U.S. patent number RE40,183 [Application Number 11/145,508] was granted by the patent office on 2008-03-25 for 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines.
This patent grant is currently assigned to Wyeth Holdings Corporation. Invention is credited to Yakov Gluzman, Joseph J. Hlavka, Ving J. Lee, Adma A. Ross, Phaik-Eng Sum.
United States Patent |
RE40,183 |
Hlavka , et al. |
March 25, 2008 |
**Please see images for:
( Certificate of Correction ) ** |
7-Substituted-9-substituted
amino-6-demethyl-6-deoxytetracyclines
Abstract
The invention is drawn to 7-substituted-9-(substituted
amino)-6-demethyl-6-deoxytetracycline compounds of the formula
##STR00001## 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.
Inventors: |
Hlavka; Joseph J. (Tuxedo Park,
NY), Sum; Phaik-Eng (Pomona, NY), Gluzman; Yakov
(Upper Saddle River, NJ), Lee; Ving J. (Los Altos, CA),
Ross; Adma A. (Airmont, NY) |
Assignee: |
Wyeth Holdings Corporation
(Madison, NJ)
|
Family
ID: |
27403589 |
Appl.
No.: |
11/145,508 |
Filed: |
June 3, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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07926091 |
Aug 13, 1992 |
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07771576 |
Oct 4, 1991 |
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Reissue of: |
08286096 |
Aug 4, 1994 |
05494903 |
Feb 27, 1996 |
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Current U.S.
Class: |
514/152; 544/154;
548/263.2; 548/300.4; 548/356.5; 549/487; 552/205; 552/203;
548/538; 548/316.4; 548/267.6; 546/195; 540/200 |
Current CPC
Class: |
C07C
237/26 (20130101); C07D 205/04 (20130101); C07D
277/46 (20130101); C07D 333/24 (20130101); C07D
333/34 (20130101); C07D 333/38 (20130101); C07D
307/68 (20130101); C07C 2603/46 (20170501) |
Current International
Class: |
A61K
31/65 (20060101); C07C 233/64 (20060101) |
Field of
Search: |
;514/152 ;552/203,205
;540/200 ;544/154 ;546/195 ;549/487
;548/263.2,267.6,538,316.4,300.4,356.5 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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109 850 |
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May 1984 |
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EP |
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901107 |
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Jul 1962 |
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GB |
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WO 84/01895 |
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May 1984 |
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WO |
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WO 89/02270 |
|
Mar 1989 |
|
WO |
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Primary Examiner: Badio; Barbara P.
Parent Case Text
This application is a continuation of application Ser. No.
07/926,091 filed Aug. 13, 1992, now abandoned, which is a
continuation-in-part of application Ser. No. 07/771,576 filed Oct.
4, 1991, now abandoned.
Claims
We claim:
1. A compound of the formula ##STR00223## 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=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.]. .Iadd.n=0.Iaddend.,
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.aR.sup.b
amino(C.sub.1-C.sub.4)alkoxy group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
.[.(CH.sub.2).sub.2W(CH.sub.2)2--.].
(.Iadd.CH.sub.2).sub.2W(CH.sub.2).sub.2--.Iaddend. 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.aR.sup.b
aminoxy group, wherein R.sup.aR.sup.b is 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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W(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.nCO-- 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-methylbutyl, 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.-hydroethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydropropyl;
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.sub.aR.sup.b-amino(C.sub.1-C.sub.4)alkoxy group
wherein R.sup.aR.sup.b is 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.aR.sup.b is .[.(CH).sub.m.]. (.Iadd.CH.sub.2).sub.m
.Iaddend.m=2-6 or --(CH.sub.2).sub.2W(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.aR.sup.b aminoxy group, wherein R.sup.aR.sup.b is 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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W(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)SO.sub.2--.]. .Iadd.R.dbd.R.sup.4'
(CH.sub.2).sub.nSO.sub.2--.Iaddend. 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, monomethylbenzlamino, 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.aR.sup.b amino
(C.sub.1-C.sub.4)alkoxy group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W--(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.aR.sup.b aminoxy
group, wherein R.sup.aR.sup.b is a straight or branched
(C.sub.1-C.sup.4)alkyl selected from methyl, ethyl, n-propyl,
1-methylethyl, n-butyl, 1-methyl-propyl, or 2-methyl-propyl or
R.sup.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl, O, S, .[.--NY.]. .Iadd.--NH.Iaddend.,
--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.nSO.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)aralkyoxy;
R.sup.aR.sup.b amino (C.sub.1-C.sub.4) alkoxy, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl, O, S,
.[.--NY.]. .Iadd.--NH .Iaddend.or --NOB and B is selected from
hydrogen or (C.sub.1-C.sub.3)alkyl; or R.sup.aR.sup.b aminoxy
group, wherein R.sup.aR.sup.b is 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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W(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.nCOOR.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'.].
.Iadd.--(CH.sub.2).sub.nCOOR.sup.7'.Iaddend. 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.2W(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.
2. The compound according to claim 1, wherein: X is selected
.[.form.]. .Iadd.from .Iaddend.amino, NR.sup.1 R.sup.2, or halogen;
the halogen is selected from bromine, chlorine, fluorine or iodine;
and when X=NR.sup.1 R.sup.2 and R.sup.1=methyl or ethyl,
R.sup.2=methyl or ethyl R is selected from R.sup.4
(CH.sub.2).sub.nCO-- or R.sup.4' (CH.sub.2).sub.nSO.sub.2--; and
when R=R.sup.4 (CH.sub.2).sub.nCO-- and n=0, R.sup.4 is selected
from .[.substituted (C.sub.6-C.sub.10)aryl group with substitution
selected from halo, (C.sub.1-C.sub.4)alkoxy, nitro, amino, or
(C.sub.1-C.sub.2)alkoxycarbonyl;.]. (C.sub.1-C.sub.4)alkoxycarbonyl
group selected from methoxycarbonyl, ethoxycarbonyl, straight or
branched propoxyl-carbonyl, straight or branched butoxycarbonyl or
allyl-oxycarbonyl; a substituted (C.sub.6-C.sub.10)aryl group with
substitution selected from halo, (C.sub.1-C.sub.4)alkoxy,
.Iadd.nitro, amino, .Iaddend.(C.sub.1-C.sub.4) alkoxycarbonyl,
.Iadd.tri.Iaddend.halo-(C.sub.1-C.sub.3)alkyl group;
(C.sub.1-C.sub.4)alkoxy group; C.sub.6-aryloxy group selected from
phenoxy or substituted phenoxy with substitution selected from
halo, (C.sub.1-C.sub.4)alkyl; (C.sub.7-C.sub.10)aralkyloxy group;
vinyloxy or substituted vinyloxy group with substitution selected
from (C.sub.1-C.sub.2)-alkyl; R.sup.aR.sup.b
amino(C.sub.1-C.sub.4)alkoxy group, wherein R.sup.aR.sup.b is a
straight or branched (C.sub.1-C.sub.4)alkyl selected from methyl,
ethyl, n-propyl, 1-methylethyl, n-butyl; or R.sup.aR.sup.b aminoxy
group, wherein R.sup.aR.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; and
when R=R.sup.4 (CH.sub.2).sub.nCO-- and n=1-4, R.sup.4 is selected
from amino; monosubstituted amino selected from straight or
branched (C.sub.1-C.sub.6)alkyl-amino, cyclopropylamino,
cyclobutylamino, benzylamino or phenylamino.Iadd., said
(C.sub.1-C.sub.6)-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.Iaddend.; disubstituted amino selected from
dimethylamino, diethylamino, ethyl(1-methylethyl)amino,
.[.monomethylbenzylamino, piperidinyl, morpholinyl.]. ,
1-imidazolyl, .Iadd.or .Iaddend.1-pyrrolyl .[.or
1-(1,2,3-triazolyl).]. ; a substituted (C.sub.6-C.sub.10)aryl group
with substitution selected from halo, (C.sub.1-C.sub.4)alkoxy,
nitro, amino, (C.sub.1-C.sub.4)alkoxycarbonyl; acyloxy or
haloacyloxy group selected from acetyl, propionyl or chloroacetyl;
(C.sub.1-C.sub.4)alkoxy group; R.sup.aR.sup.b
amino(C.sub.1-C.sub.4)alkoxy group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W(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.aR.sup.b aminoxy
group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W--(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)-alkyl, O, S, .[.--NY.]. .Iadd.--NH.Iaddend.,
--NOB and B is selected from hydrogen or (C.sub.1-C.sub.3)-alkyl;
halo (C.sub.1-C.sub.3)-alkyl group;
(C.sub.1.Iadd.-.Iaddend.C.sub.4)alkoxycarbonylamino selected from
tert-butoxycarbonylamino, allyloxycarbonylamino,
methoxycarbonylamino, ethoxycarbonylamino or propoxycarbonylamino;
.[.and when R.dbd.R.sup.4' (CH.sub.2).sub.nSO.sub.2-- and n=0,
R.sup.4' is selected from a substituted (C.sub.6-C.sub.10)aryl
group with substitution selected from halo,
(C.sub.1-C.sub.4)alkoxy, nitro, (C.sub.1-C.sub.4)
alkoxycarbonyl;.]. 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; R.sup.6 is selected from hydrogen;
straight or branched (C.sub.1-C.sub.3)alkyl selected from methyl,
ethyl, n-propyl or 1-methylethyl; with the proviso that R.sup.5 and
R.sup.6 cannot both be hydrogen; or R.sup.5 or R.sup.6 taken
together are --(CH.sub.2).sub.2W(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.
3. The compound according to claim 1 wherein said inorganic salts
comprise hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric
or sulfate.
4. The compound according to claim 1 wherein said organic salts
comprise acetate, benzoate, citrate, cysteine or other amino acids,
fumarate, glycolate, maleate, succinate, tartrate, alkylsulfonate
or arylsulfonate.
5. The compound according to claim 1 wherein said metal complexes
comprise aluminium, calcium, iron, magnesium, manganese and complex
salts.
6. A compound according to claim 1 [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5,5a,6,11, 12a-octahydro-3,
10,12,12a-tetrahydroxy-1,11-dioxo-
9-[(trifluoroacetyl)amino]-2-naphthacenecarboxamide sulfate.
7. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5,5a,6, 11,12a-octahydro-3,
10,12,12a-tetrahydroxy-9-[(methoxyacetyl)amino]-1,11-dioxo-2-naphthacenec-
arboxamide.
8. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-9-[(4-Bromo-1-oxobutyl)amino]-4,7-bis(dimethyl-
amino)-1,4, 4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
9. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5,5a,6, 11,12a-octahydro-3,
10,12,12a-tetrahydroxy-1,11-dioxo-
9-[(1-oxo-2-propenyl)amino]-2-naphthacenecarboxamide.
10. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-9-[[(Acetyloxy)acetyl]amino]-4,7-bis
(dimethylamino)-1,4, 4a,5,5a,6,11,12a-octahydro-3,10,
12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
sulfide.
11. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-9-(Benzoylamino)-4,7-bis(dimethylamino)-
1,4,4a,5,5a,6,11, 12a-octahydro-3,10,12,12a-tetrahydroxy-
1,11-dioxo-2-naphthacenecarboxamide.
12. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5
5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[(4-methyoxybenzoyl)amin-
o]-1,11-dioxo-2-naphthacenecarboxamide.
13. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5
5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[(2-methylbenzoyl)amino]-
-1,11-dioxo-2-naphthacenecarboxamide.
14. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[(2-fluorobenzoyl)amino]--
1,4,4a,5,5a,6,11,12a-octahydro-3,
10,12,12a-tetrahydroxy-1,11-dioxo-2-naphathacenecarboxamide.
15. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,
5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[(pentafluorobenzoyl)a-
mino]-1,11 -dioxo-2-naphthacenecarboxamide hydrochloride.
16. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5 ,
5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
9-[[3-(trifluoromethyl)benzoyl]amino]-2-naphthacenecarboxamide.
17. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[(2-furanylcarbonyl)amino-
]- 1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
18. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,
5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-
1,11-dioxo-9-[(2-thienylcarbonyl)amino]-2-naphthacenecarboxamide.
19. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,
5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[
(4-nitrobenzonyl)amino]-1, 11-dioxo-2-naphthacenecarboxamide.
20. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-9-[(4-Aminobenzoyl)amino]-4,7-bis-dimethylamin-
o)- 1,4, 4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-
1,11-dioxo-2-naphthacenecarboxamidesulfate.
21. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-9-[[(4-dimethylamino)benzoyl]amino]-1,4,4a,5,5a,6,11-
,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
22. A compound according to claim 1,
[7S-(7.alpha.,10a.alpha.)]-[2-[[(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a,6,6a, 7,10,10a,12-octahydro-1,8,10a,
11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]amino]-
2-oxoethyl]carbamic acid 1,1-dimethylethyl ester.
23. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-9-[(Aminoacetyl)amino]-4,7-bis(dimethylamino)-
1,4,4a,5, 5a,6,11,12a-octahydro-3,10,12,
12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
mono(trifluoroacetate).
24. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5,5a,6, 11,12a-octahydro-3,
10,12,12a-tetrahydroxy-1,11-dioxo-
9-[(phenylsulfonyl)amino]-2-naphthacenecarboxamide.
25. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-9-[[(4-Chlorophenyl)sulfonyl]amino]-
4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-tetrahydroxy-
1,11-dioxo-2-naphthacenecarboxamide.
26. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-1,4,4a,5,
5a,6,11,12a-octahydro-3,
10,12,12a-tetrahydroxy-9-[(3-nitrophenyl)sulfonyl]amino-1,11-dioxo-2-naph-
thacenecarboxamide.
27. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,- 5a,6,11,12a-octahydro-3,10,
12,12a-tetrahydroxy-9-[ [(4-nitrophenyl)sulfonyl]amino]-1,
11-dioxo-2-naphthacenecarboxamide.
28. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5, 5a,6,11,12a-octahydro-3,
10,12,12a-tetrahydroxy-1,11-dioxo-
9-[(2-thienylsulfonyl)amino]-2-naphthacenecarboxamide.
29. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-9-[[(2-(Acetylamino)-4-methyl-
5-thiazolylsulfonyl]amino]-4,7-bis(dimethylamino)-1,4,
4a,5,5a,6,11,12a-octahydro-3, 10,12,12a-tetrahydroxy-
1,11-dioxo-2-naphthacenecarboxamide.
30. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[
(ethylsulfonyl)amino]-1, 4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1, 11-dioxo-2-naphthacenecarboxamide.
31. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-9-(formylamino)- 1,4,4a,5a,6,11,
12a-octahydro-3,10,12,12a-tetrahydroxy-
1,11-dioxo-N-(1-pyrrolidinylmethyl)-2-naphthacenecarboxamide.
32. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5,5a,6, 11,12a-octahydro-3,
10,12,12a-tetrahydroxy-9-[
(methanesulfonyl)amino]-1,11-dioxo-2-naphthacenecarboxamide.
33. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5,5a,6, 11,12a-octahydro-3,
10,12,12a-tetrahydroxy-1,11-dioxo-
9-[[(phenylmethoxy-)acetyl]amino]-2-naphthacenecarboxamide.
34. A compound according to claim 1,
[7S-(7.alpha.,10a.alpha.)]-[[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a,6,6a,7, 10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-
10,12-dioxo-2-naphathacenyl]amino] oxoacetic acid ethyl ester.
35. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5,5a, 6,11,12a-octahydro-3,
10,12,12a-tetrahydroxy-9-[
(hydroxyacetyl)amino]-1,11-dioxo-2-naphthacenecarboxamide.
36. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-9-[[(methylamino)acetyl] amino]-1,
4,4a,5,5a,6,11,12a-octahydro- 3,10,12,12a-tetrahydroxy-1,
11-dioxo-2-napthacenecarboxamide hydrochloride.
37. A compound according to claim 1,
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a,6,6a,7, 10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-
10,12-dioxo-2-naphthacenyl]carbamic acid methyl ester.
38. A compound according to claim 1,
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a,6,6a,7, 10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-
10,12-dioxo-2-naphthacenyl]carbamic acid ethenyl ester.
39. A compound according to claim 1,
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimethyl-amino)-
5,5a,6,6a,7, 10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-
10,12-dioxo-2-naphthacenyl]carbamic acid ethenyl ester.
40. A compound according to claim 1,
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimethyl-amino)-
5,5a,6,6a,7, 10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-
10,12-dioxo-2-naphthacenyl]carbamic acid 2-propenyl ester.
41. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-9-[[(dimethylamino)acetyl]
amino]-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
sulfate.
42. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5,5a,6, 11,12a-octahydro-3,
10,12,12a-tetrahydroxy-9-[
(methoxyacetyl)amino]-1,11-dioxo-2-naphthacenecarboxamide
hydrochloride.
43. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-9-[[(4-Bromo-1-oxobutyl)amino]-4,7bis(dimethyl-
amino)-1,4,4a,5,5a,6,11,12a-octahydroxy-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
sulfate.
44. A compound according to claim 1
[4S-(4.alpha.,12a.alpha.)]-9-[[(Acetyloxy)acetyl]amino]-4,7-bis
(dimethylamino)-1,4, 4a,5,5a,6,11,12a-octahydro-3,10,
12,12a-tetrahydroxy-1,11-dioxo-2-napthacenecarboxamide.
45. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-9-(Benzolyamino)-4,7-bis(dimethylamino)-
1,4,4a,5,5a,6, 11,12a-octahydro-3,10,12,12a-tetra-hydroxy- 1,11
-dioxo-2-naphthacenecarboxamide sulfate.
46. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,
5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11 -dioxo-
9-[[3-(trifluoromethyl)benzoyl]amino]-2-naphthacenecarboxamide
hydrochloride.
47. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-9-[(4-Aminobenzoyl)amino]-4,7-bis(dimethylamin-
o)- 1,4, 4a,5,5a,6,11,12a-octahydro-3,10,12,
12a-tetrahydroxy-1,11-dioxo-2-napthacenecarboxamide.
48. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-9-[[(4-dimethylamino)benzoyl]amino]-1,4,4a,5,5a,6,11-
,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
hydrochloride.
49. A compound according to claim 1,
[7S-(7.alpha.,10a.alpha.)]-[2-[[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a,6,6a, 7,10,10a,12-octahydro-1,8,10a,
11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]amino]-
2-oxoethyl]carbamic acid 1,1-dimethylethyl ester hydrochloride.
50. A compound according to claim 1,
[4S-(4.alpha.,12a.alpha.)]-9-[(Aminocarbonyl)-amino]-4,7-bis(dimethylamin-
o)- 1,4,4a,5, 5a,6,11,12a-octahydro-3,10,12,
12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
51. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[
(ethylsulfonyl)amino]-1, 4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1, 11-dioxo-2-naphthacenecarboxamide
hydrochloride.
52. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5,5a,6, 11,12a-octahydro-3,
10,12,12a-tetrahydroxy-9-[
(methansulfonyl)amino]-1,11-dioxo-2-naphthacenecarboxamide
sulfate.
53. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5,5a,6, 11,12a-octahydro-3,
10,12,12a-tetrahydroxy-1,11-dioxo-
9-[[(phenylmethoxy-)acetyl]amino]-2-naphthacenecarboxamide
hydrochloride.
54. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-1,4,4a,5,5a, 6 11,12a-octahydro-3,
10,12,12a-tetrahydroxy-9-[
(hydroxyacetyl)amino]-1,11-dioxo-2-naphthacenecarboxamide
sulfate.
55. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-9-[[(dimethylamino)acetyl]
amino]-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
56. A compound according to claim 1,
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a,6,6a,7, 10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-
10,12-dioxo-2-naphthacenyl]carbamic acid methyl ester sulfate.
57. A compound according to claim 1,
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a,6,6a,7, 10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-
10,12-dioxo-2-naphthacenyl]carbamic acid (2-diethylamino)ethyl
ester hydrochloride.
58. A compound according to claim 1,
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a,6,6a,7, 10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-
10,12-dioxo-2-naphthacenyl]carbamic acid ethenyl ester sulfate.
59. A compound according to claim 1,
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a,6,6a,7, 10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-
10,12-dioxo-2-naphthacenyl]carbamic acid 2-propenyl ester
hydrochloride.
60. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-9-[[(diethylamino) acetyl]amino]-1,
4,4a,5,5a,6,11,12a-octahydro-3,10,12, 12a-tetrahydroxy-1,
11-dioxo-2-naphthacenecarboxamide sulfate.
61. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-9-[[(diethylamino) acetyl]amino]-1,
4,4a,5,5a,6,11,12a-octahydro-3,10,12, 12a-tetrahydroxy-1,
11-dioxo-2-naphthacenecarboxamide hydrochloride.
62. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-9-[[(diethylamino) acetyl]amino]-1,
11-dioxo-2-naphthacenecarboxamide.
63. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[(dimethylamino)acetyl]
amino]-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
64. A compound according to claim 1, [4S-(4.alpha.,12a.alpha.)]-4,
7-Bis(dimethylamino)-9-(chloroacetylamino)- 1,4,4a,5,5a,
6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-
1,11-dioxo-2-naphthacenecarboxamide.
65. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-9-[(Chloroacetyl)amino]-4,7-bis(dimethylamino)-1,4-
,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
66. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)amino]-4,7-bis(dimethylamino)-1,4,-
4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
67. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)amino]-4,7-bis(dimethylamino)-1,4,-
4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide (free
base).
68. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)amino]-4,7-bis(dimethylamino)-1,4,-
4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
monohydrobromide.
69. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxopropyl)amino]-
4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
hydrobromide.
70. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxopropyl)amino]-
4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
hydrobromide.
71. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-
1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-
9-[[(methylamino)acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
72. A compound according to claim 1,
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a, 6,6a,7,10,10a,12-octahydro- 1,8,10a,11-tetrahydroxy-10,
12-dioxo-2-naphthacenyl]-4-morpholineacetamide dihydrochloride.
73. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[
[(ethyamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a,-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
74. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-9-[[(Cyclopropylamino)acetyl]amino]-
4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a,-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
75. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[
[(butylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
76. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-9-[[(Diethylamino)acetyl]amino]-
4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
77. A compound according to claim 1,
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a, 6,6a,7,10,10a,12-octahydro- 1,8,10a,11-tetrahydroxy-10,
12-dioxo-2-naphthacenyl]-1-pyrrolidineacetamide
dihydrochloride.
78. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahy-
dro-3,10,12,12a-tetrahydroxy-9-[
[[(2-methylpropyl)amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
79. A compound according to claim 1,
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a, 6,6a,7,10,10a,12-octahydro-1,8,10a, 11-tetrahydroxy-10,
12-dioxo-2-naphthacenyl]-1-piperidineacetamide dihydrochloride.
80. A compound according to claim 1,
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a, 12-dioxo-2-naphthacenyl]-1H-imidazole- 1-acetamide
dihydrochloride.
81. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,
5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
9-[[(propylamino)acetyl]amino]-2-naphthacenecarboxamide
dihydrochloride.
82. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[(dimethylamino)acetyl]a-
mino]-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
83. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[
[(hexylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
84. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[2-(dimethylamino)-1-oxo-
propyl]amino]-1,4,4a,5,5a,6,11, 12a-octahydro-3,10,
12,12a-tetrahydroxy-1,11-dioxo-2-napthacenecarboxamide
dihydrochloride.
85. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,
5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[2-(methylamino)-
1-oxo-propyl]amino]-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
86. A compound according to claim 1,
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-
5,5a, 6,6a,7,10,10a,12-octahydro-1,8,10a, 11-tetrahydroxy-10,
12-dioxo-2-naphthacencyl]-alphamethyl-1-pyrrolidineacetamide
dihydrochloride.
87. A compound according to claim 1
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[4-(dimethylamino)-1-oxo-
butyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro- 3,10,
12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride.
88. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-9-[[(Butylmethylamino)acetyl]amino]-
4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecenecarboxamide
dihydrochloride.
89. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahy-
dro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
9-[[(pentylamino)acetyl]amino]-2-naphthacenecarboxamide
dihydrochloride.
90. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahy-
dro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
9-[[(phenylmethyl)amino]acetyl]amino]-2-naphthacenecarboxamide
dihydrochloride.
91. A compound according to claim 1, [7S-(7alpha,10aalpha) ]-N-[2-[
[9-(Aminocarbonyl)
-4,7-bis(dimethylamino)-5,5a,6,6a,7,10a,12-octahydro-1,8,
10a,11-tetrahydroxy-10, 12-dioxo-2-naphthacenyl]amino]-
2-oxoethyl]glycine.
92. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[(dimethylamino)acetyl]a-
mino]-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-N-(1-pyrrolidinylmethyl)-
2-naphthacenecarboxamide.
93. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[(dimethylamino)acetyl]a-
mino]-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-N-(4-morpholinylmethyl)-
2-naphthacenecarboxamide.
94. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[(dimethylamino)acetyl]a-
mino]-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-N-(1-piperidinylmethyl)-2-naphthacene-
cearboxamide.
95. A compound according to claim 1,
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl-4,7-bis(dimethylamino)-
5,5a, 6,6a,7,10,10a,12-octahydro-1,8, 10a,11-tetrahydroxy-10,
12-dioxo-2-naphthacenyl]-1-azetidineacetamide.
96. A compound according to claim 1,
[4S-(4alpha,12aalpha)]-9-[[(Cyclobutylamino)acetyl]amino]-
4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
hydrochloride.
97. A pharmaceutical composition of matter comprising a compound
according to claim 1 in association with a pharmaceutically
acceptable carrier.
98. A veterinary composition which comprises a pharmacologically
effective amount of a compound of claim 1 and a pharmaceutically
acceptable carrier.
.Iadd.99. A compound of the formula ##STR00224## 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=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-methypropyl;
and when R.sup.1=1-methylpropyl, R.sup.2=2-methylpropyl; R is
selected from R.sup.4 (CH.sub.2).sub.nCO-- or R.sup.4'
(CH.sub.2).sub.nSO.sub.2--; and n=0-4; and when R=R.sup.4
(CH.sub.2).sub.nCO-- 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.aR.sup.b
amino(C.sub.1-C.sub.4)alkoxy group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
(CH.sub.2).sub.2W(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.aR.sup.b aminoxy
group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W(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.nCO-- 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.aR.sup.b-amino(C.sub.1-C.sub.4)alkoxy group
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m m=2-6 or
--(CH.sub.2).sub.2W(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.aR.sup.b aminoxy
group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W(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)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.aR.sup.b amino (C.sub.1-C.sub.4) alkoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W--(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.aR.sup.b aminoxy
group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W(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.nSO.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.aR.sup.b amino
(C.sub.1-C.sub.4) alkoxy, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl, O, S, --NH or --NOB and B is selected
from hydrogen or (C.sub.1-C.sub.3)alkyl; or R.sup.aR.sup.b aminoxy
group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.m, m=2-6, or
--(CH.sub.2).sub.2W(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; and the pharmacologically acceptable organic and
inorganic salts or metal complexes..Iaddend.
.Iadd.100. A compound of formula I ##STR00225## wherein X is
selected from amino, NR.sup.1R.sup.2, or halogen, the halogen is
selected from bromine, chlorine, fluorine or iodine, and when X is
NR.sup.1R.sup.2, R.sup.1 is methyl or ethyl and R.sup.2 is methyl
or ethyl; R is R.sup.4(CH.sub.2).sub.nCO--; n=1-4; and R.sup.4 is
monosubstituted or disubstituted amino selected from straight or
branched (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-dimethybutyl or
1-methyl-1-ethylpropyl and pharmacologically acceptable organic and
inorganic salts or metal complexes..Iaddend.
.Iadd.101. A compound of formula I ##STR00226## wherein X is
N(CH.sub.3).sub.2 and R is R.sup.4(CH.sub.2).sub.nCO-- where n=1-4
and R.sup.4 is monosubstituted or disubstituted amino selected from
straight or branched (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 and pharmacologically acceptable organic and
inorganic salts or metal complexes..Iaddend.
.Iadd.102. A compound of formula I ##STR00227## wherein X is
N(CH.sub.3).sub.2 and R is R.sup.4(CH.sub.2).sub.nCO-- where n=1
and R.sup.4 is monosubstituted or disubstituted amino selected from
straight or branched (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 and pharmacologically acceptable organic and
inorganic salts or metal complexes..Iaddend.
.Iadd.103. A compound of the following structure: ##STR00228##
wherein R.sup.4 is a monsubstituted straight or branched
C.sub.4-alkylamino, and pharmacologically acceptable organic and
inorganic salts or metal complexes..Iaddend.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to novel
[4S-(4,12a.alpha.)]-4-(dimethylamino)-7-(substituted)-9-(substituted
amino)- 1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12
a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamides hereinafter
called 7-(substituted)-9-(substituted
amino)-6-dimethyl-6-deoxytetracyclines, which exhibit antibiotic
activity against a wide spectrum of organisms including organisms
which are resistant to tetracyclines and are useful as antibiotic
agents. The invention also relates to novel
7-(substituted)-9-(substituted
amino)-6-demethyl-6-deoxytetracycline intermediates useful for
making the novel compounds of the present invention and to novel
methods for producing the novel compounds and intermediate
compounds.
DESCRIPTION OF THE PRIOR ART
A variety of tetracycline antibiotics have been synthesized and
described for the treatment of infectious diseases in man and
animals since 1947. Tetracyclines inhibit protein synthesis by
binding to the 30S substituted of the bacterial ribosome preventing
binding of aminoacyl RNA (Chopra, Handbook of Experimental
Pharmacology, Vol. 78, 317-392, Springer-Verlag, 1985). Resistance
to tetracyclines has emerged among many clinically important
microorganisms which limit the utility to these antibiotics. There
are two major mechanisms of bacterial resistance to tetracyclines:
a) energy-dependent efflux of the antibiotic mediated by proteins
located in the cytoplasmic membrane which prevents intracellular
accumulation of tetracycline (S. B. Levy et al., Antimicrob. Agents
Chemotherapy 33, 1373-1374 (1989); and b) ribosomal protection
mediated by a cytoplasmic protein which interacts with the ribosome
such that tetracycline no longer binds or inhibits protein
synthesis (A. A. Salyers, B. S. Speers and N. B. Shoemaker, Mol.
Microbiol, 4:151-156, 1990). The efflux mechanism of resistance is
encoded by resistance determinants designated tetA-tetL. They are
common in many Gram-negative bacteria (resistance genes Class A-E),
such as Enterobacteriaceae, Pseudomonas, Haemophilus and Aeromonas,
and in Gram-positive bacteria (resistance genes Class K and L),
such as Staphylococcus, Bacillus and Streptococcus. The ribosomal
protection mechanism of resistance is encoded by resistance
determinants designated TetM, N and O, and is common in
Staphylococcus, Streptococcus, Campylobacter, Gardnerella,
Haemophilus and Mycoplasma (A. A. Seylers, B. S. Speers and N. B.
Shoemaker, Mol. Microbiol, 4:151-156 1990).
