Isophosphoramide mustard analogs and use thereof

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...

Reexamination Certificate

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C558S045000

Reexamination Certificate

active

06197760

ABSTRACT:

DESCRIPTION
Federally Sponsored Research and Development
This invention was supported by Grants R01 CA 35812 and PO1 CA 34200 from the National Cancer Institute, National Institutes of Health and, therefore, the U.S. Government might have a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms as provided for by the terms of Grants RO1 CA 35812 and PO1 CA 34200.
1. Technical Field
The present invention relates to certain analogs of isophosphoramide mustard (also referred to herein as IPM). The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention, as well as a method of using the compounds in treating cancer in a mammal.
2. Background of Invention
Even though significant advances have occurred in the treatment of cancer, it still remains a major health concern. It has been reported that cancer is the cause of death of up to one of every four Americans.
At the present time, cyclophosphamide (CPA) is the most widely used agent of the alkylating agent class in the clinical treatment of cancer. Two congeners, ifosfamide (Ifos, Holoxan®) and trofosfamide (Trofos, Ixoten®) are also in clinical use in the U.S. and/or Europe. CPA is particularly advantageous in the clinical treatment of ovarian and breast cancer, while Ifos is effective in the clinical treatment of testicular cancer and soft tissue sarcomas. Ifos is also being used in the clinical treatment of breast cancer in the combination drug regimen ICE (Ifos, carboplatin, etopside), since breast cancer is sensitive to Ifos, even occasionally when patients have not responded to CPA-based treatment, suggesting the possibility of some lack of cross resistance between these two drugs. The metabolic pathway for Ifos is shown in Scheme 1 and the metabolic pathway for CPA is closely similar to the Ifos pathway.
IPM has been identified as a major metabolite in patients treated with Ifos. It possesses a spectrum of therapeutic efficacy generally comparable to that of CPA and Ifos against experimental leukemias and solid tumors in mice and rats, as illustrated in Tables 1 and 2. It is important to note that PM is inferior to IPM against experimental solid tumors (Table 2). One limited clinical trial (Phase I) with PM has been reported, and three objective responses were observed (Nathanson et al.,
Cancer Chemother. Rep
. 51:35-39, 1967).
TABLE 1
Activity of Isophosphoramide Mustard Against L1210/0 and L1210/CPA Leukemias
(Optimal Response at ≦ LD10 Dose, from Dose-response Study)
L1210/0

L1210/CPA

Tumor burden at start of
Tumor burden at start of
Treatment = 8.5 × 10
8
cells
Treatment = 6.0 × 10
7
cells
% ILS
Net log
10
% ILS
Net log
10
MTD
Day 60
(dying
reduction in
Day 60
(dying
reduction in
Dosage*
survivors/
mice
tumor burden
survivors/
mice
tumor burden
Agent
(mg/kg
−1
)
total
only)
after therapy
total
only)
after therapy
Cyclophosphamide
200
0/10
+107
7
0/10
+57
4
Ifosfamide
431
0/10
+185
8
0/10
+85
5
289
0/9 
+114
8
0/10
+57
4
Isophosphoramide
100
0/10
+128
8
1/10
+114
7
mustard
*Treatment: i.p.; day 2 only; highest non-toxic dose (LD
10
or less, MTD) in a range of doses.

Implant: i.p.; 10
6
cells, in male CDF
1
mice.
TABLE 2
Response of Lewis Lung Carcinoma to Isophosphoramide Mustard
Implant Size: 20-30 mg; Implant Site: s.c.; Drug Treatment: i.p.
Highest
non-toxic
dosage (MTD)
Tumour-free
Log kill
Agent
Schedule
(mg kg
−1
/dose)
survivors
% ILS

total
&dgr;
Cyclophosphamide (CPA)
Day 2
200
5/10
68
>6.8
Single dose
Ifosfamide (Ifos)
Day 2
300
7/10
55
>4.5
Single dose
Phosphoramide (PM)
Day 2
200
0/10
15
1.2
mustard
Single dose
Day 2
30
0/10
17
1.5
Q5 min × 7
Isophosphoramide
Day 2
100
6/10
34
>2.1
Mustard (IPM)
Single dose

