Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-08-22
2001-04-17
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S188000, C546S002000
Reexamination Certificate
active
06218378
ABSTRACT:
FIELD OF THE INVENTION
THIS INVENTION relates to metal complexes of aryl phosphines and processes for their preparation.
BACKGROUND OF THE INVENTION
Although platinum anti-cancer drugs are currently the only metal compounds in clinical use for cancer chemotherapy, many other metal complexes have shown high antitumour activity in animal models. There is great scope for the design of metal antitumour drugs that may be less toxic and more effective than platinum complexes.
Previous work contributed to the identification of certain metal diphosphine complexes as a potential new class of anti-cancer agents. In particular, the Au(I) complex [Au(dppe)
2
]Cl (where dppe is 1,2-bis(diphenylphosphino)ethane) showed good antitumour activity against a range of tumour models in mice as disclosed in Berners-Price et al., 1986, Cancer Research 46 5486-5493. Structure activity relationships have been evaluated for a wide range of diphosphine ligands and their metal complexes as disclosed in Berners-Price et al., 1988, Structure Bonding (Berlin) 70 27-102. For complexes of the type [Au(R
2
P(CH
2
)
n
PR′
2
)
2
]X highest activity was found where R═R′=phenyl and n=2,3 or the cis-CH═CH analogue. In general, activity was reduced, or lost altogether when the phenyl substituents on the phosphine were replaced by other substituents, but retained when Au(I) is substituted by Ag(I) or Cu(I). Dppe complexes of other metals (e.g. Pt(II) and Pd(II)) were found to be less active than the phosphine alone as shown in Khohkar et al., 1990, Inorg. Biochem. 39 117 and Mirabelli et al., 1987, J. Med. Chem. 30 2181. Since the tetrahedral complexes of the Group 11 metal ions have kinetically labile M—P bonds it is possible that the metal acts as a delivery system for the cytotoxic diphosphines. The mechanism of the cytotoxic activity is, however, still unknown, although the available evidence indicates that the primary cytotoxic lesion may arise from damage to nuclear chromatin. [Au(dppe)
2
]
+
produced DNA-single strand breaks and DNA-protein crosslinks in tumour cells, with the latter being the critical lesions at low concentrations (Berners-Price et al., (1986) above).
Clinical development of [Au(dppe)
2
]Cl was precluded following the identification of severe cardiac, hepatic and vascular toxicities in preclinical trials in Beagle dogs as described in Rush et al., 1987, Toxicologist 7 59 and Hoke et al., 1989, Toxicol. Appl. Pharmacol. 100 293. These toxicities have been attributed to disruption of mitochondrial function as described in Hoke et al., 1988, Biol. Chem. 262 11203. [Au(dppe)
2
]
+
is a cation with eight hydrophobic phenyl substituents and these properties promote dissolution of the complex in the mitochondrial membrane where it uncouples oxidative phosphorylation via dissipation of the membrane potential.
Reference also may be made to Berners-Price et al., 1990, J. Med. Chem. 33 1386 which refers to cytotoxicity and anti-tumour activity of bis(diphosphino) gold chelates and, in particular, with 2- and 4-pyridyl substituents. The 2-pyridyl substituted chelates were found to demonstrate anti-tumour activity in mice while the 4-pyridyl substituted chelates were inactive.
Metal complexes of aryl phosphines are disclosed in EP0164970 and in EP0198696. EP0164970 discloses a process for preparing a pharmaceutical composition which comprises combining an inert pharmaceutically acceptable carrier or diluent with an effective tumour cell growth inhibiting amount of a metal complex of a bidentate phenyl phosphine. However, such compounds have since been shown to develop severe cardiac hepatic and vascular toxicities in pre-clinical trials in Beagle dogs as described above.
EP0198696 discloses gold complexes of a bidentate pyridyl phosphine and compositions containing same and their use as tumour cell inhibitors. However, as will be demonstrated hereinafter, the structure of such complexes of bidentate pyridyl phosphines are not believed to be correct and hence this creates difficulties in clinical assessment of such compounds.
