Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1999-03-19
2001-07-10
Barts, Samuel (Department: 1609)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S158000, C564S468000, C564S509000, C564S511000, C564S512000, C564S240000, C564S241000
Reexamination Certificate
active
06258976
ABSTRACT:
BACKGROUND OF THE INVENTION
Polyamines are considered essential in cell proliferation. The naturally occurring polyamines in mammalian cells are putrescine, spermidine and spermine. A wide variety of related amines are found in other organisms and may play critical roles in their physiology. Nevertheless, it is also known that the association of cationic polyamines with negatively charged DNA induces significant structural changes in DNA. Spermidine and spermine can cause DNA to condense and aggregate and induce reversible B-to-Z transition in certain DNA sequences (Marton, L. J. et al.,
Annu. Rev. Pharmacol. Toxicol.,
1995, 35: 55-91). This led the researches to focus their attention on the potential use of polyamines as antitumor drugs (Basu, H. S. et al.,
Biochem. J.,
1990, 269: 329-334; Yanlong Li et al.,
J. Med. Chem.,
1996, 39: 339-341).
In spite of the scientific interest raised in the last years by these compounds, relatively few papers have been published describing their synthesis.
The preparation of the spermine and spermidine analogues has been mainly accomplished up to now by condensing a diamine with acrylonitrile and by reducing the nitrile group via catalytic hydrogenation (J. Med. Chem., 7, 710-16 (1964); U.S. Pat. No. 5,097,072; U.S. Pat. No. 4,967,008; J. Pharm. Sciences, 70(8), 956-9 (1981)). The main limitation of this method is that using acrylonitrile only 3-C terminal amine chains are obtained. Other drawbacks are due to the difficulty of purification of the final compounds, which is often performed by vacuum distillation. In particular, when dicyanoethylated compounds are desired, they undergo extensive decomposition on distillation and therefor cannot be obtained in a pure form using this method. The toxicity of acrylonitrile, increased by its high volatility, may be another problem, especially in view of a large scale synthesis.
A further method that has been reported for the preparation of polyamines is the reduction of amide intermediates which can be obtained by condensing &ohgr;-amino acids with diamines or of &agr;,&ohgr;-diacids with two equivalents of diamine (J. Med. Chem., 31, 1183-1190 (1988)). However we have found that this method does not allow to prepare with good yields all the derivatives, since especially the lower alkylenyl homologues give by-products in large amount during the reduction step.
More recently the preparation of unsymmetrically substituted polyamine analogues was also reported (J. Med. Chem., 36, 2998-3004 (1993)). However the described process does need the preparation of rather complex synthons containing simultaneously three different nitrogen protecting groups. This results in a long multistep procedure which is unsuitable for industrial purposes. Moreover, the use of a mesityl protecting group is also unsuitable, since it requires acidic conditions for cleavage which can largely impair the flexibility of the method.
We have now found a new advantageous process for synthesizing polyamine derivatives.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of polyamines of formula (I):
H
2
N—(CH
2
)
n
—A—(CH
2
)
m
—NH
2
(I)
in which:
n and m, which an be the same or different, are an integer from 2 to 8;
A is —NR
1
—, —NR
1
—(CH
2
)
r
—NR
1
— or —NR
1
—(CH
2
)
r
—NR
1
—(CH
2
)
z
—NR
1
—, wherein r and z are an integer ranging from 2 to 8 and R
1
is hydrogen or a carbonyl-containing protecting group, such as a tert-butoxycarbonyl group.
More particularly, there is provided a process for the synthesis of polyamines of formula (Ia), (Ib) and (Ic):
H
2
N—(CH
2
)
n
—NR
1
—(CH
2
)
m
—NH
2
(Ia)
H
2
N—(CH
2
)
n
—NR
1
—(CH
2
)
r
—NR
1
—(CH
2
)
m
—NH
2
(Ib)
H
2
N—(CH
2
)
n
—NR
1
—(CH
2
)
r
—NR
1
—(CH
2
)
z
—NR
1
—(CH
2
)
m
—NH
2
(Ic).