Increase in life span, excluding survivors.
&dgr;
The Log
10
cell kill (total) was calculated from the following formula: Log kill = T C value/(3.32 T
4
). Where T
4
is the tumour volume-doubling time measured from a best fit straight line of the control-group tumours in exponential growth (100 400 mg range). T
4
= 1.2 for Lewis tumour in this experiment.
Comment: The observation of a 50-70% cure rate for CPA, Ifos and IPM agents indicates equivalent activity at equal host toxicity.
Another important consideration is the toxicity of CPA and Ifos. Their common dose limiting toxicity in patients is hemorrhagic cystitis, the cause of which has been attributed to a metabolite, acrolein, generated on the activation pathway (Scheme 1). Much effort has been expended on effective means of controlling this manifestation of high-dose CPA and Ifos. Acrolein has also been shown to be responsible for possible liver toxicity in the form of glutathione depletion and destruction of mixedfunction oxidase activities (cytochrome P-450, aryl hydrocarbon hydroxylase, aminopyrinedemethylase). Furthermore, acrolein was shown to be a teratogenic metabolite of CPA, and 4-hydroxy-CPA, the primary metabolite of CPA in the activation pathway, was shown to be a more potent mutagen than PM. This may be related to a more serious side effect of CPA and its congeners, i.e., bladder cancer; several reports link CPA therapy with subsequent bladder carcinoma and other malignancies, including leiomyosarcoma of the bladder, Hodgkins lymphoma, and acute myeloid leukemia, and acrolein has been proposed as a co-carcinogen in the etiology of such tumors arising in patients after CPA treatment.
Several clinical toxicities in addition to cystitis have also been attributed to Ifos, notably encephalopathy and renal toxicity. The causative metabolite in CNS toxicity has been suggested to be chloroacetaldehyde.
However, the above-discussed acrolein induced toxicities can be avoided by using IPM or a congener. Also, chloroacetaldehyde mentioned above is a metabolite that is not likely to be readily derivable from IPM or an analog. Therefore, IPM or a congener having anticancer activity would provide certain advantages over Ifos and CPA.
Another possible advantage of IPM or a congener over Ifos and CPA is that patient variability in activation of Ifos or CPA would be eliminated. Although this weakness cold be overcome by dose escalation until comparable hematologic toxicity is observed, it is probably true that many clinicians treat with historically-established doses and, if typical toxicity is not observed, may or may not escalate doses in future treatment. In either case, time is lost for patients who metabolize Ifos or CPA less efficiently than normal, and these patients may be compromised to further chemotherapy with these or other agents because of some toxicity and the possible initiation of development or selection of resistant tumor cells.
Further, direct administration of IPM or an analog would circumvent a CPA- and Ifos-type susceptibility to resistance mediated by tumor cell aldehyde dehydrogenase (ALDH) in tumors in which levels of this enzyme are effective in detoxifying aldophosphamide or aldoifosfamide. The obvious negative aspect of this phenomenon is that normal tissues will be more susceptible to typical alkylating agent toxicity, which manifests itself principally as hematologic toxicity. However, selectivity remains, as illustrated by the results shown in Table 1 and 2, in which comparable antitumor activity at equal toxicity (MTD, LD10) was observed, and by the fact that IPM was judged by the National Cancer Institute to have clinical potential. However, the clinical effectiveness of IPM has not been reported.
Finally, there could also be an economic advantage. Ifos is currently used in most sarcoma, lymphoma and germ cell carcinoma protocols. Ifos still produces hematuria despite normal precautions. If the added expense and time to properly administer Ifos and prevent toxicities could be eliminated by replacement of Ifos with IPM or a congener, the improved economics would be a major accomplishment.
Accordingly, a number of analogs of IPM have been prepared a

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