Further progress in the development of metal phosphine antitumour drugs depends on being able to separate the anti-tumour effects from toxic side effects. A major difficulty would appear to be that the presence of phenyl substituents promotes the mitochondrial toxicity, but structure activity relationships suggest that these phenyl groups are important for cytotoxic activity.
The introduction of cisplatin and other platinum-based drugs into the clinical treatment of cancer has resulted in dramatic improvements in the response rates for some tumour types, in particular, testicular, ovarian and bladder cancers. A major clinical limitation to their efficacy is the occurrence of tumours that are resistant to these drugs. The potential significance of this research is that metal phosphine anti-tumour drugs appear to have a different mechanism of action to other drugs in clinical use. Providing the unfavourable toxic side effects can be overcome these compounds offer great potential value for combination chemotherapy or for treatment of cancers that are resistant to other anti-cancer drugs and, in particular, cisplatin.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a method of treatment or inhibition of tumours using metal complexes of aryl phosphines which have selective toxicity in relation to cancer cells including cisplatin resistant human carcinoma cells lines.
A further object of the invention is to provide new metal complexes of aryl phosphines having the same clinical effect as described above.
The invention therefore in one aspect provides a method of treatment or inhibition of tumours including the steps of:
(i) exchanging one or more of the eight phenyl substituents in the compound [M(dppe)
2
]
+
where M is selected from Au(I), Ag(I) and Cu(I) by 2, 3, or 4 pyridyl substituents to provide a compound having anti-tumour activity and an octanol/water partition co-efficient between 0.01 and 25.5; and
(ii) administering said compound to a subject requiring such treatment which compound has selective toxicity to cancer cells including cisplatin resistant human carcinoma cell lines.
Compounds which have particular relevance to the present invention are covered by the following formula:
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are the same or different and may be selected from phenyl, substituted phenyl, 4 pyridyl, 3-pyridyl, 2-pyridyl wherein each of the 4-pyridyl, 3-pyridyl and 2-pyridyl may optionally be substituted;
A is selected from —(CH
2
)—
n
where n is 2 or 3 or cis —CH═CH— or
where R
9
represent carboxylate and in such case R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
may be all phenyl;
M is Au(I), Ag(I) or Cu(I);
X is monovalent anion such as nitrate or halide or any other non-toxic anion;
with the following provisos:
(i) R
1
through R
8
cannot be all phenyl; or
(ii) that when R
1
through R
8
is 2-pyridyl, and A is —(CH
2
)
2
— M cannot be Au(I).
The invention also includes within its scope new compounds of formula (I) above with the proviso that when R
1
through R
8
is the same and is 4-pyridyl, X is Cl and A is —(CH
2
)
2
— M cannot be Au(I).
It is stressed that likely substituents on the phenyl or pyridyl ring are unlikely to adversely affect the anti-tumour activity of the compounds provided that (i) the metal complexes of these substituted phosphines are stable, (ii) the complexes retain the cationic properties, and (iii) the complexes are within the range of partition co-efficients 0.01-25.5.
With regard to anions, EP0164970 indicates that for complexes of formula I, the nature of the anion does not greatly influence the anti-tumour activity. Under physiological conditions, the anion will be readily displaced by chloride which is present at concentrations up to 154 mM.
By the term “non-toxic anion” is meant any anion which has minimal or benign toxicity as discussed in U.S. Pat. No.
Berners-Price Susan Jane
Bowen Richard John
Parsons Peter Gordon
Griffith University
Knobbe Martens Olson & Bear LLP
Schroeder Ben
Shah Mukund J.
LandOfFree
Anti-tumor agents comprising pyridyl-substituted... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Anti-tumor agents comprising pyridyl-substituted..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Anti-tumor agents comprising pyridyl-substituted... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2549937