US 5,494,903 AGranted

7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines

AssigneeAmerican Cyanamid Company

InventorsJoseph J. Hlavka, Phaik-Eng Sum, Yakov Gluzman, Ving J. Lee, Adma A. Ross

Life of this patent

Estimating the term…

Abstract

The invention is drawn to 7-substituted-9-(substituted amino)-6-demethyl-6-deoxytetracycline compounds of the formula ##STR1## wherein R, X, R.sup.5 and R.sup.6 are defined in the specification. The compounds of the invention are useful as broad spectrum antibiotics.

Claims98

Dependent claims

A compound of the formula ##STR223## wherein:

X is selected from amino, NR.sup.1 R.sup.2, or halogen;
the halogen is selected from bromine, chlorine, fluorine or iodine;
R.sup.1 is selected from hydrogen, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl and 1-methylpropyl;
R.sup.2 is selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl such that when X.dbd.NR.sup.1 R.sup.2 and R.sup.1 =hydrogen,
R.sup.2 =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
and when R.sup.1 =methyl or ethyl,
R.sup.2 =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R.sup.1 =n-propyl,
R.sup.2 =n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R.sup.1 =1-methylethyl,
R.sup.2 =n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R.sup.1 =n-butyl,
R.sup.2 =n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R.sup.1 =1-methylpropyl,
R.sup.2 =2-methylpropyl;
R is selected from R.sup.4 (CH.sub.2).sub.n CO-- or R.sup.4' (CH.sub.2).sub.n SO.sub.2 --;
and n=0-4;
and when R=R.sup.4 (CH.sub.2).sub.n CO-- and n-0,
R.sup.4 is selected from amino;
monosubstituted amino selected from straight or branched (C.sub.1 -C.sub.6)alkylamino, cyclopropylamino, cyclobutylamino, benzylamino or phenylamino;
disubstituted amino selected from dimethylamino, diethylamino, ethyl(1-methylethyl)amino, monomethylbenzylamino, piperidinyl, morpholinyl, 1-imidazolyl, 1-pyrrolyl, 1-(1,2,3-triazolyl) or 4-(1,2,4-triazolyl);
a substituted (C.sub.3 -C.sub.6)cycloalkyl group with substitution selected from cyano, amino or (C.sub.1 -C.sub.3)acyl;
a substituted (C.sub.6 -C.sub.10)aryl group with substitution selected from halo, (C.sub.1 -C.sub.4)alkoxy, trihalo (C.sub.1 -C.sub.3)-alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxycarbonyl (C.sub.1 -C.sub.3)alkylamino or carboxy;
.alpha.-amino-(C.sub.1 -C.sub.4)alkyl selected from aminomethyl, .alpha.-aminoethyl, .alpha.-aminopropyl or .alpha.-amino-butyl;
carboxy (C.sub.2 -C.sub.4)-alkylamino selected from aminoacetic acid, .alpha.-aminobutyric acid or .alpha.-aminopropionic acid and the optical isomers thereof;
(C.sub.7 -C.sub.9)aralkylamino;
(C.sub.1 -C.sub.4)alkoxycarbonylamino substituted (C.sub.1 -C.sub.4) alkyl group;
.alpha.-hydroxy(C.sub.1 -C.sub.3)alkyl selected from hydroxymethyl, .alpha.-hydroxyethyl or .alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
.alpha.-mercapto (C.sub.1 -C.sub.3)alkyl selected from mercaptomethyl, .alpha.-mercaptoethyl, .alpha.-mercapto-1-methylethyl or .alpha.-mercaptopropyl;
halo-(C.sub.1 -C.sub.3)alkyl group;
a heterocycle selected from the group consisting of a five membered aromatic or saturated ring with one N, O, S or Se heteroatom optionally having a benzo or pyrido ring fused thereto, a five membered aromatic ring with two N, O, S, or Se heteroatoms optionally having a benzo or pyrido ring fused thereto, a six membered aromatic ring with one to three N, O, S or Se heteroatoms, or a six membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom;
acyl or haloacyl group selected from acetyl, propionyl, chloroacetyl, trifluoroacetyl;
(C.sub.3 -C.sub.6)cycloalcylcarbonyl, (C.sub.6 -C.sub.10)aroyl selected from benzoyl or naphthoyl;
halo substituted (C.sub.6 -C.sub.10)aroyl;
(C.sub.1 -C.sub.4) alkylbenzoyl, or (heterocycle)-carbonyl, the heterocycle as defined hereinabove;
(C.sub.1 -C.sub.4)alkoxycarbonyl selected from methoxycarbonyl, ethoxycarbonyl, straight or branched propoxylcarbonyl, straight or branched butoxycarbonyl or allyloxycarbonyl;
a substituted vinyl group with substitution selected from halogen, halo(C.sub.1 -C.sub.3)alkyl, or a substituted (C.sub.6 -C.sub.10)aryl group with substitution selected from halo, (C.sub.1 -C.sub.4)-alkoxy, trihalo(C.sub.1 -C.sub.3)alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.3)alkylamino or carboxy;
(C.sub.1 -C.sub.4)alkoxy group;