A particularly useful tetracycline compound is
7-(dimethylamino)-6-demethyl-6-deoxytetracycline, known as
minocycline (see U.S. Pat. No. 3,148,212, U.S. Pat. No. RE 26,253
and U.S. Pat. No. 3,226,436 discussed below). However, strains
harboring the tetB (efflux in gram-negative bacteria) mechanism,
but not tetK (efflux in Staphylococcus) are resistant to
minocycline. Also, strains carrying tetM (ribosomal protection) are
resistant to minocycline. This invention describes the synthesis of
novel tetracycline compounds which demonstrate significant in vitro
and in vivo activity vs. tetracycline and minocycline susceptible
strains and some tetracycline and minocycline resistant strains,
that is, those harboring the tetM (ribosomal protection) resistance
determinants.
Duggar, U.S. Pat. No. 2,482,055, discloses the preparation of
Aureomycin.RTM. (I) by fermentation which have antibacterial
activity. Growich et al., U.S. Pat. No. 3,007,965, disclose
improvements to the fermentation preparation of I. Neither of these
patents teaches or suggests the 6-demethyl-6-deoxytetracyclines.
##STR00002## Beereboom et al., U.S. Pat. No. 3,043,875 discloses
tetracycline derivatives of the formulae (II) and (III) where R is
H or CH.sub.3; R.sub.1 is H and when R is CH.sub.3, OH; R.sub.2 is
H and N(CH.sub.3).sub.2; X and Y are halogen; Z is H and halogen
and B is bromo, chloro and iodo, which have antibacterial activity.
This patent does not teach or suggest the inclusion of both
di(lower alkyl)amino or mono(layer alkyl)amino substituents (at Y
or Z) and an amino function (at B). ##STR00003## Boothe et al.,
U.S. Pat. No. 3,148,212, reissued as U.S. Pat. No. RE 26,253, and
Petisi et al., U.S. Pat. No. 3,226,436, discloses tetracycline
derivatives of the formula (IV) wherein R is hydrogen or methyl and
R.sub.1 and R.sub.2 is hydrogen, mono(lower alkyl)amino or di(lower
alkyl)amino with the proviso that R.sub.1 and R.sub.2 cannot both
be hydrogen, which are useful for treating bacterial infections.
This patent does not teach or suggest the inclusion of a 9-amino
functionality (at R.sub.2). ##STR00004##
Blackwood et al., U.S. Pat. No. 3,200,149 discloses tetracycline
derivatives of the formulae (V) and (VI) and reduction products
thereof wherein Y may be hydrogen or hydroxyl, X may be hydrogen,
chloro, iodo, or bromo, X.sub.1 may be hydrogen, amino, and lower
alkanoylamino, X.sub.2 may be hydrogen or nitro and Z is chloro or
fluoro which possess microbiological activity. This patent does not
teach or suggest the inclusion of both a di(lower alkyl)amino group
(at X) and another nitrogen functionality (at X.sub.1) on the
6-demethyl-6-deoxytetracycline nucleus. ##STR00005## Petisi et al.,
U.S. Pat. No. 3,338,963 discloses tetracycline compounds of the
formula (VII) wherein R.sub.1 and R.sub.2 are hydrogen, nitro,
amino, formylamino, acetylamino, p-(dihydroxyboryl)benzoylamino,
p-(aminobenzenesulfonyl)amino, chlorine, bromine or diazonium with
the proviso that R.sub.1 and R.sub.2 may not both be hydrogen and
with the further proviso that when R.sub.1 is chlorine or bromine,
R.sub.2 may not be hydrogen and vice versa, R.sub.3 is hydrogen or
methyl and R.sub.4 is hydrogen or hydroxy, which have
broad-spectrum antibacterial activity. This patent does not teach
or suggest the inclusion of di(lower alkyl)amino or mono(lower
alkyl)amino substituents (at R.sub.1) and amino substituents (at
R.sub.2). ##STR00006##
Bitha et al., U.S. Pat. No. 3,341,585 discloses tetracycline
compounds of the formula (VIII) wherein R.sub.5 is hydrogen,
.alpha.-hydroxy or .beta.-hydroxy, R.sub.6 is .alpha.-methyl or
.beta.- methyl, and R.sub.7 and R.sub.8 are each hydrogen,
mono(lower alkyl) amino or di(lower alkyl)amino with the proviso
that R.sub.7 and R.sub.9 cannot both be hydrogen and with the
further proviso that when R.sub.5 is hydrogen then R.sub.6 is
.alpha.-methyl. A preferred embodiment of the general formula
(VIII) is when R.sub.5 is .alpha.-hydroxy or .beta.-hydroxy,
R.sub.6 is .alpha.-methyl or .beta.-methyl, R.sub.7 is di(lower
alkyl)amino and R.sub.9 is hydrogen, which have broad-spectrum
antibacterial activity. This patent does not teach or suggest the
inclusion of both di(lower alkyl)amino or mono(lower alkyl)amino
substituents (at R.sub.7) and amino substituents (at R.sub.9).
##STR00007## Shu, U.S. Pat. No. 3,360,557 discloses
9-hydroxytetracyclines of the formula (IX) wherein R.sub.1 is
hydrogen or hydroxy, R.sub.2 is hydrogen or hydroxy, R.sub.3 is
hydrogen or methyl, R.sub.2 and R.sub.3 taken together is
methylene, and R.sub.4 is hydrogen, halogen, nitro, amino,
mono(lower alkyl)amino or di(lower alkyl)amino, which have been
found to possess antibacterial activity. This patent is restricted
to 9-hydroxytetracyclines and does not teach or suggest the
presently claimed compounds. ##STR00008## Zambrano, U.S. Pat. No.
3,360,561 discloses a process for preparing 9-nitrotetracyclines of
the formula (X) wherein R.sub.5 is hydrogen or hydroxy, R.sub.1 is
hydrogen or hydroxy, R.sub.6 is hydrogen or methyl, R.sub.1 and
R.sub.4 taken together is methylene, R.sub.2 is hydrogen, chloro or
nitro and R.sub.9 is hydrogen or nitro with the proviso that
R.sub.7 and R.sub.9 cannot both be hydrogen. This patent does not
teach or suggest the inclusion of both a di(lower alkyl)amino or
mono(lower alkyl)amino substituent (at R.sub.7) and an amino
functionality (at R.sub.9). ##STR00009## Martell et al., U.S. Pat.
No. 3,518,306 discloses 7-and/or
9-(N-nitroalkylamino)-6-demethyl-6-deoxytetracyclines of the
formula (XI) which possess in vivo antibacterial activity. This
patent does not teach or suggest the inclusion of both a di(lower
alkyl)amino or mono(lower alkyl)amino substituent at (C-7) and an
amino functionality (at C-9). ##STR00010##
In U.S. Pat. No. 5,021,407, a method of overcoming the resistance
of tetracycline resistant bacteria is disclosed. The method
involves utilizing a blocking agent compound in conjunction with a
tetracycline type antibiotic. This patent does not disclose novel
tetracycline compounds which themselves have activity against
resistant organisms.
In summary, none of the above patents teach or suggest the novel
compounds of this application. In addition, none of the above
patents teach or suggest novel tetracycline compounds having
activity against tetracycline and minocycline resistant strains as
well as strains which are normally susceptible to
tetracyclines.
SUMMARY OF THE INVENTION
This invention is concerned with novel
7-(substituted)-9-(substituted
amino)-6-demethyl-6-deoxytetracyclines, represented by formula I
and II, which have antibacterial activity; with method of treating
infectious diseases in warm blooded animals employing these new
compound; with methods of treating or controlling veterinary
diseases; with pharmaceutical preparations containing these
compounds; with novel intermediate compounds and processes for the
production of these compounds. More particularly, this invention is
concerned with compounds of formula I and II which have enhanced in
vitro and in vivo antibiotic activity against tetracycline
resistant strains as well as a high level of activity against
strains which are normally susceptible to tetracyclines.
##STR00011##
In formula I and II, X is selected from amino, NR.sup.1R.sup.2 or
halogen; the halogen is selected from bromine, chlorine, fluorine
or iodine; and when X=NR.sup.1R.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.nCO-- or R.sup.4'
(CH.sub.2).sub.nSO.sub.2--; and when R=R.sup.4(CH.sub.2).sub.nCO--
and n=0, R.sup.4 is selected from hydrogen; 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); straight or
branched (C.sub.1-C.sub.4)alkyl group selected from methyl, ethyl,
n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or
1,1-dimethylethyl; (C.sub.1-C.sub.6)cycloalkyl group selected from
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; substituted
(C.sub.3-C.sub.6)cycloalkyl group (substitution selected from
(C.sub.1-C.sub.3)alkyl, cyano, amino or (C.sub.1-C.sub.3)acyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-phenyl,
.alpha.-naphthyl or .beta.-naphthyl; substituted
(C.sub.6-C.sub.10)aryl group (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl; .alpha.-amino-(C.sub.1-C.sub.4)alkyl group selected
from aminomethyl, .alpha.-aminoethyl, .alpha.-aminopropyl or
.alpha.-aminobutyl; carboxy(C.sub.2-C.sub.4)akylamino group
selected from aminoacetic acid, .alpha.-aminobutyric acid or
.alpha.-aminopropionic acid and their optical isomers;
(C.sub.7-C.sub.9)aralkylamino group such as phenylglycyl;
(C.sub.1-C.sub.4)-alkoxycarbonylamino substituted
(C.sub.1-C.sub.4)alkyl group, substitution selected from phenyl or
p-hydroxyphenyl; .alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group
selected from hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
.alpha.-mercapto(C.sub.1-C.sub.3)alkyl group selected from
mercaptomethyl, .alpha.-mercaptoethyl, .alpha.-mercapto-1-methyl or
.alpha.-mercaptopropyl; halo(C.sub.1-C.sub.3)alkyl group such as
bromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl or
2-iodoethyl; a heterocycle group selected from a five membered
aromatic or saturated ring with one N, O, S or Se heteroatom
optionally having a benzo or pyrido ring fused thereto:
##STR00012## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00013## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00014## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl,
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; acyl or haloacyl group selected from
acetyl, propionyl, chloroacetyl, trifluoroacetyl,
(C.sub.3-C.sub.6)cycloalkylcarbonyl such as cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
(2,3-dimethylcyclopropyl)carbonyl,
(1,2-dimethylcyclopropyl)carbonyl, (2-ethylcyclopropyl)carbonyl,
(2-methylcyclopentyl)carbonyl or (3-ethylcyclobutyl)carbonyl,
(C.sub.6-C.sub.10)aroyl selected from benzoyl or naphthoyl, halo
substituted (C.sub.6-C.sub.10)aroyl such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00015## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuran, furanyl, benzofuranyl, tetrahydrothienyl, thienyl,
benzothienyl or selenazolyl, or a five membered aromatic ring with
two N, O, S or Se heteroatoms optionally having a benzo or pyrido
ring fused thereto: ##STR00016## such as imidaozly, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazolyl[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00017## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.6)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatoms such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonyl group
selected from methoxycarbonyl, ethoxycarbonyl, straight or branched
propoxylcarbonyl, straight or branched butoxycarbonyl or
allyloxycarbonyl; vinyl or substituted vinyl group [substitution
selected from (C.sub.1-C.sub.3)alkyl group, halogen,
(C.sub.6-C.sub.10)aryl group selected from phenyl,
.alpha.-naphthyl, .beta.-naphthyl, substituted
(C.sub.6-C.sub.10)aryl group (substitution selection from halo,
(C.sub.1-C.sub.6)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), halo(C.sub.1-C.sub.3)alkyl
group such as bromomethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
2-bromoethyl or 2-iodoethyl, a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00018## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuran,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl benzothienyl or
selenazolyl]; (C.sub.1-C.sub.4)alkoxy group such as allyloxy,
methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(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 group such as benzyloxy,
1-phenylethyloxy or 2-phenylethyloxy; vinyloxy or substituted
vinyloxy group (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.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.sup.b is a straight or branched (C.sub.1-C.sub.6)alkyl
selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl,
1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl or
R.sup.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O is S; or
R.sup.aR.sup.baminoxy group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; and when
R=R.sup.4(CH.sub.2).sub.nCO-- and n=1-4, R.sup.4 is selected from
hydrogen; amino; straight or branched (C.sub.1-C.sub.4)alkyl group
selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl,
1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
(C.sub.3-C.sub.6)cycloalkyl group selected from cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl; substituted
(C.sub.3-C.sub.6)cycloalkyl group (substitution selected from
(C.sub.1-C.sub.3)alkyl, cyano, amino or (C.sub.1-C.sub.3)acyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted(C.sub.6-C.sub.10)aryl group
(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.9)aralkyl group such as benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl; acyloxy or
haloacyloxy group, selected from acetyl, propionyl, chloroacetyl,
trichloroacetyl, (C.sub.3-C.sub.6)cycloalkylcarbonyl,
(C.sub.6-C.sub.10)aroyl selected from benzoyl or naphtholyl, halo
substituted (C.sub.8-C.sub.10)aroyl such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl or
4-(1-methylethyl)benzoyl, (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00019## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00020## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, imidazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00021## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimdiazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxy group such as
allyloxy, methoxy, ethoxy, n-propoxy,n-butoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(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 group such as benzyloxy,
1-phenylethyloxy or 2-phenylethyloxy; (C.sub.1-C.sub.3)alkylthio
group selected from methylthio, ethylthio, propylthio or allylthio;
C.sub.6-arylthio group selected from phenylthio or substituted
phenylthio (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 phenylsuflonyl (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 such as benzylthio,
1-phenylethylthio or 2-phenylethylthio; a heterocycle group
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00022## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuran, furanyl, benzofuranyl, tetrahydrothienyl, thienyl,
benzothienyl or selenazolyl, or a five membered aromatic ring with
two N, O, S or Se heteroatoms optionally having a benzo or pyrido
ring fused thereto: ##STR00023## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxaxolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[3,4-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O heterotom:
##STR00024## (A is selected from hydrogen; straight or branched
(C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted C.sub.6-aryl
(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.6)alkoxycarbonyl, (C.sub.1-C.sub.3)alkylamino or
carboxy); (C.sub.7-C.sub.9)aralkyl group selected from benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl) such as
.gamma.-butyrolactam, .gamma.-butyrolactone, imidazolidinone or
N-aminoimidazolidinone, or a six membered aromatic ring with one to
three N, O,S or Se heteroatoms such as pyridyl, pyridazinyl,
pyrazinyl, sym-triazinyl, unsym-triazinyl, pyrimidinyl or
(C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six membered saturated
ring with one or two N, O, S or Se heteroatoms and an adjacent
appended O heteroatom such as 2,3-dioxo-1-piperazinyl,
4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl, 2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; hydroxy group; mercapto group; mono- or
di-straight or branched chain (C.sub.1-C.sub.6)alkylamino group
selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl,
1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl,
2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,
3-methylbutyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl,
2,2-dimethylbutyl, 3-methylpentyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl or 1-methyl-1-ethylpropylamino;
(C.sub.2-C.sub.5)azacycloalkyl group such as aziridinyl,
azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or
2-methylpyrrolidinyl; carboxy(C.sub.2-C.sub.4)alkylamino group
selected from aminoacetic acid, .alpha.-aminopropionic acid,
.alpha.-aminobutyric acid and their optical
isomers; .alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group selected from
hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoromethyl, 2-bromoethyl or 2-iodoethyl; acyl or
haloacyl group 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 such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl, 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00025## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl,benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00026## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxaxolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00027## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.6)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.2)
alkylamino or carboxy); (C.sub.7-C.sub.9)aralkyl group selected
from benzyl, 1-phenylethyl, 2-phenylethyl or phenyl propyl) such as
.gamma.-butyrolactam, .gamma.-butyrolactone, imidazolidinone or
N-aminoimidazolidinone, or a six membered aromatic ring with one to
three N, O, S or Se heteroatoms such as pyridyl, pyridazinyl,
pyrazinyl, sym-triazinyl, unsym-triazinyl, pyrimidinyl or
(C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six membered saturated
ring with one or two N, O, S or Se heteroatoms and an adjacent
appended O heteroatom such as 2,3-dioxo-1-piperazinyl,
4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
-dioxothiomorpholinyl; (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.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O is S; or
R.sup.aR.sup.baminoxy group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; and when
R=R.sup.4 (CH.sub.2).sub.nSO.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-imidazolyl, 1-pyrrolyl, 1-(1,2,3-triazolyl) or
4-(1,2,4-triazolyl); straight or branched (C.sub.1-C.sub.4)alkyl
group selected from methyl, ethyl, n-propyl, 1-methylethyl,
n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
(C.sub.3-C.sub.6)cycloalkyl group selected from cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl; substituted
(C.sub.3-C.sub.6)cycloalkyl group (substitution selected from
(C.sub.1-C.sub.3)alkyl, cyano, amino or (C.sub.1-C.sub.3)acyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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.9)aralkyl group such as benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-chloroethyl, 2,2-dichloroethyl,
2,2,2-trichloroethyl, 2-bromoethyl or 2-iodoethyl; a heterocycle
group selected from a five membered aromatic or saturated ring with
one N, O, S or Se heteroatom optionally having a benzo or pyrido
ring fused thereto: ##STR00028## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00029## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00030## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl) or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three, N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy
group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; or
R.sup.aR.sup.baminoxy group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; and when
R=R.sup.4' (CH.sub.2).sub.nSO.sub.2-- and n=1-4, R.sup.4' is
selected from hydrogen; amino; straight or branched
(C.sub.1-C.sub.4)alkyl group selected from methyl, ethyl, n-propyl,
1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or
1,1-dimethylethyl; (C.sub.1-C.sub.4)carboxylalkyl group;
(C.sub.3-C.sub.6)cycloalkyl group selected from cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl; substituted
(C.sub.3-C.sub.6)cycloalkyl group (substitution selected from
(C.sub.1-C.sub.3)alkyl, cyano, amino or (C.sub.1-C.sub.3)acyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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.9)aralkyl group selected from benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl;
(C.sub.1-C.sub.4)alkoxy group such as allyloxy, methoxy, ethoxy,
n-propoxy or tert-butoxy; C.sub.6-aryloxy group selected from
phenoxy or substituted phenoxy (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 group
such as benzyloxy, 1-phenylethyloxy or 2-phenylethyloxy;
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.2)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S;
(C.sub.1-C.sub.3)alkylthio group selected from methylthio,
ethylthio or n-propylthio; C.sub.6-arylthio group selected from
phenylthio or substituted phenylthio (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 group
such as benzylthio, 1-phenylethylthio or 2-phenylethylthio; a
heterocycle group selected from a five membered aromatic or
saturated ring with one N, O, S or S heteroatom optionally having a
benzo or pyrido ring fused thereto. ##STR00031## such as pyrrolyl,
N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl,
tetrahydrothienyl, thienyl, benzothienyl, or selenazolyl, or a five
membered aromatic ring with two N, O, S or Se heteroatoms
optionally having a benzo or pyrido ring fused thereto:
##STR00032## such as imidazolyl, pyrazolyl, benzimidazolyl,
oxazolyl, benzoxazolyl, indazolyl[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00033## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (substitution selected from
halo,(C.sub.1-C.sub.6)alkoxy, trihalo(C.sub.1-C.sub.3)alkyl, nitro,
amino, cyano, (C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.3)alkylamino or carboxy); (C.sub.7-C.sub.9)-aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O,S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatoms such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4
-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; hydroxy group, mercapto group; mono- or di-
straight or branched (C.sub.1-C.sub.6) alkylamino group 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 amino, halo(C.sub.1-C.sub.3)alkyl group such
as bromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl,
2,2-dichloroethyl, 2,2,2-trichloroethyl, 2-bromoethyl or
2-iodoethyl; acyl or haloacyl group selected from acetyl,
propionyl, chloroacetyl, trifluoroacetyl,
(C.sub.3-C.sub.6)-cycloalkylcarbonyl, (C.sub.6-C.sub.10)aroyl
selected from benzoyl or naphthyl, halo substituted
(C.sub.6-C.sub.10)aroyl such as pentafluorobenzyl, 4-chlorobenzoyl,
3-bromobenzoyl or 3,4-difluorobenzyl,
(C.sub.1-C.sub.4)-alkylbenzoyl such as 4-toluoyl, 2-toluoyl or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused therein: ##STR00034## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00035## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazonyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00036## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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)akylamino or carboxy); (C.sub.7-C.sub.9)-aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidizinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonyl group
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 group selected from 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 such as benzyl, 1-phenylethyl,
2-phenylethyl or phenylpropyl; a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatoms optionally having a benzo or pyrido ring fused thereto:
##STR00037## such as pyrrolyl, N-methylimidolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00038## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5b-]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N,
O, S or Se heteroatoms and an adjacent appended O heteroatom:
##STR00039## (A is selected from hydrogen; straight or branched
(C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted C.sub.6-aryl
(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
carboxyl; (C.sub.7-C.sub.9)aralkyl group selected from benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl) such as
.gamma.-butyrolactam, .gamma.-butyrolactone, imidazolidinone or
N-aminoimidazolidinone, or a six membered aromatic ring with one to
three N, O, S or Se heteroatoms such as pyridyl, pyridazinyl,
pyrazinyl, sym-triazinyl, unsym-triazinyl, pyrimidinyl or
(C.sub.1-C.sub.3) alkylthiopyridazinyl, or a six membered saturated
ring with one or two N, O, S or Se heteroatoms and an adjacent
appended O heteroatom such as 2,3-dioxo-1-piperazinyl,
4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl, 2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,
2-dioxothiomorpholinyl; or --(CH.sub.2).sub.nCOOR.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, .beta.-naphthyl; R.sup.6 is selected from
hydrogen; straight or branched (C.sub.1-C.sub.3)alkyl group
selected from 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 such as benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocycle group
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00040## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00041## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00042## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl (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.9)aralkyl group selected from benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl) such as
.gamma.-butyrolactam, .gamma.-butyrolactone, imidazolidinone or
N-aminoimidazolidinone, or a six membered aromatic ring with one to
three N, O, S or Se heteroatoms such as pyridyl, pyridazinyl,
pyrazinyl, sym-triazinyl, unsym-triazinyl, pyrimidinyl or
(C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six membered saturated
ring with one or two N, O, S or Se heteroatoms and an adjacent
appended O heteroatom such as 2,3-dioxo-1-piperazinyl,
4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl, 2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,
2-dioxothiomorpholinyl; or --(CH.sub.2).sub.nCOOR.sup.T where n=0-4
and R.sup.T 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.2W(CH.sub.2).sub.2--, wherein W is
selected from (CH.sub.2).sub.n and n=0-1, --NH,
--(C.sub.1-C.sub.3)alkyl [straight or branched],
--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.
Preferred compounds are compounds according to the above formula I
and II in which X is selected from amino, NR.sup.1R.sup.2, or
halogen; the halogen is selected from bromine, chlorine, fluorine
or iodine; and when X=NR.sup.1R.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; R is
selected from R.sup.6(CH.sub.2).sub.nCO-- or R.sup.4'
(CH.sub.2).sub.nSO.sub.2--; and when R=R.sup.4(CH.sub.2).sub.nCO--
and n=0, R.sup.4 is selected from hydrogen; 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); straight or
branched (C.sub.1-C.sub.3)alkyl group selected from methyl, ethyl,
n-propyl or 1-methylethyl; (C.sub.1-C.sub.6)cycloalkyl group
selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
substituted (C.sub.3-C.sub.6)cycloalkyl group (substitution
selected from (C.sub.1-C.sub.3)alkyl, cyano, amino or
(C.sub.1-C.sub.3)acyl); (C.sub.6-C.sub.10)aryl group selected from
phenyl, .alpha.-naphthyl or .beta.-naphthyl; substituted
(C.sub.6-C.sub.10)aryl group (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 group selected from
aminomethyl, .alpha.-aminoethyl, .alpha.-aminopropyl or
.alpha.-aminobutyl; carboxy(C.sub.2-C.sub.4)alkylamino group
selected from aminoacetic acid, .alpha.-aminobutyric acid or
.alpha.-aminopropionic acid and their optical isomers;
(C.sub.7-C.sub.9)aralkylamino group such as phenylglycyl;
(C.sub.1-C.sub.4)alkoxycarbonylamino substituted
(C.sub.1-C.sub.4)alkyl group, substitution selected from phenyl or
p-hydroxyphenyl; .alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group
selected from hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxyprop;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-bromoethyl or 2-iodoethyl; a heterocycle
group selected from a five membered aromatic or saturated ring with
one N, O, S or Se heteroatom optionally having a benzo or pyrido
ring fused thereto: ##STR00043## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahyrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatom optionally having a benzo or
pyrido ring fused thereto: ##STR00044## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended heteroatom:
##STR00045## (A is selected from hydrogen; straight or branched
(C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted C.sub.6-aryl
(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.6)alkoxycarbonyl, (C.sub.1-C.sub.3)alkylamino or
carboxy); (C.sub.7-C.sub.9)aralkyl group selected from benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl) such as
.gamma.-butyrolactam, .gamma.-butyrolactone, imidazolidinone or
N-aminoimidazolidinone, or a six membered aromatic ring with one to
three N, O, S or Se heteroatoms such as pyridyl, pyridazinyl,
pyrazinyl, sym-triazinyl, unsym-triazinyl, pyrimidinyl or
(C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six membered saturated
ring with one or two N, O, S or Se heteroatoms and an adjacent
appended O heteroatom such as 2,3-dioxo-1-piperazinyl,
4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl, 2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; acyl or haloacyl group selected from
acetyl, propionyl, chloroacetyl, trifluoroacetyl,
(C.sub.3-C.sub.6)cycloalkylcarbonyl such as cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
(2,3-dimethylcyclopropyl)carbonyl,
(1,2-dimethylcyclopropyl)carbonyl, (2-ethylcyclopropyl)carbonyl,
(3-ethylcyclobutyl)carbonyl, (C.sub.6-C.sub.10)aroyl selected from
benzoyl or naphthoyl, halo substituted (C.sub.6-C.sub.10)aroyl such
as pentafluorobenzoyl, 4-chlorobenzoyl, 3-bromobenzoyl or
3,4-difluorobenzoyl, (C.sub.1-C.sub.4)alkylbenozyl such as
4-toluoyl, 2-methyltoluoyl or 4-(1-methylethyl)benzoyl, or
(heterocycle)carbonyl, the heterocycle selected from a five
membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00046## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto. ##STR00047## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00048## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl,
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonyl group
selected from methoxycarbonyl, ethoxycarbonyl, straight or branched
propoxylcarbonyl, straight or branched butoxycarbonyl or
allyloxycarbonyl; vinyl or substituted vinyl group [substitution
selected from (C.sub.1-C.sub.3)alkyl group, halogen,
(C.sub.6-C.sub.10)aryl group selected from phenyl,
.alpha.-naphthyl, .beta.-naphthyl, substituted
(C.sub.6-C.sub.10)aryl group (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), halo(C.sub.1-C.sub.3)alkyl
group such as bromomethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
2-bromoethyl or 2-iodoethyl, a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00049## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl]; (C.sub.1-C.sub.4)alkoxy group such as allyloxy,
methoxy, ethoxy, n-propoxy,n-butoxy or tert-butoxy; C.sub.6-aryloxy
group selected from phenoxy or substituted phenoxy (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 group such as benzyloxy,
1-phenylethyloxy or 2-phenylethyloxy; vinyloxy or substituted
vinyloxy group (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.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.sup.b is a straight chain 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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; or
R.sup.aR.sup.baminoxy group, wherein R.sup.aR.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.aR.sup.b (CH.sub.2).sub.n, n=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 [straight or branched], --NH.sub.1, --NOB
[B is selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S;
and when R=R.sup.4(CH.sub.2).sub.nCO-- and n=1-4, R.sup.4 is
selected from hydrogen; (C.sub.1-C.sub.3)alkyl group selected from
methyl, ethyl, n-propyl or 1-methylethyl; 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);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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); acryloxy or haloacryloxy group selected from acetyl,
propionyl, chloroacetyl, trichloroacetyl,
(C.sub.3-C.sub.6)cycloalkylcarbonyl, (C.sub.6-C.sub.10)aroyl
selected from benzoyl or naphthyl, halo substituted
(C.sub.6-C.sub.10)aroyl such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl,
4-(1-methylethyl)benzoyl or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00050## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00051## such as imidaozly,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazolyl[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00052## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl,
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxy group such as
allyloxy, methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.sup.b is a straight or branched (C.sub.1-C.sub.6)alkyl
selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl,
1-methylpropyl, or 2-methylpropyl or R.sup.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O, or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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-methoxypropyl or
R.sup.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(substitution selected from halo, (C.sub.1-C.sub.6)alkyl, nitro,
cyano, thiol, amino, carboxy, di(C.sub.1-C.sub.3)alkylamino);
(C.sub.1-C.sub.3)alkylthio group selected from methylthio,
ethylthio, propylthio or allylthio; C.sub.6-arylthio group selected
from phenylthio or substituted phenylthio (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 phenylsuflonyl
(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); a heterocycle group selected from a five membered
aromatic or saturated ring with one N, O, S or Se heteroatom
optionally having a benzo or pyrido ring fused thereto:
##STR00053## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00054## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00055## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl,
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; hydroxy group;
.alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group selected from
hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoromethyl, 2-bromoethyl or 2-iodoethyl; acyl or
haloacyl group selected from acetyl, propionyl, chloroacetyl,
trifluoracetyl,
(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 such as pentafluorobenzyl, 4-chlorobenzoyl,
3-bromobenzoyl or 3,4-difluorobenozyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl, or
4-(1-methylethyl)benzoyl or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00056## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00057## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00058## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl,
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonylamino group
selected from tert-butoxycarbonylamino, allyloxycarbonylamino,
methoxycarbonylamino, ethoxycarbonylamino or propoxycarbonylamino;
and when R=R.sup.4 (CH.sub.2).sub.nSO.sub.2-- and n=0, R.sup.4' is
selected from amino; monosubstituted amino selected from as
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); straight or branched (C.sub.1-C.sub.3)alkyl
group selected from methyl, ethyl, n-propyl or 1-methylethyl;
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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); a heterocycle group selected from a five membered
aromatic or saturated ring with one N, O, S or Se heteroatom
optionally having a benzo or pyrido ring fused thereto:
##STR00059## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00060## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxaxolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazol, or a five membered saturated ring with one or two,
N, O, S or Se heteroatoms and an adjacent appended O heteroatom:
##STR00061## (A is selected from hydrogen; straight or branched
(C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted C.sub.6-aryl
(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.9)aralkyl group selected from benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl) such as
.gamma.-butyrolactam, .gamma.-butyrolactone, imidazolidinone or
N-aminoimidazolidinone, or a six membered aromatic ring with one to
three N, O, S or Se heteroatoms such as pyridyl, pyridazinyl,
pyrazinyl, sym-triazinyl, unsym-triazinyl, pyrimidinyl or
(C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six membered saturated
ring with one or two N, O, S or Se heteroatoms and an adjacent
appended O heteroatom such as 2,3-dioxo-1-piperazinyl,
4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; and when
R=R.sup.4'(CH.sub.2).sub.nSO.sub.2-- and n=1-4, R.sup.4' is
selected from hydrogen; 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); straight or branched (C.sub.1-C.sub.3)alkyl
group selected from methyl, ethyl, n-propyl or 1-methylethyl;
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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.4)alkylamino or
carboxy); (C.sub.1-C.sub.4)alkoxy group such as allyloxy, methoxy,
ethoxy, n-propoxy, n-butoxy, isobutoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(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 group such as benzyloxy,
1-phenylethyloxy or 2-phenylethyloxy;
(C.sub.1-C.sub.10)carboxyalkyl group; R.sup.3 is selected from
hydrogen; straight or branched (C.sub.1-C.sub.3)alkyl group
selected from 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 such as benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocycle group
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00062## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00063## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00064## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl,
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; or --(CH.sub.2).sub.nCOOR.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 from 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 such as benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocycle group
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00065## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00066## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00067## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl,
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl, 2-dioxothiomorpholinyl;
or (CH.sub.2).sub.nCOOR.sup.T where n=0-4 and R.sup.T 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.2W(CH.sub.2).sub.2--, wherein W is selected from
(CH.sub.2).sub.n and n=0-1, --NH, --(C.sub.1-C.sub.3)alkyl
[straight or branched], --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.
