# US 7,612,081 B2 · 7-Polyaminoalkyl(oxy)iminomethylcamptothecins bearing protective groups

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- Number: US 7,612,081 B2
- Document ID: US7612081B2
- Status: Granted
- Kind: B2
- Application number: 10/564,637
- Filed: 2004-07-06
- Published: 2007-02-22
- Granted: 2009-11-03
- Earliest claimed: 2003-07-14
- Assignees: Istituto Nazionale Per Lo Studio E La Cura Dei Tumori; Sigma Tau Industrie Farvaceutiche Riunite S.p.A.
- Inventors: Giuseppe Giannini; Claudio Pisano; Loredana Vesci; Maria Ornella Tinti; Lucio Merlini; Sergio Penco; Franco Zunino
- Web page: https://patentgrep.com/patent/US7612081B2

## CPC

- C07D 491/22: in which the condensed system contains four or more hetero rings
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

Compounds are disclosed with the general formula in which the groups are as defined in the description here below and characterized by the presence of polyamine substituents on the imine/oxime residue, such amine groups being in turn protected by suitable protective groups. Said compounds are endowed with potent topoisomerase I inhibiting activity and therefore are useful as medicaments for the treatment of tumors and viral and parasite infections.

## Claims

### Claim 1

Compounds with general formula (I)
in which
m is the number 0 or 1;
Z and Z′ are an integer ranging from 0 to 2 when they are different or are an integer ranging from 1 to 2 when they are the same;
Y and Y′, which can be the same or different, are (CH2)n1; (CH2)n2—CH[NRVII(CH2)n4—NHRI]—(CH2)n3; CH2—CH[CH2—CH2]2— or (CH2)n2—N[(CH2)n4—NHRIV]—(CH2)n3;
Y″ is selected from the group consisting of H; cycloalkyl C3-C7; (CH2)n5—N[CH2—CH2]2N—(CH2)n6NHRV; (CH2)n7 CH[CH2—CH2]2NRV;
X is O, or is a simple bond;
n-n7, which can be the same or different, are an integer ranging from 0 to 5;
RI, RII, RIII, RIV, and RV, which can be the same or different, are a protective group for the nitrogen to which they are bound, said protective group is selected from the group consisting of:
CO2RVI; CO2CH2Ar; CO2-(9-fluorenylmethyl); (CH2)n5—NH CO2RVI; (CH2)n5—NHCO2CH2Ar; (CH2)n5—NHCO2-(9-fluorenylmethyl);
RVI is a straight or branched (C1-C6)alkyl;
RVII is H or RI-RV;
Ar is a C6-C12 aromatic residue, such as phenyl, optionally substituted with one or more groups selected from: halogen, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, phenyl, cyano, nitro, —NRVIIIRIX, where RVIII and RIX, which can be the same or different, are hydrogen, straight or branched (C1-C5) alkyl, or Ar is a heterocyclic group, said heterocyclic group containing at least one heteroatom selected from a nitrogen atom, optionally substituted with a (C1-C5) alkyl group, and/or oxygen and/or sulphur; said heterocycle can be substituted with one or more groups selected from halogen, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, phenyl, cyano, nitro,
—NRVIIIRIX, where RVIII and RIX, which can be the same or different, are hydrogen, straight or branched (C1-C5) alkyl, the N1-oxides, racemic mixtures, their individual enantiomers, their individual diastereoisomers, the E and Z forms, their mixtures, and pharmaceutically acceptable salts.

### Claim 2 (depends on 1)

A compound according to claim 1, in which the protective groups are selected from the group consisting of tert-butoxycarbonyl; benzyloxycarbonyl and 9-fluorenyl-methyloxycarbonyl.

### Claim 3 (depends on 1)

A compound according to claim 1, in which m is 0.

### Claim 4 (depends on 3)

A compound according to claim 3, selected from the group consisting of:
tert-butylester of 20S-(4-{[3-(7-camptothecinylidene-amino)-propyl]-tert-butoxycarbonyl-amino}-butyl)-(3-tert-butoxycarbonylaminopropyl)-carbamic acid;
tert-butylester of 20S-(4-{[3-(7-camptothecinylidene-amino)-propyl]-tertbutoxycarbonyl-amino}-butyl)-carbamic acid; and
benzyl ester of 20S-(4-{[3-(7-camptothecinylidene-amino)-propyl]-benzyloxycarbonyl-amino}-butyl)-carbamic acid.

### Claim 5 (depends on 1)

A compound according to claim 1, in which m is 1.

### Claim 6 (depends on 5)

A compound according to claim 5, selected from the group consisting of:
tert-butylester of 20RS-(4-{[3-(7-homocamptothecinylidene-amino)-propyl]-tertbutoxycarbonyl-amino}-butyl)-(3-tert-butoxycarbonylaminopropyl)-carbamic acid;
tert-butyl ester of 20RS-(4-{[3-(7-homocampto-thecinylidene-amino)-propyl]-tertbutoxycarbonyl-amino}-butyl)-carbamic acid; and
benzyl ester of 20S-(4-{[3-(7-homocamptothecinylidene-amino)-propyl]-benzyloxycarbonyl-amino}-butyl)-carbamic acid.

### Claim 7 (depends on 1)

A pharmaceutical composition containing at least one compound according to claim 1 as the active ingredient in admixture with at least one pharmaceutically acceptable vehicle and/or excipient.

### Claim 8 (depends on 1)

A method of inhibiting topoisomerase comprising administering to a subject in the need of the same an effective amount of a compound of claim 1.

### Claim 9 (depends on 1)

A method of treating cancer, wherein said cancer is non-microcytoma lung cancer or gastric cancer comprising administering to a subject in the need of the same an effective amount of a compound of claim 1.