Bis-(N,N'-bis-(2-haloethyl)amino)phosphoramidates as...

Details Bis-(N,N'-bis-(2-haloethyl)amino)phosphoramidates as... Bis-(N,N'-bis-(2-haloethyl)amino)phosphoramidates as...

2001-05-01

2003-01-14

Chang, Ceila (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S141000, C558S170000, C558S171000, C558S177000, C558S178000, C558S195000

Reexamination Certificate

active

06506739

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to bis-(N,N′-bis-(2-haloethyl)amino)phosphoramidates, pharmaceutical compositions containing them, methods of treatment using them, and processes for their preparation. The compounds possess anti-tumor activities or are capable of being modified to have anti-tumor activities; and this invention relates to the use of the compounds in methods for the treatment of tumors and, especially, for the treatment of cancer.
2. Description of Related Art
Current cancer chemotherapy protocols involve administration to patients of anti-mitotic drugs such as adriamycin, vincristine, cisplatin, doxorubicin, daunomycin and methotrexate, toxins such as diphtheria toxin, pseudomonas toxin and ricin, and anti-tumor drugs such as cyclophosphamide and isophosphamide. Cyclophosphamide is one of the most widely used anti-cancer agents in the world and is administered in combination with a number of other drugs to treat a wide variety of hematologic and solid tumors. However, several features of the cyclophosphamide detract from its clinical efficacy. For example, the drug requires metabolic activation in the liver to produce metabolites that are toxic to cancer cells. The drug is specifically toxic to the urinary bladder, and it also displays the bone marrow toxicity typical of the alkylating agent class of anti-cancer drugs. Cyclophosphamide is a potent suppressor of the immune system at the doses used to treat cancer, thus decreasing the infection-fighting ability of patients already debilitated by their disease. Finally, repeated use of cyclophosphamide frequently results in the development of resistance to the drug in a patient's cancer cells, thus rendering the drug ineffective.
Phosphoramidate derivatives have long been known in the literature and are well documented as alkylating reagents. Some of them have been found to be useful in the treatment of cancer (for a review see, DeVita, “Principles of Cancer Therapy”, pages 765-788 in Petersdorf, et al. Principles of Internal Medicine, 10
th
ed. McGraw-Hill, NY., 1983). Cyclophospharnide analogs are also well known to the literature and have been extensively derivatized (Cyclophosphamide, Merck Index, 11
th
Edition pages 429-430, U.S. Pat. No. 5,190,929). However, there have been relatively few references to bis-(N,N′-bis-(2-chloroethyl)amino) phosphoramidates (DE19524515, U.S. Pat. No. 5,306,727, WO9306120, DE3835772, GB2207674, DE3239858, EP072531). U.S. Pat. No. 5,556,942 discloses the compound
in which Z is bromine, and R is hydrogen, or R is chlorine as a synthetic reaction intermediate.
SUMMARY OF THE INVENTION
In a first aspect, this invention is phosphoramidate compounds of the formula:
where:
X is a halogen atom;
Q is O, S, or NH; and
R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or is R′CO—, R′NHCO—, R′SO
2
—, or R′NHSO
2
— where R′ is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or R-Q together is chlorine,
and the pharmaceutically acceptable salts thereof.
In a second aspect, this invention is pharmaceutical compositions comprising a therapeutically effective amount of a compound of the first aspect of the invention and at least one pharmaceutically acceptable carrier.
In a third aspect, this invention is methods of treatment of disease states in a mammal where administration of an anti-mitotic agent is beneficial, such as tumors and cancer, the method comprising to the mammal a therapeutically effective amount of a compound of the first aspect of the invention, in particular as a composition of the second aspect of the invention.
In a fourth aspect, this invention is processes for the preparation of compounds of the first aspect of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Terms used herein are based upon their recognized meanings and should be clearly understood by those skilled in the art.