Particularly preferred compounds are compounds according to the
above formula I and II in which X is selected from amino,
NR.sup.1R.sup.2, or halogen; the halogen is selected from bromine,
chlorine, fluorine or iodine; and when X=NR.sup.1R.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-methoxypropyl or 2-methylpropyl; R is
selected from R.sup.4(CH.sub.2).sub.nCO-- or R.sup.4'
(CH.sub.2).sub.nSO.sub.2--; and when R=R.sup.4(CH.sub.2).sub.nCO--
and n=0, R.sup.4 is selected from hydrogen; 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); straight or
branched (C.sub.1-C.sub.3)alkyl group selected from methyl, ethyl,
n-propyl or 1-methylethyl; (C.sub.3-C.sub.6)cycloalkyl group
selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
substituted (C.sub.3-C.sub.6)cycloalkyl group (substitution
selected from (C.sub.1-C.sub.3)alkyl, cyano, amino or
(C.sub.1-C.sub.3)acyl); (C.sub.6-C.sub.10)aryl group selected from
phenyl, .alpha.-naphthyl or .beta.-naphthyl; substituted
(C.sub.6-C.sub.10)aryl group (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, group selected from
aminomethyl, .alpha.-aminoethyl, .alpha.-aminopropyl or
.alpha.-aminobutyl; carboxy(C.sub.2-C.sub.4)alkylamino group
selected from aminoacetic acid, .alpha.-aminobutyric acid or
.alpha.-aminopropionic acid and their optical isomers,
(C.sub.7-C.sub.9)aralkylamino group such as phenylglycyl;
(C.sub.1-C.sub.4)alkoxycarbonylamino substituted
(C.sub.1-C.sub.4)alkyl group, substitution selected from phenyl or
p-hydroxyphenyl; .alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group
selected from hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoroethyl, chloromethyl, dichlorometyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-bromoethyl or 2-indoethyl, a heterocycle
group selected from a five membered aromatic or saturated ring with
one N, O, S or Se heteroatom optionally having a benzo or pyrido
ring fused thereto: ##STR00068## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00069## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00070## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl,
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; acyl or haloacyl group selected from
acetyl, propionyl, chloroacetyl, trifluoroacetyl,
(C.sub.3-C.sub.6)cycloalkylcarbonyl such as cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
(2,3-dimethylcyclopropyl)carbonyl,
(1,2-dimethylcyclopropyl)carbonyl, (2-ethylcyclopropyl)carbonyl,
(2-methylcyclopentyl)carbonyl or (3-ethylcyclobutyl)carbonyl,
(C.sub.6-C.sub.10)aroyl selected from benzoyl or naphthoyl, halo
substituted (C.sub.6-C.sub.10)aroyl such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00071## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00072## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00073## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl,
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonyl group
selected from methoxy carbonyl, ethoxycarbonyl, straight or
branched propoxycarbonyl, straight or branched butoxycarbonyl or
allyloxycarbonyl; vinyl or substituted vinyl group [substitution
selected from (C.sub.1-C.sub.3)alkyl group, halogen,
(C.sub.6-C.sub.10)aryl group selected from phenyl,
.alpha.-naphthyl, .beta.-naphthyl, substituted
(C.sub.6-C.sub.10)aroyl group (substituted 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), halo(C.sub.1-C.sub.3)alkyl
group such as bromomethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoromethyl,
2-bromomethyl or 2-iodoethyl, a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00074## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl]; (C.sub.1-C.sub.4)alkoxy group such as allyloxy,
methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(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 group such as benzyloxy,
1-phenylethyloxy or 2-phenylethyloxy; vinyloxy or substituted
vinyloxy group (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.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; and when
R=R.sup.4(CH.sub.2).sub.nCO-- and n=1-4, R.sup.4 is selected from
hydrogen; (C.sub.1--C.sub.3)alkyl group selected from methyl,
ethyl, n-propyl or 1-methylethyl; amino; monosubstituted amino
selected from straight or branched (C.sub.1-C.sub.6)alkylamino,
cyclopropylamino, cyclobutylamino, benzylamino or phenylamino;
distributed 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); (C.sub.6-C.sub.10)aryl group selected from
phenyl, .alpha.-naphthyl or .beta.-naphthyl; substituted
(C.sub.6-C.sub.10) aryl group (substitution selected from halo,
(C.sub.1-C.sub.6)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); acryloxy or haloacryloxy
group, selected from acetyl, propionyl, chloroacetyl,
trichloroacetyl, (C.sub.3-C.sub.8)cycloalkylcarbonyl,
(C.sub.6-C.sub.10)aroyl selected from benzoyl or naphthoyl, halo
substituted (C.sub.6-C.sub.10)aroyl such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl,
4-(1-methylethyl)benzoyl or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto; ##STR00075## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00076## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00077## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxy group such as
allyloxy, methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(substitution selected from halo, (C.sub.1-C.sub.4)alkyl, nitro,
cyano, thiol, amino, carboxy, di(C.sub.1-C.sub.3)alkylamino);
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S;
(C.sub.1-C.sub.3)alkylthio group selected from methylthio,
ethylthio, propylthio or allylthio; C.sub.6-arylthio group selected
from phenylthio or substituted phenylthio (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
(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); a heterocycle group selected from a five membered
aromatic or saturated ring one N, O, S or Se heteroatom optionally
having a benzo or pyrido ring fused thereto: ##STR00078## such as
pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl,
tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, or a five
membered aromatic ring with two N, O,S or Se heteroatoms optionally
having a benzo or pyrido ring fused thereto: ##STR00079## such as
imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl,
indazolyl, thiazolyl, benzothiazolyl,
3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a five
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom: ##STR00080## (A is selected
from hydrogen; straight or branched (C.sub.1-C.sub.4)alkyl;
C.sub.6-aryl; substituted C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O,S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; hydroxy group;
.alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group selected from
hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoromethyl, 2-bromoethyl or 2-iodoethyl; acyl or
haloacyl group 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 such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromophenylcarbonyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as from 4-toluoyl, 2-toluoyl or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00081## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00082## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00083## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonylamino group
selected from tert-butoxycarbonylamino, allyloxycarbonylamino,
methoxycarbonylamino, ethoxycarbonylamino or propoxycarbonylamino;
and when R=R.sup.4'(CH.sub.2).sub.nSO.sub.2-- and n=0, R.sup.4' is
selected from amino; monosubstituted amino selected from as
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); straight or branched (C.sub.1-C.sub.3)alkyl
group selected from methyl, ethyl, n-propyl or 1-methylethyl;
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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); a heterocycle group selected from a five membered
aromatic or saturated ring with one N, O, S or Se heteroatom
optionally having a benzo or pyrido ring fused thereto:
##STR00084## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00085## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00086## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; and when
R=R.sup.4'(CH.sub.2).sub.nSO.sub.2-- and n=1-4, R.sup.4' is
selected from hydrogen; 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); straight or branched (C.sub.1-C.sub.3)alkyl
group selected from methyl, ethyl, n-propyl or 1-methylethyl;
R.sub.aR.sub.bamino(C.sub.1-C.sub.6)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; R.sup.5
is selected from hydrogen; straight or branched
(C.sub.1-C.sub.3)alkyl group selected from 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 such as benzyl, 1-phenylethyl,
2-phenylethyl or phenylpropyl; a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00087## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00088## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00089## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl, 2-dioxothiomorpholinyl;
or --(CH.sub.2).sub.nCOOR.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 from 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 such as benzyl, 1-phenylethyl,
2-phenylethyl or phenylpropyl; a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00090## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00091## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00092## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl, 2-dioxothiomorpholinyl;
or (CH.sub.2).sub.nCOOR.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.2W(CH.sub.2).sub.2--, wherein W is selected from
(CH.sub.2).sub.n and n=0-1, --NH, --N(C.sub.1-C.sub.3)alkyl
[straight or branched], --N(C.sub.1-C.sub.6)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.
Most particularly preferred compounds are compounds according to
the above formula I and II in which X is selected from amino,
NR.sup.1R.sup.2, or halogen; the halogen is selected from bromine,
chlorine, fluorine or iodine; and when X=NR.sup.1R.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; R is
selected from R.sup.4(CH.sub.2).sub.nCO-- or R.sup.4
(CH.sub.2).sub.nSO.sub.2--; and when R=R.sup.4(CH.sub.2).sub.nCO--
and n=0, R.sup.4 is selected from hydrogen; 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-pyrrollyl, 1-(1,2,3-triazolyl) or 4-(1,2,4-triazolyl); straight
or branched (C.sub.1-C.sub.2)alkyl group selected from methyl or
ethyl; (C.sub.6-C.sub.10)aryl group selected from phenyl,
.alpha.-naphthyl or .alpha.-naphthyl; substituted
(C.sub.6-C.sub.10)aryl group (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);
carboxy(C.sub.2-C.sub.4)alkylamino group selected from aminoacetic
acid, .alpha.-aminobutyric acid or .alpha.-aminopropionic acid and
their optical isomers; .alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group
selected from hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-bromoethyl or 2-iodoethyl; a heterocycle
group selected from a five membered aromatic or saturated ring with
one N, O, S or Se heteroatom optionally having a benzo or pyrido
ring fused thereto: ##STR00093## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00094## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00095## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonyl group
selected from methoxycarbonyl, ethoxycarbonyl, straight or branched
propoxylcarbonyl, straight or branched butoxycarbonyl or
allyloxycarbonyl; vinyl or substituted vinyl group [substitution
selected from (C.sub.1-C.sub.3)alkyl group, halogen,
(C.sub.6-C.sub.10)aryl group selected from phenyl,
.alpha.-naphthyl, .beta.-naphthyl, substituted
(C.sub.6-C.sub.10)aryl group (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),
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-bromoethyl or 2-iodoethyl, a heterocycle
group selected from a five membered aromatic or saturated ring with
one N, O, S or Se heteroatom optionally having a benzo or pyrido
ring fused thereto: ##STR00096## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl]; (C.sub.1-C.sub.4)alkoxy
group such as allyloxy, methoxy, ethoxy, n-propoxy, n-butoxy or
tert-butoxy; C.sub.6-aryloxy group selected from phenoxy or
substituted phenoxy (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 group
such as benzyloxy, 1-phenylethyloxy or 2-phenylethyloxy; vinyloxy
or substituted vinyloxy group (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.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; and when
R=R.sup.4(CH.sub.2).sub.nCO-- and n=1-4, R.sup.4 is selected from
hydrogen; (C.sub.1-C.sub.2)alkyl group selected from methyl or
ethyl; 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); (C.sub.6-C.sub.10)aryl group selected from
phenyl, .alpha.-naphthyl or .beta.-naphthyl;
substituted(C.sub.6-C.sub.10)aryl group (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,
trichloroacetyl, (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 such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl,
4-(1-methylethyl)benzoyl or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00097## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00098## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00099## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one or two N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxy group such as
allyloxy, methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S;
.alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group selected from
hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoromethyl, 2-bromoethyl or 2-iodoethyl;
(C.sub.1-C.sub.4)alkoxycarbonylamino group selected from
tert-butoxycarbonylamino, allyloxycarbonylamino,
methoxycarbonylamino, ethoxycarbonylamino or propoxycarbonylamino;
and when R=R.sup.4'(CH.sub.2).sub.nSO.sub.2-- and n=0, R.sup.4' is
selected from amino; monosubstituted amino selected from as
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); straight or branched (C.sub.1-C.sub.2)alkyl
group selected from methyl or ethyl; (C.sub.6-C.sub.10)aryl group
selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
substituted (C.sub.6-C.sub.10)aryl group (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); a heterocycle group
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00100## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00101## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00102## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; and when
R=R.sup.4'(CH.sub.2).sub.nSO.sub.2-- and n=1-4, R.sup.4' is
selected from hydrogen; straight or branched (C.sub.1-C.sub.2)alkyl
group selected from methyl or ethyl; R.sup.5 is selected from
hydrogen; straight or branched (C.sub.1-C.sub.3)alkyl group
selected from 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 such as benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocycle group
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00103## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00104## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00105## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl, 2-dioxothiomorpholinyl;
or --(CH.sub.2).sub.nCOOR.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, .beta.-naphthyl; R.sup.6 is selected from
hydrogen; straight or branched (C.sub.1-C.sub.3)alkyl group
selected from 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 such as benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocycle group
selected from a five
membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00106## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00107## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00108## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl, 2-dioxothiomorpholinyl;
or (CH.sub.2).sub.nCOOR.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.2W(CH.sub.2).sub.2--, wherein W is selected from
(CH.sub.2).sub.n and n=0-1, --NH, --N(CH.sub.1-C.sub.3)alkyl
[straight or branched], --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.
Compounds of special interest are compounds according to the above
formula I and II in which X is selected from amino, NR.sub.1R.sub.2
or halogen; the halogen is selected from bromine, chlorine,
fluorine or iodine; and when X=NR.sup.1R.sup.2 and R.sup.1=methyl
or ethyl; R.sup.2=methyl or ethyl, R is selected from
R.sup.4(CH.sub.2).sub.nCO-- or R.sup.4' (CH.sub.2).sub.nSO.sub.2--;
and when R=R.sup.4(CH.sub.2).sub.nCO-- and n=0, R.sup.4 is selected
from hydrogen; straight or branched (C.sub.1-C.sub.2)alkyl group
selected from methyl or ethyl; a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, or S
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00109## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, or S
heteroatoms optionally having a benzo or pyrido ring fused thereto:
##STR00110## such as imidazolyl, pyrazolyl, benzimidazolyl,
oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,
3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a five
membered saturated ring with one or two N, O or S heteroatoms and
an adjacent appended O heteroatom: ##STR00111## (A is selected from
hydrogen; straight or branched (C.sub.1-C.sub.2)alkyl;
C.sub.6-aryl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone,
(C.sub.1-C.sub.4)alkoxycarbonyl group selected from
methoxycarbonyl, ethoxycarbonyl, straight or branched
propoxylcarbonyl, straight or branched butoxycarbonyl or
allyloxycarbonyl; vinyl or substituted vinyl group [substitution
selected from (C.sub.1-C.sub.2)alkyl group, (C.sub.6-C.sub.10)aryl
group selected from phenyl, .alpha.-naphthyl, .beta.-naphthyl,
substituted (C.sub.6-C.sub.10)aryl group (substitution selected
from halo, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxycarbonyl), halo(C.sub.1-C.sub.3)alkyl group
such as bromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl or
2-iodoethyl, (C.sub.1-C.sub.4)alkoxy group such as allyloxy,
methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(substitution selected from halo, (C.sub.1-C.sub.4)alkyl;
(C.sub.7-C.sub.10)aralkyloxy group such as benzyloxy,
1-phenylethyloxy or 2-phenylethyloxy; vinyloxy or substituted
vinyloxy group (substitution selected from (C.sub.1-C.sub.2)alkyl);
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.sup.b is a straight or branched (C.sub.1-C.sub.4)alkyl
selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl; or
R.sup.aR.sup.baminoxy group, wherein R.sup.aR.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; and when R=R.sup.4(CH.sub.2).sub.nCO-- and n=1-4,
R.sup.4 is selected from hydrogen; (C.sub.1-C.sub.2)alkyl group
selected from methyl or ethyl; 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, or 1-(1,2,3-triazolyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted(C.sub.6-C.sub.10)aryl group
(substitution selected from halo, (C.sub.1-C.sub.4)alkoxy, nitro,
amino, (C.sub.1-C.sub.4)alkoxycarbonyl); acyloxy or haloacyloxy
group selected from acetyl, propionyl or chloroacetyl;
(C.sub.1-C.sub.4)alkoxy group such as allyloxy, methoxy, ethoxy,
n-propoxy, n-butoxy or tert-butoxy;
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoromethyl, 2-bromoethyl or 2-iodoethyl;
(C.sub.1-C.sub.4) alkoxycarbonylamino group selected from
tert-butoxycarbonylamino, allyloxycarbonylamino,
methoxycarbonylamino, ethoxycarbonylamino or propoxycarbonylamino;
and when R=R.sup.4'(CH.sub.2).sub.nSO.sub.2-- and n=0, R.sup.4' is
selected from straight or branched (C.sub.1-C.sub.2)alkyl group
selected from methyl or ethyl; (C.sub.6-C.sub.10)aryl group
selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
substituted (C.sub.6-C.sub.10)aryl group (substitution selected
from halo, (C.sub.1-C.sub.4)alkoxy, nitro,
(C.sub.1-C.sub.4)alkoxycarbonyl); a heterocycle group selected from
a five membered aromatic or saturated ring with one N, O or S
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00112## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O or S
heteroatoms optionally having a benzo or pyrido ring fused thereto:
##STR00113## such as imidazolyl, pyrazolyl, benzimidazolyl,
oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,
3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl; and when
R=R.sup.4'(CH.sub.2).sub.nSO.sub.2-- and n=1-4, R.sup.4' is
selected from hydrogen; straight or branched (C.sub.1-C.sub.2)alkyl
group selected from methyl or ethyl; R.sup.5 is selected from
hydrogen; straight or branched (C.sub.1-C.sub.3)alkyl group
selected from methyl, ethyl, n-propyl or 1-methylethyl; R.sup.6 is
selected from hydrogen; straight or branched (C.sub.1-C.sub.3)alkyl
group selected from methyl, ethyl, n-propyl or 1-methylethyl; 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.2W(CH.sub.2).sub.2--, wherein W is selected from
(CH.sub.2).sub.n and n=0-1, --NH, --N(C.sub.1-C.sub.3)alkyl
[straight or branched], --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.
Also included in the present invention are compounds useful as
intermediates for producing the above compounds of formula I and
II. Such intermediate compounds include those having the formula:
##STR00114## wherein formula III and IV, Y is NO.sub.2; R is
selected from R.sup.4(CH.sub.2).sub.nCO-- or
R.sup.4'(CH.sub.2).sub.nSO.sub.2--; and when
R=R.sup.4(CH.sub.2).sub.nCO-- and n=0, R.sup.4 is selected from
hydrogen; 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); straight or branched (C.sub.1-C.sub.4)alkyl
group selected from methyl, ethyl, n-propyl, 1-methylethyl,
n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
(C.sub.3-C.sub.6)cycloalkyl group selected from cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl; substituted
(C.sub.3-C.sub.6)cycloalkyl group (substitution selected from
(C.sub.1-C.sub.3)alkyl, cyano, amino or (C.sub.1-C.sub.3)acyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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.9)aralkyl group selected from benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl;
.alpha.-amino(C.sub.1-C.sub.4)alkyl group selected from
aminomethyl, .alpha.-aminoethyl, .alpha.-aminopropyl or
.alpha.aminobutyl; carboxy(C.sub.2-C.sub.4)alkylamino group
selected from aminoacetic acid, .alpha.-aminobutyric acid or
.alpha.-aminopropionic acid and their optical isomers;
(C.sub.7-C.sub.9)aralkylamino group such as phenylglycyl;
(C.sub.1-C.sub.4)alkoxycarbonylamino substituted
(C.sub.1-C.sub.4)alkyl group, substitution selected from phenyl or
p-hydroxyphenyl; .alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group
selected from hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
.alpha.-mercapto(C.sub.1-C.sub.3)alkyl group selected from
mercaptomethyl, .alpha.-mercaptoethyl,
.alpha.-mercapto-1-methylethyl or .alpha.-mercaptopropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-bromoethyl or 2-iodoethyl; a heterocycle
group selected from a five membered aromatic or saturated ring with
one N, O, S or Se heteroatom optionally having a benzo or pyrido
ring fused thereto: ##STR00115## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00116## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00117## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4) alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl group selected from benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl) such as
.gamma.-butyrolactam, .gamma.-butyrolactone, imidazolidinone or
N-aminoimidazolidinone, or a six membered aromatic ring with one to
three N, O, S or Se heteroatoms such as pyridyl, pyridazinyl,
pyrazinyl, sym-triazinyl, unsym-triazinyl, pyrimidinyl or
(C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six membered saturated
ring with one or two N, O, S or Se heteroatoms and an adjacent
appended O heteroatom such as 2,3-dioxo-1-piperazinyl,
4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl- 2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; acyl or haloacyl group selected from
acetyl, propionyl, chloroacetyl, trifluoroacetyl,
(C.sub.3-C.sub.6)cycloalkylcarbonyl such as cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
(2,3-dimethylcyclopropyl)carbonyl,
(1,2-dimethylcyclopropyl)carbonyl, (2-ethylcyclopropyl)carbonyl,
(2-methylcyclopentyl)carbonyl or (3-ethylcyclobutyl)carbonyl,
(C.sub.6-C.sub.10)aroyl selected from benzoyl or naphthoyl, halo
substituted (C.sub.6-C.sub.10)aroyl such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00118## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00119## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00120## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonyl group
selected from methoxycarbonyl, ethoxycarbonyl, straight or branched
propoxylcarbonyl, straight or branched butoxycarbonyl or
allyloxycarbonyl; vinyl or substituted vinyl group [substitution
selected from (C.sub.1-C.sub.3)alkyl group, halogen,
(C.sub.6-C.sub.10)aryl group selected from phenyl,
.alpha.-naphthyl, .beta.-naphthyl, substituted
(C.sub.6-C.sub.10)aryl group (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), halo(C.sub.1-C.sub.3)alkyl
group such as bromomethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
2-bromoethyl or 2-iodoethyl, a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00121## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl];
(C.sub.1-C.sub.4)alkoxy group such as allyloxy, methoxy, ethoxy,
n-propoxy, n-butoxy or tert-butoxy; C.sub.6-aryloxy group selected
from phenoxy or substituted phenoxy (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 group
such as benzyloxy, 1-phenylethyloxy or 2-phenylethyloxy; vinyloxy
or substituted vinyloxy group (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.aR.sup.bamino(C.sub.1-C.sub.4)-alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; and when
R=R.sub.4(CH.sub.2).sub.nCO-- and n=1-4, R.sup.4 is selected from
hydrogen; amino; straight or branched (C.sub.1-C.sub.4)alkyl group
selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl,
1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
(C.sub.3-C.sub.6)cycloalkyl group selected from cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl; substituted
(C.sub.3-C.sub.6)cycloalkyl group (substitution selected from
(C.sub.1-C.sub.3)alkyl, cyano, amino or (C.sub.1-C.sub.3)acyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted(C.sub.6-C.sub.10)aryl group
(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
carboxyl); (C.sub.7-C.sub.9)aralkyl group such as benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl; acyloxy or
haloacyloxy group, selected from acetyl, propionyl, chloroacetyl,
trichloroacetyl, (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 such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl or
4-(1-methylethyl)benzoyl, (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00122## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00123## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00124## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxy group such as
allyloxy, methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(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 group such as benzyloxy,
1-phenylethyloxy or 2-phenylethyloxy; (C.sub.1-C.sub.3)alkylthio
group selected from methylthio, ethylthio, propylthio or allylthio;
C.sub.6-arylthio group selected from phenylthio or substituted
phenylthio (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 (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 such as benzylthio,
1-phenylethylthio or 2-phenylethylthio; a heterocycle group
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00125## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00126## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00127## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; hydroxy group; mercapto group; mono- or
di-straight or branched chain (C.sub.1-C.sub.6)alkylamino group
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 amino; (C.sub.2-C.sub.3)azacycloalkyl group
such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
morpholinyl or 2-methylpyrrolidinyl; carboxy(C.sub.2-C.sub.4)
alkylamino group selected from aminoacetic acid,
.alpha.-aminopropionic acid, .alpha.-aminobutyric acid and their
optical isomers; .alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group
selected from hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoromethyl, 2-bromoethyl or 2-iodoethyl; acyl or
haloacyl group 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 such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl, 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00128## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00129## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00130## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (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.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; or
R.sup.aR.sup.baminoxy group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; and when
R=R.sup.4'(CH.sub.2).sub.nSO.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-imidazolyl, 1-pyrrolyl, 1-(1,2,3-triazolyl) or
4-(1,2,4-triazolyl); straight or branched (C.sub.1-C.sub.4)alkyl
group selected from methyl, ethyl, n-propyl, 1-methylethyl,
n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
(C.sub.3-C.sub.6)cycloalkyl group selected from cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl; substituted
(C.sub.3-C.sub.6)cycloalkyl group (substitution selected from
(C.sub.1-C.sub.3)alkyl, cyano, amino or (C.sub.1-C.sub.3)acyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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.9)aralkyl group such as benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-chloroethyl, 2,2-dichloroethyl,
2,2,2-trichloroethyl, 2-bromoethyl or 2-iodoethyl; a heterocycle
group selected from a five membered aromatic or saturated ring with
one N, O, S or Se heteroatom optionally having a benzo or pyrido
ring fused thereto: ##STR00131## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00132## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00133## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy
group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; or
R.sup.aR.sup.baminoxy group, wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; and when
R=R.sup.4 (CH.sub.2).sub.nSO.sub.2-- and n=1-4, R.sup.4' is
selected from hydrogen; amino; straight or branched
(C.sub.1-C.sub.4)alkyl group selected from methyl, ethyl, n-propyl,
1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or
1,1-dimethylethyl; (C.sub.1-C.sub.4)carboxyalkyl group;
(C.sub.3-C.sub.6)cycloalkyl group selected from cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl; substituted
(C.sub.3-C.sub.6)cycloalkyl group (substitution selected from
(C.sub.1-C.sub.3)alkyl, cyano, amino or (C.sub.1-C.sub.3)acyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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.9)aralkyl group selected from benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl;
(C.sub.1-C.sub.4)alkoxy group such as allyloxy, methoxy, ethoxy,
n-propoxy or tert-butoxy; C.sub.6-aryloxy group selected from
phenoxy or substituted phenoxy (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 group
such as benzyloxy, 1-phenylethyloxy or 2phenylethyloxy;
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S;
(C.sub.1-C.sub.3)alkylthio group selected from methylthio,
ethylthio, or n-propylthio; C.sub.6-arylthio group selected from
phenylthio or substituted phenylthio (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 group
such as benzylthio, 1-phenylethylthio or 2-phenylethylthio; a
heterocycle group selected from a five membered aromatic or
saturated ring with one N, O, S or Se heteroatom optionally having
a benzo or pyrido ring fused thereto: ##STR00134## such as
pyrrolyl, N-methyl indolyl, indolyl, 2-pyrrolidinyl,
3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl,
benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00135## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00136## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl- 2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; hydroxy group, mercapto group; mono- or di-
straight or branched (C.sub.1-C.sub.6)alkylamino group 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 amino; halo(C.sub.1-C.sub.3)alkyl group such
as bromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl,
2,2-dichloroethyl, 2,2,2-trichloroethyl, 2-bromoethyl or
2-iodoethyl; acyl or haloacyl group 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 such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00137## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00138## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00139## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4) alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonyl group
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 group selected from 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 such as benzyl, 1-phenylethyl,
1-phenylethyl or phenylpropyl; a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00140## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00141## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00142## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl, 2-dioxothiomorpholinyl;
or --(CH.sub.2).sub.nCOOR.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, .beta.-naphthyl; R.sup.6 is selected from
hydrogen; straight or branched (C.sub.1-C.sub.3)alkyl group
selected from 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 such as benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocycle group
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00143## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00144## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00145## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-
2-dioxo-1-piperazinyl, 2-dioxomorpholinyl, 2-dioxothiomorpholinyl;
or --(CH.sub.2).sub.nCOOR.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.2W(CH.sub.2).sub.2--, wherein W is selected from
(CH.sub.2).sub.n and n=0-1, --NH, --N(C.sub.1-C.sub.3)alkyl
[straight or branched], --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.