C.sub.6 -aryloxy selected from phenoxy or substituted phenoxy with substitution selected from halo, (C.sub.1 -C.sub.4) alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)alkylamino;
(C.sub.7 -C.sub.10)aralkyloxy;
vinyloxy or a substituted vinyloxy group with substitution selected from (C.sub.1 -C.sub.4)alkyl, cyano, carboxy, or (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
R.sup.a R.sup.b amino(C.sub.1 -C.sub.4)alkoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or (CH.sub.2).sub.2 W(CH.sub.2)2-wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl,O,S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl;
or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O,S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl;
and when R=R.sup.4 (CH.sub.2).sub.n CO-- and n-1-4, R.sup.4 is selected from amino;
a substituted (C.sub.3 -C.sub.6)cycloalkyl group with substitution selected from cyano, amino or (C.sub.1 -C.sub.3)acyl;
a substituted(C.sub.6 -C.sub.10)-aryl group with substitution selected from halo, (C.sub.1 -C.sub.4)-alkoxy, trihalo(C.sub.1 -C.sub.3)alkyl, nitro, amino, cyano,(C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.3)alkylamino or carboxy;
acyloxy or haloacyloxy group selected from acetyl, propionyl, chloroacetyl, trichlorocetyl, (C.sub.3 -C.sub.6)cycloalkylcarbonyl, (C.sub.6 -C.sub.10)aroyl selected from benzoyl or naphthoyl, halo substituted (C.sub.6 -C.sub.10)aroyl, (C.sub.1 -C.sub.4)alkylbenzoyl, or (heterocycle)-carbonyl, the heterocycle as defined hereinabove;
(C.sub.1 -C.sub.4)alkoxy;
C.sub.6 -aryloxy selected from phenoxy or substituted phenoxy with substitution selected from halo, (C.sub.1 -C.sub.4)-alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)-alkylamino;
(C.sub.7 -C.sub.10)aralkyloxy;
(C.sub.1 -C.sub.3)alkylthio group selected from methylthio, ethylthio, propylthio or allythio;
C.sub.6 -arylthio group selected from phenylthio or substituted phenylthio with substitution selected from halo, (C.sub.1 -C.sub.4)alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)alkylamino;
C.sub.6 -arylsulfonyl group selected from phenylsulfonyl or substituted phenylsulfonyl with substitution selected from halo, (C.sub.1 -C.sub.4)alkoxy, trihalo(C.sub.1 -C.sub.3)alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.3)alkylamino or carboxy;
(C.sub.7 -C.sub.8)aralkylthio group;
a heterocycle as defined hereinabove;
hydroxy;
mercapto;
mono- or di-straight or branched chain (C.sub.1 -C.sub.6)- alkylamino with the alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl or 1-methyl-1-ethylpropyl;
(C.sub.2 -C.sub.5)azacycloalkyl group;
a carboxy(C.sub.2 -C.sub.4)alkylamino group with the carboxy alkyl selected from aminoacetic acid, .alpha.-aminopropionic acid, .alpha.-aminobutyric acid and the optical isomers thereof;
.alpha.-hydroxy(C.sub.1 -C.sub.3)alkyl selected from hydroxymethyl, .alpha.-hydroxyethyl or .alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1 -C.sub.3)alkyl group;
acyl or haloacyl selected from acetyl, propionyl, chloroacetyl, trifluoroacetyl;
(C.sub.3 -C.sub.6)cycloalkylcarbonyl;
(C.sub.6 -C.sub.10)aroyl selected from benzoyl or naphthoyl;
halo substituted (C.sub.6 -C.sub.10)aroyl;
(C.sub.1 -C.sub.4)alkylbenzoyl, or (heterocycle)carbonyl, the heterocycle as defined hereinabove;
(C.sub.1 -C.sub.4)alkoxycarbonylamino, group selected from tert-butoxycarbonylamino, allyloxycarbonylamino, methoxycarbonylamino, ethoxycarbonylamino or propoxycarbonylamino;
(C.sub.1 -C.sub.4)alkoxycarbonyl group selected from methoxycarbonyl, ethoxycarbonyl, straight or branched propoxycarbonyl, allyloxycarbonyl or straight or branched butoxycarbonyl;
R.sup.a R.sup.b - amino(C.sub.1 -C.sub.4)alkoxy group wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH).sub.m m=2-6 or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -wherein W is selected from --N(C.sub.1 -C.sub.3)-alkyl, O, S, --NH, --NOB, and B is selected from hydrogen or C.sub.1 -C.sub.3)alkyl;
or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)-alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 - wherein W is selected from --N(C.sub.1 -C.sub.3)-alkyl, O,S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl, and when R.dbd.R.sup.4' (CH.sub.2).sub.n SO.sub.2 -and n=0
R.sup.4' is selected from amino;
monosubstituted amino selected from straight or branched (C.sub.1 -C.sub.6)alkylamino, cyclopropylamino, cyclobutylamino, benzylamino or phenylamino;
