Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-07-20
1995-04-25
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546297, C07D21375, A61K 3144
Patent
active
054099439
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/00174 filed Jan. 26, 1993.
The present invention relates to novel substituted amidine derivatives, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy, in particular as gastric acid secretion inhibitors.
The present invention, therefore, provides compounds of structure (I): ##STR1## in which: Ar.sup.1 is an optionally substituted phenyl ring;
Suitably, Ar.sup.1 is an optionally substituted phenyl ring.
Suitable substituents for the phenyl ring Ar.sup.1 include, for example, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, halogen, nitro, cyano, amino, hydroxy, carbamoyl, carboxy, C.sub.1-6 alkanoyl, trifluoromethyl and C.sub.1-4 alkylenedioxy substituents such as methylenedioxy (--OCH.sub.2 O--). The phenyl rings may be substituted by a single substituent, or up to five substituents as may be synthetically accessible (for example, 2,3,4,5,6-pentafluorophenyl). Preferably, the group Ar.sup.1 is unsubstituted phenyl, or phenyl substituted by 1 or more substituents selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C.sub.1-6 alkanoyl, trifluoromethyl or by a single substituent in association with a C.sub.1-4 alkylenedioxy. The phenyl ring may be substituted by a single substituent or up to 5 substituents as may be synthetically accessible (for example, 2,3,4,5,6-pentafluorophenyl). More preferably, Ar.sup.1 is unsubstituted phenyl, or phenyl substituted by one or two substituents selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy and halogen. Most preferably Ar.sup.1 is unsubstituted phenyl or a phenyl group substituted by a single C.sub.1-6 alkyl or halogen (in particular in the 2-position of the ring), or phenyl substituted by 2 halogen atoms (in particular 2 chlorine or fluorine atoms in the 2- and 6-positions of the ring or a chlorine atom in the 2-position and a fluorine atom in the 6-position of the ring).
Suitably R.sup.1 is hydrogen or C.sub.1-4 alkyl; preferably R.sup.1 is hydrogen.
Suitably, R.sup.2 is hydrogen or C.sub.1-4 alkyl; preferably R.sup.2 is hydrogen.
Suitably, R.sup.3 is hydrogen or C.sub.1-4 alkyl; preferably R.sup.3 is hydrogen.
Suitably, R.sup.4 is hydrogen, halogen, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; preferably R.sup.4 is hydrogen.
Suitably, Ar.sup.2 is an optionally substituted phenyl ring.
Suitable substituents for the phenyl ring Ar.sup.2 include, for example, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, halogen, nitro, cyano, amino, hydroxy, carbamoyl, carboxy, C.sub.1-6 alkanoyl, trifluoromethyl and C.sub.1-4 alkylenedioxy substituents such as methylenedioxy (--OCH.sub.2 O--). The phenyl rings may be substituted by a single substituent, or up to five substituents as may be synthetically accessible.
Preferably, Ar.sup.2 is unsubstituted phenyl or phenyl substituted by a single substituent selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy or halogen. More preferably, Ar.sup.2 is unsubstituted phenyl or phenyl substituted by a single halogen atom, in particular chlorine in the 4-position of the ring.
The compounds of the present invention can be prepared by processes analogous to those known to those skilled in the art. In a further aspect, there is, therefore provided a process for preparing compounds of structure (I) and salts thereof, which comprises (a) for compounds in which X is CH.sub.2, reaction of a compound of structure (II): ##STR2## in which Ar.sup.1, R.sup.1, R.sup.3 and R.sup.4 are as described for structure (I) with a compound of structure (HI) in which Ar.sup.2 is as described for structure (I) and Y is a leaving group; (b) for compounds in which X is NR.sup.5 and R.sup.5 is hydrogen, reaction of a compound of structure (IV) ##STR3## in which Ar.sup.1, Ar.sup.2 and R.sup.1, R.sup.3 and R.sup.4 are as described for structure (I) and Y.sup.1 is a leaving group with an amine of structure H.sub.2 NR.sup.2 in which R.sup.2 is as described for structure (I); (c) for compounds in which X is NR.sup.5
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REFERENCES:
Michael J. Dimsdale, "The Synthesis of 3-and 5-Amino-1,2,4-Oxadiazoles, A Caveat", J. Heterocyclic Chem, 18:37-41 (1981).
Dhanak Dashyant
Ife Robert J.
Leach Colin A.
Davis Zinna N.
Hall Linda E.
Ivy C. Warren
Lentz Edward T.
SmithKline Beecham Intercredit B.V.
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