Preferred compounds are compounds according to the above formula
III and IV in which Y is NO.sub.2; R is selected from
R.sub.4(CH.sub.2).sub.nCO-- or R.sup.4'(CH.sub.2).sub.nSO.sub.2--;
and when R=R.sup.4(CH.sub.2).sub.nCO-- and n=0, R.sup.4 is selected
from hydrogen; 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); straight or branched (C.sub.1-C.sub.3)alkyl
group selected from methyl, ethyl, n-propyl or 1-methylethyl;
(C.sub.3-C.sub.6)cycloalkyl group selected from cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl; substituted
(C.sub.3-C.sub.6)cycloalkyl group (substitution selected from
(C.sub.1-C.sub.3)alkyl, cyano, amino or (C.sub.1-C.sub.3)acyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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 group selected from
aminomethyl, .alpha.-aminoethyl, .beta.-aminopropyl or
.alpha.-aminobutyl; carboxy(C.sub.2-C.sub.4)alkylamino group
selected from aminoacetic acid, .alpha.-aminobutyric acid or
.alpha.-aminopropionic acid and their optical isomers;
(C.sub.7-C.sub.9)aralkylamino group such as phenylglycyl;
(C.sub.1-C.sub.4)alkoxycarbonylamino substituted
(C.sub.1-C.sub.4)alkyl group, substitution selected from phenyl or
p-hydroxyphenyl; .alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group
selected from hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-bromoethyl or 2-iodoethyl; a heterocycle
group selected from a five membered aromatic or saturated ring with
one N, O, S or Se heteroatom optionally having a benzo or pyrido
ring fused thereto: ##STR00146## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolidinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00147## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00148## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)-aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; acyl or haloacyl group selected from
acetyl, propionyl, chloroacetyl, trifluoroacetyl,
(C.sub.3-C.sub.6)cycloalkylcarbonyl such as cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
(2,3-dimethylcyclopropyl)carbonyl,
(1,2-dimethylcyclopropyl)carbonyl, (2-ethylcyclopropyl)carbonyl,
(2-methylcyclopentyl)carbonyl or (3-ethylcyclobutyl)carbonyl,
(C.sub.6-C.sub.10)aroyl selected from benzoyl or naphthoyl, halo
substituted (C.sub.6-C.sub.10)aroyl such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-methyltoluoyl or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00149## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00150## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00151## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl, or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonyl group
selected from methoxycarbonyl, ethoxycarbonyl, straight or branched
propoxylcarbonyl, straight or branched butoxycarbonyl or
allyloxycarbonyl; vinyl or substituted vinyl group [substitution
selected from (C.sub.1-C.sub.3)alkyl group, halogen,
(C.sub.6-C.sub.10)aryl group selected from phenyl,
.alpha.-naphthyl, .beta.-naphthyl, substituted
(C.sub.6-C.sub.10)aryl group (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), halo(C.sub.1-C.sub.3)alkyl
group such as bromomethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
2-bromoethyl or 2-iodoethyl, a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00152## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl]; (C.sub.1-C.sub.4)alkoxy group such as allyloxy,
methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(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 group such as benzyloxy,
1-phenylethyloxy or 2-phenylethyloxy; vinyloxy or substituted
vinyloxy group (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.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein 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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; and when
R.dbd.R.sup.4(CH.sub.2).sub.nCO-- and n=1-4, R.sup.4 is selected
from hydrogen; (C.sub.1-C.sub.3)alkyl group selected from methyl,
ethyl, n-propyl or 1-methylethyl; 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); (C.sub.6-C.sub.10)aryl group selected from
phenyl, .alpha.-naphthyl or .beta.-naphthyl; substituted
(C.sub.6-C.sub.10)aryl group (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,
trichloroacetyl, (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 such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl,
4-(1-methylethyl)benzoyl or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom opionally having a benzo or pyrido ring
fused thereto: ##STR00153## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00154## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00155## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxy group such as
allyloxy, methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein 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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W--(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; C.sub.6-aryloxy group selected
from phenoxy or substituted phenoxy (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.1-C.sub.3)alkylthio group
selected from methylthio, ethylthio, propylthio or allylthio;
C.sub.6-arylthio group selected from phenylthio or substituted
phenylthio (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 (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); a heterocycle group selected from a five membered
aromatic or saturated ring with one N, O, S or Se heteroatom
optionally having a benzo or pyrido ring fused thereto:
##STR00156## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00157## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00158## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)-aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; hydroxy group;
.alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group selected from
hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoromethyl, 2-bromoethyl or 2-iodoethyl; acyl or
haloacyl group 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 such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl, or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00159## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00160## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00161## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonylamino group
selected from tert-butoxycarbonylamino, allyloxycarbonylamino,
methoxycarbonylamino, ethoxycarbonylamino or propoxycarbonylamino;
and when R.dbd.R.sup.4' (CH.sub.2).sub.2SO.sub.2-- and n=0,
R.sup.4' is selected from amino; monosubstituted amino selected
from as 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); straight or branched (C.sub.1-C.sub.3)alkyl
group selected from methyl, ethyl, n-propyl or 1-methylethyl;
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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); a heterocycle group selected from a five membered
aromatic or saturated ring with one N, O, S or Se heteroatom
optionally having a benzo or pyrido ring fused thereto:
##STR00162## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00163## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00164## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; and when
R.dbd.R.sup.4'(CH.sub.2).sub.nSO.sub.2-- and n=1-4, R.sup.4' is
selected from hydrogen; 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); straight or branched (C.sub.1-C.sub.3)alkyl
group selected from methyl, ethyl, n-propyl or 1-methylethyl;
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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 such as allyloxy, methoxy,
ethoxy, n-propoxy, n-butoxy, iso-butoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(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 group such as benzyloxy,
1-phenylethyloxy or 2-phenylethyloxy; (C.sub.1-C.sub.4)carboxyalkyl
group; R.sup.5 is selected from hydrogen; straight or branched
(C.sub.1-C.sub.3)alkyl group selected from 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 such as benzyl, 1-phenylethyl,
2-phenylethyl or phenylpropyl; a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00165## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00166## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00167## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,
2-dioxothiomorpholinyl; or --(CH.sub.2).sub.nCOOR.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 from 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 such as benzyl, 1-phenylethyl,
2-phenylethyl or phenylpropyl; a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00168## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00169## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00170## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,
2-dioxothiomorpholinyl; or (CH.sub.2).sub.nCOOR.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.2W(CH.sub.2).sub.2--, wherein W is
selected from (CH.sub.2).sub.n and n=0-1, --NH,
--N(C.sub.1-C.sub.3)alkyl [straight or branched],
--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.
Particularly preferred compounds are compounds according to the
above formula III and IV in which Y is NO.sub.2;
R is selected from R.sup.4(C.sub.2).sub.nCO-- or
R.sub.4'(CH.sub.2).sub.nSO.sub.2--; and when
R.dbd.R.sup.4(CH.sub.2).sub.nCO-- and n=0, R.sup.4 is selected from
hydrogen; 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); straight or branched (C.sub.1-C.sub.3)alkyl
group selected from methyl, ethyl, n-propyl or 1-methylethyl;
(C.sub.3-C.sub.6)cycloalkyl group selected from cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl; substituted
(C.sub.3-C.sub.6)cycloalkyl group (substitution selected from
(C.sub.1-C.sub.3)alkyl, cyano, amino or (C.sub.1-C.sub.3)acyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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 group selected from
aminomethyl, .alpha.-aminoethyl, .alpha.-aminopropyl or
.alpha.-aminobutyl; carboxy(C.sub.2-C.sub.4)alkylamino group
selected from aminoacetic acid, .alpha.-aminobutyric acid or
.alpha.-aminopropionic acid and their optical isomers;
(C.sub.7-C.sub.9)aralkylamino group such as phenylglycyl;
(C.sub.1-C.sub.4)alkoxycarbonylamino substituted
(C.sub.1-C.sub.4)alkyl group, substitution selected from phenyl or
p-hydroxyphenyl; .alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group
selected from hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-bromoethyl or 2-iodoethyl; a heterocycle
group selected from a five membered aromatic or saturated ring with
one N, O, S or Se heteroatom optionally having a benzo or pyrido
ring fused thereto: ##STR00171## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00172## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00173## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)-aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; acyl or haloacyl group selected from
acetyl, propionyl, chloroacetyl, trifluoroacetyl,
(C.sub.3-C.sub.6)cycloalkylcarbonyl such as cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
(2,3-dimethylcyclopropyl)carbonyl,
(1,2-dimethylcyclopropyl)carbonyl, (2-ethylcyclopropyl)carbonyl,
(2-methylcyclopentyl)carbonyl or (3-ethylcyclobutyl)carbonyl,
(C.sub.6-C.sub.10)aroyl selected from benzoyl or naphthoyl, halo
substituted (C.sub.6-C.sub.10)aroyl such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-methylbenzoyl or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00174## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00175## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00176## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonyl group
selected from methoxycarbonyl, ethoxycarbonyl, straight or branched
propoxylcarbonyl, straight or branched butoxycarbonyl or
allyloxycarbonyl; vinyl or substituted vinyl group [substitution
selected from (C.sub.1-C.sub.3)alkyl group, halogen,
(C.sub.6-C.sub.10)aryl group selected from phenyl,
.alpha.-naphthyl, .beta.-naphthyl, substituted
(C.sub.6-C.sub.10)aryl group (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)alkyl amino or carboxy),
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-bromoethyl or 2-iodoethyl, a heterocycle
group selected from a five membered aromatic or saturated ring with
one N, O, S or Se heteroatom optionally having a benzo or pyrido
ring fused thereto: ##STR00177## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl];
(C.sub.1-C.sub.4)alkoxy group such as allyloxy, methoxy, ethoxy,
n-propoxy,n-butoxy or tert-butoxy; C.sub.6-aryloxy group selected
from phenoxy or substituted phenoxy (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 group
such as benzyloxy, 1-phenylethyloxy or 2-phenylethyloxy; vinyloxy
or substituted vinyloxy group (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.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; and when
R.dbd.R.sup.4(CH.sub.2).sub.nCO-- and n=1-4, R.sup.4 is selected
from hydrogen; (C.sub.1-C.sub.3)alkyl group selected from methyl,
ethyl, n-propyl or 1-methylethyl; 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); (C.sub.6-C.sub.10)aryl group selected from
phenyl, .alpha.-naphthyl or .beta.-naphthyl; substituted
(C.sub.6-C.sub.10) aryl group (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,
trichloroacetyl, (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 such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl,
4-(1-methylethyl)benzoyl or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00178## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00179## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00180## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxy group such as
allyloxy, methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(substitution selected from halo, (C.sub.1-C.sub.4)alkyl, nitro,
cyano, thiol, amino, carboxy, di(C.sub.1-C.sub.3)alkylamino);
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein 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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; (C.sub.1-C.sub.3)alkylthio group
selected from methylthio, ethylthio, propylthio or allylthio;
C.sub.6-arylthio group selected from phenylthio or substituted
phenylthio (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 (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); a heterocycle group selected from a five membered
aromatic or saturated ring one N, O, S or Se heteroatom optionally
having a benzo or pyrido ring fused thereto: ##STR00181## such as
pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl,
tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, or a five
membered aromatic ring with two N, O, S or Se heteroatoms
optionally having a benzo or pyrido ring fused thereto:
##STR00182## such as imidazolyl, pyrazolyl, benzimidazolyl,
oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,
3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a five
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom: ##STR00183## (A is selected
from hydrogen; straight or branched (C.sub.1-C.sub.4)alkyl;
C.sub.6-aryl; substituted C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; hydroxy group;
.alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group selected from
hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoromethyl, 2-bromoethyl or 2-iodoethyl; acyl or
haloacyl group 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 such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromophenylcarbonyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as from 4-toluoyl, 2-toluoyl or
4-(1-methylethyl)benzoyl, or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00184## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a
benzo-or pyrido ring fused thereto: ##STR00185## such as
imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl,
indazolyl, thiazolyl, benzothiazolyl,
3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a five
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom: ##STR00186## (A is selected
from hydrogen; straight or branched (C.sub.1-C.sub.4)alkyl;
C.sub.6-aryl; substituted C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonylamino group
selected from tert-butoxycarbonylamino, allyloxycarbonylamino,
methoxycarbonylamino, ethoxycarbonylamino or
propoxycarbonylamino;
and when R.dbd.R.sup.4' (CH.sub.2).sub.nSO.sub.2-- and n=0,
R.sup.4' is selected from amino; monosubstituted amino selected
from as 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); straight or branched (C.sub.1-C.sub.3)alkyl
group selected from methyl, ethyl, n-propyl or 1-methylethyl;
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted (C.sub.6-C.sub.10)aryl group
(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); a heterocycle group selected from a five membered
aromatic or saturated ring with one N, O, S or Se heteroatom
optionally having a benzo or pyrido ring fused thereto:
##STR00187## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00188## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00189## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; and when
R.dbd.R.sub.4'(CH.sub.2).sub.nSO.sub.2-- and n=1-4, R.sup.4' is
selected from hydrogen; 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); straight or branched (C.sub.1-C.sub.3)alkyl
group selected from methyl, ethyl, n-propyl or 1-methylethyl;
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W-(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W--(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; R.sup.5
is selected from hydrogen; straight or branched
(C.sub.1-C.sub.3)alkyl group selected from 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 such as benzyl, 1-phenylethyl,
2-phenylethyl or phenylpropyl; a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00190## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00191## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00192## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,
2-dioxothiomorpholinyl; or --(CH.sub.2).sub.nCOOR.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 from 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 such as benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocycle group
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00193## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00194## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00195## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,
2-dioxothiomorpholinyl; or (CH.sub.2).sub.nCOOR.sup.7' where n=0-4
and R.sup.7' 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.2W(CH.sub.2).sub.2--, wherein W is
selected from (CH.sub.2).sub.n and n=0-1, --NH,
--N(C.sub.1-C.sub.3)alkyl [straight or branched],
--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.
Most particularly preferred compounds are compounds according to
the above formula III and IV in which Y is NO.sub.2;
R is selected from R.sup.4(CH.sub.2).sub.nCO-- or
R.sup.4'(CH.sub.2).sub.nSO.sub.2--; and when
R.dbd.R.sup.4(CH.sub.2).sub.nCO-- and n=0, R.sup.4 is selected from
hydrogen; 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-pyrrollyl, 1-(1,2,3-triazolyl) or
4-(1,2,4-triazolyl); straight or branched (C.sub.1-C.sub.2)alkyl
group selected from methyl or ethyl; (C.sub.6-C.sub.10)aryl group
selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
substituted (C.sub.6-C.sub.10)aryl group (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);
carboxy(C.sub.2-C.sub.4)alkylamino group selected from aminoacetic
acid, .alpha.-aminobutyric acid or .alpha.-aminopropionic acid and
their optical isomers; .alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group
selected from hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, 2-bromoethyl or 2-iodoethyl; a heterocycle
group selected from a five membered aromatic or saturated ring with
one N, O, S or Se heteroatom optionally having a benzo or pyrido
ring fused thereto: ##STR00196## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00197## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00198## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxycarbonyl group
selected from methoxycarbonyl, ethoxycarbonyl, straight or branched
propoxylcarbonyl, straight or branched butoxycarbonyl or
allyloxycarbonyl; vinyl or substituted vinyl group [substitution
selected from (C.sub.1-C.sub.3)alkyl group, halogen,
(C.sub.6-C.sub.10)aryl group selected from phenyl,
.alpha.-naphthyl, .beta.-naphthyl, substituted
(C.sub.6-C.sub.10)aryl group (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), halo(C.sub.1-C.sub.3)alkyl
group such as bromomethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,
2-bromoethyl or 2-iodoethyl, a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00199## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl]; (C.sub.1-C.sub.4)alkoxy group such as allyloxy,
methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(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 group such as benzyloxy,
1-phenylethyloxy or 2-phenylethyloxy; vinyloxy or substituted
vinyloxy group (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.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W--(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S; and when
R.dbd.R.sup.4(CH.sub.2).sub.nCO-- and n=1-4, R.sup.4 is selected
from hydrogen; (C.sub.1-C.sub.2)alkyl group selected from methyl or
ethyl; 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); (C.sub.6-C.sub.10)aryl group selected from
phenyl, .alpha.-naphthyl or .beta.-naphthyl; substituted
(C.sub.6-C.sub.10)aryl group (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,
trichloroacetyl, (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 such as pentafluorobenzoyl,
4-chlorobenzoyl, 3-bromobenzoyl or 3,4-difluorobenzoyl,
(C.sub.1-C.sub.4)alkylbenzoyl such as 4-toluoyl, 2-toluoyl,
4-(1-methylethyl)benzoyl or (heterocycle)carbonyl, the heterocycle
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00200## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00201## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended heteroatom:
##STR00202## (A is selected from hydrogen; straight or branched
(C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted C.sub.6-aryl
(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.9)aralkyl group selected from benzyl,
1-phenylethyl, 2-phenylethyl or phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; (C.sub.1-C.sub.4)alkoxy group such as
allyloxy, methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S;
.alpha.-hydroxy(C.sub.1-C.sub.3)alkyl group selected from
hydroxymethyl, .alpha.-hydroxyethyl or
.alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoromethyl, 2-bromoethyl or 2-iodoethyl;
(C.sub.1-C.sub.4)alkoxycarbonylamino group selected from
tert-butoxycarbonylamino, allyloxycarbonylamino,
methoxycarbonylamino, ethoxycarbonylamino or
propoxycarbonylamino;
and when R.dbd.R.sup.4'(CH.sub.2).sub.nSO.sub.2-- and n=0, R.sup.4'
is selected from amino; monosubstituted amino selected from as
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); straight or branched (C.sub.1-C.sub.2)alkyl
group selected from methyl or ethyl; (C.sub.6-C.sub.10)aryl group
selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
substituted (C.sub.6-C.sub.10)aryl group (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); a heterocycle group
selected from a five membered aromatic or saturated ring with one
N, O, S or Se heteroatom optionally having a benzo or pyrido ring
fused thereto: ##STR00203## such as pyrrolyl, N-methylindolyl,
indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,
tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl,
thienyl, benzothienyl or selenazolyl, or a five membered aromatic
ring with two N, O, S or Se heteroatoms optionally having a benzo
or pyrido ring fused thereto: ##STR00204## such as imidazolyl,
pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl,
thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00205## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl) such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl or
2-dioxothiomorpholinyl; and when R.dbd.R.sup.4'
(CH.sub.2).sub.nSO.sub.2-- and n=1-4, R.sup.4' is selected from
hydrogen; straight or branched (C.sub.1-C.sub.2)alkyl group
selected from methyl or ethyl; R.sup.5 is selected from hydrogen;
straight or branched (C.sub.1-C.sub.3)alkyl group selected from
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 such as benzyl, 1-phenylethyl,
2-phenylethyl or phenylpropyl; a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00206## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00207## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00208## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,
2-dioxothiomorpholinyl; or --(CH.sub.2).sub.nCOOR.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, .beta.-naphthyl;
R.sup.6 is selected from hydrogen; straight or branched
(C.sub.1-C.sub.3)alkyl group selected from 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 such as benzyl, 1-phenylethyl,
2-phenylethyl or phenylpropyl; a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, S or Se
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00209## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, S or
Se heteroatoms optionally having a benzo or pyrido ring fused
thereto: ##STR00210## such as imidazolyl, pyrazolyl,
benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl,
benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or
pyridylimidazolyl, or a five membered saturated ring with one or
two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom: ##STR00211## (A is selected from hydrogen; straight or
branched (C.sub.1-C.sub.4)alkyl; C.sub.6-aryl; substituted
C.sub.6-aryl (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.9)aralkyl
group selected from benzyl, 1-phenylethyl, 2-phenylethyl or
phenylpropyl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone, or a six membered
aromatic ring with one to three N, O, S or Se heteroatoms such as
pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl,
pyrimidinyl or (C.sub.1-C.sub.3)alkylthiopyridazinyl, or a six
membered saturated ring with one or two N, O, S or Se heteroatoms
and an adjacent appended O heteroatom such as
2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,
4-methyl-2,3-dioxo-1-piperazinyl,
4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,
2-dioxothiomorpholinyl; or (CH.sub.2).sub.nCOOR.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.2W(CH.sub.2).sub.2--, wherein W is
selected from (CH.sub.2).sub.n and n=0-1, --NH,
--N(C.sub.1-C.sub.3)alkyl [straight or branched],
--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.
Compounds of special interest are compounds according to the above
formula III and IV in which Y is NO.sub.2;
R is selected from R.sup.4(CH.sub.2).sub.nCO-- or
R.sup.4'(CH.sub.2).sub.nSO.sub.2--; and when
R.dbd.R.sup.4(CH.sub.2).sub.nCO-- and n=0, R.sup.4 is selected from
hydrogen; straight or branched (C.sub.1-C.sub.2)alkyl group
selected from methyl or ethyl; a heterocycle group selected from a
five membered aromatic or saturated ring with one N, O, or S
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00212## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O, or S
heteroatoms optionally having a benzo or pyrido ring fused thereto:
##STR00213## such as imidazolyl, pyrazolyl, benzimidazolyl,
oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,
3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a five
membered saturated ring with one or two N, O or S heteroatoms and
an adjacent appended O heteroatom: ##STR00214## (A is selected from
hydrogen; straight or branched (C.sub.1-C.sub.2)alkyl;
C.sub.6-aryl)
such as .gamma.-butyrolactam, .gamma.-butyrolactone,
imidazolidinone or N-aminoimidazolidinone;
(C.sub.1-C.sub.4)alkoxycarbonyl group selected from
methoxycarbonyl, ethoxycarbonyl, straight or branched
propoxylcarbonyl, straight or branched butoxycarbonyl or
allyloxycarbonyl; vinyl or substituted vinyl group [substitution
selected from (C.sub.1-C.sub.2)alkyl group, (C.sub.6-C.sub.10)aryl
group selected from phenyl, .alpha.-naphthyl, .beta.-naphthyl,
substituted (C.sub.6-C.sub.10)aryl group (substitution selected
from halo, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxycarbonyl), halo(C.sub.1-C.sub.3)alkyl group
such as bromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl or
2-iodoethyl, (C.sub.1-C.sub.4)alkoxy group such as allyloxy,
methoxy, ethoxy, n-propoxy, n-butoxy or tert-butoxy;
C.sub.6-aryloxy group selected from phenoxy or substituted phenoxy
(substitution selected from halo, (C.sub.1-C.sub.4)alkyl);
(C.sub.7-C.sub.10)aralkyloxy group such as benzyloxy,
1-phenylethyloxy or 2-phenylethyloxy; vinyloxy or substituted
vinyloxy group (substitution selected from (C.sub.1-C.sub.2)alkyl);
R.sup.aR.sup.bamino (C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.sup.b is a straight or branched (C.sub.1-C.sub.4)alkyl
selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl; or
R.sup.aR.sup.baminoxy group, wherein R.sup.aR.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; and when R.dbd.R.sup.4(CH.sub.2).sub.nCO-- and
n=1-4, R.sup.4 is selected from hydrogen; (C.sub.1-C.sub.2)alkyl
group selected from methyl or ethyl; 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, or 1-(1,2,3-triazolyl);
(C.sub.6-C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl
or .beta.-naphthyl; substituted(C.sub.6-C.sub.10)aryl group
(substitution selected from halo, (C.sub.1-C.sub.4)alkoxy, nitro,
amino, (C.sub.1-C.sub.4)alkoxycarbonyl); acyloxy or haloacyloxy
group selected from acetyl, propionyl or chloroacetyl;
(C.sub.1-C.sub.4)alkoxy group such as allyloxy, methoxy, ethoxy,
n-propoxy, n-butoxy or tert-butoxy;
R.sup.aR.sup.bamino(C.sub.1-C.sub.4)alkoxy group, wherein
R.sup.aR.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.aR.sup.b is
(CH.sub.2).sub.n, n=2-6, or --(CH.sub.2).sub.2W(CH.sub.2).sub.2--
wherein W is selected from --N(C.sub.1-C.sub.3)alkyl [straight or
branched], --NH, --NOB [B is selected from hydrogen or
(C.sub.1-C.sub.3)alkyl], O or S; or R.sup.aR.sup.baminoxy group,
wherein R.sup.aR.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.aR.sup.b is (CH.sub.2).sub.n, n=2-6, or
--(CH.sub.2).sub.2W--(CH.sub.2).sub.2-- wherein W is selected from
--N(C.sub.1-C.sub.3)alkyl [straight or branched], --NH, --NOB [B is
selected from hydrogen or (C.sub.1-C.sub.3)alkyl], O or S;
halo(C.sub.1-C.sub.3)alkyl group such as bromomethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoromethyl, 2-bromoethyl or 2-iodoethyl;
(C.sub.1-C.sub.4)alkoxycarbonylamino group selected from
tert-butoxycarbonylamino, allyloxycarbonylamino,
methoxycarbonylamino, ethoxycarbonylamino or
propoxycarbonylamino;
and when R.dbd.R.sup.4'(CH.sub.2).sub.nSO.sub.2-- and n=0, R.sup.4'
is selected from straight or branched (C.sub.1-C.sub.2)alkyl group
selected from methyl or ethyl; (C.sub.6-C.sub.10)aryl group
selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
subsituted (C.sub.6-C.sub.10)aryl group (substitution selected from
halo, (C.sub.1-C.sub.4)alkoxy, nitro,
(C.sub.1-C.sub.4)alkoxycarbonyl); a heterocycle group selected from
a five membered aromatic or saturated ring with one N, O or S
heteroatom optionally having a benzo or pyrido ring fused thereto:
##STR00215## such as pyrrolyl, N-methylindolyl, indolyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,
furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or
selenazolyl, or a five membered aromatic ring with two N, O or S
heteroatoms optionally having a benzo or pyrido ring fused thereto:
##STR00216## such as imidazolyl, pyrazolyl, benzimidazolyl,
oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,
3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl; and when
R.dbd.R.sup.4'(CH.sub.2).sub.nSO.sub.2-- and n=1-4, R.sup.4' is
selected from hydrogen; straight or branched (C.sub.1-C.sub.2)alkyl
group selected from methyl or ethyl; R.sup.5 is selected from
hydrogen; straight or branched (C.sub.1-C.sub.3)alkyl group
selected from methyl, ethyl, n-propyl or 1-methylethyl;
R.sup.6 is selected from hydrogen; straight or branched
(C.sub.1-C.sub.3)alkyl group selected from methyl, ethyl, n-propyl
or 1-methylethyl; 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.2W(CH.sub.2).sub.2--, wherein W is selected from
(CH.sub.2).sub.n and n=0-1, --NH, --N(C.sub.1-C.sub.3)alkyl
[straight or branched], --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.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The novel compounds of the present invention may be readily
prepared in accordance with the following schemes.
The starting 7-(substituted amino)-6-demethyl-6-deoxytetracyclines
described in formula 1, wherein X.dbd.NR.sup.1R.sup.2 and
R.sup.1.dbd.R.sup.2 (1a) and X=NHR.sup.1 (1b) or the salts thereof
are prepared by procedures known to those skilled in the art
including those described in U.S. Pat. Nos. 3,226,436 and
3,518,306. ##STR00217##
The starting 7-(substituted amino)-6-demethyl-6-deoxytetracyclines
described in formula 1 wherein X.dbd.NR.sup.1R.sup.2 and
R.sup.1.dbd.R.sup.2 (1c) are prepared according to Scheme 1.
##STR00218## In accordance with Scheme 1, a
7-(monoalkylamino)-6-demethyl-6-deoxytetracycline, 1b, in which
X.dbd.NHR.sup.1 is reductively alkylated with an aldehyde to give
an unsymmetrical dialkylamino, 1c. ##STR00219##
In accordance with Scheme II, a 7-(substituted
amino)-6-demethyl-6-deoxytetracycline or its salts, 1a or 1c, is
treated with
a) a metal nitrate salt; such as calcium, potassium or sodium; and
a strong acid; such as sulfuric acid, trifluoroacetic acid,
methanesulfonic acid or perchloric acid or
b) nitric acid and a strong acid; such as sulfuric acid,
trifluoroacetic acid, methanesulfonic acid or perchloric acid; to
form the corresponding 7-(substituted
amino)-9-nitro-6-demethyl-6-deoxytetracycline 2.
To produce the 9-(amino)-7-(substituted
amino)-6-demethyl-6-deoxytetracyclines, 3, compound 2 or its salts
is treated with hydrogen in an acidic alcohol solvent, in the
presence of a suitable catalyst such as, for example:
a) any supported catalyst; such as 0.5-23% palladium-on-carbon,
0.5-25% palladium-on-barium, 0.5-25% platinum-on-carbon or 0.5-25%
rhodium-on-carbon;
b) any reducible supported catalyst; such as Raney nickle or
platinum oxide; or
c) a homogeneous hydrogenation catalyst; such as
tris(triphenylphosphine)rhodium (I) chloride; to obtain the
9-amino-7-(substituted amino)-6-demethyl-6-deoxytetracycline,
3.
Alternatively, the 9-(amino)-7-(substituted
amino)-6-demethyl-6-deoxytetracyclines, 3, are obtained by treating
with:
a) stannous chloride dihydrate as described by R. B. Woodward, Org.
Syn., Coll. Vol. 3,453 (1955);
b) a soluble metal sulfide, preferably sodium sulfide, in alcoholic
solvents as described by G. R. Robertson, Org. Syn., Coll. Vol. 1,
52 (1941);
c) an active metal in mineral acid; such as iron, tin or zinc in
dilute hydrochloric acid;
d) active metal couples; such as copper-zinc, tin-mercury or
aluminum amalgam in dilute acid; or
e) transfer hydrogenation using triethylammonium formate and a
supported catalyst as described by I. D. Entwistle et al., J. Chem.
Soc., Perkin 1, 443 (1977).
Preferably, the 9-(amino)-7-(substituted
amino)-6-demethyl-6-deoxytetracyclines, 3, are obtained as
inorganic salts such as hydrochloric, hydrobromic, hydroiodic,
phosphoric, nitric or sulfate. ##STR00220##
SCHEME III
In accordance with Scheme III, a 9-(amino)-7-(substituted
amino)-6-demethyl-6-deoxytetracycline or its salts, 3, is treated
with an acyl chloride, acyl anhydride, mixed acyl anhydride,
sulfonyl chloride or sulfonyl anhydride in the presence of a
suitable acid scavenger in a variety of solvents to form the
corresponding 9-(acyl or sulfonyl amino)-7-(substituted
amino)-6-demethyl-6-deoxytetracycline, 4. The acid scavenger is
selected from sodium bicarbonate, sodium acetate, pyridine,
triethylamine, N,O-bis(trimethylsilyl)acetamide,
N,O-bis(trimethylsilyl)trifluoroacetamide or a basic ion-exchange
resin. The solvents are selected from water-tetrahydrofuran,
N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidione,
hexamethylphosphoramide, 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone or 1,2-dimethoxyethane.
Alternatively, in accordance with Scheme III, a
9-acylamino)-6-demethyl-6-deoxytetracycline, 5a, prepared by the
procedures described in U.S. Pat. No. 3,239,499, or a
9-(sulfonylamino)-6-demethyl-6-deoxytetracycline, 5b, prepared by
the procedures described in this invention, is treated with a
halogenation agent such as bromine, N-bromoacetamide,
N-bromosuccinimide, iodine monochloride, benzyltrimethylammonium
chloride iodine monochloride complex or N-iodosuccinimide to give
the corresponding 9-(acyl or
sulfonylamino)-7-halo-6-demethyl-6-deoxytetracycline, 6.
Similarly, compound 5a or 5b can be treated with: a) a metal
nitrate such as calcium, potassium or sodium; and a strong acid
such as sulfuric, trifluoroacetic, methanesulfonic acid or
trifluoromethanesulfonic; or b) nitric acid and a strong acid such
as sulfuric, trifluoroacetic, methanesulfonic,
trifluoromethanesulfonic or perchloric acid to give the
corresponding 9-(acyl or sulfonyl
amino)-7-nitro-6-demethyl-6-deoxytetracycline, 7. ##STR00221##
In accordance with Scheme IV, a 9-(acyl or sulfonyl
amino)-7-nitro-6-demethyl-6-deoxytetracycline, 7, is selectively
N-alkylated with aldehydes or ketones in the presence of acid and
hydrogen to the corresponding 7,9-di(substituted amino)-6-demethyl-
6-deoxytetracycline, 8, by methodology known to those skilled in
the art (U.S. Pat. Nos. 3,226,436 and 3,518,306). ##STR00222##
In accordance with Scheme V, Compounds 4,6,7, or 8 are selectively
N-alkylated in the presence of formaldehyde and either a primary
amine such as methylamine, ethylamine, benzylamine, methyl
glycinate, (L or D)lysine, (L or D)alanine or their substituted
congeners; or a secondary amine such morpholine, pyrrolidine,
piperidine or their substituted congeners to give the corresponding
Mannich base adduct, 9,10,11 or 12, or the desired intermediate or
of the biologically active 7-(substituted)-9-(substituted
amino)-6-demethyl- 6-deoxytetracyclines. Contempleted equivalents
include those substituted morpholine, pyrrolidine or piperidine
moieties wherein the substituents are chosen to provide the
requisite increase in solubility without adversely affecting
antibacterial activity.
