Dolastatin 10 derivatives

Details Dolastatin 10 derivatives Dolastatin 10 derivatives

2002-07-15

2004-05-18

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S330000, C530S332000, C548S571000, C548S572000

Reexamination Certificate

active

06737409

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel dolastatin 10 derivatives having anti-tumor activity and improved side effects, the use of these compounds in the treatment of tumors, pharmaceutical compositions containing those compounds as well as to processes and intermediates for the preparation of these compounds.
BACKGROUND OF THE INVENTION
Microtubules are known to be the main component of spindles in a mitotic apparatus of eucaryotic cells, and are also involved in many other basic and essential cell functions. Tubulin, a component of microtubules, has attracted our attention for many years as a good molecular target for anticancer therapy (
Exp. Opin. Ther. Patents
1999, 9(8): 1069-1081). In fact, tubulin inhibitors such as taxanes and vinca alkaloids are currently used as important anticancer drugs for the treatment of various solid tumors. However, their efficacy is limited and their toxicity such as myelotoxicity is severe because they lack tumor selective activity. Dolastatin 10 is known to be a potent antimitotic peptide, isolated from the marine mollusk
Dolabella auricularia
, which inhibits tubulin polymerization and is a different chemical class from taxanes and vincas (
Curr. Pharm. Des.
1999, 5: 139-162). Preclinical studies of dolastatin 10 have demonstrated activities against a variety of murine and human tumors in cell cultures and animal models. Dolastatin 10 and two synthetic dolastatin derivatives, Cemadotin and TZT-1027 (
Drugs of the future
1999, 24(4): 404-409) are currently in Phase I and II clinical trials. While this new class of compounds has yielded certain new anti-tumor agents, these agents have safety drawbacks, such as myelotoxicity, neurotoxicity and some other adverse events.
SUMMARY OF THE INVENTION
Surprisingly it has been found that certain dolastatin 10 derivatives having various thio-groups at the dolaproine part show significantly improved anti-tumor activity and therapeutic index in human cancer xenograft models.
Accordingly, the present invention relates to novel compounds of formula I
wherein
R
1
, R
2
and R
3
are each independently selected from hydrogen or (C
1
-C
4
)-alkyl;
R
4
is selected from the group consisting of
hydrogen;
alkyl optionally substituted with one to three substituents selected from the group consisting of hydroxy, alkoxy, amino, mono- or di-alkylamino, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbonyloxy, carbamoyloxy and halogen;
alkenyl;
alkinyl;
(C
3
-C
7
)-cycloalkyl;
aryl optionally substituted with one to three substituents selected from the group consisting of halogen, alkoxycarbonyl, carbamoyl, sulfamoyl,
alkylcarbonyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkyl-carbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino and benzyl;
aralkyl wherein the aryl group optionally substituted with one to three substituents selected from the group consisting of halogen, alkoxycarbonyl, carbamoyl, sulfamoyl, alkylcarbonyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkylcarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino and benzyl; and
heterocyclylalkyl;
R
5
is selected from the group consisting of
(C
1
-C
6
)-alkylamino;
hydroxy;
(C
3
-C
7
)-cycloalkylamino optionally substituted by phenyl or benzyl;
arylamino;
aralkylamino having (C
1
-C
4
)-alkylene and wherein the aryl group optionally may be substituted with one to three substituents selected from the group consisting of halogen, alkoxycarbonyl, sulfamoyl, alkylcarbonyloxy, carbamoyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkylcarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino and benzyl;
(C
1
-C
4
)-alkoxy;
benzhydrazino;
heterocyclyl optionally substituted with one to three substituents selected from the group consisting of benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarbamoyloxy, amino, mono- or di-alkylamino, acylamino, alkoxy-carbonylamino, phenyl and halogen;
heterocyclylamino;
heterocycloalkylamino wherein the heterocyclyl group optionally may be substituted with one to three substituents selected from the group consisting of benzyl, benzhydryl, alkyl, hydroxy, alkoxy, alkylcarbamoyloxy, amino, dialkylamino, acylamino, alkoxycarbonylamino and halogen;
aralkyloxy and aralkyl, both optionally substituted with one to three substituents from the group consisting of halogen, alkoxycarbonyl, sulfamoyl, alkylcarbonyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkylcarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino, aminosulfonyl and benzyl;
and
n is 0, 1 or 2;
or a pharmaceutical acceptable salt thereof.
These compounds have an anti-tumor activity and are useful for the treatment of malignant diseases, particularly of colorectal cancer, lung cancer, breast cancer, stomach cancer, cervical cancer and bladder cancer.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to described the invention herein.
The term “alkyl” as used herein, alone or in combination, means a straight-chain or branched-chain hydrocarbon group containing a maximum of 12, preferably a maximum of 6, carbon atoms, e.g., methyl, ethyl, n-propyl, 2-methylpropyl (iso-butyl), 1-methylethyl (iso-propyl), n-butyl, and 1,1-dimethylethyl (t-butyl), and more preferably a maximum of 4 carbon atoms. The alkyl group may be unsubstituted or may be substituted with one or more substituents, preferably with one to three substituents, most preferably with one substituent. The substituents are selected from the group consisting of hydroxy, alkoxy, amino, mono- or di-alkylamino, acetoxy, alkylcarbonyloxy, carbamoyloxy, alkoxycarbonyl, carbamoyl or halogen.
The term “alkenyl” as used therein, alone or in combination, refers to a hydrocarbon chain as defined for alkyl having at least one olefinic double bond (including for example, vinyl, allyl and butenyl) and having the general formula C
m
H
2m−1
wherein m is an integer greater than 2, preferably m is an integer of 2 to 7.
The term “alkynyl” refers to a hydrocarbon chain as defined for alkyl having at least one triple bond (including for example propynyl, butyn-(1)-yl, etc) and having the general formula C
m
H
2m−2
wherein m is an integer greater than 2, preferably m is an integer of 2 to 7.
The term “(C
3
-C
7
)-cycloalkyl” signifies a saturated, cyclic hydrocarbon group with 3-7 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and the like. The cycloalkyl group may be unsubstituted or substituted with one or more substituents, preferably with one to three substituents, most preferably with one substituent. The substituents are selected from alkyl, phenyl, amino, hydroxy or halogen, preferably is phenyl.
The term “alkylene” refers to a biradical branched or unbranched hydrocarbon chain containing 1 to 4 carbon atoms, such as methylene (—CH
2
—), ethylene, propylene, isopropylene and butylene.
The term “aryl” refers to an aromatic carbocyclic radical, i.e. a 6 or 10 membered aromatic or partially aromatic ring, e.g. phenyl (i.e. “Ph”), naphthyl or tetrahydro-naphthyl, preferably phenyl or naphthyl, and most preferably phenyl. The aryl moiety is optionally substituted with one or more subsituents, preferably with one to three, most preferably one, selected from the group consisting of halogen, preferably fluorine, chlorine, alkoxycarbonyl, (e.g. methoxycarbonyl), alkylcarbonyloxy (e.g., acetoxy), cyano, alkyl, alkoxy, phenyl, phenoxy, trifluormethyl, trifluormethoxy, alkylthio, hydroxy, carbamoyloxy, alkylcarbonylamino, heterocyclyl, sulfamoyl (i.e. H
2
NSO
2
—), amino, 1,3-dioxolyl, or 1,4-dioxolyl. Especially preferred substituents are alkyl, alkoxy, hydroxy, halogen, amino, alkylamino, dialkylamino, alkylthio

Affiliated with

Also associated with

Rating

Dolastatin 10 derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Dolastatin 10 derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Dolastatin 10 derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3209444