disubstituted amino selected from dimethylamino, diethylamino, ethyl(1-methylethyl)amino, monomethylbenzylamino, piperidinyl, morpholinyl, 1-imidazoyl, 1-pyrrolyl, 1-(1,2,3-triazolyl) or 4-(1,2,4-triazolyl);
a substituted (C.sub.3 -C.sub.6)cycloalkyl group with substitution selected from cyano, amino or (C.sub.1 -C.sub.3)acyl;
halo(C.sub.1 -C.sub.3)alkyl group;
a heterocycle as defined hereinabove;
R.sup.a R.sup.b amino (C.sub.1 -C.sub.4) alkoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)-alkyl selected from methyl, ethyl, n-propyl, 1-methyl-ethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W--(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3) alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)-alkyl;
or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methyl-propyl, or 2-methyl-propyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3) alkyl, O, S, --NY, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3) alkyl;
and when R.dbd.R.sup.4' (CH.sub.2).sub.n SO.sub.2 -- and n=1-4,
R.sup.4 ' is selected from C.sub.1 -C.sub.4)carboxyalkyl;
a substituted (C.sub.3 -C.sub.6)cyclalkyl group with substitution selected from cyano, amino or (C.sub.1 -C.sub.3)-acyl;
(C.sub.1 -C.sub.4)alkoxy;
C.sub.6 -aryloxy selected from phenoxy or substituted phenoxy with substitution selected from halo, (C.sub.1 -C.sub.3)alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3) alkylamino;
(C.sub.7 -C.sub.10)aralkyloxy;
R.sup.a R.sup.b amino (C.sub.1 -C.sub.4) alkoxy, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)-alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 --wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O,S, --NY, or NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl;
or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O,S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl;
(C.sub.1 -C.sub.3) alkylthio selected from methylthio, ethylthio or n-propylthio;
C.sub.6 -arylthio selected from phenylthio or substituted phenylthio with substitution selected from halo, (C.sub.1 -C.sub.3)alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)alkylamino;
(C.sub.7 -C.sub.8) aralkylthio;
a heterocycle as defined hereinabove;
hydroxy;
mercapto;
mono- or di-straight or branched (C.sub.1 -C.sub.6)alkyl- amino group the alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl or 1-methyl-1-ethylpropyl;
halo (C.sub.1 -C.sub.3) alkyl;
acyl or haloacyl selected from acetyl, propionyl, chloro-acetyl, trifluoroacetyl;
(C.sub.3 -C.sub.6) cycloalkylcarbonyl;
(C.sub.6 -C.sub.10) aroyl selected from benzoyl or naphthoyl;
halo substituted (C.sub.6 -C.sub.10)aroyl, (C.sub.1 -C.sub.4) alkylbenzoyl, or (heterocycle) carbonyl, the heterocycle as defined hereinabove;
(C.sub.1 -C.sub.4)alkoxycarbonyl selected from methoxycarbonyl, ethoxycarbonyl, straight or branched propoxycarbonyl, allyloxycarbonyl or straight or branched butoxycarbonyl;
R.sup.5 is selected from hydrogen;
straight or branched (C.sub.1 -C.sub.3) alkyl selected from methyl, ethyl n-propyl or 1-methylethyl;
(C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
(C.sub.7 -C.sub.9) aralkyl group;
a heterocycle as defined hereinabove;
or --(CH.sub.2).sub.n COOR.sup.7 where n=0-4 and R.sup.7 is selected from hydrogen;
straight or branched (C.sub.1 -C.sub.3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl;
or (C.sub.6 -C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
R.sup.6 is selected from hydrogen;
straight or branched (C.sub.1 -C.sub.3)alkyl group selected form methyl, ethyl, n-propyl or 1-methylethyl;
(C.sub.6 -C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
(C.sub.7 -C.sub.9)-aralkyl group;
a heterocycle as defined hereinabove;
or --CH.sub.2).sub.n (COOR.sup.7' where n=0-4 and R.sup.7' is selected from hydrogen;
straight or branched (C.sub.1 -C.sub.3)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl;
or (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
with the proviso that R.sup.5 and R.sup.6 cannot both be hydrogen;
or R.sup.5 and R.sup.6 taken together are --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 --, wherein W is selected from (CH.sub.2).sub.q and q=0-1, --NH, --N(C.sub.1 -C.sub.3)-alkyl, --N(C.sub.1 -C.sub.4) alkoxy, oxygen, sulfur or substituted congeners selected from (L or D) proline, ethyl (L or D) prolinate, morpholine, pyrrolidine or piperidine;
and the pharmacologically acceptable organic and inorganic salts or metal complexes.