The 7-(substituted)-9-(substituted
amino)-6-demethyl-6-deoxytetracyclines may be obtained as metal
complexes such as aluminum, calcium, iron, magnesium, mamganese and
complex salts; inorganic and organic salts and corresponding
Mannich base adducts using methods known to those skilled in the
art (Richard C. Larock, Comprehensive Organic Transformations, VCH
Publishers, 411-415, 1989). Preferably, the 7-(substituted)-
9-(substituted amino)-6-demethyl-6-deoxytetracyclines are obtained
as inorganic salts such as hydrochloric, hydrobromic, hydroiodic,
phosphoric, nitric or sulfate; or organic salts such as acetate,
benzoate, citrate, cysteine or other amino acids, fumarate,
glycolate, maleate, succinate, tartrate alkylsulfonate or
aryl-sulfonate. In all cases, the salt formation occurs with the
C(4)-dimethylamino group. The salts are preferred for oral and
parenteral administration.
BIOLOGICAL ACTIVITY
Methods for in Vitro antibacterial evaluation (Tables I-V)
The minimum inhibitory concentration (MIC), the lowest
concentration of the antibiotic which inhibits growth of the test
organism, is determined by the agar dilution method using 0.1 ml
Muller-Hinton II agar (Baltimore Biological Laboratories) per well.
An inoculum level of 1-5.times.10.sup.5 CFU/ml, and a range of
anitbiotic concentrations (32-0,004 .mu.g/ml) is used. MIC is
determined after the plates are incubated for 18 hours at
35.degree. C. in a forced air incubator. The test organisms
comprise genetically defined strains that are sensitive to
tetracycline and resistant strains that are insensitive to
tetracycline, either by preventing the antibiotic from interacting
with bacterial ribosomes (tetM) or by a tetK encoded membrane
protein which confers tetracycline resistance by energy-dependent
efflux of the antibiotic from the cell. E. coli in Vitro Protein
translation System (Table VI)
An in vitro, cell free, protein translation system using extracts
from E. coli strain MRE 600 (tetracycline-sensitive) and a
derivative of MRE 600 containing the tetM determinant has been
developed based on literature methods. [J. M. Pratt, Coupled
TranScription-translation in Prokaryotic Cell-free Systems,
Transcription and Translation, a Practical Approach, (B. D. Hames
and S. J, Higgins, eds.) p. 179-209, IRL Press, Oxford-Washington,
1984]
The antibiotics are added to exponentially growing cultures of
tetracycline-susceptible E. coli at growth inhibitory
concentrations. After 30 minutes, excess antibiotic is removed from
the bacteria by centrifugation and the organism is resuspended in
fresh growth medium. The ability of bacteria to resume growth is
monitored. Washing of inhibited cells alleviates growth inhibition
due to chlortetracycline, but not that caused by polymyxin. This
reflects the different binding characteristics of the drugs.
Chlortetracycline binds reversibly to bacterial ribosomes, while
polymyxin remains tightly associated with its target, the
cytoplasmic membrane, and continues to prevent bacterial growth
even when excess antibiotic is removed.
In Vivo Antibacterial Evaluation (Table VII)
The therapeutic effects of tetracyclines are determined against
acute lethal infections with various staphylococcal and E. coli
strains. Female mice, strain CD-1 (Charles River Laboratories),
20.+-.2 grams, are challenged by an intraperitoneal injection of
sufficient bacteria (suspended in broth or hog mucin) to kill
non-treated controls within 24-48 hours. Antibacterial agents,
contained in 0.5 ml of 0.2% aqueous agar, are administered
subcutaneously or orally 30 minutes after infection. When an oral
dosing schedule is used, animals are deprived of food for 5 hours
before and 2 hours after infection. Five mice are treated at each
does level. The 7 day survival ratios from 3 separate tests are
pooled for calculation of median effective dose (ED.sub.50).
E. coli in vitro Protein Translation System(Table VIII)
An in vitro, cell free, protein translation system using extracts
from E. coli stain MRE600 (tetracycline sensitive) and a derivative
of MRE600 containing the tetM determinant has been developed based
on literature methods [J. M. Pratt, Coupled
Transcription-translation in Prokaryotic Cell-free Systems,
Transcription and Translation, a Practical Approach, (B. D. Hames
and S. J. Higgins, eds) p. 179-209, IRL Press, Oxford-Washington,
1984].
Using the systems described above, the novel tetracycline compounds
of the present invention are tested for their ability to inhibit
protein synthesis in vitro. Briefly, each 10.mu.l reaction contains
S30 extract (a whole extract) made from either tetracycline
sensitive cells or an isogenic tetracycline resistant (tetM)
strain, low molecular weight components necessary for transcription
and translation (i.e. ATP and GTP), a mix of 19 amino acids (no
methionine), .sup.35S labeled methionine, DNA template (either
pBR322 or pUC119), and either DMSO (control) or the novel
tetracycline compound to be tested ("Novel Tc") dissolved in
DMSO.
The reactions are incubated for 20 minutes at 37.degree. C. Timing
is initiated with the addition of the S30 extract, the lase
component to be added. After 30 minutes, 2.5 .mu.l of the reaction
is remobed and mixed with 0.5 ml of 1N NaOH to destroy RNA and
tRNA. Two ml of 25% trichloroacetic acid is added and the mixture
incubated at room temperature for 15 minutes. The trichloracetic
acid precipitated material is collected on Whatman GF/C filters and
washed with a solution of 10% trichloracetic acid. The filters are
dried and the retained radioactivity, representing incorporation of
.sup.35S-methionine into polypeptides, is counted using standard
liquid scintillation methods.
The percent inhibition (P.I.) of protein synthesis is determined to
be: .times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. .times..times. ##EQU00001##
Testing Results
The claimed compounds exhibit antibacterial activity against a
spectrum of tetracycline sensitive and resistant Gram-positive and
Gram-negative bacteria, especially, strains of E. coli, S. aureus
and E. faecalis, containing the tetM resistance determinants (Table
I). Notable is 7-(dimethylamino)-9-(formylamino)-
6-demethyl-6-deoxytetracycline, as shown in Tables I and IV, which
has good in vitro activity against tetracycline resistant strains
containing the tetM resistance determinant (such as S. aureus UBMS
88-5, S. aureus UBMS 90-1 and 90-2, E. coli UBMS 89-1 and 90-4) and
is equally as effective as minocycline against susceptible
strains.
7-(Dimethylamino)-9-(formylamino)-6-demethyl- 6-deoxytetracycline
demonstrates effective activity against minocycline susceptible
stains including a variety of recently isolated bacteria from
clinical sources (Table V). With the exception of some Protens
spp.,
7-(dimethylamino)-9-(formylamino)-6-demethyl-6-deoxytetracycline's
activity is superior to that of minocycline against other
isolates.
Protein synthesis, directed by cell-free extracts from the
tetracycline susceptible strain MRE-600, are inhibited by
tetracycline, minocycline and the
7-(dimethylamino)-9-(formylamino)-6-demethyl-6-deoxytetracycline of
this invention (Table 6). Protein synthesis, directed by cell-free
extracts from strain MRE 600 (tetM), is resistant to tetracycline
and minocycline, since 50% inhibition of protein synthesis required
addition of approximately 5-fold more antibiotic than in extracts
prepared from stain MRE 600 (Table VI). However, in contrast,
7-(dimethylamino)-9-(formylamino)-6-demethyl-6-deoxytetracycline
effectively inhibited protein synthesis in extracts prepared from
either MRE 600 or MRE 600 (tetM) (Table VI). The evidence presented
indicates that 7-(dimethylamino)-9-(formylamino)-
6-demethyl-6-deoxy-tetracycline is an inhibitor of protein
synthesis at the ribosome level. The ability of
7-(dimethylamino)-9-(formylamino)-6-demethyl-6-deoxytetracycline to
inhibit bacterial growth almost certainly reflects directed
inhibition of bacterial synthesis. If so, then it is expected, like
other tetracyclines, to exhibit a bacteriostatic effect against
susceptible bacteria.
7-(Dimethylamino)-9-(formylamino)-6-demethyl- 6-deoxytetracycline
binds reversibly to its target (the fibosome) since bacterial
growth resumed when the compound was removed from the cultures by
washing of the organism. Therefore, the ability of
7-(dimethylamino)- 9-(formylamino)-6-demethyl-6-deoxytetracycline
to inhibit bacterial growth appears to be a direct consequence of
its ability to inhibit protein synthesis at the ribosome level.
The enhanced activity (Table VII) of
7-(dimethylamino)-9-(formylamino)-6-demethyl-6-deoxytetracycline
against tetracycline susceptible and resistant organisms (tetM) is
also demonstrated in vivo in animals infected with S. aureus UBMS
90-1 and 90-2. The ED.sub.50's (Table VII) obtained for
7-(dimethylamino)- 9-(formylamino)-6-demethyl-6-deoxytetracycline
are lower than those of minocycline.
The improved efficacy of 7-(dimethylamino)-
9-(formylamino)-6-demethyl-6-deoxytetracycline is demonstrated by
the in vitro activity against isogenic strains into which the
resistance determinants, such as tetM, were cloned (Tables I-IV);
the inhibition of protein synthesis by tetM ribosomes (Table VI);
and the in vivo activity against experimental infections caused by
strains resistant to the tetracylcines, due to the presence of
resistance determinants, such as tetM (Table VII).
As can be seen from Tables I-V, compounds of the invention may be
used to prevent or control important veterinary diseases such as
mastitis, diarrhea, urinary tract infections, skin infections, ear
infections, wound infections and the like.
TABLE-US-00001 LEGEND FOR COMPOUNDS LETTER NAME A
7-(Dimethylamino)-9-(formylamino)-6-demethyl-6-de- oxytetracyline B
9-(Acetylamino)-7-(dimethylamino)-6-demethyl-6-de- oxytetracylcine
C 7-(Diethylamino)-9-(formylamino)-6-demethyl-6-de- oxytetracyline
D 7-(Diethylamino)-9-(formylamino)-6-demethyl-6-de- oxytetracycline
disulfate E 9-(Acetylamino)-7-(diethylamino)-6-demethyl-6-de-
oxytetracycline disulfate F
9-(Acetylamino)-7-(diethylamino)-6-demethyl-6-de- oxytetracycline G
9-(Formylamino)-7-iodo-6-demethyl-6-deoxytetracyc- line sulfate H
9-(Acetylamino)-7-iodo-6-demethyl-6-deoxytetracyc- line sulfate I
7-(Dimethylamino)-9[(trifluoroacetyl)amino]-6-de-
methyl-6-deoxytetracycline sulfate J
7-(Dimethylamino)-9-[[(phenylmethoxy)acetyl]-
amino]-6-demethyl-6-deoxytetracycline K
9-[[(Acetyloxy)acetyl]amino]-7-(dimethylamino)-6-
demethyl-6-deoxytetracycline L
7-(Dimethylamino)-9-[(hydroxyacetyl)amino]-6-de-
methyl-6-deoxytetracycline M
9-[(Aminoacetyl)amino]-7-(dimethylamino)-6-demeth-
yl-6-deoxytetracycline mono(trifluoroacetate) N
(7S-(7.alpha.,10a.alpha.)]-[[9-(aminocarbonyl)-7-(dimethyl-
amino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-
tetrahydroxy-10,12-dioxo-2-naphthacenyl]amino]- oxoacetic acid
ethyl ester O 7-(Dimethylamino)-6-demethyl-6-deoxytetracycline
hydrochloride (minocycline hydrochloride) P
9-(Benzoylamino)-7-(dimethylamino)-6-demethyl-6- deoxytetracycline
Q 7-(Dimethylamino)-9-[(4-methoxybenzoyl)amino]-6-
demethyl-6-deoxytetracycline R
7-(Dimethylamino)-9-[(2-methylbenzoyl)amino]-6-de-
methyl-6-deoxytetracycline S
7-(Dimethylamino)-9-[(2-fluorobenzoyl)amino]-6-de-
methyl-6-deoxytetracycline T
7-(Dimethylamino)-9-[(pentafluorobenzoyl)amino]-6-
demethyl-6-deoxytetracycline U
7-(Dimethylamino)-9-[[3-(trifluoromethyl)benzoyl]-
amino]-6-demethyl-6-deoxytetracycline V
7-(Dimethylamino)-9-[(4-nitrobenzoyl)amino]-6-de-
methyl-6-deoxytetracycline W
7-(Dimethylamino)-9-[[(4-dimethylamino)benzoyl]-
amino]-6-demethyl-6-deoxytetracycline X
9-[(4-Aminobenzoyl)amino]-7-(dimethylamino)-6-de-
methyl-6-deoxytetracycline sulfate Y
7-(Dimethylamino)-9-[(2-furanylcarbonyl)amino]-6-
demethyl-6-deoxytetracycline Z
7-(Dimethylamino)-9-[(2-thienylcarbonyl)amino]-6-
demethyl-6-deoxytetracycline AA
7-(Dimethylamino)-9-[[(4-nitrophenyl)sulfonyl)-
amino]-6-demethyl-6-deoxytetracycline BB
7-(Dimethyl)-9-[(3-nitrophenyl)sulfonyl]-
amino]-6-demethyl-6-deoxytetracycline CC
7-(Dimethylamino)-9-[(phenylsulfonyl)amino]-6-de-
methyl-6-deoxytetracycline DD
7-(Dimethylamino)-9-[(2-thienylsulfonyl)amino]-6-
demethyl-6-deoxytetracycline EE
9-[[(4-Chlorophenyl)sulfonyl]amino]-7-(dimethyl-
amino)-6-demethyl-6-deoxytetracycline FF
7-(Dimethylamino)-9-[(methylsulfonyl)amino)-6-de-
methyl-6-deoxytetracycline GG
9-[[[(2-Acetylamino)-4-methyl-5-thiazolyl]sulfon-
yl]amino]-7-(dimethylamino)-6-demethyl-6-deoxyte- tracycline HH
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimeth-
ylamino)-5,5a,6,6a,8,10,10a,12-octahydro-1,8,10a-
11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]car- bamic acid methyl
ester II 7-(Dimethylamino)-9-([(dimethylamino)acetyl]-
amino)-6-demethyl-6-deoxytetracycline sulfate TC Tetracycline
hydrochloride JJ (4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-
[[(dimethylamino)acetyl)amino)-1,4,4a,5,5a,6,11-
12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
2-naphthacenecarboxamide disulfate KK
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-
[[(dimethylamino)acetyl)amino]-1,4,4a,5,5a,6,11-
12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-di-
oxo-2-naphthacenecarboxamide dihydrochloride LL
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-
[[dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,-
12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
2-naphthacenecarboxamide MM
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,
4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahy-
droxy-9-[[(methylamino)acetyl]amino]-1,11-dioxo-
2-naphthacenecarboxamide dihydrochloride NN
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,
7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octa-
hydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naph-
thacenyl]-4-morpholineacetamide dihydrochloride OO
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-
[[(ethylamino)acetyl]amino)-1,4,4a,5,5a,6,11,12a-
octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
2-naphthacenecarboxamide dihydrochloride PP
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-
[[(butylamino)actyl]amino]-1,4,4a,5,5a,6,11,12a-
octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-
naphthacenecarboxamide dihydrochloride QQ
[(4S-(4alpha,12aalpha)]-9[[(Cyclopropylamino)acetyl)-
amino]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,-
12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
2-naphthacenecarboxamide dihydrochloride RR
[4S-(4alpha,12aalpha)]-9-[[(Diethylamino)acetyl)-
amino]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11-
12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
2-naphthacenecarboxamide dihydrochloride SS
(7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-
bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro
1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacen-
yl]-1-pyrrolidineacetamide dihydrochloride TT
[4S-(alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,
4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-
9-[[[(2-methylpropyl)amino]acetyl]amino]-1,11-
dioxo-2-naphthacenecarboxamide dihydrochloride UU
(7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,-
7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahy-
dro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphtha-
cenyl)-1-piperidineacetamide dihydrochloride VV
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,-
7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahy-
dro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naph-
thacenyl]-1H-imidazole-1-acetamide dihydrochloride WW
[4S-(4alpha,12aalpha)]-4,7-bis(dimethylamino)-1,4,
4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-
1,11-dioxo-9-[[(propylamino)acetyl]amino]-2- naphthacenecarboxamide
dihydrochloride XX [4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-
([2-(dimethylamino)-1-oxopropyl]amino)-1,4,4a,5,
5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,
11-dioxo-2-naphthacenecarboxamide dihydrochloride YY
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,
4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-
9-[[2-(methylamino)-1-oxopropyl]amino]-1,11-
dioxo-2-naphthacenecarboxamide dihydrochloride ZZ
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-
[[4-(dimethylamino)-1-oxobutyl]amino]-1,4,4a,5,
5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,
11-dioxo-2-naphthacenecarboxamide dihydrochloride AAA
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-
bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahy-
dro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naph-
thacenyl)-alpha-methyl-1-pyrrolidineacetamide di- hydrochloride BBB
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-
[[(hexylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-
octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-
naphthacenecarboxamide dihydrochloride CCC
[4S-(4alpha,12aalpha)]-9-[[(Butylmethylamino)-
acetyl]amino]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,
6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-
dioxo-2-naphthacenecarboxamide dihydrochloride DDD
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,
4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-
1,11-dioxo-9-[[(pentylamino)acetyl]amino]-2- naphthacenecarboxamide
dihydrochloride EEE
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,
4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahy-
droxy-1,11-dioxo-9-[[[(phentylmethyl)amino]acetyl]-
amino]-2-naphthacenecarboxamide dihydrochloride FFF
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-
[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,
12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
N-(1-pyrrolidinylmethyl)-2-naphthacenecarboxamide GGG
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-
[[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,
12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
N-(4-morpholinylmethyl)-2-naphthacenecarboxamide HHH
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-
[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,
12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
N-(1-piperidinylmethyl)-2-naphthacenecarboxamide III
[4S-(4alpha,12aalpha)]-9-[(Bromoacetyl]amino]-4,-
7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahy-
dro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naph- thacenecarboxamide
dihydrochloride JJJ
[4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxopropyl)-
amino]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,
12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
2-naphthacenecarboxamide hydrobromide KKK
[7S-(7alpha,10aalpha)-N-[2-[[9-(Aminocarbonyl)-4,-
7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahy-
dro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphtha-
cenyl]amino]-2-oxoethyl]glycine LLL
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-
bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahy-
dro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphtha-
cenyl)-1-azetidenacetamide MMM
(4S-(4alpha-12aalpha)]-9-[[(Cyclobutylamino)ace-
tyl]amino]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,
12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
2-naphthacenecarboxamide
TABLE-US-00002 TABLE I ANTIBACTERIAL ACTIVITY OF
9-(ACYLAMINO)-7-(SUBSTITUTED)-6-DEMETHYL-6-DEOXYTETRACYCLINES MIC
(.mu.g/ml) COMPOUND ORGANISM A B C D E F G H I S. aureus UBMS 88-5
(tetM) 0.06 0.12 0.12 0.25 4 0.5 1 1 16 S. aureus UBMS 88-4
(Sensitive) 0.015 .ltoreq.0.06 0.03 0.12 0.5 0.25 <0.015 0.25 8
S. aureus UBMS 90-1 (tetM) 0.06 ND 0.5 0.5 8 2 4 1 16 S. aureus
UBMS 90-2 (tetM) 0.03 ND 0.12 0.12 2 0.5 0.5 0.5 16 S. aureus UBMS
90-3 (Sensitive) .ltoreq.0.015 ND 0.03 0.06 0.5 0.12 0.03 0.12 4 S.
aureus UBMS 88-7 (tetK) 2 4 0.25 2 4 2 16 16 16 S. aureus IVES 2943
(meth. 4 64 1 4 8 2 32 32 ND resistant) S. aureus IVES 1983 (meth.
8 ND 1 4 16 4 32 32 32 resistant) S. aureus ATCC 19213 (Sensitive)
.ltoreq.0.015 0.12 .ltoreq.0.015 0.015 .ltoreq.0.015 .ltoreq.0.015
ND 0.12 1 S. aureus Smith (Sensitive) .ltoreq.0.015 0.12 0.03 0.03
0.5 0.12 0.03 0.12 8 S. haemolyticus AVAH 88-3 0.03 ND 0.12 ND 8 2
0.06 2 0.5 E. faecalis 12201 0.12 0.5 0.5 1 16 4 16 2 16 E.
faecalis ATCC 29212 .ltoreq.0.015 0.12 0.06 0.12 2.0 0.25 0.25 0.25
8 E. coli UBMS 88-1 (tetB) 32 >128 16 >32 >32 >32
>32 >128 >32 E. coli UBMS 88-2 (Sensitive) 0.12 2 0.25 0.5
>32 32 1 >128 32 E. coli UBMS 89-1 (tetM) 0.12 ND 1 ND 32 4 1
128 32 E. coli UBMS 89-2 (Sensitive) 0.12 ND 0.5 0.5 >32 32 1 16
32 E. coli ATCC 25922 0.06 2 0.25 0.5 32 4 0.5 16 32 MIC (.mu.g/ml)
COMPOUND ORGANISM J K L M N O HH II S. aureus UBMS 88-5 (tetM) 4
0.25 4 1 32 2 0.25 0.12 S. aureus UBMS 88-4 (Sensitive) 2 0.12 4 1
2 .ltoreq.0.015 0.03 0.06 S. aureus UBMS 90-1 (tetM) 4 0.25 8 2
>32 4 1 0.25 S. aureus UBMS 90-2 (tetM) 2 0.06 2 0.5 32 2 0.25
0.06 S. aureus UBMS 90-3 (Sensitive) 0.5 0.03 1 0.5 1 .ltoreq.0.015
0.03 0.06 S. aureus UBMS 88-7 (tetK) 2 32 >32 >32 8 0.06 0.5
1 S. aureus IVES 2943 (meth. 4 32 >32 >32 32 1 2 1 resistant)
S. aureus IVES 1983 (meth. 4 32 >32 >32 >32 1 2 1
resistant) S. aureus ATCC 29213 (Sensitive) 0.06 .ltoreq.0.015 0.5
0.5 0.25 .ltoreq.0.015 .ltoreq.0.015 0- .03 S. aureus Smith
(Sensitive) 0.5 .ltoreq.0.015 0.5 1 2 .ltoreq.0.015 0.03 0.12 S.
haemolyticus AVAH 88-3 4 0.5 16 1 4 0.03 0.25 0.25 E. faecalis
12201 2 0.25 4 0.25 32 4 2 0.12 E. faecalis ATCC 29212 4 0.06 2
0.25 32 0.5 0.25 0.03 E. coli UBMS 88-1 (tetB) >32 16 >32 2
>32 8 16 0.25 E. coli UBMS 88-2 (Sensitive) >32 4 >32 2
>32 0.5 ND ND E. coli UBMS 89-1 (tetM) >32 1 >32 2 >32
16 4 0.12 E. coli UBMS 89-2 (Sensitive) >32 8 >32 2 >32
0.5 4 0.25 E. coli ATCC 25922 32 4 32 2 32 0.25 2 0.12
TABLE-US-00003 TABLE II ANTIBACTERIAL ACTIVITY OF 9-(AROYLAMINO)
AND
9-(HETEROYLAMINO)-7-(SUBSTITUTED)-6-DEMETHYL-6-DEOXYTETRACYCLINES
MIC (.mu.m/gl) COMPOUND ORGANISM P O R S T U V W X Y Z Q S. aureus
UBMS 88-5 (tetM) 4 8 4 2 4 1 2 32 8 16 8 2 S. aureus UBMS 88-4
(Sensitive) 4 8 2 2 4 0.5 2 8 1 4 8 .gtoreq.0.015 S. aureus UBMS
90-1 (tetM) 4 8 8 4 4 1 2 16 16 32 4 4 S. aureus UBMS 90-2 (tetM) 4
8 2 1 2 1 1 8 8 8 4 2 S. aureus UBMS 90-3 (Sensitive) 1 4 1 1 2 0.5
0.5 8 1 2 2 .ltoreq.0.015 S. aureus UBMS 88-7 (tetK) 8 16 4 8 4 1 4
16 8 >32 32 0.06 S. aureus IVES 2943 (meth. 16 8 4 8 4 1 4 8
>32 >32 32 4 resistant) S. aureus IVES 1983 (meth. 8 16 8 4 4
1 8 8 >32 >32 32 4 resistant) S. aureus ATCC 29213
(Sensitive) 0.25 1 0.12 0.5 1 0.5 0.5 2 0.5 0.5 0.5 .ltoreq.0.015
S. aureus Smith (Sensitive) 1 4 1 1 4 1 0.5 4 1 2 2 .ltoreq.0.015
S. haemolyticus AVAH 88-3 4 8 8 4 4 1 4 16 8 >32 8 0.03 E.
faecalis 12201 8 8 8 4 4 1 4 16 32 32 8 4 E. faecalis ATCC 29212 4
8 2 4 4 1 4 8 8 8 8 0.5 E. coli UBMS 88-1 (tetB) >32 >32 2
>32 >32 >32 >32 >32 >32 >32 &- gt;32 8 E.
coli UBMS 88-2 (Sensitive) >32 >32 >32 >32 >32
>32 >32 >32 >3- 2 >32 >32 8 E. coli UBMS 89-1
(tetM) ND ND ND ND ND >32 >32 >32 >32 >32 >32 16
E. coli UBMS 89-2 (Sensitive) >32 >32 >32 >32 >32
.gtoreq.32 >32 >32 &- gt;32 >32 >32 0.5 E. coli
ATCC 25922 >32 >32 >32 >32 >32 .gtoreq.32 >32
>32 >32 - >32 >32 0.25
TABLE-US-00004 TABLE III ANTIBACTERIAL ACTIVITY OF
9-(SULFONYLAMINO)- 7-(SUBSTITUTED)-6-DEMETHYL-6-DEOXYTETRACYCLINES
MIC (.mu.m/gl) COMPOUND ORGANISM AA BB CC DD EE FF GG Q S. aureus
UBMS 88-5 (tetM) 0.12 ND 4 0.5 0.12 0.25 16 4 S. aureus UBMS 88-4
(Sensitive) 0.12 1 0.03 0.5 0.12 0.25 4 0.03 S. aureus UBMS 90-1
(tetM) 0.5 2 4 1 0.25 0.25 32 2 S. aureus UBMS 90-2 (tetM) 0.12 0.5
0.05 0.25 0.12 0.06 4 2 S. aureus UBMS 90-3 (Sensitive) 0.06 0.12 4
0.25 0.12 0.12 2 .ltoreq.0.015 S. aureus UBMS 88-7 (tetK) 2 4 4 2 1
8 32 0.0.6 S. aureus IVES 2943 (meth. 4 4 4 4 0.5 16 >32 2
resistant) S. aureus IVES 1983 (meth. 8 8 4 4 1 16 32 1 resistant)
S. aureus ATCC 29213 (Sensitive) 0.12 0.06 .ltoreq.0.015 0.03 0.03
0.03 0.5 .ltoreq.0.015 S. aureus Smith (Sensitive) 0.12 0.25 4 0.03
0.12 0.12 2 >0.015 S. haemolyticus AVAH 88-3 2 4 4 2 ND ND ND
0.06 E. faecalis 12201 ND ND ND ND ND ND ND 8 E. faecalis ATCC
29212 0.12 0.12 0.06 0.25 0.06 0.06 1 0.5 E. coli UBMS 88-1 (tetB)
16 >32 16 32 >32 8 >32 16 E. coli UBMS 88-2 (Sensitive) 8
4 8 8 >32 2 >32 0.5 E. coli UBMS 89-1 (tetM) 4 ND ND ND ND ND
32 16 E. coli UBMS 89-2 (Sensitive) 16 16 16 16 >32 2 >32 0.5
E. coli ATCC 25922 4 2 2 4 >32 2 >32 0.5
TABLE-US-00005 TABLE IA ANTIBACTERIAL ACTIVITY OF
9-(ACYLAMINO)-7-(SUBSTITUTED)- 6-DEMETHYL-6-DEOXYTTRACYCLINES JJ KK
LL MM NN OO PP E. coli UBMS 88-1 TetB 0.25 0.25 0.25 1 >32 1 0.5
E. coli J3272 Tet sens. 0.25 0.12 0.12 1 >32 1 0.5 E. coli
MC4100 Tet sens. NT NT NT NT NT NT NT E. coli MC4100 TetB 0.25 0.25
0.25 1 >32 1 0.5 E. coli PRP1 TetA 2 1 1 16 >32 2 1 E. coli
J3272 TetC 1 1 0.5 8 >32 2 0.5 E. coli UBMS 89-1 TetM 0.25 0.12
0.12 1 32 1 0.25 E. coli UBMS 89-2 Tet Sens. 0.25 0.25 0.12 1
>32 1 0.5 E. coli J2175 0.25 0.25 0.12 1 >32 1 0.25 E. coli
BAJ9003 0.03 0.03 NG 0.25 0.5 0.12 0.12 E. coli UBMS 90-4 TetM 0.25
0.25 0.25 CONT CONT 0.5 0.25 E. coli UBMS 90-5 0.25 0.25 0.12 1
>32 1 0.5 E. coli #311 (MP) 0.25 0.25 0.12 1 >32 1 0.25 E.
coli ATCC 25922 0.25 0.25 0.12 1 >32 1 0.25 E. coli J3272 TetD
0.12 0.12 0.06 0.05 32 0.5 0.25 S. marcescens FPOR 8733 4 2 2 16
>32 8 2 X. maltophilia NEMC 87210 0.5 0.25 0.25 8 32 2 0.5 Ps.
aeruginosa ATCC 27853 8 4 4 16 >32 16 16 S. aureus NEMC
8769/89-4 0.06 0.06 .ltoreq.0.015 0.5 0.5 0.5 0.12 S. aureus UBMS
88-4 0.25 0.12 0.06 0.5 2 1 0.25 S. aureus UBMS 88-5 TetH 0.25 0.25
0.12 0.5 4 1 0.5 S. aureus UBMS 88-7 TetK 1 0.25 0.5 16 32 8 2 S.
aureus UBMS 90-1 TetM 0.25 0.25 0.12 1 4 1 0.5 S. aureus UBMS 90-3
0.12 0.03 0.06 0.5 2 0.5 0.25 S. aureus UBMS 90-2 TetM 0.25 0.12
0.12 0.5 2 0.5 0.5 S. aureus IVES 2943 2 1 1 32 >32 8 2 S.
aureus ROSE (MP) 2 1 1 32 >32 8 2 S. aureus SMITH (MP) 0.12 0.06
0.06 0.5 2 0.5 0.12 S. aureus IVES 1983 2 1 1 16 >32 8 2 S.
