Derivatives of physiologically active substance K-252

A compound represented by formula (Ia) and a pharmacologically acceptable salt thereof:

• ##STR37## {wherein Xa is alkoxycarbonyl having 3 to 6 carbon atoms, ##STR38## (wherein R.sup.8 and R.sup.9 are independently hydrogen, lower alkyl or hydroxy-substituted lower alkyl, or R.sup.8 is hydrogen and R.sup.9 is hydroxy), or --CH.sub.2 Ab [wherein Ab is hydroxy, azido, lower alkylthio, lower alkylsulfenyl, ##STR39## (wherein either R.sup.10a or R.sup.11a is hydrogen and the other is hydrogen lower alkyl, or both are lower alkyl;
• or R.sup.10a and R.sup.11a are combined together to form --CH.sub.2 CH.sub.2;l --O--CH.sub.2 CH.sub.2 --)];
• and Ya is hydroxy;
• or Xa and Ya are combined together to form, as --Xa--Ya--, --O--, --CH.sub.2 --O--, --CH.sub.2 O--CO--O--, --CH.sub.2 --o--CS--O--, --CH.sub.2 --NH--CO--O-- or --CH.sub.2 --o--SO--O--}.

A K-252 derivative represented by formula (Ib) and a pharmacologically acceptable salt thereof:

• ##STR40## [wherein R.sup.1a represents hydrogen, methyl, hydroxymethyl, bromine, hydroxy, lower alkoxy or --NR.sup.5 R.sup.6 (wherein either R.sup.5 or R.sup.6 is hydrogen and the other is hydrogen, carbamoyl or lower alkylaminocarbonyl, or both are lower alkyl) and R.sup.3 is hydrogen, or R.sup.1a and R.sup.3 are the same and represent hydroxy, lower alkoxy or amino;
• R.sup.4a is hydrogen, chlorine, carbamoyl or lower alkyl;
• W.sub.1 and W.sub.2 are hydrogen or both are combined together to represent oxygen;
• Xb is formyl, hydroxymethyl, lower alkoxycarbonyl, --CH.dbd.N--R.sup.12 (wherein R.sup.12 is hydroxy, amino, guanidino or 2-imidazolylamino), and Yb is hydroxy or carbamoyloxy, or Xb and Yb are combined together to form, as --Xb--Yb--, --CH.sub.2 --NH--CS--O-- or ##STR41## (wherein R.sup.14a is lower alkylthio);
• with the priviso that:
• when W.sub.1 and W.sub.2 is oxygen, both R.sup.1a and R.sup.3 are hydrogen, Xb is lower alkoxycarbonyl or hydroxymethyl, R.sup.4a is hydrogen or lower alkyl and Yb is hydroxy;
• when Yb is carbamoyloxy, R.sup.1a, R.sup.3, W.sub.1 and W.sub.2 are all hydrogen, R.sup.4a is carbamoyl and Xb is lower alkoxycarbonyl;
• when R.sup.4a is chlorine, R.sup.1a, R.sup.3, W.sub.1 and W.sub.2 are all hydrogen and Xb is lower alkoxycarbonyl;
• when R.sup.4a is lower alkyl, R.sup.1a and R.sup.3 are hydrogen, W.sub.1 and W.sub.2 are oxygen and Xb is lower alkoxycarbonyl or hydroxymethyl;
• when Xb is formul or --CH.dbd.N--R.sup.12, R.sup.1a, R.sup.3, R.sup.4a, W.sub.1 and W.sub.2 are all hydrogen;
• when Xb is hydroxymethyl, R.sup.1a and R.sup.3 are hydrogen and W.sub.1 and W.sub.2 are oxygen;
• when Xb and Yb are combined together to form, as --Xb--Yb--, ##STR42## R.sup.1a, R.sup.3, R.sup.4a, W.sub.1 and W.sub.2 are all hydrogen;
• and the combinations wherein R.sup.1a, R.sup.3, R.sup.4a, W.sub.1 and W.sub.2 are all hydrogen and Xb is lower alkoxycarbonyl are excluded].