The term “halogen” or “halo” includes fluorine, chlorine, bromine, and iodine. Preferred halogens are chlorine and bromine.
The term “alkyl”, as in “alkyl” or “alkyloxy”, means a C
1
-C
20
monovalent hydrocarbyl group which may be linear, branched, or cyclic. The term “lower alkyl”, as in “lower alkyl”, “halo-lower alkyl”, “aryl(lower)alkyl”, or “heteroaryl(lower)alkyl”, means a fully saturated monovalent hydrocarbon group having from 1 to 10 carbon atoms containing only carbon and hydrogen atoms, and which may be cyclic, branched or straight chain. This term is exemplified by groups such as methyl, ethyl, isopropyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclopropylmethyl, cyclohexyl or cyclohexylmethyl. In the context of the present invention, a lower alkyl of 1 to 6 carbon atoms is preferred.
The term “substituted alkyl or substituted lower alkyl” is an alkyl or lower alkyl, respectively, which is mono-, di-, or trisubstituted with a group selected from aryl, R
1
-substituted aryl, heteroaryl, nitro, cyano, halogen, —OR
1
, —SR
1
, —C(O)R
1
, —OC(O)R
1
, —C(O)OR
1
, —NR
1
2
, —SO
2
OR
1
, —OSO
2
R
1
, —SO
2
NR
1
2
, —NR
1
SO
2
R
1
, —CONR
1
2
, or —NR
1
C(O)R
1
, where each R
1
is, independently, hydrogen, lower alkyl, R
2
-substituted lower alkyl, aryl, R
2
-substituted aryl, heteroaryl, heteroaryl(lower)alkyl, R
2
-substituted aryl(lower)alkyl, or aryl(lower)alkyl and each R
2
is, independently, hydroxy, halogen, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower alkyl or amino. Substituted alkyls or substituted lower alkyls which are substituted with one to three of the substituents selected from the group consisting of cyano, halo, lower alkyloxy, thio, nitro, amino, and hydroxy are particularly preferred.
The term “halo-lower alkyl” means a lower alkyl substituted with one to three halo groups, such as —CF
3
, —CH
2
CF
3
and —CH
2
CCl
3
.
The term “aryl(lower)alkyl” means a lower alkyl which is substituted with an aryl. A “substituted aryl(lower)alkyl” means an aryl(lower)alkyl having one to three substituents on the aryl portion or the alkyl portion of the radical, or both.
The term “heteroaryl(lower)alkyl” means a lower alkyl which is substituted with a heteroaryl. A “substituted heteroaryl(lower)aryl” means a heteroaryl(lower)alkyl having one to three substituents on the heteroaryl portion or the alkyl portion of the radical, or both.
The term “lower alkyloxy” means an —OR
3
radical, where R
3
is a lower alkyl.
The term “aryl”, as in “aryl”, “aryloxy”, and “aryl(lower)alkyl”, means a monovalent group derived from an aromatic hydrocarbon containing 6 to 20 ring carbon atoms, having a single ring (e.g., phenyl), or two or more condensed rings, preferably 2 to 3 condensed rings (e.g., naphthyl), or two or more aromatic rings, preferably 2 to 3 aromatic rings, which are linked by a single bond (e.g., biphenyl). The aryl is preferably C
6
-C
16
and even more preferably, C
6
to C
14
.
The term “substituted aryl” means an aryl substituted with one to three substituents selected from alkyl, substituted alkyl, halogen, cyano, nitro, —SR
1
, —OR
1
, —C(O)R
1
, —OC(O)R
1
, —SO
2
OR
1
, —OSO
2
R
1
, —SO
2
NR
1
2
, —NR
1
SO
2
R
1
, —C(O)OR
1
, —NR
1
2
, —CONR
1
2
, or —NR
1
C(O)R
1
, where each R
1
is, independently, hydrogen, lower alkyl, R
2
-substituted lower alkyl, aryl, R
2
-substituted aryl, heteroaryl, heteroary(lower)alkyl, aryl(lower)alkyl, or R
2
-substituted aryl(lower)alkyl and each R
2
is, independently hydroxy, halo, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower alkyl or amino. In addition, any two adjacent substituents on the aryl may optionally together form a lower alkylenedioxy. Particularly preferred substituents on the substituted aryl include hydroxy, halo, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower akyl, halo-lower alkyl, or amino.
The term “heteroaryl”, as in heteroaryl and heteroaryl(lower)alkyl, means a radical derived from an aromatic hydrocarbon containi

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