Modified prodrug forms of AP/AMP

Details Modified prodrug forms of AP/AMP Modified prodrug forms of AP/AMP

2001-10-15

2002-10-01

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S305000, C546S306000

Reexamination Certificate

active

06458816

ABSTRACT:

BACKGROUND OF THE INVENTION
The reductive conversion of ribonucleotides to deoxyribonucleotides by the enzyme Ribonuclcotide Reductase (RR) is a crucial, rate-controlling step in the pathway leading to the biosynthesis of DNA. (Cory, J. G. In “Inhibitors of Ribonucleotide Diphosphate Reductase Activity”,
International Encyclopedia of Pharmacology and Therapeutics,
Cory, J. G.; Cory, A. H., Eds.; Pergamon Press: New York, (1989); Section 128, pp 1-16). Since deoxyribonucleotides are present in extremely low levels in mammalian cells, an excellent correlation exists between tumor growth rate and specific activity of ribonucleotide reductase (Elford, et al.,
J. Biol. Chem.
(1970), 245, 5228). Mammalian Ribonucleotide Reductase is composed of two dissimilar proteins, often referred to as R1, which binds the ribonucleotide substrate, and R2, which contains non-heme iron and a free tyrosyl radical (Reichard, P.; Ehrenberg, A.
Science,
(1983), 221, 514). Both R1 and R2 contribute to the activity of the enzyme.
Currently, there are two broad classes of RR inhibitors. The first class includes nucleoside analogs whose mechanism of action involves binding to the R1 subunit of the enzyme; several of these are in clinical development. Among these, 2′,2′-difluoro-2′-deoxycytidine (Gemcitabine, Trade name: Gemzar, Eli Lilly) was recently approved by the FDA for the treatment of pancreatic cancer (Baker, et al.,
J. Med. Chem.
(1991), 34, 1879), and 2′-fluoromethylene-2′-deoxycytidine is being evaluated in clinical trials for the treatment of various tumors (McCarthy, J. R. and Sunkara, P. S. In
Design, Synthesis, and Antitumor Activity of An Inhibitor of Ribonucleotide Reductase,
Weiner, D. B.; Williams, W. V. Eds.; CRC Press:Boca Raton, (1994), 68 1364). The second class of RR inhibitors includes N-hydroxyurea (Reichard & Ehrenberg,
Science,
(1983), 221, 514 and Wright, et al.,
Cell Biol.
(1990), 68, 1364) and HCTs [N-Heterocyclic Carboxaldehyde Thiosemicarbazones], which act by destroying the free radical of the R2 subunit. HCTs have been demonstrated to be the most potent inhibitors of ribonucleotide reductase, being 80-5000 fold more effective than N-hydroxyurea in vitro (See, Liu, et al.,
J. Med. Chem.
(1992), 35, 3672 and
J. Med. Chem.
(1995), 38, 4234).
It is also broadly accepted that HCTs exert their enzyme inhibitory effect through their high binding affinity for iron on the R2 subunit, since iron is an essential element at the active site of ribonucleotide reductase. Several years ago, a phase 1 clinical evaluation of the lead compound in this series, 5-HP ( DeConti, et al.,
Cancer Res.
(1972), 32, 1455 and Moore, et al.,
Cancer Res.
(1971), 31, 235) demonstrated that, while the compound gave good activity in animal models it was inactive in patients with solid tumors presumably due to its rapid metabolism in humans. Modification of 5-HP through the introduction of steric hindrance and replacement of the hydroxy group with an amino moiety has resulted in a series of 3-amino-bearing compounds (e.g., 1A (3-AP) and 1B (3-AMP) (See Below)). Among these agents, 3-AP possesses excellent antitumor activity (Liu, et al.,
J. Med. Chem.
(1992), 35, 3672) and drastically reduced clearance rates. It is currently in Phase 1 clinical trials. A single dose clinical trial was halted once the drug reached a pharmacokinetic endpoint without displaying any drug related toxicities. Additional Phase 1 studies of extended dosing schedules (daily times 5 and 96 hour continuous infusion) are in progress.
Despite the in vivo activity displayed by 3-AP, the therapeutic potential of this compound may be limited by its poor water-solubility. Therefore, to improve its water solubility and therapeutic index, the synthesis of two phosphate-bearing water-soluble prodrugs 2 (para 3-AP prodrug) and 3 (ortho 3-AP prodrug) was developed. The phosphate-bearing prodrugs were designed to give good water-solubility at neutral pH and increased bioavailability.