aureus ATCC 29213 0.03 .ltoreq.0.015 0.06 1 2 1 0.25 S. hemolyticus
AVHAH 88-3 0.25 0.12 0.12 1 32 1 0.25 Enterococcus 12201 0.12 0.12
0.06 0.25 2 0.25 0.12 E. faecalis ATCC 29212 0.12 0.06 0.06 0.25 2
0.25 0.12 QQ RR SS TT UU VV WW E. coli UBMS 88-1 TetB 4 1 0.25 0.5
0.5 >32 0.25 E. coli J3272 Tet sens. 2 1 0.25 0.5 0.5 >32
0.25 E. coli MC4100 Tet sens. NT NT NT NT NT NT NT E. coli MC4100
TetB 2 1 0.25 0.5 0.5 >32 0.25 E. coli PRP1 TetA 32 2 0.5 2 1
>32 1 E. coli J3272 TetC 8 1 0.25 0.5 0.5 >32 0.25 E. coli
UBMS 89-1 TetM 1 0.25 0.12 0.25 0.12 >32 0.25 E. coli UBMS 89-2
Tet Sens. 2 1 0.25 0.5 0.5 >32 0.25 E. coli J2175 2 1 0.25 0.5
0.5 >32 0.25 E. coli BAJ9003 0.25 0.06 .ltoreq.0.015 0.06 0.06 1
0.06 E. coli UBMS 90-4 TetM 2 0.5 0.25 0.5 0.5 >32 0.25 E. coli
UBMS 90-5 2 1 0.25 0.5 0.5 >32 0.25 E. coli #311 (MP) 2 0.5 0.12
0.5 0.25 >32 0.25 E. coli ATCC 25922 2 0.5 0.25 0.5 0.25 >32
0.25 E. coli J3272 TetD 2 0.25 0.12 0.12 0.25 >32 0.12 S.
marcescens FPOR 8733 >32 4 2 4 4 >32 2 X. maltophilia NEMC
87210 2 0.25 0.5 0.5 0.12 >32 0.5 Ps. aeruginosa ATCC 27853
>32 32 16 16 32 >32 8 S. aureus NEMC 8769/89-4 0.12 0.06 0.03
0.03 0.06 4 0.06 S. aureus UBMS 88-4 0.5 0.25 0.25 0.25 0.25 8 0.25
S. aureus UBMS 88-5 TetH 0.5 0.25 0.25 0.25 0.25 32 0.25 S. aureus
UBMS 88-7 TetK 4 0.5 0.5 2 0.25 32 1 S. aureus UBMS 90-1 TetM 0.5
0.25 0.25 0.25 0.25 32 0.12 S. aureus UBMS 90-3 0.5 0.25 0.12 0.12
0.12 4 0.12 S. aureus UBMS 90-2 TetM 0.5 0.25 0.25 0.25 0.12 16
0.25 S. aureus IVES 2943 16 1 1 2 0.25 >32 2 S. aureus ROSE (MP)
16 1 1 2 0.5 >32 2 S. aureus SMITH (MP) 0.25 0.25 0.12 0.12 0.12
4 0.12 S. aureus IVES 1983 8 0.25 0.5 2 0.5 >32 2 S. aureus ATCC
29213 0.5 0.12 0.12 0.25 0.12 8 0.25 S. hemolyticus AVHAH 88-3 2
0.5 0.25 0.25 0.12 >32 0.25 Enterococcus 12201 0.5 0.12 0.12
0.25 0.12 4 0.12 E. faecalis ATCC 29212 0.25 0.12 0.12 0.25 0.06 4
0.25 XX YY ZZ AAA BBB CCC DDD E. coli UBMS 88-1 TetB 0.5 0.5 >32
0.5 0.5 1 0.5 E. coli J3272 Tet sens. 0.5 0.5 NT NT NT NT NT E.
coli MC4100 Tet sens. NT NT 2 0.12 0.25 0.25 0.12 E. coli MC4100
TetB 1 0.5 >32 0.5 0.5 2 1 E. coli PRP1 TetA 1 1 32 0.5 0.5 1
0.5 E. coli J3272 TetC 1 2 32 0.5 0.5 1 0.5 E. coli UBMS 89-1 TetM
0.12 0.5 32 0.12 0.25 0.25 0.25 E. coli UBMS 89-2 Tet Sens. 0.5 0.5
16 0.5 0.25 2 0.5 E. coli J2175 0.5 0.5 16 0.5 0.25 2 0.5 E. coli
BAJ9003 0.06 0.06 1 0.06 0.06 0.12 0.12 E. coli UBMS 90-4 TetM 0.5
0.5 16 0.5 0.25 1 0.5 E. coli UBMS 90-5 0.5 0.5 16 0.5 0.25 2 0.5
E. coli #311 (MP) 0.5 0.5 16 0.25 0.5 1 0.5 E. coli ATCC 25922 0.5
0.5 8 0.25 0.12 1 0.5 E. coli J3272 TetD 0.25 0.25 4 0.12 0.12 0.5
0.25 S. marcescens FPOR 8733 4 8 >32 4 4 16 8 X. maltophilia
NEMC 87210 0.5 4 32 0.5 4 0.25 0.5 Ps. aeruginosa ATCC 27853 32 16
>32 >32 16 >32 32 S. aureus NEMC 8769/89-4 0.12 0.12 1
0.12 0.06 0.12 0.25 S. aureus UBMS 88-4 0.25 0.5 2 0.25 0.25 0.5
0.5 S. aureus UBMS 88-5 TetH 0.25 0.5 8 0.25 0.5 0.5 0.5 S. aureus
UBMS 88-7 TetK 1 4 16 0.5 2 1 2 S. aureus UBMS 90-1 TetM 0.25 0.25
8 0.5 0.25 1 1 S. aureus UBMS 90-3 0.25 0.12 2 0.25 0.06 0.25 0.5
S. aureus UBMS 90-2 TetM 0.25 0.25 4 0.25 0.25 0.25 0.5 S. aureus
IVES 2943 1 8 >32 0.5 4 1 4 S. aureus ROSE (MP) 1 8 >32 2 16
2 4 S. aureus SMITH (MP) 0.25 0.25 2 0.25 0.12 0.5 0.25 S. aureus
IVES 1983 1 4 >32 0.5 4 1 4 S. aureus ATCC 29213 0.25 0.5 2 0.25
0.25 0.5 1 S. hemolyticus AVHAH 88-3 0.5 0.5 8 0.5 0.5 0.5 0.5
Enterococcus 12201 0.12 0.25 8 0.12 0.25 0.25 0.25 E. faecalis ATCC
29212 0.12 0.12 4 0.12 0.12 0.12 0.25 EEE FFF GGG HHH III E. coli
UBMS 88-1 TetB 2 0.25 0.25 0.25 >32 E. coli J3272 Tet sens. NT
NT NT NT 16 E. coli MC4100 Tet sens. 0.5 0.06 0.06 0.12 NT E. coli
MC4100 TetB 4 0.25 0.25 0.25 >32 E. coli PRP1 TetA 4 2 1 2
>32 E. coli J3272 TetC 2 1 1 0.5 >32 E. coli UBMS 89-1 TetM
0.5 0.12 0.12 0.25 4 E. coli UBMS 89-2 Tet Sens. 4 0.25 0.25 0.25
32 E. coli J2175 4 0.25 0.25 0.25 32 E. coli BAJ9003 0.25
.ltoreq.0.015 0.03 0.03 0.25 E. coli UBMS 90-4 TetM 0.5 0.12 0.25
0.25 -- E. coli UBMS 90-5 0.5 0.25 0.25 0.25 16 E. coli #311 (MP)
0.5 0.25 0.25 0.25 8 E. coli ATCC 25922 0.5 0.12 0.12 0.25 16 E.
coli J3272 TetD 0.5 0.12 0.12 0.12 32 S. marcescens FPOR 8733 4 4 4
4 >32 X. maltophilia NEMC 87210 1 0.25 0.5 0.5 4 Ps. aeruginosa
ATCC 27853 32 8 8 8 >32 S. aureus NEMC 8769/89-4 0.12 0.25 0.25
0.25 0.12 S. aureus UBMS 88-4 0.25 0.12 0.12 0.25 0.5 S. aureus
UBMS 88-5 TetH 0.5 0.12 0.12 0.25 1 S. aureus UBMS 88-7 TetK 2 1 1
0.5 2 S. aureus UBMS 90-1 TetM 0.5 0.12 0.25 0.25 1 S. aureus UBMS
90-3 0.25 0.12 0.12 0.12 0.5 S. aureus UBMS 90-2 TetM 0.25 0.12
0.12 0.12 0.5 S. aureus IVES 2943 2 2 2 2 4 S. aureus ROSE (MP) 8 2
2 2 8 S. aureus SMITH (MP) 0.25 0.12 0.12 0.12 0.5 S. aureus IVES
1983 2 2 2 2 4 S. aureus ATCC 29213 0.5 0.12 0.25 0.25 0.5 S.
hemolyticus AVHAH 88-3 2 0.25 0.5 0.5 2 Enterococcus 12201 0.25
0.12 0.12 0.12 1 E. faecalis ATCC 29212 0.25 0.06 0.06 0.06 0.5 JJJ
KKK LLL MMM E. coli UBMS 88-1 TetB >32 >32 0.5 0.5 E. coli
J3272 Tet sens. >32 >32 0.25 0.06 E. coli MC4100 Tet sens. NT
32 NT NT E. coli MC4100 TetB >32 >32 0.5 0.25 E. coli PRP1
TetA >32 >32 1 4 E. coli J3272 TetC >32 >32 0.5 0.5 E.
coli UBMS 89-1 TetM 32 >32 0.25 0.25 E. coli UBMS 89-2 Tet Sens.
>32 >32 0.5 0.5 E. coli J2175 >32 >32 0.25 0.25 E. coli
BAJ9003 4 16 0.06 0.03 E. coli UBMS 90-4 TetM >32 >32 0.25
0.25 E. coli UBMS 90-5 >32 >32 0.25 0.5 E. coli #311 (MP)
>32 >32 0.25 0.25 E. coli ATCC 25922 >32 >32 0.25 0.25
E. coli J3272 TetD >32 >32 0.12 0.12 S. marcescens FPOR 8733
>32 >32 2 8 X. maltophilia NEMC 87210 16 >32 1 0.5 Ps.
aeruginosa ATCC 27853 >32 >32 8 32 S. aureus NEMC 8769/89-4 4
32 0.12 0.5 S. aureus UBMS 88-4 8 32 0.25 0.25 S. aureus UBMS 88-5
TetH 8 >32 0.25 0.25 S. aureus UBMS 88-7 TetK 16 >32 2 4 S.
aureus UBMS 90-1 TetM 16 >32 0.25 0.5 S. aureus UBMS 90-3 2 16
0.12 0.12 S. aureus UBMS 90-2 TetM 8 32 0.25 0.25 S. aureus IVES
2943 32 >32 2 4 S. aureus ROSE (MP) >32 >32 2 8 S. aureus
SMITH (MP) 4 16 0.25 0.25 S. aureus IVES 1983 32 >32 2 4 S.
aureus ATCC 29213 4 32 2 0.25 S. hemolyticus AVHAH 88-3 16 >32
0.25 0.24 Enterococcus 12201 16 >32 0.25 0.24 E. faecalis ATCC
29212 16 16 0.25 0.25 NG = No Growth CONT = Contaminated NT = Not
Tested
TABLE-US-00006 TABLE IV Susceptibility of Sensitive and Resistant
(tetM) Organisms to Tetracyclines MIC (.mu.g/ml) Organisms A O TC
E. coli UBMS 88-2 (Sensitive) 0.12 0.5 ND E. coli UBMS 90-4 (tetM)
1 64 64 S. aureus UBMS 88-4 (Sensitive) <0.015 0.03 0.12 S.
aureus UBMS 88-5 (tetM) 0.03 2 32 S. aureus UBMS 90-3 (Sensitive)
<0.015 0.03 0.12 S. aureus UBMS 90-1 (tetM) 0.12 4 32 N.
gonorrhoeae IL 611 (Sensitive) 0.06 0.5 ND N. gonorrhoeae 6418
(tetM) 1 >32 >32 E. faecalis UBMS 90-6 (tetM) 0.12 8 32 E.
faecalis UBMS 90-7 (tetM) 0.5 8 32
TABLE-US-00007 TABLE V In vitro Activity of Compounds A and O
Against Clinical Isolates MIC (.mu.g/ml).sup.+ Organism No. Tested
Antibiotic Range MIC.sub.50 MIC.sub.90 Neisseria (9) A 0.015-1.00
0.03 1.00 gonorrhoeae O 0.03->32.00 0.25 >32.00 Haemophilus
(18) A <0.008-0.06 0.06 0.06 influenzae O 0.06-0.25 0.12 0.25
Enterococcus (14) A <0.015-2.00 0.12 1.00 faecalis O
<0.015-16.00 4.00 16.00 Enterococcus (11) A <0.015-2.00 0.06
2.00 faecium O <0.015-16.00 8.00 16.00 Escherichia coli (10) A
0.06->32.00 0.25 >32.00 O 0.12-32.00 0.25 16.00 Klebsiella
(10) A 0.25->32.00 0.50 0.50 pneumoniae O 1.00->32.00 1.00
4.00 Proteus spp. (9) A 0.50->32.00 2.00 >32.00 indole + O
1.00->32.00 16.00 >32.00 Bacteroides spp. (15) A
<0.15-4.00 0.25 2.00 O <0.15-16.00 1.00 4.00 In Vitro
Activity of KK and Comparative Antibiotics vs Recent Clinical and
Agricultural Isolates MIC (.mu.g/ml) Organism [No. Tested] KK O TC
Staphylococcus aureus, [15] 0.12-2 0.06-4 0.25->64
methicillin-resistant Staphylococcus aureus, [15] 0.12-0.25
0.03-0.12 0.12-1 methicillin-susceptible Staphylococcus [16] 0.12-8
0.03-1 0.12->64 Coagulase-negative, methicillin-susceptible
Enterococcus faecalis [10] 0.015-0.12 0.03-16 0.12-64 Enterococcus
faecium [10] 0.03-0.12 0.03-16 0.12-64 Enterococcus spp. [8]
0.015-0.06 0.03-16 0.12->64 Vancomycin-resistant Streptococcus
pyogenes [10] 0.06-0.12 0.03-2 0.12-16 Streptococcus agalactiae
[10] 0.06-0.25 0.12-16 0.25-64 Streptococcus pneumoniae [10]
0.03-0.25 0.06-0.5 0.12-2 Listeria monocytogenes [8] 0.06-0.12
0.015-0.03 0.12-0.5 Escherichia coli [30] 0.12-4 0.25-32 0.5->64
(Clinical) Escherichia coli [15] 0.12-4 1-16 2->64
(Agricultural) Shigella spp. [14] 0.06-0.5 0.25-8 0.25->64
Klebsiella pneumoniae [10] 0.25-8 0.5-8 0.5->64 Klebsiella
oxytoca [10] 0.5-1 0.5-4 0.5-1 Citrobacter freundii [10] 0.25-8
0.03-32 0.5-16 Citrobacter diversus [10] 0.25-1 0.25-4 0.5-4
Salmonella spp. [11] 0.25-0.5 0.5-16 0.5->64 (Clinical)
Salmonella cholerasuis [15] 0.5-16 2->64 1->64 (Agricultural)
Serratia mercescens [10] 2-8 1-8 8->64 Enterobacter cloacae [10]
0.5-1 0.25-4 0.5-2 Enterobacter aerogenes [10] 0.5-1 0.5-1 0.5-1
Providencia spp. [13] 2-8 4->64 1->64 Proteus mirabilis [26]
1-32 1-32 0.5-64 Proteus vulgaris [18] 0.5-4 0.5-16 0.25-64
Morganella morganii [16] 0.5-4 0.25-32 0.25->64 Pseudomonas
aeruginosa [10] 1-16 1-16 2-32 Xanthomonas maltophilia [10] 0.5-2
0.12-1 8-16 Moraxeila catarrhalis [18] 0.06-0.12 0.03-0.12 0.06-0.5
Neisseria gonorrhoeae [14] 0.25-1 0.5-64 1->64 Haemophilus
influenzae [15] 0.5-2 0.5-2 1-32 Pasturella multocida [17]
0.03-0.25 0.015-4 0.06-16 (Agricultural & Clinical) Bordetella
bronchiseptica [10] 0.12 0.06-0.12 0.12-0.25 (Agricultural)
Bacteroides fragilis [11] 0.06-0.2 <0.008-16 0.25->64
Bacteroides fragilis group [10] 0.06-2 <0.008-4 0.25-32
Bacteroides spp. [9] 0.03-1 0.03-16 0.25->64 Clostridium
difficile [12] 0.03 0.015-16 0.12-32 Clostridium perfringens [16]
0.03-1 <0.008-16 0.015-16 Clostridium spp. [9] 0.015-0.12
<0.008-16 0.015-64 Anaerobic Gram [15] 0.015-0.06 0.05-8
4->64 (+) Cocci .sup.+MIC.sub.50 = minimum concentration
required to inhibit 50% of strains tested. MIC.sub.90 = minimum
concentration required to inhibit 90% of strains tested
TABLE-US-00008 TABLE VI Inhibition of Protein Synthesis Directed by
E. coli Cell-free Ribosomes with Tetracyclines IC.sub.50
(.mu.g/ml).sup.+ Antibiotic TC Sensitive Host Tet M Host
Tetracycline 0.6 2.0 Compound O 0.4 2.0 Compound A <0.3 0.4
.sup.+Concentration of antibiotic required to inhibit protein
synthesis by 50% compared to a drug-free control
TABLE-US-00009 TABLE VII In vivo Protective Activity of Compounds A
and O in Mice Infected with Staphylococci Containing the tetM
Determinant Organism Compound ED.sub.50 (mg/kg).sup.+ S. aureus
UBMS 90-1 A 0.22 O 1.7 S. aureus UBMS 90-2 A 0.49 O 3.0 In Vitro
Protective Activity in Mice Compounds (ED.sub.50 (mg/kg) Route of
Antibiotic Organism Administration JJ KK LL PP RR SS TT S. aureus
SMITH (sens) Oral 9.6 8-16 4-8 >16 8-16 8-16 8-16 S. aureus
SMITH (sens) Intraveneous 0.61 0.68 0.25-0.5 1-2 -- 1-2 1-2 S.
aureus SMITH (sens) Subcutaneous 0.66 -- -- -- -- -- -- Escherichia
coli Intraveneous -- 2.49 -- -- -- -- -- UBMS 90-4 (Tet-M) Route of
Antibiotic Organism Administration BBB WW XX YY AAA DDD EEE O S.
aureus SMITH (sens) Oral 4-8 >16 8-16 >16 >16 8-16 8-16
0.74 S. aureus SMITH (sens) Intraveneous 1.8 0.82 0.5-1 0.5-1 -- --
-- 0.37 S. aureus SMITH (sens) Subcutaneous -- -- -- -- -- -- -- --
Escherichia coli Intraveneous -- -- -- -- -- -- -- >32 UBMS 90-4
(Tet-M) .sup.+Median effective dose protecting 50% of the infected
mice, single subcutaneous dosing.
TABLE-US-00010 TABLE VIII In Vitro Transcription and Protein
Translation Sensitivity to Tetracycline Compounds COMPOUND %
INHIBITION Organism Concentration Wild Type S30 TetM S30 KK 1.0
mg/ml 92 95 0.5 mg/ml 90 96 0.25 mg/ml 89 93 0.12 mg/ml 84 93 0.06
mg/ml 82 89 0.03 mg/ml 81 75 MM 1.0 mg/ml 99 99 0.2 mg/ml 98 97
0.06 mg/ml 95 92 OO 1.0 mg/ml 99 99 0.2 mg/ml 97 95 0.06 mg/ml 94
87 QQ 1.0 mg/ml 99 99 0.2 mg/ml 97 95 0.06 mg/ml 92 85 RR 1.0 mg/ml
99 99 0.2 mg/ml 97 97 0.06 mg/ml 93 90 VV 1.0 mg/ml 99 98 0.2 mg/ml
93 92 0.06 mg/ml 91 79 WW 1.0 mg/ml 99 98 0.2 mg/ml 99 97 0.06
mg/ml 93 88 XX 1.0 mg/ml 98 97 0.2 mg/ml 96 89 0.06 mg/ml 85 78
Minocycline 1.0 mg/ml 98 68 0.2 mg/ml 89 43 0.06 mg/ml 78 0
When the compounds are employed as antibacterials, they can be
combined with one or more pharmaceutically acceptable carriers, for
example, solvents, diluents and the like, and may be administered
orally in such forms as tablets, capsules, dispersible powders,
granules, or suspensions containing, for example, from about 0.05
to 5% of suspending agent, syrups containing, for example, from
about 10 to 50% of sugar, and elixirs containing, for example, from
about 20 to 50% ethanol, and the like, or parenterally in the form
of sterile injectable solutions or suspensions containing from
about 0.05 to 5% suspending agent in an isotonic medium. Such
pharmaceutical preparations may contain, for example, from about 25
to about 90% of the active ingredient in combination with the
carrier, more usually between about 5% and 60% by weight.
An effective amount of compound from 2.0 mg/kg of body weight to
100.0 mg/kg of body weight should be administered one to five times
per day via any typical route of administration including but not
limited to oral, parenteral (including subcutaneous, intravenous,
intramuscular, intrasternal injection or infusion techniques),
topical or rectal, in dosage unit formulations containing
conventional non-toxic pharmaceutically acceptable carriers,
adjuvants and vehicles. It will be understood, however, that the
specific dose level and frequency of dosage for any particular
patient may be varied and will depend upon a variety of factors
including the activity of the specific compound employed, the
metabolic stability and length of action of that compound, the age,
body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity
of the particular condition, and the host undergoing therapy.
These active compounds may be administered orally as well as by
intravenous, intramuscular, or subcutaneous routes. Solid carriers
include starch, lactose, dicalcium phosphate, microcrystalline
cellulose, sucrose and kaolin, while liquid carriers include
sterile water, polyethylene glycols, non-ionic surfactants and
edible oils such as corn, peanut and sesame oils, as are
appropriate to the nature of the active ingredient and the
particular form of administration desired. Adjuvants customarily
employed in the preparation of pharmaceutical compositions may be
advantageously included, such as flavoring agents, coloring agents,
preserving agents, and antioxidants, for example, vitamin E,
ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of
ease of preparation and administration are solid compositions,
particularly tablets and hard-filled or liquid-filled capsules.
Oral administration of the compounds is preferred.
These active compounds may also be administered parenterally or
intraperitoneally. Solutions or suspensions of these active
compounds as a free base or pharmacologically acceptable salt can
be prepared in water suitably mixed with a surfactant such as
hydroxy-propylcellulose. Dispersions can also be prepared in
glycerol, liquid, polyethylene glycols and mixtures thereof in
oils. Under ordinary conditions of storage and use, these
preparations contain a preservative to prevent the growth of
microorganisms.
The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacterial and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oil.
The invention will be more fully described in conjunction with the
following specific examples which are not to be construed as
limiting the scope of the invention.
EXAMPLE 1
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-oct-
ahydro-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-2-naphthacenecarboxamid-
e sulfate (1:1)
To a stirred ice bath cooled solution of 0.444 g of
[4S-(4.alpha.,12a.alpha.)]-4,7-bis(dimethylamino)-1,4,4a,5,5a,-
6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarbo-
xamide hydrochloride, prepared by the procedure described in U.S.
Pat. No. 3,226,436, dissolved in 15 ml of sulfuric acid is added
0.101 g of sodium nitrate. The mixture is stirred in the cold for
45 minutes followed by the dropwise addition to 500 ml of diethyl
ether. The resulting solid is collected, washed with diethyl ether
and dried to give 0.6 g of the desired product as a solid.
MS(FAB): m/z 503(M+H) and 601(M+H.sub.2SO.sub.4+H).
EXAMPLE 2
[4S-(4.alpha.,12a.alpha.)]-9-Amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11-
,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamid-
e sulfate (1:1)
A mixture of 2.0 g of product from Example 1 in 20 ml of
2-methoxyethanol is stirred for 10 minutes and filtered. The
filtrate is shaken, in a pressure bottle, with 1.0 g of 10%
palladium-on-carbon and 5 ml of 2N sulfuric acid, under 30 lbs. of
hydrogen pressure, for 1 hour. The reaction mixture is filtered and
the filtrate concentrated in vacuo to half volume. The solution is
poured into 100 ml of diethyl ether, the solid collected, washed
with diethyl ether and dried to give 1.6 g of the desired product
as a solid.
MS(FAB): m/z 473(M+H).
EXAMPLE 3
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-(formylamino)-1,4,4a,5-
,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthaceneca-
rboxamide
To a stirring 0.degree. C. solution of 3.0 g of product from
Example 2, 0.451 g of anhydrous sodium acetate and 50 ml of 98%
formic acid is added, dropwise, 7.4 ml of acetic anhydride. The
reaction is stirred at 0.degree. C. for 10 minutes followed by
stirring at room temperature for 1 hour. The mixture is poured into
500 ml of diethyl ether and the precipitate collected. The solid is
washed with diethyl ether and dried to give 2.9 g of the desired
product.
MS (FAB): m/z 501 (M+H).
EXAMPLE 4
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)]-9-(formylamino)-
1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a,tetrahydroxy-1,11-dioxo-2-naph-
thacenecarboxamide sulfate
To a solution of 3.5 g of product from Example 3 in 150 ml of
distilled water is added sufficient 0.75N sulfuric acid to bring
the reaction solution of pH 3.6. The solution is lyophilized to
give 3.6 g of the desired salt.
MS (FAB): m/z 501 (M+H).
EXAMPLE 5
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)]-9-forylamino)-1,4,4a,5,-
5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecar-
boxamide monohydrochloride
To a solution of 3.5 g of product from Example 3 in 150 ml of
distilled water is added sufficient 0.75N hydrochloric acid to
bring the reaction solution of pH 3.6. The solution is lyophilized
to give 3.6 g of the desired salt.
MS (FAB): m/z 501 (M+H).
EXAMPLE 6
[4S-(4.alpha.,12a.alpha.)]-9-(Acetylamino)]-4,7-bis(dimethylamino)-1,4,4a,-
5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenec-
arboxamide
To a stirring solution of 0.468 g of product from Example 2 in 5 ml
of water is added 0.50 g of sodium acetate and 0.2 ml of acetic
anhydride. The reaction is stirred at room temperature for 10
minutes followed by the addition of 0.2 ml of concentrated ammonium
hydroxide. After stirring 5 hours at room temperature, the reaction
is treated with 0.5 ml of concentrated sulfuric acid. The reaction
solution is extracted with 4 portions of n-butyl alcohol and the
aqueous layer is concentrated in vacuo to dryness. The residue is
triturated with 20 ml of methyl alcohol, filtered and the organic
layer is concentrated in vacuo to give 0.35 g of the desired
product.
MS(FAB): m/z 515 (M+H).
EXAMPLE 7
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-oct-
ahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[(trifluoroacetyl)amino]-2-na-
phthacenecarboxamide sulfate
A mixture of 0.20 g of product from Example 2 and 3.0 ml of
trifluoroacetic anhydride is stirred at room temperature for 6
hours. The reaction liquid is decanted from the solid residue. The
solid is dried, dissolved in 10 ml of methyl alcohol, stirred for
20 minutes and the mixture is poured into 100 ml of diethyl ether.
The solid is collected and dried to give 0.16 g of the desired
product.
MS (FAB): m/z 569 (M+H).
EXAMPLE 8
[4S-(4.alpha.,12a.alpha.)]-7-(Diethylamino)-4-(dimethylamino)-1,4,4a,5,5a,-
6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-2-naphthace-
necarboxamide sulfate (1:2).
To a stirred ice cooled solution of 0.660 g of
[4S-(4.alpha.,12a.alpha.)]-7-(diethylamino)-4-(dimethylamino)-1,4,4a,
5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacene-
carboxamide hydrochloride, prepared by the procedure described in
U.S. Pat. No. 3,226,436, dissolved in 15 ml of sulfuric acid is
added 0.151 g of sodium nitrate. The mixture is stirred in the cold
followed by dropwise addition to 500 ml of diethyl ether. The
resulting solid is collected, washed with diethyl ether and dried
to give 0.8 g of the desired product as a solid.
MS(FAB): m/z 531(M+H) and 629(M+H.sub.2SO.sub.4+H).
EXAMPLE 9
[4S-(4.alpha.,12a.alpha.)]-9-Amino-7-(diethylamino)-4-(dimethylamin)-1,4,4-
a,5,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthac-
enecarboxamide sulfate (1:2)
The title compound is prepared by the procedure of Example 2, using
0.82 g of product from Example 8, to give 0.65 g of the desired
product as a solid. .sup.1H NMR (CD.sub.3SOCD.sub.3):
.delta.4.25(s,1H,4-H) and 7.27(s,1H,8-H).
MS(FAB): m/z 501(M+H) and 599(M+H.sub.2SO.sub.4+H).
EXAMPLE 10
[4S-(4.alpha.,12a.alpha.)]-7-(Diethylamino)-4-(dimethylamino)-9-(formylami-
no)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,1212a
-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide sulfate (1:2)
To a solution of 0.238 g of product from Example 9 in 6 ml of
formic acid is added 0.035 g of sodium acetate and 0.75 ml of
acetic anhydride. The reaction mixture is stirred at room
temperature for 1.5 hours then poured into 200 ml of diethyl ether.
The solid is collected and dried at 50.degree. C. to give 0.125 g
of the desired product.
MS(FAB): m/z 529 (M+H) and 627 (M+H.sub.2SO.sub.4+H).
EXAMPLE 11
[4S-(4.alpha.,12a.alpha.)]-9-(Acetylamino)-7-(diethylamino)-4-(dimethylami-
no)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-n-
aphthacenecarboxamide sulfate (1:2)
To a solution of 0.16 g of product from Example 9 in 0.6 ml of
water is added 0.125 g of sodium acetate. After stirring for 5
minutes, 0.05 ml of acetic anhydride is added. The reaction is
stirred for 15 minutes, 0.025 ml of ammonium hydroxide is added and
the stirring continued for an additional 5 minutes. The mixture is
acidified with 0.125 ml of sulfuric acid, extracted with n-butyl
alcohol and concentrated in vacuo. The residue is dissolved in
methyl alcohol and added to diethyl ether. The solid is collected
and dried to give 0.10 g of the desired product.
MS(FAB): m/z 543 (M+H) and 641 (M+H.sub.2SO.sub.4+H).
EXAMPLE 12
[4S-(4.alpha.,12a.alpha.)]-7-(Diethylamino)-4-(dimethylamino)-9-(formylami-
no)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,1212a-tetrahydroxy-1,11-dioxo-2-na-
phthacenecarboxamide
A solution of 0.2 g of product from Example 10 in 10 ml of water is
treated with sodium acetate to achieve pH 5-6. The mixture is
extracted with chloroform. The organic extracts are dried with
sodium acetate, concentrated in vacuo and the solid triturated with
diethyl ether/hexane to give 0.11 g of the desired product.
MS (FAB): m/z 529 (M+H).
