Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-06
2001-05-08
Rotman, Alan L. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S103000
Reexamination Certificate
active
06229015
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention
The invention relates to a process for the preparation of (5-[[&ohgr;-(dialkylamino)alkyl]amino]-8-hydroxyimidazo[4,5,1-de]acridin-6-ones of general formula (I),
wherein R
1
and R
2
represent alkyl groups of 1 to 4 carbon atoms which may be the same or different and n is 2 to 5.
These compounds show anti-neoplastic activity, in particular against leukaemia, melanomas or colon adenocarcinomas, as more fully set forth in Z. Mazerska et al., Anti-Cancer Drug Design 11, 73-88 (1996).
The invention further relates to certain new 1-[[&ohgr;-(dialkylamino)alkyl]amino]-4-substituted-7-hydroxyacridin-9(10H)-ones, useful as intermediates in the process of the invention and also having anti-neoplastic activity.
2. Description of the Related Art
Methods of preparation of the imidazoacridinones of general formula I are known from PCT Application WO-A-92/15583 and W. Cholody et al. J. Med. Chem 35, 378-382 (1992), and depend on cyclisation of amines of general formula (II). The amines (II) can be prepared by a multi step process, as described in the above patent application and shown in Scheme 1:
It was a problem that the 7-hydroxy-4-amino-1-[[&ohgr;-(dialkylamino)alkyl]amino]acridin-9(10H)-one compounds of formula II are unstable. See particularly W. Cholody et al. J. Med. Chem. 35, 378-382 (1992), at page 379, right-hand column. This problem might be overcome by running the reduction and cyclisation as a single step in a “one pot reaction”, by heating the nitro compounds of formula III with Raney nickel and formic acid. This reaction was carried out in the context of synthesising some imidazo[4,5,1-de][1,4]-diazepino[5,6,7-mn]acridines, see W. Cholody et al., J. Heterocyclic Chem. 29, 1749-1752 (1992). This procedure does not require isolation of the unstable amine (II). Unfortunately, however, another problem arose. The purification of the preferred compound 5-[[2-(diethylamino)ethyl]amino]-8-hydroxyimidazo[4,5,1-de]acridin-6-one, of formula I, wherein R
1
and R
2
are ethyl and n is 2, free of nickel ions is difficult because both the compound and nickel ions are soluble in acidic solution, but precipitated by adding alkali. This is a serious problem, expected to arise to a greater or less degree with all the compounds of formula I, especially as they are intended for pharmaceutical use.
When, to avoid contamination by nickel ions, the reduction-cyclisation mixture composed of Raney nickel and formic acid was replaced by formic acid and palladium, the product compounds of formula (I) decomposed slowly during the reaction.
SUMMARY OF THE INVENTION
It has now been found that the last-mentioned problem can be solved if the reduction is carried out in formic acid at room temperature or slightly above, in the presence of palladium catalyst and either (a) a hydrogen-provider such as hydrogen gas or (b) formate ions, substantially all the palladium catalyst is removed and the substantially palladium-free solution is heated to effect cyclisation. Further, this method provided an unexpected, additional benefit. Namely, the order of the operations of deprotecting the hydroxy groups and reacting the 4-chloro compound with the amine could be reversed and the deprotection could then be carried out in the same one-step reaction as the reduction and cyclisation. By this means three reactions can be carried out in one step, thus reducing the overall number of steps from four to two.
The reduction reaction produces an N-formyl compound as intermediate. This N-formyl compound is then cyclised. The overall Scheme is shown below as Scheme 2:
Accordingly, the present invention provides a process of preparing a compound of formula (I):
wherein R
1
and R
2
are alkyl groups of 1 to 4 carbon atoms and n is from 2 to 5, which comprises reacting a 1-chloro-7-(protected hydroxy)-4-nitroacridin-9(10H)-one of Formula (IV-P):
wherein A is a hydroxy-protecting group removable by reduction, with an &ohgr;-(dialkylamino)alkylamine of formula
NH
2
—(CH
2
)
n
NR
1
R
2
in which n, R
1
and R
2
are as defined above, to produce a 7-(protected hydroxy)-4-nitro-1-[[&ohgr;-(dialkylamino)alkyl]amino]acridin-9(10H)-one of formula (III-P):
in which A, n, R
1
and R
2
are as defined above,
reducing the compound of formula (III-P) at a temperature of from 15 to 50° C. with a reducing agent stronger than formic acid, such as hydrogen gas or formate anions, in the presence of a palladium catalyst and formic acid, removing substantially all the residual palladium and heating the remaining reaction mixture, typically at a temperature above 50° C., to effect cyclisation to the corresponding compound of formula (I).
The compound of formula (I), if produced as an addition salt, may be converted to the free base and vice versa. Any known procedures for these purposes may be used.
The invention further includes the N-formyl compounds (II-For) of formula shown in Scheme 2 per se, their preparation by isolation from the above-described filtrate from which substantially all the palladium has been removed, and their conversion to the corresponding compound of formula I comprising heating to effect cyclisation.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The process of the invention requires as starting material a 4-nitro-1-chloro compound of formula (IV-P) in which the hydroxy group is protected. These compounds IV-P can be prepared by preliminary steps shown in Scheme 3 below:
The hydroxy-protecting group, A, may be any which prevents the —OH from reacting with the carboxylic acid function of the benzoic acid derivative in Scheme 3 and may be removed by reduction, preferably benzyl (PhCH
2
—). Other such usable protecting groups include allyl, 4-(dimethylaminocarbonyl)benzyl or arylbenzyl carbonate.
An example of a preparation in accordance with Scheme 3 can be found in Example 2 of European Patent EP-B-0145226 (Warner-Lambert Co.), the disclosure of which is herein incorporated by reference.
Turning now to the process of the invention shown in Scheme 2, the amination step may be carried out in any of the ways described in PCT Application WO-A-92/15583 or in European Patent EP-B-0145226, the disclosures of which in relation thereto are herein incorporated by reference. Preferably amination is by heating at moderately elevated temperature, e.g. 40 to 80° C., in an inert solvent such as dimethylformamide.
The preferred classes of compounds of formula (I) are those in which n is 2 or 3; also those in which R
1
and R
2
are the same, especially both methyl or both ethyl, so the same preferences (separately or together) apply to the amine reactant.
The reduction can be carried out by using hydrogen gas. While this reaction is best carried out at room temperature, say 15-30° C., the benefits of the invention are diminished, but not extinguished, at higher temperatures up to 50° C., especially up to 40° C. Alternatively the reduction can be carried out by using a salt of formic acid, for example ammonium formate, instead of hydrogen, and raising the temperature to between 30 and 50° C. In either case, formic acid, preferably at 80-98% w/v in water, is used. Preferably the formic acid is at 90-97% strength. The palladium catalyst may be present in any amount conventional in this reaction. It is removed from the reaction after reduction is judged to be complete, which is usually within the range 5 to 30 hours, typically 20 hours, at room temperature, depending on the amount of catalyst and stirring rate, and a correspondingly shorter time at slightly elevated temperature. Conveniently it is removed by filtration. The resultant reaction mixture, substantially free of palladium, is then heated to effect cyclisation, preferably to a temperature of above 50° C. and preferably from 80° C. up to reflux. No additional solvent is necessary, formic acid serving this purpose.
The cyclisation reaction is preferably carried out in the presenc
Konieczny Marek Tadeusz
Konopa Jerzy Kazimierz
BTG International Limited
Nixon & Vanderhye
Rotman Alan L.
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