Claims for Patent: 5,529,990

Summary for Patent: 5,529,990

Title:	Method for treating bacterial infection with novel 7-substituted-9-substituted amino 6-demethyl-6-deoxytetracyclines
Abstract:	The disclosure is drawn to a method of using novel 7-substituted-9-(substituted amino)-6-demethyl-6-deoxytetracycline compounds to treat infections caused by a wide spectrum of bacterial organisms, including those which are resistant to tetracycline.
Inventor(s):	Hlavka; Joseph J. (Tuxedo Park, NY), Sum; Phaik-Eng (Pomona, NY), Gluzman; Yakov (Upper Saddle River, NJ), Lee; Ving J. (Monsey, NY), Ross; Adma A. (Airmont, NY)
Assignee:	American Cyanamid Company (Wayne, NJ)
Application Number:	08/455,446
Patent Claims:	1. A method for the treatment or control of bacterial infections in warm-blooded animals which comprises administering to said animal a pharmacologically effective amount of a compound of the formula: ##STR222## 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, 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-(1,2,4triazolyl); 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; (C.sub.3 -C.sub.6)cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; a substituted (C.sub.3 -C.sub.6)cycloalkyl group with 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 selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; 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.7 -C.sub.9) aralkyl selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; .alpha.-amino-(C.sub.1 -C.sub.4)alkyl selected from aminomethyl, .alpha.-aminoethyl, .alpha.-aminopropyl or .alpha.-aminobutyl; 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; vinyl or a substituted vinyl group with substitution selected from (C.sub.1 -C.sub.3) alkyl, halogen, (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl, .beta.-naphthyl, halo(C.sub.1 -C.sub.3)alkyl, or a substituted (C.sub.6 -C.sub.10)aryl group with substitution selected from halo, (C.sub.1 -C.sub.4)alkoxy, trihalo(C.sub.1 -C.sub.3)alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.3)alkylamino or carboxy; (C.sub.1 -C.sub.4)alkoxy group; C.sub.6 -aryloxy selected from phenoxy or substituted phenoxy with substitution selected from halo, (C.sub.1 -C.sub.4) alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)alkylamino; (C.sub.7 -C.sub.10)aralkyloxy; vinyloxy or a substituted vinyloxy group with substitution selected from (C.sub.1 -C.sub.4)alkyl, cyano, carboxy, or (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; R.sup.a R.sup.b amino(C.sub.1 -C.sub.4)alkoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or (CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl; or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl; and when R=R.sup.4 (CH.sub.2).sub.n CO-- and n-1-4, R.sup.4 is selected from 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 selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; a substituted (C.sub.3 -C.sub.6)cycloalkyl group with 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 selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; 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.7 -C.sub.10)aralkyl; 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, (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 allylthio; C.sub.6 -arylthio group selected from phenylthio or substituted phenylthio with substitution selected from halo, (C.sub.1 -C.sub.4)alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)alkylamino; C.sub.6 -arylsulfonyl group selected from phenylsulfonyl or substituted phenylsulfonyl with substitution selected from halo, (C.sub.1 -C.sub.4)alkoxy, trihalo(C.sub.1 -C.sub.3) alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.3) alkylamino or carboxy; (C.sub.7 -C.sub.8)aralkylthio group; a heterocycle as defined hereinabove; hydroxy; mercapto; mono- or di-straight or branched chain (C.sub.1 -C.sub.6)- alkylamino with the alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl or 1-methyl-1-ethylpropyl; (C.sub.2 -C.sub.5 )azacycloalkyl group; a carboxy(C.sub.2 -C.sub.4)alkylamino group with the carboxy alkyl selected from aminoacetic acid, .alpha.-aminopropionic acid, .alpha.-aminobutyric acid and the optical isomers thereof; .alpha.-hydroxy(C.sub.1 -C.sub.3)alkyl selected from hydroxymethyl, .alpha.