EXAMPLE 13
[4S-(4.alpha.,12a.alpha.)]-9-(Acetylamino)-7-(diethylamino)-4-(dimethylami-
no)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-n-
aphthacenecarboxamide
A solution of 0.25 g of product from Example 11 in 10 ml of water
is treated with sodium acetate to achieve pH 6. The mixture is
extracted with chloroform. The organic extracts are dried with
sodium acetate, concentrated in vacuo and the solid triturated with
diethyl ether/hexane to give 0.090 g of the desired product.
MS(FAB): m/z 543 (M+H).
EXAMPLE 14
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-7-(ethylmethylamino)-1,4,4a,5-
,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthaceneca-
rboxamide hydrochloride
A solution of 0.460 g of
[4S-(4.alpha.,12a.alpha.)]-4-(dimethylamino)-
7-(ethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,-
11-dioxo-2-naphthacenecarboxamide hydrochloride, prepared by the
procedure described in U.S. Pat. No. 3,226,436, in 0.5 ml of 97%
formic acid and 0.75 ml of 40% aqueous formaldehyde is heated at
reflux temperature for 2 hours, concentrated to 1/2 volume and
poured into diethyl ether. The resulting solid is collected, washed
with diethyl ether and dried to give 0.30 g of the desired
product.
EXAMPLE 15
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-7-(ethylmethylamino)-1,4,4a,5-
,5a,6,11,12a-octahydro-3.10.12,12a-tetrahydroxy-9-nitro-1,11-dioxo-2-napht-
hacenecarboxamide sulfate
The title compound is prepared by the procedure of Example 8, using
0.460 g of product from Example 14, 15 ml of sulfuric acid and
0.101 g of sodium nitrate to give 0.5 g of the desired product.
EXAMPLE 16
[4S-(4.alpha.,12a.alpha.)-9-Amino-4-(dimethylamino)-7-(ethylmethylamino)-
1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naph-
thacenecarboxamide sulfate
The title compound is prepared by the procedure of Example 2, using
1.0 g of product from Example 15, 20 ml of 2-methoxyethanol, 1.0 g
of 10% palladium-on-carbon and 5 ml of 2N sulfuric acid to give 0.8
g of the desired product.
EXAMPLE 17
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-7-(ethylmethylamino)-9-(formy-
lamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
-2-naphthacenecarboxamide sulfate
The title compound is prepared by the procedure of Example 3, using
1.5 g of product from Example 16, 0.235 g of anhydrous sodium
acetate, 25 ml of 98% formic acid and 3.7 ml of acetic anhydride to
give 1.35 g of the desired product.
EXAMPLE 18
[4S-(4.alpha.,12a.alpha.)]-9-(Acetylamino)-4-(dimethylamino)-1,4,4a,5,5a,6-
,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxa-
mide sulfate
To a solution of 3.2 g of [4S-(4.alpha.,12a.alpha.)]-9-amino-
4-dimethylamino-1,2,3,4,4a,5,5a,6,11,11a,12,
12a-dodecahydro-10,12a.alpha.-dihydroxy-1,3,11,12-tetraoxo-2-naphthacenec-
arboxamide, prepared by the procedure described in U.S. Pat. No.
3,239,499, in 50 ml of water is added a solution of 2.5 g of sodium
acetate in 12 ml of water. The mixture is cooled to 0.degree. C.
and 1 ml of acetic anhydride is added with stirring. The reaction
is stirred for 20 minutes, 0.5 ml of ammonium hydroxide is added
and stirred for 5 minutes. Two and one half ml of sulfuric acid is
added, the reaction is extracted twice with n-butyl alcohol, the
combined organic layers are washed with water and concentrated in
vacuo. The residue is dissolved in methyl alcohol and added
dropwise to 500 ml of diethyl ether. The solid is collected and
dried to give 2.3 g of the desired product.
MS(FAB): m/z 472 (M+H) and 570 (M+H.sub.2SO.sub.4+H).
EXAMPLE 19
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-9-(formylamino)-1,4,4a,5,5a,6-
,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxa-
mide monohydrochloride
To a 0.degree. C. solution of 1.06 g of
[4S-(4.alpha.,12a.alpha.)]-9-amino-4-dimethylamino-1,2,3,4,5a,
6,11,11a,12,12a-dodecahydro-10,12a.alpha.-dihydroxy-1,3,11,
12-tetraoxo-2-naphthacenecarboxamide, prepared by the procedures
described in U.S. Pat. No. 3,239,499, in 50 ml of formic acid is
added 2.4 ml of acetic anhydride. After stirring for 5 minutes, the
cooling bath is removed and the reaction is stirred for 55 minutes.
The mixture is added to 400 ml of diethyl ether. The resulting
solid is collected, washed with diethyl ether and dried to give 1.1
g of the desired product.
MS (FAB): m/z 458 (M+H).
This procedure is a modification of U.S. Pat. No. 3,239,499.
EXAMPLE 20
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-9-(formylamino)-1,4,4a,5,5a,6-
,11,12a-octahydro-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-2-naphthacene-
carboxamide sulfate
To a well stirred 0.degree. C. solution of 0.278 g of product from
Example 19 in 10 ml of sulfuric acid is added, in portions, 0.1344
g of N-iodosuccinimide. The reaction is stirred at 0.degree. C. for
20 minutes then poured into 500 ml of diethyl ether. The resulting
solid is collected, washed with diethyl ether and dried to give
0.251 g of the desired product.
MS (FAB): m/z 584 (M+H).
EXAMPLE 21
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-9-(formylamino)-1,4,4a,5,5a,6-
,11,12a-octahydro-3,10,12,12a-tetrahydroxy-7-nitro-1,11-dioxo-2-naphthacen-
ecarboxamide sulfate
To a well stirred 0.degree. C. solution of 0.278 g of product from
Example 19 in 10 ml of sulfuric acid is added 0.3 ml of 10% nitric
acid in sulfuric acid. The reaction is stirred at 0.degree. C. for
20 minutes then poured into 500 ml of diethyl ether. The resulting
solid is collected, washed with diethyl ether and dried to give
0.26 g of the desired product.
MS (FAB): m/z 503 (M+H).
EXAMPLE 22
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-9-(formylamino)-7-[(1-methyle-
thyl)amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-d-
ioxo-2-naphthacenecarboxamide sulfate
A solution of 0.2 g of product from Example 21 (1:2 salt), 0.5 ml
of acetone, 0.5 ml of 0.5N sulfuric acid and 10 ml of
2-methoxyethanol is shaken under 35 lbs. of hydrogen, in the
presence of platinum oxide, for 2 hours. The catalyst is removed by
filtration, the filtrate concentrated in vacuo to 1/2 volume and
poured into diethyl ether. The resulting solid is collected and
dried to give 0.135 g of the desired product.
EXAMPLE 23
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-oct-
ahydro-3,10,12,12a-tetrahydroxy-9-[(methoxyacetyl)amino]-1,11-dioxo-2-naph-
thacenecarboxamide
To a well stirred solution of 0.055 g of product from Example 2,
0.200 g of sodium bicarbonate and 1 ml of N-methylpyrrolidone is
added a solution of 0.011 g of methoxyacetyl chloride in 0.5 ml of
acetonitrile. After 5 minutes, the suspension is filtered and the
filtrate diluted with 50 ml of tert-butyl methyl ether. The
resulting solid is collected and dried to give 0.040 g of the
desired product.
MS(FAB): m/z 545 (M+H).
EXAMPLE 24
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-(cyclopropylcarbonylam-
ino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2--
naphthacenecarboxamide
The title compound is prepared by the procedure of Example 23,
using 0.055 g of product from Example 2, 0.20 g of sodium
bicarbonate, 1.0 ml N-methylpyrrolidone, 0.010 g of
cyclopropanecarbonyl chloride and 0.5 ml of acetonitrile to give
0.030 g of the desired product.
EXAMPLE 25
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-(chloroacetylamino)-1,-
4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtha-
cenecarboxamide
The title compound is prepared by the procedure of Example 23,
using 0.055 g of product from Example 2, 0.20 g of sodium
bicarbonate, 1 ml of N-methylpyrrolidone, 0.013 g of chloroacetyl
chloride and 0.5 ml of acetonitrile to give 0.035 g of the desired
product.
EXAMPLE 26
[4S-(4.alpha.,12a.alpha.)]-9-[(4-Bromo-1-oxobutyl)amino]-4,7-bis(dimethyla-
mino)-1,4,4a,5,5a,6,11,12a-octahydro-
3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
The title compound is prepared by the procedure of Example 23,
using 0.055 g of product from Example 2, 0.20 g of sodium
bicarbonate, 1 ml of N-methylpyrrolidone, 0.025 g of 4-bromobutyryl
chloride and 0.5 ml of acetonitrile to give 0.050 g of the desired
product.
MS(FAB): m/z 622 (M+H).
EXAMPLE 27
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-oct-
ahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[(1-oxo-2-propenyl)amino]-2-n-
aphthacenecarboxamide
The title compound is prepared by the procedure of Example 23,
using 0.055 g of product from Example 2, 0.20 g of sodium
bicarbonate, 1.0 ml N-methylpyrrolidone, 0.011 g of acryloyl
chloride and 0.5 ml of acetonitrile to give 0.040 g of the desired
product.
MS (FAB): 513 (M+H).
EXAMPLE 28
[4S-(4.alpha.,12a.alpha.)]-9-[[(Acetyloxy)acetyl]amino]-4,7-Bis(dimethylam-
ino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2--
naphthacenecarboxamide
The title compound is prepared by the procedure of Example 23,
using 0.055 g of product from Example 2, 0.20 g of sodium
bicarbonate, 1.0 ml of N-methylpyrrolidone, 0.013 g of
acetoxyacetyl chloride and 0.5 ml of acetonitrile to give 0.040 g
of the desired product.
MS (FAB): m/z 573 (M+H).
EXAMPLE 29
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-(phenylthioacetylamino-
)-1,4,4a,5,5a,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-napht-
hacenecarboxamide
The title compound is prepared by the procedure of Example 23,
using 0.110 g of product from Example 2, 0.40 g of sodium
bicarbonate, 4.0 ml of N-methylpyrrolidone, 0.035 g of
phenylthioacetyl chloride and 0.5 ml of acetonitrile to give 0.075
g of the desired product.
EXAMPLE 30
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-(pyruvylamino)1,4,4a,5-
,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthaceneca-
rboxamide
The title compound is prepared by the procedure of Example 23,
using 0.110 g of product from Example 2, 0.40 g of sodium
bicarbonate, 1.0 ml of N-methylpyrrolidone, 0.018 g of pyruvyl
chloride and 0.5 ml of acetonitrile to give 0.060 g of the desired
product.
EXAMPLE 31
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-(ethoxycarbonylacetyla-
mino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-
-naphthacenecarboxamide
The title compound is prepared by the procedure of Example 23,
using 0.055 g of product from Example 2, 0.20 g of sodium
bicarbonate, 1.0 ml of N-methylpyrrolidone, 0.013 g of ethyl
malonyl chloride and 0.5 ml of acetonitrile to give 0.035 g of the
desired product.
EXAMPLE 32
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-(4-bromophenylacetylam-
ino)-1,4,4a,5,5a,6,11,12-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-n-
aphthacenecarboxamide
The title compound is prepared by the procedure of Example 23,
using 0.055 g of product from Example 2, 0.20 g of sodium
bicarbonate, 1.0 ml of N-methylpyrrolidone, 0.018 g of
4-bromophenylacetyl chloride and 0.5 ml of acetonitrile to give
0.040 g of the desired product.
EXAMPLE 33
[4S-(4.alpha.,12a.alpha.)]-9-(Benzoylamino)4,7-bis(dimethylamino)-1,4,4a,5-
,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthaceneca-
rboxamide
To a vigorously stirring solution of 0.066 g of product from
Example 2, 0.085 g of sodium acetate and 3 ml of tetrahydrofuran is
added 0.015 ml of benzoyl chloride and 0.25 ml of water. The
reaction is stirred for 1 hour. The organic layer is decanted,
washed with saturated sodium chloride, dried and concentrated in
vacuo. The residue is chromatographed on acid-washed diatomaceous
earth using a two phase system of hexane:ethyl
acetate:2-methyoxyethanol:water (50:50:17:6) to give in the second
void volume 0.030 g of the desired product as an orange solid.
MS(FAB): m/z 577 (M+H).
.sup.1H NMR (d.sub.6-DMSO): .delta.2.45
(s,6H,C(4)N(CH.sub.3).sub.2), 2.57(s, 6-H,C(7)N(CH.sub.3).sub.2),
7.5-7.6(m,3H, benzoyl), 7.86(s,1H, H-8), 7.96(d,J=7 Hz,2H,
benzoyl).
EXAMPLES 34-41 (Table I)
Substantially following the method described in detail hereinabove
in Example 33 using [4S-(4.alpha.,12a.alpha.)]-
9-amino-4,7-bis(dimethylamino)-1,4,4a,
5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacene-
carboxamide sulfate (product from Example 2), the compounds of this
invention listed below in Examples 34-41 are prepared.
TABLE-US-00011 TABLE I Ex. Acid Chloride Product Spectra 34
4-Methoxybenzoyl [4S-(4alpha,12aalpha)]-4,7- MS(FAB): m/z 607(M+H);
.sup.1H NMR chloride Bis(dimethylamino)-1,4,4a,5 (d.sub.6-DMSO):
delta 2.45(s, 6H, 5a,6,11,12a-octahydro-3,10, C(4)NMe.sub.2),
2.57(s, 6H, C(7) 12,12a-tetrahydroxy-9-[(4- NMe.sub.2), 7.06(d,
J=9Hz, 2H of 4- methoxybenzoyl)amino]-1,11- methoxybenzoyl),
7.84(s, 1H, dioxo-2-naphthacenecarbox- H-8), 7.97(d, J=9Hz, 2H of
4- amide methoxybenzoyl) 35 2-Methylbenzoyl
[4S-(4alpha,12aalpha)]-4,7- MS(FAB): m/z 591(M+H); .sup.1H NMR
chloride Bis(dimethylamino)-1,4,4a,5 (d.sub.6-DMSO): delta 2.52(m,
12H, 5a,6,11,12a-octahydro-3,10, C(4)NMe.sub.2 &
C(7)NMe.sub.2), 7.25- 12,12a-tetrahydroxy-9-[(2- 7.56(m, 4H from
2-methylben- methylbenzoyl)amino]-1,11- zoyl), 7.98(s, 1H, H-8)
dioxo-2-naphthacenecarbox- amide 36 2-Fluorobenzoyl
[4S-(4alpha,12aalpha)]-4,7- MS(FAB): m/z 595(M+H); .sup.1H NMR
chloride Bis(dimethylamino)-9-[(2- (d.sub.6-DMSO): delta 2.47-2.51
fluorobenzoyl)amino]-1,4,4a, (m, 6H, C(4)NMe.sub.2), 2.57(bs, 6H,
5,5a,6,11,12a-octahydro-3,10, C(7)NMe.sub.2), 7.39(m, 2H from
12,12a-tetrahydroxy-1,11- 2-fluorobenzoyl), 7.63(m, 1H
dioxo-2-naphthacenecarbox- from 2-fluorobenzoyl), (m, amide 1H from
2-fluorobenzoyl), 8.24(s, 1H, H-8) 37 Pentafluoro-
[4S-(4alpha,12aalpha)]-4,7- MS(FAB): m/z 667(M+H); .sup.1H NMR
benzoyl chloride Bis(dimethylamino)-1,4,4a, (d.sub.6-DMSO): delta
2.5(m, 12H, 5,5a,6,11,12a-octahydro-3,10, C(4)NMe.sub.2 &
C(7)NMe.sub.2), 8.08 12,12a-tetrahydroxy-9- (s, 1H, H-8)
[(pentafluorobenzoyl)amino]- 1,11-dioxo-2-naphthacenecar- boxamide
38 3-Trifluoro- [4S-(4alpha,12aalpha)-4,7- MS(FAB): m/z 645(M+H);
.sup.1H NMR methylbenzoyl Bis(dimethylamino)-1,4,4a,5,
(d.sub.6-DMSO): delta 2.50(m, 6H, chloride
5a,6,11,12a-octahydro-3,10, C(4)NMe.sub.2), 2.57(m, 6H, C(7)
12,12a-tetrahydroxy-1,11- NMe.sub.2), 7.85(m, 2H of 3-tri-
dioxo-9-[[3-(trifluoro- fluoromethylbenzoyl), 7.99
methyl)benzoyl]amino)-2- (m, 1H of 3-trifluoromethyl-
naphthacenecarboxamide benzoyl), 8.28(1H of 3-tri-
fluoromethylbenzoyl), 8.33 (s, 1H, H-8), 8.31-8.42(m, 2H) 39
2-Furoyl [4S-(4alpha,12aalpha)]-4,7- MS(FAB): m/z 567(M+H); .sup.1H
NMR chloride Bis(dimethylamino)-9-[(2- (d.sub.6-DMSO): delta
2.47(m, 6H, furanylcarbonyl)amino]-1,4, C(4)NMe.sub.2), 2.56(s, 6H,
C(7) 4a,5,5a,6,11,12a-octahydro- NMe.sub.2), 6.73(s, 1H of furanyl)
3,10,12,12a-tetrahydroxy- 7.31(s, 1H of furanyl), 7.95
1,11-dioxo-2-naphthacene- (s, 1H of furanyl), 8.00(s, carboxamide
1H, H-8) 40 2-Thiophene- [4S-(4alpha,12aalpha)]-4,7- MS(FAB): m/z
583(M+H); .sup.1H NMR carbonyl Bis(dimethylamino)-1,4,4a,
(d.sub.6-DMSO): delta 2.49(m, 6H, chloride 5,5a,6,11,12a-octahydro-
C(4)NMe.sub.2), 2.56(s, 6H, C(7) 3,10,12,12a-tetrahydroxy-
NMe.sub.2), 7.21(m, 1H of 1,11-dioxo-9-[(2-thienyl- thienyl),
7.70(s, 1H, H-8), carbonyl)amino]-2-naphtha- 7.85(m, 1H of
thienyl), 8.01 cenecarboxamide (m, 1H of thienyl) 41 4-Nitro-
[4S-(4alpha,12aalpha)]-4,7- MS(FAB): m/z 622(M+H); .sup.1H NMR
benzoyl Bis(dimethylamino)-1,4,4a, (d.sub.6-DMSO): delta 2.50(m,
6H, chloride 5,5a,6,11,12a-octahydro- C(4)NMe.sub.2), 2.57(s, 6H,
C(7) 3,10,12,12a-tetrahydroxy-9- NMe.sub.2), 7.76(s, 1H, H-8), 8.20
[(4-nitrobenzoyl)amino]- (d, J=9Hz, 2H of 4-nitrobenzoyl),
1,11-dioxo-2-naphthacene- 8.36(d, J=9Hz, 2H of 4- carboxamide
nitrobenzoyl)
EXAMPLE 42
[4S-(4.alpha.,12a.alpha.)]-9-[(4-Aminobenzoyl)amino]-4,7-Bis(dimethylamino-
)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-nap-
hthacenecarboxamide sulfate
A mixture of 0.030 g of product from Example 41, 0.010 g of 10%
palladium-on-carbon, 1.5 ml of 2-methoxyethanol and 0.175 ml of 2N
sulfuric acid, in a pressure bottle, is shaken under 30 lbs. of
hydrogen pressure for 40 minutes. The catalyst is removed by
filtration and the filtrate is concentrated in vacuo and
codistilled with benzene. The oily residue is dissolved in 0.5 ml
of 2-methoxyethanol, precipitated with diethyl ether and the solid
collected to give 0.018 g of the desired product.
MS (FAB): m/z 592 (M+H).
EXAMPLE 43
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-[[(4-dimethylamino)ben-
zoyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-d-
ioxo-2-naphthacenecarboxamide
A mixture of 0.065 g of product from Example 41, 2.0 ml of
2-methoxyethanol, 0.025 g of 10% palladium-on-carbon, 0.4 ml of 2N
sulfuric acid and 0.3 ml of 37% aqueous formaldehyde, in a pressure
bottle, is shaken under 30 lbs. of hydrogen pressure for 50
minutes. The catalyst is removed by filtration and the filtrate is
concentrated in vacuo and codistilled with heptane. The oily
residue is dissolved in 1.0 ml of 2-methoxyethanol, precipitated
with diethyl ether to give 0.085 g of the desired product as the
sulfate salt. The sulfate salt is dissolved in 0.5 ml of water and
6 ml of tetrahydrofuran followed by the addition of 0.10 g of
sodium acetate. The organic layer is washed with saturated sodium
chloride, dried and concentrated in vacuo. The residue is
triturated with ethyl acetate/heptane to give 0.035 g of the
desired product as the free base.
MS(FAB): m/z 620 (M+H)
.sup.1H NMR (d.sub.6-DMSO): .delta.2.50(m,6H,C(4)NMe.sub.2),
2.57(s, 6H, C(7)NMe.sub.2), 3.33(s,6H, NMe.sub.2 of
4-dimethylaminobenzoyl), 7.76(s,1H,H-8), 8.20(d,J=9 Hz,2H of
4-dimethylaminobenzoyl), 8.37(d,J=9 Hz,2H of
4-dimethylaminobenzoyl).
EXAMPLE 44
[7S-(7.alpha.,10a.alpha.)]-[2-[[9-(Aminocarbonyl)-4,7-Bis(dimethylamino)-5-
,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-napht-
hacenyl]amino]-2-oxoethyl]carbamic acid 1,1-dimethylethyl ester
A mixture of 0.850 g of product from Example 2 (as the disulfate),
0.680 g of sodium acetate in 25 ml of tetrahydrofuran and 5 ml of
water is stirred at 25.degree. C. for 5 minutes. The solution is
treated with 0.359 g of (succinimyloxycarbonyl)methyl carbamic acid
tert-butyl ester, stirred for 2 hours and extracted with
chloroform. The organic layer is concentrated in vacuo to give 0.50
g of the desired product.
MS (FAB): m/z 630 (M+H).
EXAMPLE 45
[4S-(4.alpha.,12a.alpha.)]-9-[(Aminoacetyl)amino]-4,7-Bis(dimethylamino)-1-
,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphth-
acenecarboxamide mono(trifluoroacetate)
A solution of 0.030 g of product from Example 44 and 1.0 ml of
trifluoroacetic acid is maintained at 24.degree. C. for 24 hours
followed by concentrating in vacuo. The residue is triturated with
methyl alcohol and the solid collected to give 0.024 g of the
desired product.
MS (FAB): m/z 530 (M+H).
EXAMPLE 46
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-[[(dimethylamino)acety-
l]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-diox-
o-2-naphthacenecarboxamide sulfate
A mixture of 0.030 g of product from Example 45, 0.020 g of 10%
palladium-on-carbon, 0.5 ml of 37% formaldehyde, 1.5 ml of
2-methoxyethanol and 0.175 ml of 2N sulfuric acid, in a pressure
bottle, is shaken under 30 lbs. of hydrogen pressure for 40
minutes. The catalyst is removed by filtration and the filtrate is
concentrated in vacuo and codistilled with benzene. The oily
residue is dissolved in 0.5 ml of 2-methoxyethanol, precipitated
with diethyl ether and the precipitate collected to give 0.025 g of
the desired product.
EXAMPLE 47
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-oct-
ahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[(phenylsulfonyl)amino]-2-nap-
hthacenecarboxamide
A mixture of 0.30 g of product from Example 2, 0.40 g of sodium
acetate in 10 ml of tetrahydrofuran and 1.5 ml of water is stirred
for 10 minutes under argon. The organic layer is separated, dried
over anhydrous sodium sulfate and treated with 0.125 ml of
benzenesulfonyl chloride and 0.60 g of sodium bicarbonate. The
reaction is stirred vigorously for 1.5 hours. The organic layer is
decanted and codistilled with heptane. The residue is dissolved in
ethyl acetate, dried and concentrated in vacuo. The residue is
chromatographed on diatomaceous earth using hexane:ethyl
acetate:2-methoxyethanol:water (35:65:15:5) to give 0.036 g of the
desired product as a yellow solid.
MS(FAB): m/z 613 (M+H).
.sup.1H NMR (CDCl.sub.3): .delta.2.44(bs,6H,C(4)NMe.sub.2),
2.55(s,6H, C(7)-NMe.sub.2, 7.38-7.45(m,2H,m-H's from
benzenesulfonyl), 7.52-7.56(m,1H,p-H from benzenesulfonyl),
7.58(s,1H,H-8), 7.78(d,J=7 Hz,2H,o-H's from benzenesulfonyl).
EXAMPLES 48-53 (Table II)
Substantially following the method described in detail hereinabove
in Example 47 using [4S-(4.alpha.,12a.alpha.)]-
9-amino-4,7-bis(dimethylamino)-1,4,4a,
5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacene-
carboxamide sulfate (product from Example 2) and the appropriate
alkyl, aryl or heteroarylsulfonyl chloride, the compounds of this
invention listed below in Examples 48-53 are prepared.
TABLE-US-00012 TABLE II Ex. Sulfonyl Chloride Product Spectra 48
4-Chlorobenzene- [4S-(4alpha,12aalpha)]-9- MS(FAB): m/z 622(M+H);
.sup.1H NMR sulfonyl chloride [[(4-chlorophenyl)sulfonyl]-
(d.sub.6-DMSO): delta 2.48(m, 12H, amino]-4,7-bis(dimethyl-
C(4)NMe.sub.2 & C(7)NMe.sub.2), 7.16
amino)-1,4,4a,5,5a,6,11,12a (s, 1H, H-8), 7.62 d, J=9Hz, 2H
tetrahydroxy-1,11-dioxo-2- of 4-chlorobenzenesulfonyl),
naphthacenecarboxamide 7.75(d, J=9Hz, 2H of 4-chloro-
benzenesulfonyl) 49 3-Nitrobenzene- [4S-(4alpha,12aalpha)]-4,7-
MS(FAB): m/z 658(M+H); .sup.1H NMR sulfonyl chloride
Bis(dimethylamino)-1,4,4a,5 (d.sub.6-DMSO): delta 2.44-2.45
5a,6,11,12a-octahydro-3,10, (m, 12H, C(4)NMe.sub.2) &
C(7)NMe.sub.2 12,12a-tetrahydroxy-9-[(3- 7.51-7.62(m, 3H of
3-nitro- nitrophenyl)sulfonyl]amino]- benzenesulfonyl), 7.74-7.78
1,11-dioxo-2-naphthacenecar- (m, 1H of 3-nitrobenzenesul- boxamide
fonyl), 7.75(s, 1H, H-8) 50 4-Nitrobenzene-
[4S-(4alpha,12aalpha)]-4,7- MS(FAB): m/z 658(M+H); .sup.1H NMR
sulfonyl chloride Bis(dimethylamino)-1,4,4a,5, (CDCl.sub.3): delta
2.46(s, 6H, C(4) 5a,6,11,12a-octahydro-3,10, NMe.sub.2), 2.58(s, 6H
C(7)NMe.sub.2) 12,12a-tetrahydroxy-9- 7.59(s, 1H, H-8), 7.96(d, J=
[[(4-nitrophenyl)sulfonyl) 9Hz, 2H of 4-nitrobenzene-
amino]-1,11-dioxo-2- sulfonyl), 8.25(d, J=9Hz,
naphthacenecarboxamide 2H of 4-nitrobenezene- sulfonyl). 51
2-Thiophene [4S-(4alpha,12aalpha)]-4,7- MS(FAB): m/z 619(M+H);
.sup.1H NMR sulfonyl Bis(dimethylamino)-1,4,4a,5, (d.sub.6-DMSO):
delta 2.50(m, 6H, chloride 5a,6,11,12a-octahydro-3,10,
C(4)NMe.sub.2), 2.54(s, 6H, C(7) 12,12a-tetrahydroxy-1,11-
NMe.sub.2), 7.14(m, 1H of thienyl), dioxo-9-[(2-thienylsulfonyl)
7.20(m, 1H of thienyl), 7.51 amino]-2-naphthacenecarbox- (s, 1H of
thienyl), 7.91(s, amide 1H, H-8) 52 2-Acetamido-4-
[4S-(4alpha,12aalpha)]-4- MS(FAB): m/z 691(M+H); .sup.1H NMR
methyl-5-thiazole [[)2-(Acetylamino)-4-methyl- (CDCl.sub.3) delta
2.21(s, 3H, thia- sulfonyl 5-thiazolyl]sulfonyl]amino]- zoyl H
CCONH), 2.40(s, 3H, chloride 4,7-bis(dimethylamino)-1,4, thiazoyl
H.sub.3C), 2.54(s, 6H, C(4) 4a,5,5a,6,11,12a-octahydro- NMe.sub.2),
2.51(s, 6H, C(7)NMe.sub.2), 3,10,12,12a-tetrahydroxy-1, 7.68(s, 6H,
C(7)NMe.sub.2, 7.65(s, 11-dioxo-2-naphthacenecar- 1H, H-8) boxamide
53 Ethane sulfonyl [4S-(4alpha,12aalpha)]-4,7- MS(FAB): m/z
565(M+H); .sup.1H NMR chloride Bis(dimethylamino)-9- (CDCl.sub.3):
delta 0.88(t, 3H, CH.sub.3 [(ethylsulfonyl)amino]-1,4,
CH.sub.2SO.sub.2), 2.4-2.6(m, 12H, C(4) 4a,5,5a,6,11,12a-octahydro-
NMe.sub.2 & C(7)NMe.sub.2), 3.34(q, 2H,
3,10,12,12a-tetrahydroxy- CH.sub.3CH.sub.2SO.sub.2) 7.61(s, 1H,
H-8) 1,11-dioxo-2-naphthacene- carboxamide
EXAMPLE 54
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-(formylamino)-1,4,4a,5-
a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-N-(1-pyrrolidinyl-
methyl)-2-naphthacenecarboxamide
A solution of 0.30 g of product from Example 3 and 1.2 equivalents
of 30% aqueous formaldehyde in 6.0 ml of 2-methoxyethanol is
treated with 5.0 equivalents of pyrrolidine. The reaction is
stirred vigorously at room temperature for 1.5 hours. The
crystalline solid is collected and dried to give 0.25 g of the
desired product.
MS(FAB): m/z 584 (M+H).
EXAMPLE 55
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-oct-
ahydro-3,10,12,12a-tetrahydroxy-9-[(methanesulfonyl)amino]-1,11-dioxo-2-na-
phthacenecarboxamide
A mixture of 0.30 g of product from Example 2, 0.40 g of sodium
acetate in 10 ml of tetrahydrofuran and 1.5 ml of water is stirred
for 10 minutes at room temperature under argon. The organic layer
is separated, dried over sodium sulfate, filtered and treated with
0.10 ml of methanesulfonyl chloride and 0.60 g of sodium
bicarbonate. The reaction is stirred vigorously for 1.5 hours. The
organic layer is decanted and codistilled with heptane. The residue
is dissolved in ethyl acetate, dried and concentrated in vacuo. The
crude product is chromatographed on diatomaceous earth using
hexane:ethyl acetate:2-methoxyethanol:water (35:65:15:5) to give
0.016 g of the desired product as a yellow solid.
