US 5,994,353 A · Aromatic compounds and pharmaceutical compositions containing them

Abstract

The invention relates to compounds of formula I and pharmaceutically acceptable salts and in vivo hydrolysable esters and amides thereof and processes for their preparation, their use as therapeutic agents and pharmaceutical compositions containing them. ##STR1## In formula I, A is a ring system in which the --CH(R.sup.3)N(R.sup.2)B--R.sup.1 and --OR.sup.4 groups are positioned in a 1,2 relationship to one another on ring carbon atoms. B is a ring system having R.sup.1 in a 1,3 or 1,4 relationship with the --CH(R.sup.3)N(R.sup.2)-- linking group. R.sup.2 is hydrogen or C.sub.1 -C.sub.6 -alkyl, R.sup.3 is hydrogen, methyl or ethyl, and R.sup.4 is C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -cycloalkyl-C.sub.1 -C.sub.3 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, N-oxides of --NR.sup.2, where chemically possible, or S-oxides of sulphur containing rings, where chemically possible. A, B, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may be substituted, as defined in the specification.

A compound of formula (I):

##STR20## wherein:
ring A is unsubstituted or substituted, provided that the --CH(R.sup.3)N(R.sup.2)B--R.sup.1 and --OR.sup.4 groups are positioned in a 1,2 relationship to one another on ring atoms, and the ring atom positioned ortho to the OR.sup.4 group (and therefore in the 3-position relative to the --CH(R.sup.3)N(R.sup.2)-- linking group) is not substituted, where:
ring A substituents are selected from halo, trifluoromethyl, nitro, hydroxy, amino, (C.sub.1 -C.sub.4)alkylamino, di(C.sub.1 -C.sub.4)alkylamino, cyano, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkylS(O).sub.p -where p is 0, 1 or 2;
(C.sub.1 -C.sub.6)alkyl optionally substituted with hydroxy, amino, halo, nitro or cyano;
CF.sub.3 S(O).sub.p -where p is 0, 1 or 2;
carbamoyl, (C.sub.1 -C.sub.4)alkylcarbamoyl, di(C.sub.1 -C.sub.4)alkylcarbamoyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.4)alkoxycarbonylamino, (C.sub.1 -C.sub.4)alkanoylamino, (C.sub.1 -C.sub.4)alkanoyl(N-(C.sub.1 -C.sub.4)alkyl)amino, (C.sub.1 -C.sub.4)alkanesulphonamido, benzenesulphonamido, aminosulphonyl, (C.sub.1 -C.sub.4)alkylaminosulphonyl, (C.sub.1 -C.sub.4)alkanoylaminosulphonyl, di(C.sub.1 -C.sub.4)alkylaminosulphonyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.4)alkanoyloxy, (C.sub.1 -C.sub.6)alkanoyl, formyl(C.sub.1 -C.sub.4)alkyl, trifluoro(C.sub.1 -C.sub.3)alkylsulphonyl, hydroxyimino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.4)alkoxyimino(C.sub.1 -C.sub.6)alkyl and (C.sub.1 -C.sub.6)alkylcarbamoylamino;
ring B is unsubstituted or substituted, where:
ring B substituents are selected from halo, trifluoromethyl, nitro, hydroxy, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkyl, amino, (C.sub.1 -C.sub.4)alkylamino, di(C.sub.1 -C.sub.4)alkylamino, cyano, (C.sub.1 -C.sub.6)alkyl S(O).sub.p -- where p is 0, 1 or 2;
carbamoyl, (C.sub.1 -C.sub.4)alkylcarbamoyl and di(C.sub.1 -C.sub.4)alkylcarbamoyl
R.sup.1 is positioned on ring B in a meta or para relationship with the --CH(R.sup.3)N(R.sup.2)-- linking group;
and
R.sup.1 is selected from carboxy, carboxy(C.sub.1 -C.sub.3)alkyl, tetrazolyl, tetrazolyl(C.sub.1 -C.sub.3)alkyl, tetronic acid, hydroxamic acid and sulphonic acid;
or
R.sup.1 is of the formula --CONR.sup.a R.sup.a1, wherein R.sup.a is hydrogen or (C.sub.1 -C.sub.6)alkyl, and R.sup.a1 is hydrogen, (C.sub.1 -C.sub.6)alkyl optionally substituted by halo, amino, (C.sub.1 -C.sub.4)alkylamino, di(C.sub.1 -C.sub.4)alkylamino, hydroxy, nitro, cyano, trifluoromethyl, (C.sub.1 -C.sub.4)alkoxy or (C.sub.1 -C.sub.4)alkoxycarbonyl;
(C.sub.2 -C.sub.6)alkenyl provided the double bond is not in the 1-position;
(C.sub.2 -C.sub.6)alkynyl provided the triple bond is not in the 1-position;
