Process for preparing amine platinum complexes

Details Process for preparing amine platinum complexes Process for preparing amine platinum complexes

2000-04-11

2003-02-11

Huang, Evelyn Mei (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S008000, C546S009000, C546S010000, C544S004000, C556S136000, C556S137000, C514S184000, C514S188000

Reexamination Certificate

active

06518428

ABSTRACT:

TECHNICAL FIELD
The present invention relates to the area of platinum drugs. In particular, it relates to an improved process for preparing platinum complexes having the general formula (Ia) or (Ib):
wherein:
L and L′ may be the same or different, provided that L′ may be NH
3
, but L may not be NH
3
; and
L and L′ are each an amine or substituted amine that coordinates to the Pt atom through a nitrogen atom and is a heterocyclic amine or heteroaromatic amine or is represented by NRR′R″, wherein R, R′, or R″ are independently selected from the group consisting of:
hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, nonaromatic or aromatic heterocyclic groups; and
preferably L is a substituted amine wherein the substituent sterically hinders access of the Pt atom to a DNA strand of cell, preferably a tumor cell; and
A may be the same or different and is a halogen or a leaving group such as hydroxy, alkoxide, carboxylate and may be the same or different or form a bi-dentate carboxylate, phosphoncarboxylate, diphosphonate or sulfate; and
Y is a halogen, hydroxy, carboxylate, carbamate or carbonate ester.
BACKGROUND
U.S. Pat. No. 4,329,299 and 5,665,771 describe platinum compounds and their usefulness as antitumor drugs. These two patents disclose platinum compounds that encompass complexes of the formula cis-[PtA
2
(L′)(L)] and c,t,c-[PtA
2
Y
2
(L′)(L)], where A is a leaving group such as halogen, hydroxyl or carboxylate, L is an amine coordinated through the nitrogen atom and L′ is an ammonium or substituted amine. The process for preparing these complexes disclosed in the patents are known in the art (Hydes, P. C. U.S. Pat. No. 4,329,299 (1982); Murrer, B. A. U.S. Pat. No. 5,665,771 (1997); Braddock, P. D.; Connors, T. A.; Jones, M.; Khokhar, A. R.; Melzack, D. H.; Tobe, M. L.
Chem
.-
Biol. Interactions
1975, 11, 145-161; and Giandomenico, C. M.; Abrams, M. J.; Murrer, B. A.; Vollano, J. F.; Rheinheimer, M. I.; Wyer, S. B.; Bossard, G. E.; Higgins (III), J. D.
Inorg. Chem
. 1995, 34, 1015-1021). This process is illustrated in
FIG. 1
with the synthesis of cis-[PtCl
2
(NH
3
)(L)] and c,t,c-[PtCl
2
(OH)
2
(NH
3
)(L)] as examples. From the readily available and commonly used K
2
[PtCl
4
] starting material, the synthesis of cis-[PtCl
2
(NH
3
)(L)] involves four steps and the synthesis of c,t,c-[PtCl
2
Y
2
(NH
3
)(L)] requires five steps. The synthesis of these complexes according to the process known in the art gives low overall yield. U.S. Pat. No. 4,329,299 discloses an overall yield from K
2
[PtCl
4
] of less than 8%, while overall yields of 20-30% have been reported in U.S. Pat. No. 5,665,771 and in the literature (Khokhar et al. and Giandomenico et al.). The low overall yield is due to the many stages involved in the process and to the difficult and low yielding conversion of [PtCl
2
(NH
3
)
2
] to [PtCl
3
(NH
3
)]
−
, which requires the use of expensive Pt catalyst. The synthesis of K[PtCl
3
(NH
3
)] from [PtCl
2
(NH
3
)
2
] is also not particularly robust and large scale synthesis producing K[PtCl
3
(NH
3
)] of consistent quality is difficult to achieve. The process described above further requires the use of silver and iodide ions, and generates silver and iodide contaminated waste products.
U.S. Pat. No. 4,533,502 and UK Patent GB 2137198A disclose a synthetic process to prepare [PtX
2