MS (FAB): m/z 551 (M+H).
EXAMPLE 56
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-[(methanesulfonyl)amin-
o]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-N-(p-
yrrolidinylmethyl)-2-naphthacenecarboxamide
A solution of 0.30 g of product from Example 55 and 1.2 equivalents
of 30% aqueous formaldehyde in 6.0 ml of 2-methoxyethanol is
treated with 5.0 equivalents of pyrrolidine. The reaction is
stirred vigorously at room temperature for 1.5 hours. The
crystalline solid is collected and dried to give 0.250 g of the
desired product.
MS(FAB): m/z 634 (M+H).
EXAMPLE 57
4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octa-
hydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[(phenylmethoxy)acetyl]amino]-
-2-naphthacenecarboxamide
The title compound is prepared by the procedure of Example 23,
using 0.055 g of product from Example 2, 0.20 g of sodium
bicarbonate, 1.0 ml of N-methylpyrrolidine, 0.018 g of
benzyloxyacetyl chloride and 0.5 ml of acetonitrile to give 0.060 g
of the desired product.
MS (FAB): m/z 622 (M+H).
EXAMPLE 58
[7S-(7.alpha.,10a.alpha.)]-[[9-(Aminocarbonyl)-4,7-Bis(dimethylamino)-5,5a-
,6,6a,7,10,10a12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthace-
nyl]amino] oxo-acetic acid ethyl ester
The title compound is prepared by the procedure of Example 23,
using 0.055 g of product from Example 2, 0.20 g of sodium
bicarbonate, 1.0 ml of N-methylpyrrolidone, 0.015 g of ethyl oxalyl
chloride and 0.5 ml of acetonitrile to give 0.030 g of the desired
product.
MS(FAB): m/z 574 (M+H).
EXAMPLE 59
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-oct-
ahydro-3,10,12,12a-tetrahydroxy-9-[(hydroxyacetyl)amino]-1,11-dioxo-2-naph-
thacenecarboxamide
A mixture of 0.048 g of product from Example 28 and 0.6 ml of
concentrated sulfuric acid is stirred at room temperature for 2
hours, poured into diethyl ether and the precipitated salt
collected. The salt is dissolved in 10 ml of tetrahydrofuran, 0.250
g of sodium acetate is added and the mixture stirred for 1 hour.
The reaction is filtered and the filtrate is concentrated in vacuo.
The residue is chromatographed on a poly(styrene-vinyl
benzene)copolymer column with water:acetonitrile (1:1) to give
0.018 g of the desired product as a light yellow solid.
MS (FAB): m/z 532 (M+H).
EXAMPLE 60
[4S-(4.alpha.,12a.alpha.)]-9-(Acetylamino)-4-(dimethylamino)-1,4,4a,5,5a,6-
,11,12a-octahydro-3,10,12,12a-tetra-hydroxy-1,11-dioxo-2-naphthacenecarbox-
amide sulfate
To a 0.degree. C. solution of 1.06 g of [4S-(4.alpha.,12a.alpha.)]-
9-amino-4-(dimethylamino)-1,2,3,4,4a,5,5a,6,11,11a,12,
12a-dodecahydro-10,12a.alpha.-dihydroxy-1,
3,11,12-tetraoxo-2-naphthacenecarboxamide, prepared by the
procedures described in U.S. Pat. No. 3,239,499, in 50 ml of acetic
acid is added 2.4 ml of acetic anhydride. After 5 minutes, the
reaction is allowed to warm to room temperature. The reaction
mixture is poured into 500 ml of diethyl ether and the resulting
precipitate is collected. The precipitate is washed with diethyl
ether and dried to give 1.1 g of the desired product.
MS(FAB): m/z 472 (M+H).
EXAMPLE 61
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-9-(acetylamino)-1,4,4a,5,5a,6-
,11,12a-octahydro-3,10,12,12a-tetrahydroxy-7-iodo-1,11-dioxo-2-naphthacene-
carboxamide sulfate
To a stirring 0.degree. C. solution of 0.278 g of product from
Example 60 in 10 ml of sulfuric acid is added, portionwise, 0.1344
g of N-iodosuccinimide. After stirring at 0.degree. C. for 20
minutes, the reaction mixture is poured into 400 ml of diethyl
ether. The resultant precipitate is collected, washed with diethyl
ether and dried to give 1.1 g of the desired product as a
solid.
MS(FAB): m/z 598 (M+H) and 696 (M+H.sub.2SO.sub.4+H).
EXAMPLE 62
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-Bis(dimethylamino)-5,5a,-
6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthace-
nyl]carbamic acid methyl ester
To a room temperature mixture of 0.60 g of product from Example 2
in 2 ml of 1-methyl-2-pyrrolidinone is added 0.60 g of sodium
bicarbonate. The mixture is stirred for 5 minutes followed by the
addition of 0.12 ml of methyl chloroformate. The reaction is
stirred at room temperature for 30 minutes and filtered into 200 ml
of t-butyl methyl ether. The resulting solid is collected and dried
to give 0.370 g of the desired product.
MS(FAB): m/z 531 (M+H).
.sup.1H NMR (d.sub.6DMSO): .delta.2.6(s,12H,C(4)NMe.sub.2 and
C(7)NMe.sub.2), 3.7(m,3H,o-CH.sub.3), 7.8(s,1H,H-3),
8.7(s,1H,aromatic NH), 9.1(d,2H,CONH.sub.2).
EXAMPLE 63
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5a,-
6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthace-
nyl]carbamic acid (2-diethylamino) ethyl ester
The title compound is prepared by the procedure of Example 62,
using 0.443 g of product from Example 2, 2 ml of
1-methyl-2-pyrrolidone, 0.165 g of .beta.-diethylaminoethyl
chlorocarbonate hydrochloride and 0.443 g of sodium bicarbonate to
give 0.350 g of the desired product.
.sup.1H NMR (d.sub.6DMSO):
.delta.1.2(m,6H,-N(CH.sub.2CH.sub.3).sub.2), 2.5(s, 6H,
C(7)NMe.sub.2), 2.7(s,6H,C(4)NMe.sub.2), 3.4(m,2H,
OCH.sub.2CH.sub.2N), 3.51(m,4H,-N(CH.sub.2CH.sub.3).sub.2),
4.0(m,2H,--OCH.sub.2CH.sub.2N), 6.8(s,1H,H-3),
9.0(d,2H,CONH.sub.2).
EXAMPLE 64
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5a,-
6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthace-
nyl] carbamic acid ethenyl ester
The title compound is prepared by the procedure of Example 62,
using 0.189 g of product from Example 2, 1 ml of
1-methyl-2-pyrrolidone, 0.75 ml of acetonitrile, 0.20 g of sodium
bicarbonate and 0.037 g of vinyl chloroformate to give 0.133 g of
the desired product.
MS (FAB): m/z 548 (M+H).
.sup.1H NMR (d.sub.6DMSO+TFA): .delta.4.35(s,1H,H-7), 4.6(d,1H,
CH.dbd.CH.sub.2cis), 4.9 (d, 1H, CH.dbd.CH.sub.2,trans), 7.2(m, 2H,
--O--CH.dbd.CH.sub.2), 8.1(s,1H,H-3), 9.6 &
9.1(s,2H,CONH.sub.2), 9.61(s,H,aromatic NH)
EXAMPLE 65
[7S-(7.alpha.,10a.alpha.)]-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5a,-
6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthace-
nyl]carbamic acid 2-propenyl ester
The title compound is prepared by the procedure of Example 62,
using 0.213 g of product from Example 2, 1 ml of
1-methyl-2-pyrrolidone, 0.75 ml of acetonitrile, 0.20 g of sodium
bicarbonate and 0.054 g of allyl chloroformate to give 0.143 g of
the desired product.
.sup.1H NMR (d.sub.6DMSO+TFA): .delta.4.65(d,2H,.dbd.CHCH.sub.2),
5.25(d,1H, CH.dbd.CH.sub.2cis), 5.4(d,1H,CH.dbd.CH.sub.2trans), 6.0
(m,1H,CH.sub.2.dbd.CH.sub.2), 8.1(s,1H,H-3), 9.1(s,1H,aromatic NH),
9.6 & 9.0 (s,2H, CONH.sub.2).
Substantially following the methods described in detail hereinabove
in Example 23, the compounds of this invention listed below in
Examples 66-82 are prepared. Example 72 uses the appropriate
anhydride rather than the acid chloride.
EXAMPLE 66
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-9-[[(4-fluorophenoxy)acetyl]a-
mino]-1,4,4,a,5,5,a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-7-iodo-1,1-
1-dioxo-2-naphthacenecarboxamide.
EXAMPLE 67
[7S-(7.alpha.,10a.alpha.)]-N-[9-(Aminocarbonyl)-4,7-Bis(dimethylamino)-5,5-
a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphtha-
cenyl]-2-thiopheneacetamide.
EXAMPLE 68
[4S-(4.alpha.,12a.alpha.)]-9-[[(Dimethylamino)acetyl]amino]-4,7-bis(dimeth-
ylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-diox-
o-2-naphthacenecarboxamide.
EXAMPLE 69
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydr-
o-
3,10,12,12a-tetrahydroxy-7-iodo-9-[[(methylthio)acetyl]amino]-1,11-diox-
o-2-naphthacenecarboxamide.
EXAMPLE 70
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydr-
o-3,10,12,12a-tetrahydroxy-7-[(1-methylethyl)amino]-1,11-dioxo-9-[(3,3,3-t-
richloro-1-oxopropyl)amino]- 2-naphthacenecarboxamide.
EXAMPLE 71
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-[(1,3-dioxo-3-phenylpr-
opyl)amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,12-d-
ioxo-2-naphthacenecarboxamide.
EXAMPLE 72
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-9-[4-(dimethylamino)-1-o-
xobutyl]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-diox-
o-2-naphthacenecarboxamide.
EXAMPLE 73
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydr-
o-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[(phenylsulfonyl)acetyl]amino]-2--
naphthacenecarboxamide.
EXAMPLE 74
[7S-(7.alpha.,10a.alpha.)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6-
a,7,10,10a-octahydro-1,8,10a,11-tetrahydroxy-4-iodo-10,12-dioxo-2-naphthac-
enyl]-5-methyl-2-furanacetamide.
EXAMPLE 75
[7S-(7.alpha.,10a.alpha.)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5-
a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphtha-
cenyl]-2-thiazoleacetamide.
EXAMPLE 76
[7S-(7.alpha.,10a.alpha.)]-2-[[[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5-
,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-napht-
hacenyl]amino]carbonyl]benzoic acid.
EXAMPLE 77
[7S-(7.alpha.,10a.alpha.)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5-
a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphtha-
cenyl]-3-methyl-2-oxo-1-imidazolidineacetamide.
EXAMPLE 78
[7S-(7.alpha.,10a.alpha.)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5-
a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphtha-
cenyl]-5,6-dimethylpyrazinecarboxamide.
EXAMPLE 79
[7S-(7.alpha.,10a.alpha.)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5-
a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphtha-
cenyl]-3-methyl-3H-imidazo[4,5-b]pyridine-2-acetamide.
EXAMPLE 80
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-oct-
ahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[(pentafluorophenyl)acetyl]a-
mino]-2-naphthacenecarboxamide.
EXAMPLE 81
[7S-(7.alpha.,10a.alpha.)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5-
a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-4-iodo-10,12-dioxo-2--
naphthacenyl]-4-ethyl-2,3-dioxo-1-piperazinecarboxamide.
EXAMPLE 82
[7S-(7.alpha.,10a.alpha.)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5-
a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphtha-
cenyl]-4-ethyl-2,3-dioxo-1-piperazinecarboxamide.
EXAMPLES 83-86
Substantially following the methods described in detail hereinabove
in Example 44, the compounds of this invention listed below in
Examples 83-86 are prepared.
EXAMPLE 83
[7S-(7.alpha.,10a.alpha.)]-[2-[[9-Aminocarbonyl-4,7-bis(dimethylamino)-5,5-
a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy.[.1,12.].
.Iadd.10,12.Iaddend.-dioxo-2-napthacenyl]amino]-2-oxoethyl]carbamic
acid 1,1-dimethyl ester.
EXAMPLE 84
[7S-[2(S*),(7.alpha.,10a.alpha.)]]-[2-[[9-(Aminocarbonyl)-4-(diethylamino)-
- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-
1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]
amino]-1-methyl-2-oxoethyl]carbamic acid 1,1-dimethylethyl
ester.
EXAMPLE 85
[7S-[2(S*),(7.alpha.,10a.alpha.)]]-[2-[[9-(Aminocarbonyl)-4,7-bis
(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,
10a,11-tetrahydroxy-10,12-dioxo-2- naphthacenyl]amino]-
2-oxo-1-phenylethyl]carbamic acid 1,1-dimethylethyl ester.
EXAMPLE 86
[7S-[2(S*),(7.alpha.,10a.alpha.)]]-[4-[[9-(Aminocarbonyl)-4,7-bis
(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,
10a,11-tetrahydroxy-10,12-dioxo-2- naphthacenyl]amino]-
3-[[(1,1-dimethylethoxy)carbonyl]amino]-4-oxobutanoic acid
1,1-dimethylethyl ester.
EXAMPLES 87-91
Substantially following the methods described in detail hereinabove
in Examples 45, the compounds of this invention listed below in
Examples 87-91 are prepared.
EXAMPLE 87
[4S-(4.alpha.,12a.alpha.)]-9-[(Aminoacetyl)amino]-7-(diethylamino)-4-(dime-
thylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-di-
oxo-2-naphthacenecarboxamide.
EXAMPLE 88
[4S-(4.alpha.,9(S*),12a.alpha.)]-9-[(2-Amino-1-oxopropyl)amino]-7-(dimethy-
lamino)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-
hydroxy-1,11-dioxo-2-naphthacenecarboxamide.
EXAMPLE 89
[4S-(4.alpha.,9(S*),12a.alpha.)]-9-[(Aminophenylacetyl)amino]-4,7-bis(dime-
thylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-di-
oxo-2-naphthacenecarboxamide.
EXAMPLE 90
[7S-[2(S*),7.alpha.,10a.alpha.)]]-3-Amino-4-[[9-(aminocarbonyl)-4,7-bis(di-
methylamino)-5,5a,6,6a,7,10,10a,12-octahydro-
1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]amino]-4-oxobutanoic
acid.
EXAMPLE 91
[7S-[2(S*),7.alpha.,10a.alpha.)]]-4-[[9-(Aminocarbonyl)-4,7-bis(dimethylam-
ino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10,10a-tetrahydroxy-10,12-dioxo-2-
-naphthacenyl]amino]-3-(dimethylamino)-4-oxobutanoic acid.
EXAMPLES 92-94
Substantially following the methods described in detail hereinabove
in Example 47, the compounds of this invention listed below in
Examples 92-94 are prepared.
EXAMPLE 92
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-9-[[(2,2-dimethylpropyl)sulfo-
nyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-7-[(1-m-
ethylethyl)amino]-1,11-dioxo-2-naphthacenecarboxamide.
EXAMPLE 93
[7S-(7.alpha.,10a.alpha.)]-4-[[[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5-
,5a,6,6a,7,10,10a,12-octahydro-1,8,10,10a,11-tetrahydroxy-10,12-dioxo-2-na-
phthacenyl]amino] sulfonyl]butanoic acid.
EXAMPLE 94
[4S-(4.alpha.,12a.alpha.)]-4-(Dimethylamino)-9-[[(1,1-dimethylethyl)sulfon-
yl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-7-iodo-1-
,11-dioxo-2-naphthacenecarboxamide.
EXAMPLE 95
[4S-(4.alpha.,12a.alpha.)]-4,7-Bis(dimethylamino]-9-[[(diethylamino)acetyl-
]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-
-2-naphthacenecarboxamide sulfate
The title compound is prepared by the procedure of Example 46,
using 0.030 g of product from Example 45, 0.020 g of 10%
palladium-on-carbon, 2.5 equivalents of acetaldehyde, 1.5 ml of
2-methoxyethanol and 0.175 ml of 2N sulfuric acid to give the
desired product as a solid.
EXAMPLE 96
Dimethylaminoacetyl chloride hydrochloride
A mixture of 15 g of N,N-dimethylglycine hydrochloride (pulverized
and dried in a vacuum oven at 45.degree.-50.degree. C. for 24
hours) and 13.85 ml of thionyl chloride is heated, very slowly, in
a sand bath to 78.degree. C. and kept at this temperature for 11/2
hours. Toluene is added to the mixture and the excess liquid is
removed by pipette. This step is repeated several times. The solid
is then transferred to a Buchner funnel, washed with methylene
chloride and dried under vacuum at 50.degree. C. for 24 hours to
yield 14.2 g of the desired intermediate.
EXAMPLE 97
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[(dimethylamino)acetyl]am-
ino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2--
naphthacenecarboxamide dihydrochloride
To a mixture of 6.68 g of 9-amino-4,7-bis(dimethylamino)-
6-demethyl-6-deoxytetracycline in 120 ml of DMPU and acetonitrile
is added 6.57 g of sodium carbonate. The mixture is stirred for 5
minutes, followed by the addition of 2.83 g of product from Example
96. The reaction is stirred for 1 hour, filtered and the filtrate
is added slowly to a mixture of methylene chloride/diethyl ether
(1200 ml/400 ml). The solid is collected, dissolved in 250 ml
methyl alcohol and added slowly to 1600 ml of methylene chloride.
The precipitate is collected, washed with diethyl ether and dried
to give 5.75 g of the desired product.
MS(FAB): m/z 558 (M+H).
EXAMPLE 98
[4S-4alpha,12aalpha)]-9-[(Chloroacetyl)amino]-4,7-bis(dimethylamino)-1,4,4-
a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacen-
ecarboxamide dihydrochloride
To a room temperature solution of 0.334 g of
9-amino-4,7-bis(dimethyamino)-6-dimethyl-6-deoxytetracycline
sulfate, 6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)pyrimidinone, hereinafter called DMPU, and 2 ml of
acetonitrile is added 0.318 g of sodium carbonate. The mixture is
stirred for 5 minutes followed by the addition of 0.068 g of
chloroacetyl chloride. The reaction is stirred for 30 minutes,
filtered, and the filtrate added dropwise to 100 ml of diethyl
ether, containing 1 ml of 1M hydrochloric acid in diethyl ether.
The resulting solid is collected and dried to give 0.340 g of the
desired product.
MS (FAB): m/z 549 (M+H).
EXAMPLE 99
[4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)amino]-4,7-bis(dimethylamino)-1,4,4-
a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacen-
ecarboxamide dihydrochloride
The title compound is prepared by the procedure of Example 98,
using 0.668 g of 9-amino-4,7-bis(dimethylamino)-
6-dimethyl-6-deoxytetracycline sulfate, 6 ml of DMPU, 2 ml of
acetonitrile, 0.636 g of sodium carbonate and 0.215 g of
bromoacetyl chloride. Seven tenths of a gram of the desired product
is obtained.
MS(FAB): m/z 593 (M+H).
EXAMPLE 100
[4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)amino]-4,7-bis(dimethylamino)-1,4,4-
a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacen-
ecarboxamide (free base)
To 0.20 g of product from Example 99 in 3 ml of
1,3-dimethyl-2-imidazolidenone is added 0.30 g of sodium
bicarbonate. The reaction is stirred at room temperature for 15
minutes and filtered. The filtrate is added to 15 ml of diethyl
ether and the resulting precipitate is collected to give 0.150 g of
the desired product as the free base.
EXAMPLE 101
[4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)amino]-4,7-bis(dimethylamino)-1,4,4-
a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacen-
ecarboxamide monohydrobromide
To a solution of 5.01 g of 9-amino-4,7-bis(dimethylamino)-
6-dimethyl-6-deoxytetracycline, 100 ml of DMPU and 25 ml of
acetonitrile is added 5.0 g of sodium carbonate. The reaction is
stirred, under argon, at room temperature for 5 minutes, followed
by the addition of 3.03 g of bromoacetyl bromide. The stirring is
continued for an additional hour. The solid is collected and the
filtrate is added slowly to isopropyl alcohol/diethyl ether (200
ml/750 ml). The yellow solid is collected, washed with isopropanol
and diethyl ether to give 5.77 g of the desired intermediate.
MS(FAB): m/z 593 (M+H).
EXAMPLE 102
[4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxopropyl)amino]-4,7-bis(dimethylamin-
o)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-na-
phthacenecarboxamide hydrobromide
The title compound is prepared by the procedure of Example 98,
using 1.00 g of 9-amino-4,7-bis(dimethylamino)-
6-demethyl-6-deoxytetracycline, 1.0 g of sodium carbonate and 0.648
g of 2-bromopropionyl bromide to give 0.981 g of the desired
product.
MS(FAB): m/z 607 (M+H).
EXAMPLE 103
[4S-(4alpha,12aalpha)]-9-[(4-Bromo-1-oxobutyl)amino]-7-bis(dimethylamino)--
1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-napht-
hacenecarboxamide dihydrochloride
The title compound is prepared by the procedure of Example 98,
using 1.34 g of 9-amino-4,7-bis(dimethylamino)-
6-demethyl-6-deoxytetracycline sulfate, 1.3 g of sodium carbonate,
24 ml of DMPU, 8 ml of acetonitrile and 0.389 g of 4-bromobutyryl
chloride to give 1.45 g of the desired product.
EXAMPLE 104
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[(dimethylamino)acetyl]am-
ino]-1,4,4a,5,5a,6,11,12a-octa-hydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-
-naphthacenecarboxamide dihydrochloride
To a solution of 0.15 g of product from Example 99 in 4 ml of DMPU
is added 0.85 g of dimethylamine (40% in water). The reaction is
stirred for 20 minutes followed by concentration in vacuo to remove
any excess dimethylamine. The mixture is filtered and the filtrate
added, dropwise, to 70 ml of isopropyl alcohol/diethyl ether (1:1).
To this solution is added 1 ml of 1M hydrochloric acid/diethyl
ether. The resulting precipitate is collected, washed with
isopropyl alcohol and diethyl ether, and dried to give 0.11 g of
the desired product.
MS(FAB): m/z 558 (M+H).
EXAMPLE 105
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahyd-
ro-3,10,12,12a-tetrahydroxy-9-[[(methylamino)acetyl]amino]-1,11-dioxo-2-na-
phthacenecarboxamide dihydrochloride (331,256)
A mixture of 0.1258 g of product from Example 99, 5 ml of 40%
methylamine in water and 5 ml of methyl alcohol, under Argon, is
stirred at room temperature for 30 minutes. The excess methylamine
is removed in vacuo and the residue diluted with a small volume of
methyl alcohol. The diluted reaction solution is added dropwise to
100 ml of diethyl ether containing 1 ml of 1M hydrochloric acid in
diethyl ether and 10 ml of isopropyl alcohol. The resulting solid
is collected and dried to give 0.106 g of the desired product.
MS(FAB): m/z 544 (M+H).
Substantially following the methods described in detail herein
above in Example 105, the compounds of this invention listed below
in Examples 106-125 are prepared.
TABLE-US-00013 Starting Material Example Prod. of NS(FAB): # Name
Exp. Reactant Rx Time m/z 106
[7S-(7alpha,10aalpha)]-N-[9-Aminocarbonyl)-4,7-bis(di- 99
Morpholine 0- .5 hr. 600(M+H)
methylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-
tetrahydroxy-10,12-dioxo-2-naphthacenyl]-4-morpholineacet- amide
dihydrochloride 107
[4S-(4alpha,12aalpha,)]-4,7-Bis(dimethylamino)-9-[[(ethyl- 99
Ethylami- ne 2 hr 558(M+H)
amino)acetyl]amino]-1,4,4a,5,5a,6,11,12,-octahydro-3,10,- (70% in
water) 12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydrochloride. 108
[4S-(4alpha,12aalpha)]-9-[[(Cyclopropylamino)acetyl]amino]- 99
Cyclopr- opylamine 2 hr. 570(M+H)
4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,-
12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide di-
hydrochloride. 109
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[(butyl- 99
Butylamin- e 2 hr. 586(M+H)
amino)acetyl]amino]-1,4,4.,5,5a,6,11,12a-octahydro-3,10,12,-
12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide dihy-
drochloride. 110
[4S-(4alpha,12aalpha)]-9-[[(Diethylamino)acetyl]amino]-4,7- 99
Diethyl- amine 2 hr. 586(M+H)
bis(dimethylamino)-1,4,4a,5,5a,6,11,12,-octahydro-3,12,12,-
12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboximide dihy-
drochloride. 111
[7S-(7alpha,10aalpha)-N-]9-(Aminocarbonyl)-4,7-bis(dimethyl- 99
Pyrrol- idine 0.5 hr. 584(M+H)
amino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10,,11-tetrahydr-
oxy-10,12-dioxo-2-naphthacenyl]-1-pyrrolidineacetamide dihy-
drochloride. 112
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a- 99
Isobutyl- amine 2 hr. 586(M+H)
6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[[2-methyl-
propyl)amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarbox- aide
dihydrochloride. 113
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(di- 99
Piperidine - 1 hr. 598(M+H)
methylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-
tetrahydroxy-10,12-dioxo-2-naphthacenyl]-1-piperidineacet- amide
dihydrochloride. 114
[7S-(7alpha,10aalpha)]-N-]-(Aminocarbonyl)-4,7-bis(di- 99 Imidazole
1 hr. 579(M+H)
methylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-
tetrahydroxy-10,12-dioxo-2-naphthacenyl]-1H-imidazole-1- -acetemide
dihydrochloride. 115
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a- 99
Propylam- ine 0.75 hr. 570(M+H)
6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-
[[(propylamino)acetyl]amino)-2-naphthacenecarboxamide
dihydrochloride. 116
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[dimethyl- 99
Dimethy- lamine 0.5 hr. 558(M+H)
amino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,
12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide disulfate. 117
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[dimethyl- 99
Dimethy- lamine 0.5 hr. 558(M+H)
amino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,
12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide. 118
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[hexyl- 99
n-Hexylami- ne 2 hr. 614(M+H)
amino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,-
12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide dihydro-
chloride. 119
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[2-(dimethyl- 102
Dim- ethylamine 2.5 hr. 572(M+H)
amino)-1-oxopropyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10, (40%
in water) 12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydro- chloride. 120
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11, 102
Me- thylamine 2 hr. 558(M+H)
12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[2-(methylamino)-1- (40%
in water) oxopropyl]amino]-1,11-dioxo-2-naphthacenecarboxamide
dihydro- chloride. 121
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethyl- 102
Pyrr- olidine 1 hr. 598(M+H)
amino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-
10,12-dioxo-2-naphthacenyl]-alpha-methyl-1-pyrrolidine- acetamide
dihydrochloride. 122
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[(4-(dimethyl- 103
Di- methylamine 2 hr. 586(M+H)
amino)-1-oxobutyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10, (40%
in water) 12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
dihydro- chloride. 123
[4S-(4alpha,12aalpha)]-9-[[(Butylmethylamino)acetyl]amino]- 99
N-methy- lbutylamine 2 hr. 600(M+H)
4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,
12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide dihydro-
chloride. 124
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a- 99
Amylamin- e 2 hr. 600(M+H)
6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-
[[[(pentylamino)acetyl]amino]-2-naphthacenecarboxamide
dihydrochloride. 125
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a- 99
Benzylam- ine 1 hr. 620(M+H)
6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-
[[[(phenylmethyl)amino]acetyl]amino]-2-naphthacenecarboxamide
dihydrochloride.
EXAMPLE 126
[7S-(7alpha,10aalpha)]-N-[2-[[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5-
a,6,6a,7,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacen-
yl]amino]- 2-oxoethyl]glycine phenylmethyl ester
To 0.30 g of benzylglycine hydrochloride in 3 ml of
1,3-dimethyl-2-imidazolidinone is added 0.60 g of sodium
bicarbonate. The mixture is stirred at room temperature for 15
minutes and filtered. To the filtrate is added 0.20 g of product
from Example 100. The reaction mixture is sirred at room
temperature for 1 hour and then added to diethyl ether. The
resulting solid is collected.
EXAMPLE 127
[7S-(7alpha,10aalpha)]-N-[2-[[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5-
a,6,6a,7,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacen-
yl]amino]- 2-oxoethyl]glycine
One-tenth of a gram of product from Example 126 in 10 ml of
monomethyl ethylene glycol is reduced catalytically, in a Parr
shaker, with 0.10 g of 10% palladium on carbon, at 30 psi of
hydrogen, for 2 hours. The reaction mixture is filtered and the
filtrate concentrated to give 0.050 g of the desired product.
CI-MS: m/z 588 (M+H).
General Procedure for the Preparation of Mannich Bases
A mixture of 0.5 g of product from Example 117, 3 ml of t-butyl
alcohol, 0.55 ml of 37% formaldehyde, and 0.55 ml of pyrrolidine,
morpholine or piperidine is stirred at room temperature for 30
minutes followed by heating at 100.degree. C. for 15 minutes. The
reaction mixture is cooled to room temperature and triturated with
diethyl ether and hexane. The solid is collected, washed with
diethyl ether and hexane, and dried to give the desired
product.
In this manner the following compounds are made:
EXAMPLE 128
[4S-(4alpha,
12aalpha)]-4,7-Bis(dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a-
,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-N-(1-pyrrolid-
inyl-methyl)-2-naphthacenecarboxamide
EXAMPLE 129
[4S-(4alpha, 12aalpha)]-4,7-Bis(dimethylamino)-9-[[
(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-t-
etrahydroxy-1,11-dioxo-N-(4-morpholinyl-methyl)-2-naphthacenecarboxamide
EXAMPLE 130
[4S-(4alpha,
12aalpha)]-4,7-Bis(dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a-
,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-N-(1-piperdin-
ylmethyl)-2-naphthacenecarbonoxide
EXAMPLE 131
[7S-7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5a,6,6-
a,7,10,10a,12,octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-napthacenyl]-
-1-azetidineacetamide
The title compound is prepared by the procedure of Example 105
using 0.20 g of product form Example 99, 0.50 g of azetidine and 5
ml of DMPU to give 0.126 g of the desired product.
MS(FAB): m/z 570 (M+H).
EXAMPLE 132
[4S-(4alpha,12aalpha)]-9-[[(Cyclobutylamino)acetyl]amino]-4,7-bis(dimethyl-
amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo--
2-naphthacenecarboxamide hydrochloride
To a solution of 0.200 g of 9-(bromoacetylamino)-
7-dimethylamino-6-demethyl-6-deoxytetracycline in 2 ml of
1,3-demethyl-2-imidazolidinone is added 0.1 ml of cyclobutylamine.
The resulting solution is stirred at room temperature for 45
minutes and then added to 50 ml of diethyl ether. An oil layer is
formed and the diethyl ether layer is decanted and the oil is
dissolved in 5 ml of 0.1N methanolic hydrogen chloride. The
resulting solution is added to 50 ml of diethyl ether, yielding
0.050 g of solid.
MS(FAB): m/z 584 (M+H).
* * * * *