-hydroxyethyl or .alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl; halo(C.sub.1 -C.sub.3)alkyl group; acyl or haloacyl selected from acetyl, propionyl, chloroacetyl, trifluoroacetyl; (C.sub.3 -C.sub.6) cycloalkylcarbonyl; (C.sub.6 -C.sub.10)aroyl selected from benzoyl or naphthoyl; halo substituted (C.sub.6 -C.sub.10)aroyl; (C.sub.1 -C.sub.4)alkylbenzoyl, or (heterocycle)carbonyl, the heterocycle as defined hereinabove; (C.sub.1 -C.sub.4)alkoxycarbonylamino, group selected from tert-butoxycarbonylamino, allyloxycarbonylamino, methoxycarbonylamino, ethoxycarbonylamino or propoxycarbonylamino; (C.sub.1 -C.sub.4)alkoxycarbonyl group selected from methoxycarbonyl, ethoxycarbonyl, straight or branched propoxycarbonyl, allyloxycarbonyl or straight or branched butoxycarbonyl; R.sup.a R.sup.b -amino(C.sub.1 -C.sub.4)alkoxy group wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH).sub.m, m=2-6 or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O, S, --NH, --NOB, and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl; or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)-alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)-alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl, and when R=R.sup.4' (CH.sub.2).sub.n SO.sub.2 -- and n=0 R.sup.4' is selected from amino; monosubstituted amino selected from straight or branched (C.sub.1 -C.sub.6)alkylamino, cyclopropylamino, cyclobutylamino, benzylamino or phenylamino; disubstituted amino selected from dimethylamino, diethylamino, ethyl(1-methylethyl)amino, monomethylbenzylamino, piperidinyl, morpholinyl, 1-imidazolyl, 1-pyrrolyl, 1-(1,2,3-triazolyl) or 4-(1,2,4-triazolyl); 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; (C.sub.3 -C.sub.6) cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; a substituted (C.sub.3 -C.sub.6)cycloalkyl group with 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 selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; 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.7 -C.sub.9)aralkyl; halo(C.sub.1 -C.sub.3)alkyl group; a heterocycle as defined hereinabove; R.sup.a R.sup.b amino (C.sub.1 -C.sub.4)alkoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)-alkyl selected from methyl, ethyl, n-propyl, 1-methyl-ethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W--(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)-alkyl; or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methyl-propyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3) alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3) alkyl; and when R=R.sup.4' (CH.sub.2).sub.n SO.sub.2 -- and n=1-4, R.sup.4' is selected from hydrogen; straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1methylpropyl, 2-methyl-propyl or 1,1-dimethylethyl; (C.sub.1 -C.sub.4) carboxyalkyl; (C.sub.3 -C.sub.6)cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; a substituted (C.sub.3 -C.sub.6) cycloalkyl group with 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 selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; a substituted (C.sub.6 -C.sub.10)aryl group with substitution selected from halo, (C.sub.1 -C.sub.4)alkoxy, tri-halo(C.sub.1 -C.sub.3) alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4) alkoxy-carbonyl, (C.sub.1 -C.sub.3) alkylamino or carboxy; (C.sub.7 -C.sub.9)aralkyl selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; (C.sub.1 -C.sub.4)alkoxy; C.sub.6 -aryloxy selected from phenoxy or substituted phenoxy with substitution selected from halo, (C.sub.1 -C.sub.3)alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3 ) alkylamino; (C.sub.7 -C.sub.10)aralkyloxy; R.sup.a R.sup.b amino (C.sub.1 -C.sub.4) alkoxy, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)-alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O, S, --NH, or NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl; or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl; (C.sub.1 -C.sub.3) alkylthio selected from methylthio, ethylthio or n-propylthio; C.sub.6 -arylthio selected from phenylthio or substituted phenylthio with substitution selected from halo, (C.sub.1 -C.sub.3)alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)alkylamino; (C.sub.7 -C.sub.8) aralkylthio; a heterocycle as defined hereinabove; hydroxy; mercapto; mono- or di- straight or branched (C.sub.1 -C.sub.6)alkyl- amino group the alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl or 1-methyl-1-ethylpropyl; halo (C.sub.1 -C.sub.3) alkyl; acyl or haloacyl selected from acetyl, propionyl, chloro-acetyl, trifluoroacetyl; (C.sub.3 -C.sub.6) cycloalkylcarbonyl; (C.sub.6 -C.sub.10) aroyl selected from benzoyl or naphthoyl; halo substituted (C.sub.6 -C.sub.10)aroyl, (C.sub.1 -C.sub.4) alkylbenzoyl, or (heterocycle) carbonyl, the heterocycle as defined hereinabove; (C.sub.1 -C.sub.4)alkoxycarbonyl selected from methoxycarbonyl, ethoxycarbonyl, straight or branched propoxycarbonyl, allyloxycarbonyl or straight or branched butoxycarbonyl; R.sup.5 is selected from hydrogen; straight or branched (C.sub.1 -C.sub.3) alkyl selected from methyl, ethyl n-propyl or 1-methylethyl; (C.sub.6 -C.sub.10) aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; (C.sub.7 -C.sub.9) aralkyl group; a heterocycle as defined hereinabove; or --(CH.sub.2).sub.n COOR.sup.7 where n=0-4 and R.sup.7 is selected from hydrogen; straight or branched (C.sub.1 -C.sub.3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; or (C.sub.6 -C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; R.sup.6 is selected from hydrogen; straight or branched (C.sub.1 -C.sub.3)alkyl group selected form methyl, ethyl, n-propyl or 1-methylethyl; (C.sub.6 -C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; (C.sub.7 -C.sub.9)-aralkyl group; a heterocycle as defined hereinabove; or --(CH.sub.2).sub.n COOR.sup.7' where n=0-4 and R.sup.7' is selected from hydrogen; straight or branched (C.sub.1 -C.sub.3)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl; or (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; with the proviso that R.sup.5 and R.sup.6 cannot both be hydrogen; or R.sup.5 and R.sup.6 taken together are --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 --, wherein W is selected from (CH.sub.2).sub.q and q=0-1, --NH, --N(C.sub.1 -C.sub.3)--alkyl, --N(C.sub.1 -C.sub.4) alkoxy, oxygen, sulfur or substituted congeners selected from (L or D)proline, ethyl(L or D)prolinate, morpholine, pyrrolidine or piperidine; and the pharmacologically acceptable organic and inorganic salts or metal complexes. 2. A method for the treatment or control of bacterial infections in warm-blooded animals caused by bacteria having the TetM and TetK resistant determinants which comprises administering to said animal a pharmacologically effective amount of a compound of the formula: ##STR223## wherein: X is selected from amino, NR.sup.1 R.sup.2 or halogen; the halogen is selected from bromine, chlorine, fluorine or iodine; is 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, 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 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 selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; a substituted (C.sub.3 -C.sub.6)cycloalkyl group with 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 selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; 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.7 -C.sub.9) aralkyl selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; .alpha.-amino-(C.sub.1 -C.sub.4)alkyl selected from aminomethyl, .alpha.-aminoethyl, .alpha.-aminopropyl or .alpha.-aminobutyl; 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; vinyl or a substituted vinyl group with substitution selected from (C.sub.1 -C.sub.3) alkyl, halogen, (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl, .beta.-naphthyl, halo(C.sub.1 -C.sub.3)alkyl, or a substituted (C.sub.6 -C.sub.10)aryl group with substitution selected from halo, (C.sub.1 -C.sub.4)-alkoxy, trihalo(C.sub.1 -C.sub.3)alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.3)alkylamino or carboxy; (C.sub.1 -C.sub.4)alkoxy group; C.sub.6 -aryloxy selected from phenoxy or substituted phenoxy with substitution selected from halo, (C.sub.1 -C.sub.4) alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)alkylamino; (C.sub.7 -C.sub.10)aralkyloxy; vinyloxy or a substituted vinyloxy group with substitution selected from (C.sub.1 -C.sub.4)alkyl, cyano, carboxy, or (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; R.sup.a R.sup.b amino(C.sub.1 -C.sub.4)alkoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or (CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl; or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub. 1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O,S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl; and when R=R.sup.4 (CH.sub.2).sub.n CO-- and n-1-4, R.sup.4 is selected from 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 selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; a substituted (C.sub.3 -C.sub.6)cycloalkyl group with 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 selected from phenyl, .alpha.