116 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/286,096Filed 4 Aug 1994 · continuation
Priority: 4 Oct 1991
Granted: 27 Feb 1996
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 333/38
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07C 237/26
Having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the…:…
C07D 205/04
Not condensed with other rings: having no double bonds between ring members or between ring members and non-ring members
C07D 277/46
Acylated amino or imino radicals: by carboxylic acids, or sulfur or nitrogen analogues thereof

Family

Serial771,576Parent of this continuation-in-part · filed 4 Oct 1991
Serial926,091Parent of this continuation · filed 13 Aug 1992
US 5,494,903 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the formula ##STR223## wherein:

X is selected from amino, NR.sup.1 R.sup.2, or halogen;
the halogen is selected from bromine, chlorine, fluorine or iodine;
R.sup.1 is selected from hydrogen, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl and 1-methylpropyl;
R.sup.2 is selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl such that when X.dbd.NR.sup.1 R.sup.2 and R.sup.1 =hydrogen,
R.sup.2 =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
and when R.sup.1 =methyl or ethyl,
R.sup.2 =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R.sup.1 =n-propyl,
R.sup.2 =n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R.sup.1 =1-methylethyl,
R.sup.2 =n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R.sup.1 =n-butyl,
R.sup.2 =n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R.sup.1 =1-methylpropyl,
R.sup.2 =2-methylpropyl;
R is selected from R.sup.4 (CH.sub.2).sub.n CO-- or R.sup.4' (CH.sub.2).sub.n SO.sub.2 --;
and n=0-4;
and when R=R.sup.4 (CH.sub.2).sub.n CO-- and n-0,
R.sup.4 is selected from amino;
monosubstituted amino selected from straight or branched (C.sub.1 -C.sub.6)alkylamino, cyclopropylamino, cyclobutylamino, benzylamino or phenylamino;
disubstituted amino selected from dimethylamino, diethylamino, ethyl(1-methylethyl)amino, monomethylbenzylamino, piperidinyl, morpholinyl, 1-imidazolyl, 1-pyrrolyl, 1-(1,2,3-triazolyl) or 4-(1,2,4-triazolyl);
a substituted (C.sub.3 -C.sub.6)cycloalkyl group with substitution selected from cyano, amino or (C.sub.1 -C.sub.3)acyl;
a substituted (C.sub.6 -C.sub.10)aryl group with substitution selected from halo, (C.sub.1 -C.sub.4)alkoxy, trihalo (C.sub.1 -C.sub.3)-alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxycarbonyl (C.sub.1 -C.sub.3)alkylamino or carboxy;
.alpha.-amino-(C.sub.1 -C.sub.4)alkyl selected from aminomethyl, .alpha.-aminoethyl, .alpha.-aminopropyl or .alpha.-amino-butyl;
carboxy (C.sub.2 -C.sub.4)-alkylamino selected from aminoacetic acid, .alpha.-aminobutyric acid or .alpha.-aminopropionic acid and the optical isomers thereof;
(C.sub.7 -C.sub.9)aralkylamino;
(C.sub.1 -C.sub.4)alkoxycarbonylamino substituted (C.sub.1 -C.sub.4) alkyl group;
.alpha.-hydroxy(C.sub.1 -C.sub.3)alkyl selected from hydroxymethyl, .alpha.-hydroxyethyl or .alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
.alpha.-mercapto (C.sub.1 -C.sub.3)alkyl selected from mercaptomethyl, .alpha.-mercaptoethyl, .alpha.-mercapto-1-methylethyl or .alpha.-mercaptopropyl;
halo-(C.sub.1 -C.sub.3)alkyl group;
a heterocycle selected from the group consisting of a five membered aromatic or saturated ring with one N, O, S or Se heteroatom optionally having a benzo or pyrido ring fused thereto, a five membered aromatic ring with two N, O, S, or Se heteroatoms optionally having a benzo or pyrido ring fused thereto, a six membered aromatic ring with one to three N, O, S or Se heteroatoms, or a six membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom;
