Tetrahydroquinoline derivatives as EAA antagonists

Details Tetrahydroquinoline derivatives as EAA antagonists Tetrahydroquinoline derivatives as EAA antagonists

2000-10-30

2002-11-12

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S311000, C514S314000, C514S235500, C544S128000, C546S165000

Reexamination Certificate

active

06479488

ABSTRACT:

This application is a 371 of PCT/EP97/04440, filed on Aug. 14, 1997.
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.
EPA0386839 describes 1,2,3,4-tetrahydroquiolines possessing at least one substituent at the 4 position and an acidic group at the 2 position and which are specific antagonists of N-methyl-D-aspartate (NMDA) receptors.
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).
We have found a novel group of 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 good in vivo activity when administered systemically eg intravenously (iv).
Thus the present invention provides a compound of formula (I)
or a salt, or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO
2
R
2
or COR
2
wherein R
2
represents hydroxy, methoxy, amino, alkylamino or dialkylamino; m is zero or an integer 1 or 2;
R
1
represents a group (CH
2
)nCN, —CH═CHR
3
, (CH
2
)nNHCOCH
2
R
4
or O(CH
2
)pNR
5
R
6
; R
3
represents cyano or the group COR
7
;
R
4
represents alkoxy or a group NHCOR
8
;
R
5
and R
6
each represent independently hydrogen or alkyl, or
R
5
and R
6
together with the nitrogen atom to which they are attached represent a heterocyclic group, or R
5
is hydrogen and R
6
is the group COR
9
;
R
7
represents an alkoxy, amino or hydroxyl group;
R
8
represents a hydrogen atom or optionally substituted alkyl, alkoxy, phenyl, heteroaryl or heterocyclic group;
R
9
is the group R
8
or the group NR
10
R
11
wherein
R
10
represents hydrogen or alkyl group;
R
11
represents optionally substituted alkyl, phenyl, heteroaryl, heterocyclic or cycloalkyl group;
n is zero or an integer from 1 to 4; p is an integer from 2 to 4.
In compounds of formula (I) the exocyclic double bond is in the trans (E) configuration.
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 earth metal salts such as sodium, potassium, calcium, and 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.
Compounds of formula (I) and in particular the base addition salts thereof e.g. sodium salt have been found to have an advantageous profile of solubility in water.
The term 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 including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.
The term optionally substituted alkyl as used herein refers to an alkyl group as defined above and which is substituted by one or more hydroxy, carboxyl, and amino groups.
The term halogen refers to a fluorine, chlorine, bromine or iodine atom.
The term heteroaryl refers to a 5 or 6 membered heteroaryl group in which the 5-membered heteroaryl group contains 1 or 2 heteroatoms selected from oxygen sulphur or nitrogen and the 6-membered heteroaryl group containing 1 or 2 nitrogen atoms.
Examples of suitable heteroaryl groups include furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, and pyrimidinyl.
The term optionally substituted phenyl refers to a phenyl group substituted with up to 3 substituents selected from halogen, C1-4 alkyl, C1-4 alkoxy, amino,alkylamino,hydroxy, trifluoromethyl, carboxyl or methoxycarbonyl.
The term cycloalkyl refers to a C
3-7
cycloalkyl group which may optionally be substituted by 1 or 2 C
1-4
alkyl groups e.g cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl cycloheptyl or 2-methylcyclohexyl.
The term optionally substituted heterocyclic group refers to 5-7 membered saturated heterocyclic groups containing one or two heteroatoms selected from oxygen, sulphur or nitrogen. Examples of suitable groups containing a single heteroatom include tetrahydropyranyl e.g. 4-tetrahydropyranyl, pyrrolidinyl e.g 2 or 3 pyrrolidinyl, piperidinyl e.g 4- or 3-piperidinyl and N-substituted derivatives therefore (e.g. N-alkyl such as e.g. methyl or N-acyl such as N-alkanoyl e.g. acetyl or N-alkoxycarbonyl e.g. ethoxycarbonyl), piperidino or pyrrolidino. Examples of suitable groups containing 2 heteroatoms include morpholino, thiomophlino or piperazino.
When R
5
and R
6
together with the nitrogen atom to which they are attached represent an heterocyclic group this is a saturated 5-7 membered ring optionally containing an additional heteroatom selected from oxygen, sulphur or nitrogen.
Examples of such groups include morpholino, 2,6 dimethylmorpholino, piperidino, pyrrolidino, piperazino or N-methylpiperazino.
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 groups R and R1. Also when R1 is the group CH═CHR
3
, the group may exist in the cis or trans configuration or mixtures. It is to be understood that all stereoisomers including enantiomers, diastereoisomers and geometric isomers and mixtures thereof are encompassed within the scope of the present invention.
It will be appreciated that the compounds of formula (I) may be produced in vivo by metabolism of a suitable prodrug. Such prodrugs include for example physiologically acceptable metabolically labile esters of compounds of the general formula (I). These may be formed by esterification, for example of any of the carboxylic acid groups in the parent compound of general formula (I) with, where appropriate, prior protection of any other reactive groups present in the molecule, followed by deprotection if required. Examples of such metabolically labile esters include C
1-4
alkyl esters e.g. methyl or ethyl esters, substituted or unsubstituted aminoalkyl esters (e.g. aminoethyl, 2-(N,N-diethylamino) ethyl, or 2-(4-morpholino)ethyl esters or acyloxyalkyl esters such as, acyloxymethyl or 1-acyloxyethyl e.g. pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 1-acetoxyethyl, 1-(1-methoxy-1-methyl)ethylcarbonyloxyethyl, 1-benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-(4-tetrahydropyranyloxy)carbonyloxyethyl or 1-(4-tetrahydropyranyl)carbonyloxyethyl.
For compounds of formula (I) m is conveniently 1 or 2 and within these compounds those wherein R is at the 5 and/or 7 position ar

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