A K-252 derivative represented by formula (Ic) and a pharmacologically acceptable salt thereof:

• ##STR43## wherein R.sup.1b represents hydrogen, methyl, hydroxy, chlorine, hydroxymethyl, lower alkoxy, bromine or --NR.sup.5 R.sup.6 (wherein either R.sup.5 or R.sup.6 is hydrogen and the other is hydrogen, carbamoyl or lower alkylaminocarbonyl, or both are lower alkyl) and R.sup.3a is hydrogen, or R.sup.1b and R.sup.3a are the same and represent hydroxy, lower alkoxy or amino;
• R.sup.2 is hydrogen or amino;
• R.sup.4b is hydrogen, amino or --CH.sub.2 CH.sub.2 R.sup.7 (wherein R.sup.7 is bromine, amino, di-lower alkylamino, hydroxy or hydroxy-substituted lower alkylamino);
• W.sub.1 and W.sub.2 are hydrogen or both are combined together to represent oxygen;
• Xc is hydrogen, lower alkoxycarbonyl, hydroxyaminocarbonyl or CH.sub.2 Ad {wherein Ad is hydroxy, ##STR44## [wherein either R.sup.10b or R.sup.11b is hydrogen and the other is hydrogen, allyl, carboxylic acid-substituted lower alkyl, dihydroxy-substituted lower alkyl, a residue of an .alpha.-amino acid in which the hydroxy of the carboxylic acid is removed or lower alkoxycarbonyl-substituted lower alkyl;
• or both are chlorine-substituted lower alkyl;
• or R.sup.10b and R.sup.11b are combined together to form --CH.sub.2 CH.sub.2 --Va--CH.sub.2 CH.sub.2 -- (wherein Ba is --CH.sub.2 --, --NH-- or --S--)], --N.dbd.CH--NMe.sub.2, ##STR45## Yc is hydroxy;
• or Xc and Yc are combined together to form, as --Xc--Yc--, --CH.sub.2 --NR.sup.13c --CO;13 O-- [wherein R.sup.13c is lower alkyl, allyl, formylmethyl, --CH.sub.2 CH(OH--CH.sub.2 OH, ##STR46## (wherein R.sup.14b is lower alkyl);
• with the proviso that:
• when W.sub.1 and W.sub.2 are oxygen, R.sup.1b, R.sup.2 and R.sup.3a are all hydrogen;
• when R.sup.4b is amino or --CH.sub.2 CH.sub.2 R.sup.7, W.sub.1 and W.sub.2 are oxygen;
• when R.sup.1b is methyl, hydroxy, hydroxymethyl, lower alkoxy, bromine or --NR.sup.5 R.sup.6, R.sup.2 and R.sup.4b are hydrogen and Xc is hydroxymethyl;
• when R.sup.1b is chlorine, R.sup.2 and R.sup.4b are hydrogen and Xc is lower alkoxycarbonyl or hydroxymethyl;
• when R.sup.2 is amino, R.sup.1b and R.sup.4b are hydrogen and Xc is lower alkoxycarbonyl or hydroxymethyl;
• when Xc is hydrogen or CH.sub.2 Ae (wherein the Ae representation is the same as the above Ad representation excluding hydroxy and amino), R.sup.1b, R.sup.2, R.sup.3a, R.sup.3a, W.sub.1 and W.sub.2 are all hydrogen;
• when Xc is hydroxyaminocarbonyl, R.sup.1b, R.sup.2, R.sup.3a and R.sup.4b are all hydrogen and W.sub.1 and W.sub.2 are oxygen;
• when Xc is lower alkoxycarbonyl and W.sub.1 and W.sub.2 are oxygen, R.sup.4b is --CH.sub.2 CH.sub.2 R.sup.7a (wherein R.sup.7a is bromine or di-lower alkylamino);
• when Xc is aminomethyl, R.sup.1b, R.sup.2 and R.sup.3a are hydrogen, W.sub.1 and W.sub.2 are oxygen and R.sup.4b is hydrogen or amino;
• when Xc is hydroxymethyl and W.sub.1 and W.sub.2 are oxygen, R.sup.4b is amino or --CH.sub.2 CH.sub.2 R.sup.7 ;
• when Xc and Yx are combined together to represent, as --Xc--Yc--, --CH.sub.2 --NR.sup.13d --CO--O-- (wherein the R.sup.13d representation is the same as the above R.sup.13c representation excluding lower alkyl) or ##STR47## R.sup.1b, R.sup.2, R.sup.3a, R.sup.4b, W.sub.1 and W.sub.2 are all hydrogen;
• when Xc and Yc are combined together to represent, as --Xc--Yc--, --CH.sub.2 --NR.sup.13e --CO--O-- (wherein R.sup.13e is lower alkyl), R.sup.1b, R.sup.2, R.sup.3a and R.sup.4b are hydrogen and W.sub.1 and W.sub.2 are oxygen;
• and the combinations wherein R.sup.1b, R.sup.2, R.sup.3a, R.sup.4b, W.sub.1 and W.sub.2 are hydrogen, Xc is methoxycarbonyl and Yc is hydroxy and the combinations wherein R.sup.1b, R.sup.2, R.sup.3a, R.sup.4b, W.sub.1 and W.sub.2 are hydrogen, Xc is hydroxymethyl and Yc is hydroxy are removed.