acyl or haloacyl group selected from acetyl, propionyl, chloroacetyl, trifluoroacetyl;
(C.sub.3 -C.sub.6)cycloalcylcarbonyl, (C.sub.6 -C.sub.10)aroyl selected from benzoyl or naphthoyl;
halo substituted (C.sub.6 -C.sub.10)aroyl;
(C.sub.1 -C.sub.4) alkylbenzoyl, or (heterocycle)-carbonyl, the heterocycle as defined hereinabove;
(C.sub.1 -C.sub.4)alkoxycarbonyl selected from methoxycarbonyl, ethoxycarbonyl, straight or branched propoxylcarbonyl, straight or branched butoxycarbonyl or allyloxycarbonyl;
a substituted vinyl group with substitution selected from halogen, halo(C.sub.1 -C.sub.3)alkyl, or a substituted (C.sub.6 -C.sub.10)aryl group with substitution selected from halo, (C.sub.1 -C.sub.4)-alkoxy, trihalo(C.sub.1 -C.sub.3)alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.3)alkylamino or carboxy;
(C.sub.1 -C.sub.4)alkoxy group;
C.sub.6 -aryloxy selected from phenoxy or substituted phenoxy with substitution selected from halo, (C.sub.1 -C.sub.4) alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)alkylamino;
(C.sub.7 -C.sub.10)aralkyloxy;
vinyloxy or a substituted vinyloxy group with substitution selected from (C.sub.1 -C.sub.4)alkyl, cyano, carboxy, or (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
R.sup.a R.sup.b amino(C.sub.1 -C.sub.4)alkoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or (CH.sub.2).sub.2 W(CH.sub.2)2-wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl,O,S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl;
or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O,S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl;
and when R=R.sup.4 (CH.sub.2).sub.n CO-- and n-1-4, R.sup.4 is selected from amino;
a substituted (C.sub.3 -C.sub.6)cycloalkyl group with substitution selected from cyano, amino or (C.sub.1 -C.sub.3)acyl;
a substituted(C.sub.6 -C.sub.10)-aryl group with substitution selected from halo, (C.sub.1 -C.sub.4)-alkoxy, trihalo(C.sub.1 -C.sub.3)alkyl, nitro, amino, cyano,(C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.3)alkylamino or carboxy;
acyloxy or haloacyloxy group selected from acetyl, propionyl, chloroacetyl, trichlorocetyl, (C.sub.3 -C.sub.6)cycloalkylcarbonyl, (C.sub.6 -C.sub.10)aroyl selected from benzoyl or naphthoyl, halo substituted (C.sub.6 -C.sub.10)aroyl, (C.sub.1 -C.sub.4)alkylbenzoyl, or (heterocycle)-carbonyl, the heterocycle as defined hereinabove;
(C.sub.1 -C.sub.4)alkoxy;
C.sub.6 -aryloxy selected from phenoxy or substituted phenoxy with substitution selected from halo, (C.sub.1 -C.sub.4)-alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)-alkylamino;
(C.sub.7 -C.sub.10)aralkyloxy;
(C.sub.1 -C.sub.3)alkylthio group selected from methylthio, ethylthio, propylthio or allythio;
C.sub.6 -arylthio group selected from phenylthio or substituted phenylthio with substitution selected from halo, (C.sub.1 -C.sub.4)alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)alkylamino;
C.sub.6 -arylsulfonyl group selected from phenylsulfonyl or substituted phenylsulfonyl with substitution selected from halo, (C.sub.1 -C.sub.4)alkoxy, trihalo(C.sub.1 -C.sub.3)alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.3)alkylamino or carboxy;
(C.sub.7 -C.sub.8)aralkylthio group;
a heterocycle as defined hereinabove;
hydroxy;
mercapto;