Preliminary in vitro evaluation of the 3-AP prodrugs showed that they were rapidly converted to 3-AP by alkaline phosphatase enzyme. In contrast the in vivo PK studies in Beagle dogs showed that 3-AP released from ortho phosphate-bearing prodrug 3 with a half-life of 14.2h, whereas para prodrug 2 has a half-life of 1.5h. Prodrugs 2 and 3 were also evaluated in the M-109 solid tumorbearing mice in vivo against 3-AP and cytoxan. The results from these experiments showed that the ortho prodrug 3 has better efficacy with reduced toxicity than the parent 3-AP and has comparable activity to that of cytoxan. With the aim to further improve the biological and pharmaceutical profiles and to maximize the therapeutic utility of the 3-AP prodrugs, a series of ortho phosphate-bearing prodrugs were
OBJECTS OF THE INVENTION
In one aspect of the invention, an object of the present invention is to provide compounds, pharmaceutical compositions and methods for the treatment of neoplasia, including cancer, in patients.
In another aspect of the invention, an object of the present invention is to provide methods of treating neoplasia utilizing compositions which exhibit favorable and enhanced characteristics of activity, pharmacokinetics, bioavailability and reduced toxicity.
It is yet another object of the invention to provide compositions and methods for the treatment of cancers which are resistant to treatment with traditional chemotherapeutic agents.
One or more of these and/or other objects of the invention may be readily gleaned from the description of the invention which follows.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to compounds according to the structure:
Where
R is H or CH
3
;
R
2
is phosphate which can be the free acid or salt;
R
3
is H, F, Cl, Br, I, OCH
3
, OCF
3
, CF
3
or a C
1
-C
3
alkyl group;
R
4
is H, F, Cl, Br, I, OCH
3
, OCF
3
,CF
3
, NO
2
, CN, SO
2
CF
3
, COOCH
3
, SF
5
, SO
2
CH
3
, COCH
3
, NH
2
, N(CH
3
)
2
, SCH
3
, OH; and
R
5
and R
6
are each independently H, F, Cl, Br, I, OCH
3
, OCF
3
, CF
3
, NO
2
, CN, SO
2
CF
3
, COOCH
3
, SF
5
, SO
2
CH
3
, COCH
3
, NH
2
, N(CH
3
)
2
, SCH
3
or OH, with the proviso that when any two of R
3
, R
4
, R
5
or R
6
are other than H, the other two of R
3
, R
4
, R
5
or R
6
are H.
In particularly preferred aspects of compounds according to the present invention, R
4
is Cl, F or Br (preferably, Cl) when R
3
, R
5
and R
6
are H. In other preferred aspects according to the present invention, R
5
is F, Cl, OCH
3
or OCF
3
(preferably F) when R
3
, R
4
and R
6
are H. Still in other preferred aspects according to the present invention when two of R
3
, R
4
, R
5
or R
6
are selected from F, Cl, Br or I, (preferably, both substituents are the same and more preferably, both substituents are Cl), the other two of R
3
, R
4
, R
5
or R
6
are H. In still other preferred aspects of the present invention, when R
4
and R
5
or R
5
and R
6
are both F or Cl (preferably, both are Cl), then the other of R
3
and R
6
or R
3
and R
4
are both H. Compounds according to the present invention and especially the preferred compositions according to the present invention, as set forth above, are extremely effective compounds for the treatment of neoplasia, including cancer, and exhibit at least one or more of significantly enhanced anti-neoplasia activity, enhanced higher maximum tolerated doses (MTD) with reduced toxicity and prolonged half-life consistent with favorable pharmacokinetics compared to para or ortho 3-AP prodrugs 2 and 3. This represents an unexpected result. Thus, preferred compounds according to the present invention may be used at much higher doses, to greater effect against neoplasia, including cancer and with enhanced half-life in the blood stream and reduced toxicity.
Compounds according to the present invention may be used in pharmaceutical compositions having biological/pharmacological activity for the treatment of, for example, neoplasia, including cancer, as well as a number of other conditions and/or disease s

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