Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1993-02-26
1995-06-13
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D25700
Patent
active
054244234
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to 1,7-disubstituted 1,4,7,10-tetraazacyclododecanes which are useful intermediates for chelating agents and to a process for the preparation thereof.
BACKGROUND OF THE INVENTION
The chemistry of polyazamacrocycles with coordinating side arms, which increase the ligating ability of the macrocycles, has developed quickly over the last decade (P. V. Dernhardt and G. A. Lawrance, Coord. Chem. Rev., 1990, 104,297) . Derivatives of 1,4,7,10-tetraazacyclododecane (TAZA) which contain additional donor groups, have been widely investigated due to the applications found for some of their metal complexes. Relevant examples are given by the use of the Gd complex of 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) as a contrast agent for in vivo magnetic resonance imaging (M. Magerstaedt, O. A. Gansow, M. W. Brechbiel, D. Colcher, L. Baltzer, R. H. Knop, M. E. Girton Naegele and M., Magn. Reson. Med., 1986, 3, 808) and of .sup.90 Y complexed DOTA derivatives attached to monoclonal antibodies in radioimmunotherapy (D. Parker, Chem. Soc. Rev., 1990, 19, 271; S. V. Deshpande, S. J. De Nardo, D. L. Kukis, M. K. Moi, M. J. McCall, G. L. De Nardo and C. F. Meares, J. Nucl. Med., 1990, 31, 473). Well known are derivatives of TAZA bearing four identical residues on the nitrogen atoms. On the contrary, TAZA derivatives containing different. coordinating side arms on the nitrogen atoms have received little attention, likely due to the difficulties involved in their synthesis. In this context, 1,7-disubstituted-1,4,7,10-tetraazacyclododecanes can be very useful in order to obtain chelating agents with prefixed symmetry. These compounds can, in principle, be synthesized (T. A. Kaden, Top. Curr. Chem., 1984, 121, 154) by classical condensation according to Richman and Atkins (J. E. Richman and T. J. Atkins, J. Am. Chem. Soc., 1974, 96, 2268; T. J. Atkins, J. E. Richman and W. F. Oettle, Org. Synth., 58, 86). However, the nature of the residues, which can be introduced into positions 1 and 7 by this synthetic approach, is severely limited by the harsh conditions required, in particularly during the deprotecting steps.
SUMMARY OF THE INVENTION
A preferred embodiment of this invention relates to these compounds useful for the selective preparation of chelating agents with prefixed symmetry, said compounds consisting in 1,7-disubstituted derivatives of 1,4,7,10-tetraazacyclodecane of general formula (I) ##STR1## wherein R is a formyl group, is un substituted or not substituted by a group able to bind to proteins (such as OH, NH.sub.2, COOH, CHO, SH) or by their precursors (such as NO.sub.2, NO, CN, COOR), b) a phenylalkyl group C.sub.7 -C.sub.19 which is unsubstituted or substituted on the phenyl radical by one or more C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or halogen groups or by groups able to bind to proteins (such as OH, NH.sub.2, COOH, CHO, SH) or by their precursors (such as NO.sub.2, NO, CN, COOR), c) a group alkoxy(C.sub.1 -C.sub.4)carbonylmethyl or 2-[alkoxy(C.sub.1 -C.sub.4)carbonyl]ethyl, d) a group of formula:
The compounds of formula I are meant for the preparation of chelates with prefixed symmetry derived from 1,4,7,10-tetraazacyclododecane, by substituting the hydrogen atoms in 4 and 10 positions with specific functional groups, if necessary after converting the formyl group in 1- and/or the substituents in 7-position of the macrocycle into other suitable groups.
Non-limitating examples of compounds of formula (I) are the ones wherein R.sub.1 is alkyl C.sub.6 -C.sub.18, benzyl, triphenylmethyl, t-butoxycarbonylmethyl, or a group of formula --(CH.sub.2).sub.n --R.sub.2 wherein n=1 or 2 and R.sub.2 is a group --CH(OCH.sub.3).sub.2, --CH(OC.sub.2 H.sub.5).sub.2 or 1,3-dioxol-2-yl.
Another preferred embodiment of the invention relates to a process for the preparation of compounds of formula (I), according to the reaction scheme underneath given: ##STR2##
According to this scheme, the mono-substituted compounds of formula (II) (where R.sub.1 has the m
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Anelli Pier L.
Murru Marcella
Uggeri Fulvio
Virtuani Mario
Dibra S.p.A.
Shah Mukund J.
Sripada P. K.
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