mono- or di-straight or branched chain (C.sub.1 -C.sub.6)- alkylamino with the alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl or 1-methyl-1-ethylpropyl;
(C.sub.2 -C.sub.5)azacycloalkyl group;
a carboxy(C.sub.2 -C.sub.4)alkylamino group with the carboxy alkyl selected from aminoacetic acid, .alpha.-aminopropionic acid, .alpha.-aminobutyric acid and the optical isomers thereof;
.alpha.-hydroxy(C.sub.1 -C.sub.3)alkyl selected from hydroxymethyl, .alpha.-hydroxyethyl or .alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1 -C.sub.3)alkyl group;
acyl or haloacyl selected from acetyl, propionyl, chloroacetyl, trifluoroacetyl;
(C.sub.3 -C.sub.6)cycloalkylcarbonyl;
(C.sub.6 -C.sub.10)aroyl selected from benzoyl or naphthoyl;
halo substituted (C.sub.6 -C.sub.10)aroyl;
(C.sub.1 -C.sub.4)alkylbenzoyl, or (heterocycle)carbonyl, the heterocycle as defined hereinabove;
(C.sub.1 -C.sub.4)alkoxycarbonylamino, group selected from tert-butoxycarbonylamino, allyloxycarbonylamino, methoxycarbonylamino, ethoxycarbonylamino or propoxycarbonylamino;
(C.sub.1 -C.sub.4)alkoxycarbonyl group selected from methoxycarbonyl, ethoxycarbonyl, straight or branched propoxycarbonyl, allyloxycarbonyl or straight or branched butoxycarbonyl;
R.sup.a R.sup.b - amino(C.sub.1 -C.sub.4)alkoxy group wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH).sub.m m=2-6 or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -wherein W is selected from --N(C.sub.1 -C.sub.3)-alkyl, O, S, --NH, --NOB, and B is selected from hydrogen or C.sub.1 -C.sub.3)alkyl;
or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)-alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 - wherein W is selected from --N(C.sub.1 -C.sub.3)-alkyl, O,S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl, and when R.dbd.R.sup.4' (CH.sub.2).sub.n SO.sub.2 -and n=0
R.sup.4' is selected from amino;
monosubstituted amino selected from straight or branched (C.sub.1 -C.sub.6)alkylamino, cyclopropylamino, cyclobutylamino, benzylamino or phenylamino;
disubstituted amino selected from dimethylamino, diethylamino, ethyl(1-methylethyl)amino, monomethylbenzylamino, piperidinyl, morpholinyl, 1-imidazoyl, 1-pyrrolyl, 1-(1,2,3-triazolyl) or 4-(1,2,4-triazolyl);
a substituted (C.sub.3 -C.sub.6)cycloalkyl group with substitution selected from cyano, amino or (C.sub.1 -C.sub.3)acyl;
halo(C.sub.1 -C.sub.3)alkyl group;
a heterocycle as defined hereinabove;
R.sup.a R.sup.b amino (C.sub.1 -C.sub.4) alkoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)-alkyl selected from methyl, ethyl, n-propyl, 1-methyl-ethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W--(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3) alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)-alkyl;
or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methyl-propyl, or 2-methyl-propyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3) alkyl, O, S, --NY, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3) alkyl;
and when R.dbd.R.sup.4' (CH.sub.2).sub.n SO.sub.2 -- and n=1-4,
R.sup.4 ' is selected from C.sub.1 -C.sub.4)carboxyalkyl;
a substituted (C.sub.3 -C.sub.6)cyclalkyl group with substitution selected from cyano, amino or (C.sub.1 -C.sub.3)-acyl;
(C.sub.1 -C.sub.4)alkoxy;
C.sub.6 -aryloxy selected from phenoxy or substituted phenoxy with substitution selected from halo, (C.sub.1 -C.sub.3)alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3) alkylamino;
(C.sub.7 -C.sub.10)aralkyloxy;