-naphthyl or .beta.-naphyhyl; 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.7 -C.sub.10)aralkyl; 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, (C.sub.1 -C.sub.4)alkylbenzyl 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 allylthio; 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 -arylsulfinyl group selected from phenylsulfonyl or substituted phenylsulfonyl with substitution selected from halo, (C.sub.1 -C.sub.4)alkoxy, trihalo(C.sub.1 -C.sub.3)alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.3) alkylamino or carboxy; (C.sub.7 -C.sub.8)aralkylthio group; a heterocycle as defined hereinabove; hydroxy; mercapto; mono- or di-straight or branched chain (C.sub.1 -C.sub.6)--alkylamino with the alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl or 1-methyl-1-ethylpropyl; (C.sub.2 -C.sub.5)azacycloalkyl group; a carboxy(C.sub.2 -C.sub.4)alkylamino group with the carboxy alkyl selected from aminoacetic acid, .alpha.-aminopropionic acid, .alpha.-aminobutyric acid and the optical isomers thereof; .alpha.-hydroxy(C.sub.1 -C.sub.3)alkyl selected from hydroxymethyl, .alpha.-hydroxyethyl or .alpha.-hydroxy-1-methylethyl or .alpha.-hydroxypropyl; halo(C.sub.1 -C.sub.3)alkyl group; acyl or haloacyl selected from acetyl, propionyl, chloroacetyl, trifluoroacetyl; (C.sub.3 -C.sub.6) cycloalkylcarbonyl; (C.sub.6 -C.sub.10)aroyl selected from benzoyl or naphthoyl; halo substituted (C.sub.6 -C.sub.10)aroyl; (C.sub.1 -C.sub.4)alkylbenzoyl, or (heterocycle)carbonyl, the heterocycle as defined hereinabove; (C.sub.1 -C.sub.4)alkoxycarbonylamino, group selected from tert-butoxycarbonylamino, allyloxycarbonylamino, methoxycarbonylamino, ethoxycarbonylamino or propoxycarbonylamino; (C.sub.1 -C.sub.4)alkoxycarbonyl group selected from methoxycarbonyl, ethoxycarbonyl, straight or branched propoxycarbonyl, allyloxycarbonyl or straight or branched butoxycarbonyl; R.sup.a R.sup.b -amino(C.sub.1 -C.sub.4)alkoxy group wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH).sub.m m= 2-6 or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -wherein W is selected from --N(C.sub.1 -C.sub.3)-alkyl, O, S, --NH, --NOB, and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl; or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4) -alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)-alkyl, O,S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl, and when R=R.sup.4' (CH.sub.2).sub.n SO.sub.2 -- and n=0 R.sup.4' is selected from amino; monosubstituted amino selected from straight or branched (C.sub.1 -C.sub.6)alkylamino, cyclopropylamino, cyclobutylamino, benzylamino or phenylamino; disubstituted amino selected from dimethylamino, diethylamino, ethyl(1-methylethyl)amino, monomethylbenzylamino, piperidinyl, morpholinyl, 1-imidazolyl, 1-pyrrolyl, 1-(1,2,3-triazolyl) or 4-(1,2,4-triazolyl); 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; (C.sub.3 -C.sub.6) cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; a substituted (C.sub.3 -C.sub.6)cycloalkyl group with 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 selected from phenyl, .beta.-naphthyl or B-naphthyl; 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.7 -C.sub.9)aralkyl; halo(C.sub.1 -C.sub.3)alkyl group; a heterocycle as defined hereinabove; R.sup.a R.sup.b amino (C.sub.1 -C.sub.4)alkoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)-alkyl selected from methyl, ethyl, n-propyl, 1-methyl-ethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W--(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3) alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)-alkyl; or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methyl-propyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3) alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3) alkyl; and