The new process is accomplished by means of a simple multistep procedure which makes use of a 2-nitrobenzenesulfonyl protecting group as both a protecting and an activating group for the nitrogen atom to be functionalized. This protecting group has recently been described as a protecting group for benzylamines (Tetrahedron Letters, 36(36), 6373-4 (1995)) which requires a neutral cleavage and it provided particularly suitable for our process, especially in combination with a carbonyl-containing protecting group, such as a tert-butoxycarbonyl group.
The process of the present invention has some advantages with respect to the prior art methods, such as (i) a high flexibility, which allows the preparation of a broad series of polyamines both symmetrical and unsymmetrical with various length of the alkylene chains; (ii) high yields with no need for further purification of the products; (iii) possibility to obtain easily BOC-protected intermediates useful for further chemical processing.
Another object of the present invention is to provide a process for obtaining polyamine derivatives of formula (II):
H
2
N—(CH
2
)
n
—NH—C(═NR
1
)—NH—(CH
2
)
m
—NH
2
(II)
wherein n, m and R
1
have the above meanings.
A further object of the present invention are the polyamine derivatives of formula (II), or salts thereof with pharmaceutically acceptable acids, having antitumor properties.
The polyamine derivatives of formulas (I) and (II), especially when R
1
is a tert-butoxycarbonyl group or another suitable carbonyl-containing protecting group (see Greene (1981)
Protective Groups in Organic Synthesis
for exemplary protecting groups), are also particularly suitable intermediates for the preparation of bridged compounds in which the linker is a polyamine moiety, such as for example bis-platinum complexes. For ease of reference, only tert-butoxycarbonyl is exemplified in this application. However, a worker of skill in the art would be able to choose another suitable carbonyl-containing protecting group for use in accordance with the present invention. Other suitable carbonyl-containing protecting groups are thus contemplated within the scope of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The process for the preparation of the polyamines of formula (Ia) is accomplished according to the following steps:
(1) alkylation of 2-nitrobenzenesulfonamide with one equivalent of a phthaloylalkyl halide of formula (III):
Phth═N—(CH
2
)
n
—Hal (III)
in which Phth═N— is a phthalimido group, n has the above meaning and Hal is a halogen atom, such as chlorine, bromine or iodine. This reaction is performed in the presence of a base, preferably an alkaline or alkaline-earth carbonate or bicarbonate, more preferably potassium carbonate. A solvent may be used, such as acetonitrile; the reaction temperature ranges from room temperature to the boiling point of the solvent;
(2) further alkylation of the intermediate product of step (1) with a halide of formula (IIIa):
Phth═N—(CH
2
)
m
—Hal (IIIa)
in which Phth═N—, m and Hal are as above described. The reaction can be performed in the same conditions of step (1);
3) removal of the 2-nitrobenzenesulfonyl group by means of thiophenol/triethylamine in acetonitrile, as described in Tetrahedron letters, 36(36), 6373-4 (1995);
(4) protection of the central nitrogen atom by reaction with a protecting group containing a carbonyl group, such as di-tert-butyldicarbonate ((Boc)
2
O) in the presence of a base, such as aqueous sodium bicarbonate;
(5) hydrolysis of the two phthalimido groups by reaction with hydrazine in a solvent, to give the compounds of formula (Ia) in which R
1
is tert-butoxycarbonyl group.
If the polyamines with R
1
=hydrogen are desired, a simplified procedure can be employed, in which the intermediate from step (3) is simply hydrolyzed with hydrazine (reaction conditions of step (4)) to give the wanted polyamines.
The process for the preparation of the polyamines of formula (Ib) is accomplished according to the following steps:
(6) reaction of a diamine of formula H
2
N—(CH
2
)
r
—NH
2
with two equivalents of 2-nitrobenzenesulfonyl chloride in a solvent such as methylene chloride and in the presence of a base su
Gupta Ramesh C.
Johnson Francis
Arent Fox Kintner & Plotkin & Kahn, PLLC
Barts Samuel
LandOfFree
Process for the preparation of polyamines and polyamine... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of polyamines and polyamine..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of polyamines and polyamine... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2526839