R.sup.a R.sup.b amino (C.sub.1 -C.sub.4) alkoxy, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)-alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 --wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O,S, --NY, or NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl;
or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O,S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl;
(C.sub.1 -C.sub.3) alkylthio selected from methylthio, ethylthio or n-propylthio;
C.sub.6 -arylthio selected from phenylthio or substituted phenylthio with substitution selected from halo, (C.sub.1 -C.sub.3)alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)alkylamino;
(C.sub.7 -C.sub.8) aralkylthio;
a heterocycle as defined hereinabove;
hydroxy;
mercapto;
mono- or di-straight or branched (C.sub.1 -C.sub.6)alkyl- amino group the alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl or 1-methyl-1-ethylpropyl;
halo (C.sub.1 -C.sub.3) alkyl;
acyl or haloacyl selected from acetyl, propionyl, chloro-acetyl, trifluoroacetyl;
(C.sub.3 -C.sub.6) cycloalkylcarbonyl;
(C.sub.6 -C.sub.10) aroyl selected from benzoyl or naphthoyl;
halo substituted (C.sub.6 -C.sub.10)aroyl, (C.sub.1 -C.sub.4) alkylbenzoyl, or (heterocycle) carbonyl, the heterocycle as defined hereinabove;
(C.sub.1 -C.sub.4)alkoxycarbonyl selected from methoxycarbonyl, ethoxycarbonyl, straight or branched propoxycarbonyl, allyloxycarbonyl or straight or branched butoxycarbonyl;
R.sup.5 is selected from hydrogen;
straight or branched (C.sub.1 -C.sub.3) alkyl selected from methyl, ethyl n-propyl or 1-methylethyl;
(C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
(C.sub.7 -C.sub.9) aralkyl group;
a heterocycle as defined hereinabove;
or --(CH.sub.2).sub.n COOR.sup.7 where n=0-4 and R.sup.7 is selected from hydrogen;
straight or branched (C.sub.1 -C.sub.3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl;
or (C.sub.6 -C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
R.sup.6 is selected from hydrogen;
straight or branched (C.sub.1 -C.sub.3)alkyl group selected form methyl, ethyl, n-propyl or 1-methylethyl;
(C.sub.6 -C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
(C.sub.7 -C.sub.9)-aralkyl group;
a heterocycle as defined hereinabove;
or --CH.sub.2).sub.n (COOR.sup.7' where n=0-4 and R.sup.7' is selected from hydrogen;
straight or branched (C.sub.1 -C.sub.3)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl;
or (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
with the proviso that R.sup.5 and R.sup.6 cannot both be hydrogen;
or R.sup.5 and R.sup.6 taken together are --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 --, wherein W is selected from (CH.sub.2).sub.q and q=0-1, --NH, --N(C.sub.1 -C.sub.3)-alkyl, --N(C.sub.1 -C.sub.4) alkoxy, oxygen, sulfur or substituted congeners selected from (L or D) proline, ethyl (L or D) prolinate, morpholine, pyrrolidine or piperidine;
and the pharmacologically acceptable organic and inorganic salts or metal complexes.

116 more elements

Facts

Application

08/286,096Filed 4 Aug 1994 · continuation

Priority

4 Oct 1991

Granted

27 Feb 1996

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 333/38
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07C 237/26
Having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the…:…
C07D 205/04
Not condensed with other rings: having no double bonds between ring members or between ring members and non-ring members
C07D 277/46
Acylated amino or imino radicals: by carboxylic acids, or sulfur or nitrogen analogues thereof