atom;
R
2
represents phenyl which may be substituted with up to 3 groups selected from halogen, hydrogen, or (CH
2
)
n
R
3
wherein R
3
is COR
4
, NR
6
R
5
, NHCOR
7
, NHCONR
9
R
8
or NH SO2 R
10
group or R
2
is a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen; or 6 membered heteroaryl group containing 1 to 3 nitrogen atoms
R
4
represents an amino or a hydroxyl;
R
5
and R
6
each independently represents hydrogen or C
1-4
alkyl group or
R
5
and R
6
together with the nitrogen atom to which they are attached represent a saturated 5-7 membered heterocyclic group optionally containing an additional heroatom selected from oxygen,sulphur or nitrogen
R
7
represents a hydrogen atom or C
1-4
alkyl, C
1-4
alkoxy, or phenyl;
R
8
represents hydrogen or C
1-4
alkyl group;
R
9
represents hydrogen, optionally substituted C
1-4
alkyl (optionally substituted by one or more hydroxy carboxyl and amino group), phenyl;
R
11
represents hydrogen or C
1-4
alkyl group;
R
10
represents hydrogen, C
1-4
alkyl or a nitrogen protecting group;
n is zero or an integer from 1 to 2 with the proviso that when X is a carbon atom linked to the group Y via a double bond then R
1
is hydrogen;
For use in medicine the salts of the compounds of formula (I) will be physiologically acceptable thereof. Other salts however may be useful in the preparation of the compounds of formula (I) or physiologically acceptable salts thereof. Therefore, unless otherwise stated, references to salts include both physiologically acceptable salts and non-physiologically acceptable salts of compounds of formula (I).
Suitable physiologically acceptable salts of compounds of the invention include base addition salts and, where appropriate, acid addition salts.
Suitable physiologically acceptable base addition salts of compounds of formula (I) include alkali metal or alkaline metal salts such as sodium, potassium, calcium, magnesium and ammonium salts, formed with amino acids (e.g. lysine and arginine) and organic bases (e.g. procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methyl glucosamine).
The compounds of formula (I) and/or salts thereof may form solvates (e.g. hydrates) and the invention includes all such solvates.
The term halogen refers to a fluorine, chlorine, bromine or iodine atom.
The term C
1-4
alkyl as used herein as a group or part of a group refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atom, examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.
When R
2
is a 5 or 6 membered heteroaryl group this may be for example furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridyl or pyrimidinyl.
When R
5
and R
6
together with the nitrogen atom to which they are attached form a saturated 5-7 membered heterocyclic group optionally containing an additional heroatom selected from oxygen, sulphur or nitrogen this may be morpholino, 2,6 dimethylmorpholino, thiomorpholino, piperidino, pyrrolidino, piperazino or N-methylpiperazino.
When R
2
is a substituted phenyl group this is conveniently a mono substituted phenyl group. The substituent is conveniently in the meta position or more conveniently in the para position.
When X—Y represents a double bond, the compounds of formula (I) possess at least one asymmetric carbon atom (namely the carbon atom occupying the 2 position of the 1, 2, 3, 4 tetrahydroquinoline ring system) and other asymmetric carbon atoms are possible in the group R
2
. It is to be understood that all enantiomers and diastereomers and mixtures thereof are encompassed within the scope of the present invention.
When X-Y represents a single bond, the compounds of formula (I) possess at least two asymmetric carbon atoms (namely the carbon atom occupying the 2 and 4 position of the 1, 2, 3, 4 tetrahydroquinoline ring system) and these may be represented by the formulae (1a,1b,1c and 1d).
The solid wedge shaped bond indicates that the bond is above the plane of the paper and is referred to as the &bgr; configuration. The broken indicates that the bond is below the plane of the paper and is referred to as &agr; configura

Affiliated with

Also associated with

Rating

Tetrahydroquinoline derivatives as glycine antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Tetrahydroquinoline derivatives as glycine antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tetrahydroquinoline derivatives as glycine antagonists will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2883851