carboxyphenyl, 5- or 6-membered heterocyclyl(C.sub.1 -C.sub.3)alkyl, 5- or 6-membered heteroaryl(C.sub.1 -C.sub.3)alkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl, or R.sup.a and R.sup.a1 together with the amide nitrogen to which they are attached form an amino acid residue or ester thereof;
wherein any heterocyclyl or heteroaryl group in R.sup.a1 is optionally-substituted by halo, hydroxy, nitro, cyano, trifluoromethyl, (C.sub.1 -C.sub.4)alkoxy or (C.sub.1 -C.sub.4)alkoxycarbonyl,;
or
R.sup.1 is of the formula --CONHSO.sub.2 R.sup.b, wherein R.sup.b is (C.sub.1 -C.sub.6)alkyl optionally substituted by halo, hydroxy, nitro, cyano, trifluoromethyl, (C.sub.1 -C.sub.4)alkoxy, amino, (C.sub.1 -C.sub.4)alkylamino, di(C.sub.1 -C.sub.4)alkylamino or (C.sub.1 -C.sub.4)alkoxycarbonyl;
(C.sub.2 -C.sub.6)alkenyl provided the double bond is not in the 1-position;
(C.sub.2 -C.sub.6)alkynyl provided the triple bond is not in the 1-position;
5- or 6-membered heterocyclyl(C.sub.1 -C.sub.3)alkyl, 5- or 6-membered heteroaryl(C.sub.1 -C.sub.3)alkyl, phenyl(C.sub.1 -C.sub.3)alkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl or phenyl;
wherein any phenyl, heterocyclyl or heteroaryl group in R.sup.b is optionally-substituted by halo, trifluoromethyl, nitro, hydroxy, amino, cyano, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkyl-S(O).sub.p -- where p is 0, 1 or 2;
(C.sub.1 -C.sub.6)alkyl, carbamoyl, (C.sub.1 -C.sub.4)alkylcarbamoyl, di(C.sub.1 -C.sub.4)alkylcarbamoyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.4)alkoxycarbonylamino, (C.sub.1 -C.sub.4)alkanoylamino, (C.sub.1 -C.sub.4)alkanoyl(N-(C.sub.1 -C.sub.4)alkyl)amino, (C.sub.1 -C.sub.4)alkanesulphonamido, benzenesulphonamido, aminosulphonyl, (C.sub.1 -C.sub.4)alkylaminosulphonyl, di(C.sub.1 -C.sub.4)alkylaminosulphonyl, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.4)alkanoyloxy, (C.sub.1 -C.sub.6)alkanoyl, formyl(C.sub.1 -C.sub.4)alkyl, hydroxyimino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.4)alkoxyimino(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkylcarbamoylamino;
or
R.sup.1 is of the formula --SO.sub.2 N(R.sup.c).sub.2, wherein R.sup.c at each occurrence is selected from hydrogen and (C.sub.1 -C.sub.4)alkyl;
or
R.sup.1 is of formula (IA), (IB) or (IC):
##STR21## wherein:
in compounds of Formula (IA), X is CH or nitrogen,
in compounds of Formula (IA), (IB) or (IC), Y is oxygen or sulphur,
in compounds of Formula (IC), Z is CH.sub.2, NR.sup.d or oxygen,
in compounds of Formula (IB), Y' is oxygen or NR.sup.d, and
in compounds of Formula (IA), (IB) or (IC), R.sup.d is hydrogen or (C.sub.1 -C.sub.4)alkyl, provided that compounds of formulae (IA), (IB) and (IC) each have no more than one ring oxygen and at least two ring heteroatoms;
R.sup.2 is selected from hydrogen, (C.sub.1 -C.sub.6)alkyl optionally substituted by hydroxy, cyano or trifluoromethyl;
(C.sub.2 -C.sub.6)alkenyl provided the double bond is not in the 1-position;
(C.sub.2 -C.sub.6)alkynyl provided the triple bond is not in the 1-position;
phenyl(C.sub.1 -C.sub.3)alkyl and pyridyl(C.sub.1 -C.sub.3)alkyl;
R.sup.3 is selected from hydrogen, methyl or ethyl;
R.sup.4 is selected from optionally substituted (C.sub.1 -C.sub.6)alkyl, optionally substituted (C.sub.3 -C.sub.7)cycloalkyl(C.sub.1 -C.sub.3)alkyl and optionally substituted (C.sub.3 -C.sub.7)cycloalkyl;
an N-oxide of --NR.sup.2, where chemically possible;
an S-oxide of sulphur containing rings, where chemically possible;
or a pharmaceutically-acceptable salt thereof.

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Aromatic compounds and pharmaceutical compositions containing them

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Aromatic compounds and pharmaceutical compositions containing them

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Abstract

Claims14