Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Patent
1992-06-09
1994-04-05
Lee, Mary C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
558161, 562 13, C07F 940, C07F 938
Patent
active
053006712
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to diphosphonic acids having antitumor activity, a process for the preparation thereof and pharmaceutical compositions containing them.
Gem-diphosphonic acids and the salts thereof are known and used in the treatment of osteoporosis and bone resorption (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 antitumor 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 tumours. In fact, beside having the bone tropism characteristic of diphosphonic acids, they also have the typical cytotoxic activity of molecules bearing dialkylating functions.
It has now been found that 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 antitumor 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, therefore, provides 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; or, together with the adjacent nitrogen atom, a group of formula ##STR2## therein the groups --N(R.sub.3)-- and --(CA.sub.2).sub.n -- may be in the 1,1; 1,2; 1,3 or 1,4 position of the ring; an ortho, meta or para -substituted aralkylene of formula ##STR3## an alkylene chain containing at least one hetero-atom of formula --[CH(CH.sub.3)].sub.p --(CH.sub.2).sub.nl --X--(CH.sub.2).sub.n --; m is the integer 5 or 6; n and n.sub.1 are an integer from 1 to 5; p is zero or 1 and X is O, S, ##STR4## or the ureido group --NH--CO--NH--; R.sub.3 is hydrogen, straight or branched C.sub.1 -C.sub.9 alkyl, C.sub.3 -C.sub.6 cycloalkyl, benzyl, phenyl or p-methoxybenzyl; aralkylene chain of formula ##STR5## in which n is as above defined; R.sub.4 is hydrogen, straight or branched C.sub.1 -C.sub.4 alkyl, or it is a group of formula ##STR6## in which R.sub.7 and R.sub.8, which are the same or different, are hydrogen, straight or branched C.sub.1 -C.sub.6 alkyl, phenyl, benzyl, p-methoxybenzyl, or one of R.sub.7 and R.sub.8 is as above defined and the other one is a group of formula ##STR7## in which R.sub.9 is hydrogen, straight or branched C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, p-methoxyphenyl, straight or branched C.sub.1 -C.sub.4 alkoxy, halo-C.sub.1 -C.sub.4 -alkoxy; R.sub.5 and R.sub.6 are haloethyl (2-chloroethyl, 2-bromoethyl, 2-iodoethyl) or R.sub.5 and R.sub.6, together with the nitrogen atom to which they are bound, are a 1-aziridinyl residue of formula ##STR8##
The present invention also includes racemic and diastereoisomeric mixtures as well as the single enantiomers and diastereoisomers of the compounds of formula (I).
The present invention further comprises the pharmaceutically acceptable salts of the compounds of formula (I), for example with inorganic bases, such as the salts with alkali metals (e.g. sodium or potassium) or with alkaline-earth metals (e.g. calcium or magnesium), or the ammonium salts; the salts with organic bases, such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, t-butylamine, dimethylamine, diethylamine, diethanolamine, trimethylamine, triethylamine, piperidine, pyridine, picoline, dicyclohexylamine; the organic acid addition salts, such as: formate, acetate, trifluoroacetate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate salts; the inorganic acid addition salts, such as hydrochloride, hydrobromide, sulphate, hydrogen sul
REFERENCES:
patent: 4608368 (1986-08-01), Blum et al.
patent: 4666895 (1987-05-01), Bosies et al.
Journal of The National Cancer Institute, "Nude Rat Model for Studying Metastasis of Human Tumor Cells to Bone and Bone Marrow" vol. 82, No. 5, Mar. 7, 1990, pp. 408-412.
Effects of New Bisphosphonic Acids on Tumor-Induced Bone Destruction in the Rat, J. Cancer Res clin Oncol (1986) 111:335-341.
"Protective Effects of a Prophylactic Treatment with the Bisphosphonate 3-Amino-1-Hydroxypropane-1,1-Bisphosphonic Acid on the Development of Tumor Osteopathies in the Rat: Experimental Studies with the Walker Carcinosarcoma 256.sup.1," Oncology 45: 41-46 (1988).
Chemical Abstracts, vol. 109, No. 17, Oct. 24, 1988.
Wingen, F. et al. J. Cancer Res. Clin. Oncol. 1986, 111, 209-219.
Marmonti et al. Clinical and Experimental Metastasis vol. 10, Suppl. 1, pp. 53-54, Aug. 1992.
Nakai et al. Cancer Res. 53, 5395-5399 (1992).
Livi Valeria
Menta Ernesto
Spinelli Silvano
Tognella Sergio
Ambrose M.
Boehringer Mannheim Italia S.p.A.
Lee Mary C.
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