US 5,892,043 AGranted

Camptothecin derivatives

AssigneeTanabe Seiyaku Co., Ltd.

InventorsKenji Tsujihara, Takayuki Kawaguchi, Satoshi Okuno, Toshiro Yano

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Abstract

A camptothecin derivative comprising a compound of the formula I!: ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are (A) adjacent two groups combine to form alkylene, or both are H, and one of the remaining three groups is --X.sub.n --Alk.sub.m --R.sup.6, and the other two are H, alkyl or halogen, or (B) adjacent two groups combine to form alkylene, and one of the carbon atoms of said alkylene group is substituted by --X.sub.n --Alk.sub.m --R.sup.6, and the remaining three groups are H, alkyl or a halogen, and one or two --CH.sub.2 -- of the alkylene in (A) or (B) may optionally be replaced by --O--, --S-- or --NH--, X is --O-- or --NH--, Alk is alkylene, R.sup.6 is --NH.sub.2, ##STR2## or --OH, m and n are both 0 or 1, or m is 1 and n is 0, which camptothecin compound is bound to a polysaccharide having carboxyl groups via an amino acid or a peptide, or a pharmaceutically acceptable salt thereof. Said camptothecin derivatives show enhanced antitumor activities but few side effects and are useful as a medicament.

Claims17

Dependent claims

A camptothecin derivative, comprising

(i) a camptothecin compound of the formula (I):
##STR28## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are (A) among R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5, two groups being adjacent each other combine to form an alkylene group, or both are a hydrogen atom, and one of the remaining three groups of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is a group of the formula:
--X.sub.n--(Alk).sub.m --R.sup.6, and the other two groups are a hydrogen atom, an alkyl group or a halogen atom, or
(B) among R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5, two groups being adjacent each other combine to form an alkylene group, and one of the carbon atoms of said alkylene group is substituted by a group of the formula --X.sub.n --(Alk).sub.m--R.sup.6, and the remaining three groups of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are a hydrogen atom, an alkyl group or a halogen atom, and one or two methylene groups of the alkylene group in (A) or (B) may optionally be replaced by --O--, --S-- or --NH--,
X is --O--OR --NH--,
Alk is an alkylene group,
R.sup.6 is --NH.sub.2, a group of the formula:
##STR29## m and n are both 0 or 1, or m is 1 and n is 0, (ii) a polysaccharide bearing one or more carboxyl groups, and
(iii) an amino acid or a peptide, wherein the polysaccharide is bonded to the amino acid or peptide via said one or more carboxyl groups, and wherein said amino acid or peptide is bonded, in turn, to R.sup.6 of the camptothecin compound (I), or
a pharmaceutically acceptable salt thereof.

7 more elements

A process for preparing a camptothecin derivative comprising

(i) a campothecin compound of the formula (I):
##STR31## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are (A) among R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5.sub.1 two groups being adjacent each other combine to form an alkylene group, or both are a hydrogen atom, and one of the remaining three groups of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is a group of the formula:
--X.sub.n --(Alk).sub.m --R.sup.6, and the other two groups are a hydrogen atom, an alkyl group or a halogen atom, or
(B) among R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5, two groups being adjacent each other combine to form an alkylene group, and one of the carbon atoms of said alkylene group is substituted by a group of the formula --X.sub.n --(Alk).sub.m --R.sup.6, and the remaining three groups of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are a hydrogen atom, an alkyl group or a halogen atom, and one or two methylene groups of the alkylene group in (A) or (B) may optionally be replaced by --O--, --S-- or --NH--,
X is --O--OR --NH--,
Alk is an alkylene group,
R.sup.6 is --NH.sub.2, a group of the formula:
##STR32## m and n are both 0 or 1, or m is 1 and n is 0, (ii) a polysaccharide bearing one or more carboxyl groups, and
(iii) an amino acid or a peptide, wherein the polysaccharide is bonded to the amino acid or peptide via said one or more carboxyl groups, and wherein said amino acid or peptide is bonded, in turn, to R.sup.6 of the camptothecin compound (I), or a pharmaceutically acceptable salt thereof, wherein said process comprises:
reacting the camptothecin compound (I) with an amino acid or a peptide,
removing the protecting group of an amino group or a carboxyl group from the resulting product when an amino group or a carboxyl group thereof is protected,
reacting the resulting product with a polysaccharide having one or more carboxyl groups, and then, if required,
converting the resulting derivative into a pharmaceutically acceptable salt thereof.

10 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/773,182Filed 27 Dec 1996
Priority: JP 8-34357528 Dec 1995
Granted: 6 Apr 1999
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C08B 37/0018
Alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; -D-Glucans; -D-Glucans, e.g. isolichenan or nigeran; -D-Glucans; -D-Glucans, e.g.…:…
A61K 47/61
The modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule: the organic macromolecular…
A61K 47/65
The modifying agent being a protein, peptide or polyamino acid: peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
A61P 35/00
Antineoplastic agents