when R=R.sup.4' (CH.sub.2).sub.n SO.sub.2 -- and n=1-4, R.sup.4' is selected from hydrogen; straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methyl-propyl or 1,1-dimethylethyl; (C.sub.1 -C.sub.4) carboxyalkyl; (C.sub.3 -C.sub.6)cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; a substituted (C.sub.3 -C.sub.6) cycloalkyl group with 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 selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; a substituted (C.sub.6 -C.sub.10)aryl group with substitution selected from halo, (C.sub.1 -C.sub.4)alkoxy, tri-halo(C.sub.1 -C.sub.3) alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxy-carbonyl, (C.sub.1 -C.sub.3) alkylamino or carboxy; (C.sub.7 -C.sub.9)aralkyl selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; (C.sub.1 -C.sub.4)alkoxy; C.sub.6 -aryloxy selected from phenoxy or substituted phenoxy with substitution selected from halo, (C.sub.1 -C.sub.3)alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3) alkylamino; (C.sub.7 -C.sub.10)aralkyloxy; R.sup.a R.sup.b amino (C.sub.1 -C.sub.4) alkoxy, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)-alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O, S, --NH, or NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl; or R.sup.a R.sup.b aminoxy group, wherein R.sup.a R.sup.b is a straight or branched (C.sub.1 -C.sub.4)alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, or 2-methylpropyl or R.sup.a R.sup.b is (CH.sub.2).sub.m, m=2-6, or --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 -- wherein W is selected from --N(C.sub.1 -C.sub.3)alkyl, O, S, --NH, --NOB and B is selected from hydrogen or (C.sub.1 -C.sub.3)alkyl; (C.sub.1 -C.sub.3) alkylthio selected from methylthio, ethylthio or n-propylthio; C.sub.6 -arylthio selected from phenylthio or substituted phenylthio with substitution selected from halo, (C.sub.1 -C.sub.3)alkyl, nitro, cyano, thiol, amino, carboxy, di(C.sub.1 -C.sub.3)alkylamino; (C.sub.7 -C.sub.8) aralkylthio; a heterocycle as defined hereinabove; hydroxy; mercapto; mono- or di- straight or branched (C.sub.1 -C.sub.6)alkyl- amino group the alkyl selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl or 1-methyl-1-ethylpropyl; halo (C.sub.1 -C.sub.3) alkyl; acyl or haloacyl selected from acetyl, propionyl, chloro-acetyl, trifluoroacetyl; (C.sub.3 -C.sub.6) cycloalkylcarbonyl; (C.sub.6 -C.sub.10) aroyl selected from benzoyl or naphthoyl; halo substituted (C.sub.6 -C.sub.10)aroyl, (C.sub.1 -C.sub.4)alkylbenzoyl, or (heterocycle) carbonyl, the heterocycle as defined hereinabove; (C.sub.1 -C.sub.4)alkoxycarbonyl selected from methoxycarbonyl, ethoxycarbonyl, straight or branched propoxycarbonyl, allyloxycarbonyl or straight or branched butoxycarbonyl; R.sup.5 is selected from hydrogen; straight or branched (C.sub.1 -C.sub.3)alkyl selected from methyl, ethyl n-propyl or 1-methylethyl; (C.sub.6 -C.sub.10) aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; (C.sub.7 -C.sub.9) aralkyl group; a heterocycle as defined hereinabove; or --(CH.sub.2).sub.n COOR.sup.7 where n=0-4 and R.sup.7 is selected from hydrogen; straight or branched (C.sub.1 -C.sub.3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; or (C.sub.6 -C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; R.sup.6 is selected from hydrogen; straight or branched (C.sub.1 -C.sub.3)alkyl group selected form methyl, ethyl, n-propyl or 1-methylethyl; (C.sub.6 -C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; (C.sub.7 -C.sub.9)-aralkyl group; a heterocycle as defined hereinabove; or --(CH.sub.2).sub.n COOR.sup.7' where n=0-4 and R.sup.7' is selected from hydrogen; straight or branched (C.sub.1 -C.sub.3)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl; or (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; with the proviso that R.sup.5 and R.sup.6 cannot both be hydrogen; or R.sup.5 and R.sup.6 taken together are --(CH.sub.2).sub.2 W(CH.sub.2).sub.2 --, wherein W is selected from (CH.sub.2).sub.q and q=0-1, --NH, --N(C.sub.1 -C.sub.3)-alkyl, --N(C.sub.1 -C.sub.4) alkoxy, oxygen, sulfur or substituted congeners selected from (L or D)proline, ethyl(L or D)prolinate, morpholine, pyrrolidine or piperidine; and the pharmacologically acceptable organic and inorganic salts or metal complexes.