Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-09-30
2000-02-22
Huang, Evelyn
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514339, 514418, 514419, 546256, 5462781, 548491, A61K 3144, A61K 3140, C07D40112, C07D40114, C07D20926
Patent
active
060280859
DESCRIPTION:
BRIEF SUMMARY
This invention relates to compounds having pharmacological activity, processes for their preparation, to compositions containing, them and to their use in the treatment of CNS disorders.
Compounds having 5HT.sub.2C receptor antagonist activity are known in the art. For example PCT/EP96/00368 discloses indoline derivatives as 5HT.sub.2C antagonists.
However certain 5HT.sub.2C receptor antagonists exhibit poor solubility which may lead to decreased activity. It has now been found that pyridinium derivatives of certain known 5HT.sub.2C receptor antagonists show increased solublility and increased in vivo activity. It is believed that these new compounds are converted to their `parent` compounds prior/during/or after absorption and so may increase the bioavailability of the `parent` compound. The compounds of the invention may therefore act as prodrugs and are defined as prodrugs herein.
The present invention therefore provides, in a first aspect, a prodrug of a 5HT.sub.2C receptor antagonist wherein the prodrug has a quaternary ammonium group, in particular a quaternary pyridinium group.
Preferably the invention provides a compound of formula (I): ##STR2## wherein: R.sup.1 and R.sup.2 groups are each independently hydrogen, C.sub.1-6 alkyl optionally substituted by NR.sup.12 R.sup.13, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkylthio, cyano, nitro, halogen, CF.sub.3, C.sub.2 F.sub.5, NR.sup.12 R.sup.13, CONR.sup.12 R.sup.13, NR.sup.12 COR.sup.13, S(O).sub.p NR.sup.12 R.sup.13, CHO, OCF.sub.3, SCF.sub.3, COR.sup.14, CH.sub.2 OR.sup.14, CO.sub.2 R.sup.14 or OR.sup.14 where p is 1 or 2 and R.sup.12, R.sup.13 and R.sup.14 are independently hydrogen, C.sub.1-6 alkyl, optionally substituted aryl or optionally substituted arylC.sub.1-6 alkyl, or R.sup.1 and R.sup.2 are N.sup.+ I.sup.- R.sup.12 R.sup.13 CR.sup.12 R.sup.13 OCOR.sup.14 where R.sup.12, R.sup.13 and R.sup.14 are as defined above and I is a counter ion; ##STR3## in which: X and Y are both nitrogen, one is nitrogen and the other is carbon or a CR.sup.5 group or one is a CR.sup.5 group and the other is carbon or a CR.sup.5 group; C.sub.1-6 alkyl optionally substituted by one or more fluorine atoms, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkylC.sub.1-6 alkoxy, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyloxy, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl, C.sub.1-6 alkylthio, C.sub.3-6 cycloalkylthio, C.sub.3-6 cycloalkyl-C.sub.1-6 alkylthio, C.sub.1-6 alkoxy, hydroxy, halogen, nitro, OCF.sub.3, SCF.sub.3, SO.sub.2 CF.sub.3, SO.sub.2 F, formyl, C.sub.2-6 alkanoyl, cyano, optionally substituted phenyl or thienyl, NR.sup.12 R.sup.13, CONR.sup.12 R.sup.13 or CO.sub.2 R.sup.14 where where R.sup.12, R.sup.13 and R.sup.14 are as defined for R.sup.1 ; or R.sup.6 and R.sup.7 form part of an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring; ##STR4## in which X and Y are both nitrogen, one is nitrogen and the other is a CR.sup.5 group or X and Y are both CR.sup.5 groups and R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined in formula (I); and ##STR5## in which R.sup.6, R.sup.7, X and Y are as defined in formula (i) and Z is O, S, CH.sub.2 or NR.sup.15 where R.sup.15 is hydrogen or C.sub.1-6 alkyl; saturated monocyclic or bicyclic heterocyclic rings said heterocyclic rings containing a quaternary nitrogen atom and up to two further heteroatoms selected from nitrogen, oxygen or sulphur; and alkyl or A is an optionally substituted phenyl or an optionally substituted 5- to 7-membered heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur.
C.sub.1-6 Alkyl groups, whether alone or as part of another group, may be straight chain or branched.
Suitably R.sup.1 and R.sup.2 groups are each independently hydrogen, C.sub.1-6 alkyl optionally substituted by NR.sup.12 R.sup.13, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkylthio, cyano, nitro, halogen, CF.sub.3, C.sub.2 F.sub.5, NR.sup.12 R.sup.13, CONR.sup.12 R.sup.13, NR.sup.12 COR.sup.13, S(O).sub.p NR.sup.12 R.sup.13, CHO, OCF.sub.3, SCF.sub.3, CO
REFERENCES:
Database Crossfire, Beilstein, XP002001373.
Database Crossfire, Beilstein, XP002001374.
Database Crossfire, Beilstein, XP002001375.
Huang Evelyn
King William T.
Kinzig Charles M.
Simon Soma G.
SmithKline Beecham Plc
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