(L)(L′)] where L and L′ are ligands bonded through amine nitrogen and L≠L′ (Rochon, F. D.; Kong, P.-C. UK Patent GB2137198A (1984) and Rochon, F. D.; Kong, P.-C. U.S. Pat. No. 4,533,502 (1985)). The process is known in the art and the details of this synthetic process has been published (Courtot, P.; Rumin, R.; Peron, A.; Girault, J. P. J.
Organometallic Chem
. 1978, 145, 343-357 and Rochon, F. D.; Kong, P.-C.
Can. J. Chem
. 1986, 64, 1894-1896).
FIG. 2
illustrates the process with [PtCl
2
(L)(L′)] as an example. From K
2
[PtCl
4
], the process disclosed in U.S. Pat. No. 4,533,502 and UK Patent GB 2137198A involves 4 steps and the isolation of 3 intermediate products. The oligomer intermediate product is represented by [PtLI
2
]
x
where x=2 to 4; multiple oligomer species are possible. The overall yield from K
2
[PtCl
4
] was not disclosed in the patent. Silver and iodide ions are used in the process and corresponding silver and iodide contaminated wastes are generated.
[PtCl
3
L]
−
, where L is an amine other than NH
3
, represent an intermediate in the present invention. The preparation of [PtCl
3
L]
−
from a dilute solution of K
2
[PtCl
4
] in dimethylformamide (DMF) where L are pyridine and pyridine derivatives has been reported (Rochon, F. D.; Kong, P.-C.
Can. J. Chem
. 1978, 56, 441-445 and Rochon, F. D.; Beauchamp, A. L.; Bensimon, C.
Can. J. Chem
. 1996, 74, 2121-2130). The preparation of [PtCl
3
L]
−
in solvents other than DMF or H
2
O, or with amine other than pyridine and pyridine derivatives have not been reported. The synthesis of K[PtCl
3
L] in DMF as reported in the literature was performed at 65-80° C. and the yields of the isolated product ranged from 40% to 90% depending on the pyridine derivative. Synthesis of [PtCl
3
L]
−
in DMF can produce reactive or unstable Pt DMF complexes that could interfere with subsequent reactions or decompose to give insoluble black Pt impurities. For example in
Can. J. Chem
. 1978, 56, 441, Rochon et al reported the precipitation of insoluble black material when K[PtCl
3
(2,6-dimethylpyridine)] was dissolved in aqueous solution. It was also reported that an oily paste that contained [PtCl
2
(DMF)(pyridine derivative)] and other impurities was obtained during the isolation of K[PtCl
3
(4-methylpyridine)] and K[PtCl
3
(pyridine)]. Examples of [PtCl
2
(DMF)L] complexes have been reported (Kong, P.-C.; Rochon, F. D.;
Can. J. Chem
. 1979, 57, 682-684; Rochon, F. D.; Kong, P.-C.; Melanson, R.
Can. J. Chem
. 1980, 58, 97-101; and Rochon, F. D.; Melanson, R.; Doyon, M.; Butler, I. S.
Inorg. Chem
. 1994, 33, 4485-4493).
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are incorporated in their entirety by reference herein. Specifically, the present application claims benefit of priority to U.S. provisional patent application serial No. 60/128,939, which was filed on Apr. 13, 1999 and which provisional patent application is incorporated in its entirety by reference herein.
DISCLOSURE OF THE INVENTION
The present invention describes a more efficient and economical process for preparing Pt complexes of the form cis-[PtA
2
(L′)(L)] (formula Ia) and c,t,c-[PtA
2
Y
2
(L′)(L)] (formula Ib) directly from inexpensive and readily available platinum starting material, preferably tetrahaloplatinite like [PtCl
4
]
2−
or [PtBr
4
]
2−
.
wherein:
L and L′ may be the same or different, provided that L′ may be NH
3
, but L may not be NH
3
; and
L and L′ are each an amine or substituted amine that coordinates to the Pt atom through a nitrogen atom and is a heterocyclic amine or heteroaromatic amine or is represented by NRR′R″, wherein R, R′, or R″ are independently selected from the group consisting of:
hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, nonaromatic or aromatic heterocyclic groups; and
prefe

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