Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus acids or salts thereof
Patent
1993-10-08
1995-08-29
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus acids or salts thereof
548957, 558155, 558159, 560 38, 560 47, 560169, 560172, C07F 938, C07F 940, A61K 3166
Patent
active
054461871
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP92/00746, Apr. 3, 1993.
The present invention relates to diphosphonic acid having a marked antitumor activity, to a process for the preparation thereof and to pharmaceutical compositions containing them.
Gem-diphosphonic acids and the salts thereof are known and used in the therapy of osteoporosis and in the treatment of bone resorption (see EP 96.931, EP 252.504, BE 896.453, BE 903.519, DE 3.016.289, DE 3.540.150, DE 2.534.391).
Moreover, diphosphonic acid esters having pesticide activity are disclosed in U.S. Pat. No. 3,906,062. However, no compounds described in the above mentioned patents have been reported to have intrinsic antitumour activity.
DE 3.425.812 discloses 1,1-diphosphonic acid derivatives having a bis[(haloalkyl)amino]phenyl residue as agents useful for the treatment of bone tumors. In fact, beside having the bone tropism characteristic of diphosphonic acids, they also have the typical cytotoxic activity of molecules bearing dialkylating functions.
Metotrexate diphosphonic analogs are described in WO 88/06158 to be useful agents in the treatment of bone tumours.
EP 0197478 describes aminoacyl-derivatives of alkylenediphosphonic acids having therapeutic activity in the treatment of osteoporosis, Paget's disease, Betcherew's disease and tumor mediate bone resorption.
It has now been found that aminoacyl diphosphonic acid derivatives characterized by the presence of a bond which can be physiologically hydrolyzed, connecting the diphosphonic derivative with a dialkylating residue, have, compared with the above cited compounds, advantageous antitumour and antimetastatic properties, which could not be predicted on the basis of their chemical structure and of the presumed bioconversion thereof into the separate components (diphosphonic derivative and alkylating derivative).
The present invention relates to compounds of formula (I) ##STR1## wherein: R.sub.1 and R.sub.2, which can be the same or different, are hydrogen or C.sub.1 -C.sub.4 alkyl; or branched C.sub.1 -C.sub.12 alkyl; alkylene chain containing at least one hetero-atom of formula --[CH(CH.sub.3)].sub.p --(CH.sub.2).sub.n.sbsb.1 --X--(CH.sub.2).sub.n -- or, together with the adjacent nitrogen atom, a group of formula ##STR2## if R.sup.3 is absent, heterocyclic rings of formula ##STR3## an ortho, meta or para substituted aralkyl of formula ##STR4## in which chain or groups X is O, S, N--CH.sub.3 ; -C.sub.6 cycloalkyl, benzyl, phenyl, or p-methoxybenzyl; aralkyl chain of formula ##STR5## wherein n is as defined above; alkyl, or R.sub.4 represents a group ##STR6## wherein R.sub.12 and R.sub.13, which are the same or different, are hydrogen, straight or branched C.sub.1 -C.sub.6 alkyl, phenyl, benzyl, para-methoxybenzyl, or one of R.sub.12 and R.sub.13 is as defined above and the other one is a group of formula: ##STR7## wherein R.sub.14 is hydrogen, straight or branched C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, para-methoxybenzyl, straight or branched C.sub.1 -C.sub.4 alkoxyl, halo-C.sub.1 -C.sub.4 alkoxyl; 2-iodoethyl) or R.sub.5 and R.sub.6, taken together with the nitrogen atom to which they are linked, are a 1-azyridinyl group of formula ##STR8## R.sub.7, R.sub.8, R.sub.9 e R.sub.10, which are the same or different, taken together with the ##STR9## group to which they are linked, are the residue from a D or L amino acid; R.sub.11 is hydrogen or straight or branched C.sub.1 -C.sub.12 alkyl chain; formula ##STR10##
The present invention also relates to racemates, diastereoisomers and optically pure forms of compounds of general formula I.
The present invention also relates to the pharmaceutically acceptable salts of compounds of general formula (I), for example with inorganic bases, such as salts with alkali metals (such as sodium or potassium) or alkaline-earth metals (such as calcium or magnesium) or ammonium salts; salts with organic bases such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, t-butylamine, dimethylamine, diethylamine, diethanolamine, trimethylamine, triethylamine, p
REFERENCES:
patent: 4608368 (1986-08-01), Blum et al.
patent: 4666895 (1987-05-01), Bosies et al.
patent: 5019651 (1991-05-01), Kieczykowski
patent: 5300671 (1994-04-01), Tognella et al.
WO A, 9 105 791 May 2, 1991.
Livi Valeria
Menta Ernesto
Spinelli Silvano
Tognella Sergio
Boehringer Mannheim Italia S.p.A.
Dees Jos,e G.
Frazier Barbara S.
LandOfFree
Aminoacyl derivatives of gem-diphosphonic acids, a process for t does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Aminoacyl derivatives of gem-diphosphonic acids, a process for t, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aminoacyl derivatives of gem-diphosphonic acids, a process for t will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1820455