Camptothecin derivatives

A process for preparing a camptothecin compound derivative comprising (A) a camptothecin represented by the formula (I):

• ##STR44## wherein R.sup.1 is a lower alkyl group, which may optionally be substituted by groups selected from the group consisting of a protected or unprotected hydroxy, mercapto and amino group, X.sup.1 is a group of the formula:
• --NHR.sup.2 (R.sup.2 is a hydrogen atom or a lower alkyl group) or a group of the formula:
• --OH, and Alk is a straight chain or branched chain alkylene group having optionally an oxygen atom in the chain thereof, bonded to (C) an amino acid or a peptide at X.sup.1 of the compound (I), or a salt thereof, which process comprises reacting an aminocarbonyl compound represented by the formula (II):
• ##STR45## wherein X.sup.3 is R.sup.3 --N(R.sup.2)-- or R.sup.3 --O--, R.sup.3 is a group which is prepared by removing a hydroxy group from the carboxyl group of an amino acid or peptide having a protected amino group, and R.sup.1, R.sup.2 and Alk are the same as defined above, with a pyranoindolidine represented by the formula (2):
• ##STR46## removing the protecting group of an amino group from the resulting compound, and then, if required, converting the resulting compound into a salt thereof.

A process for preparing a camptothecin compound represented by the formula (I):

• ##STR47## wherein R.sup.1 is a lower alkyl group, which may optionally be substituted by groups selected from the group consisting of a protected or unprotected hydroxy, mercapto and amino group, X.sup.1 is a group of the formula:
• --NHR.sup.2 (R.sup.2 is a hydrogen atom or a lower alkyl group) or a group of the formula:
• --OH, and Alk is a straight chain or branched chain alkylene group having optionally an oxygen atom in the chain thereof, or a salt thereof, which comprises reacting an aminocarbonyl compound represented by the formula (1):
• ##STR48## wherein X.sup.2 is a protecting group --N(R.sup.2)-- or a protecting group --O--, and R.sup.1, R.sup.2 and Alk are the same as defined above, with a pyranoindolidine represented by the formula (2):
• ##STR49## removing the protecting group from the resulting compound, and then, if required, converting the resulting compound into a salt thereof.

A process for preparing a camptothecin-polysaccharide complex comprising (A) a camptothecin compound represented by the formula (I):

• ##STR50## wherein R.sup.1 is a lower alkyl group, which may optionally be substituted by groups selected from the group consisting of a protected or unprotected hydroxy, mercapto and amino group, X.sup.1 is a group of the formula:
• --NHR.sup.2 (R.sup.2 is a hydrogen atom or a lower alkyl group) or a group of the formula:
• --OH, and Alk is a straight chain or branched chain alkylene group having optionally an oxygen atom in the chain thereof, (B) a polysaccharide having carboxyl groups bonded to (C) an amino acid or a peptide, said amino acid or peptide being bonded to X.sup.1 of the compound (I), or a pharmaceutically acceptable salt thereof, which process comprises:
• (1) reacting an aminocarbonyl compound represented by the formula (1):
• ##STR51## wherein x.sup.2 is a protecting group --N(R.sup.2)-- or a protecting group --O--, and R.sup.1, R.sup.2 and Alk are the same as defined above, with a pyranoindolidine represented by the formula (2):
• ##STR52## removing the protecting group therefrom:
• (2) reacting the resulting compound (I) with an amino acid or a peptide, removing the protecting group of an amino group or a carboxyl group from the resulting compound when an amino group or a carboxyl group thereof is protected;
• and
• (3) reacting the resulting compound having an amino acid or a peptide with a polysaccharide having carboxyl groups, and then, if required, converting the resulting compound into a pharmaceutically acceptable salt thereof.

A process for preparing a camptothecin:

• polysaccharide complex comprising (A) a camptothecin compound represented by the formula (I):
• ##STR53## wherein R.sup.1 is a lower alkyl group, which may optionally be substituted by groups selected from the group consisting of a protected or unprotected hydroxy, mercapto and amino group, X.sup.1 is a group of the formula:
• --NHR.sup.2 (R.sup.2 is a hydrogen atom or a lower alkyl group) or a group of the formula:
• --OH, and Alk is a straight chain or branched chain alkylene group having optionally an oxygen atom in the chain thereof, (B) a polysaccharide having carboxyl groups bonded to (C) an amino acid or a peptide, said amino acid or peptide being bonded to X.sup.1 of the compound (I), or a pharmaceutically acceptable salt thereof, which comprises
• (1) reacting an aminocarbonyl compound represented by the formula (II) ##STR54## wherein X.sup.3 is R.sup.3 --N(R.sup.2)-- or R.sup.3 --O--, R.sup.3 is a group which is prepared by removing a hydroxy group from the carboxyl group of an amino acid or peptide having a protected amino group, and R.sup.1, R.sup.2 and Alk are the same as defined above, with a pyranoindolidine represented by the formula (2):
• ##STR55## removing the protecting group of an amino group from the resulting compound;
• (2) reacting the resulting compound having an amino acid or a peptide with a polysaccharide having carboxyl groups, and then, if required, converting the resulting compound into a pharmaceutically acceptable salt thereof.