Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus acids or salts thereof
Patent
1993-10-08
1995-08-15
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus acids or salts thereof
558155, 558159, C07F 938, C07F 940, A61K 3166
Patent
active
054421020
DESCRIPTION:
BRIEF SUMMARY
This application is a 35 C.S.C. 371 of PCT/EP92/00745, filed Apr. 3, 1992.
The present invention relates to diphosphonic acids having a marked antitumour 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 treatment of osteoporosis and of bone resorption (see EP 96.931, EP 197,478 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 tumours. 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.
Moreover, nitrosoureas, in which the nitrosocarbamoyl residue is bound to an amino acid or to ester or amido derivatives thereof, are known to have favourable pharmacokinetic and therapeutical properties in the treatment of leukemias (see: Arch. Pharm., 317, 481 (1984); J.Cancer Res. Oncol., 108, 249 (1984); J. Med. Chem. 25, 829 (1982)).
FR 2,536,075 discloses (N-(2-cloroethyl-N-nitrosoureido) phosphonic acid derivatives useful in the therapy of tumors and carcinomas.
Now it has been found that diphosphonic acid derivatives bearing the residue from a chloroethylnitrosourea have a high affinity to bone tissue, wherein the cytotoxic species is mainly released, and therefore they have advantageous antitumour and antimetastatic properties, compared with the above cited compounds.
The present invention relates to compounds of formula (I) ##STR1## wherein:
R.sub.1 and R.sub.2, which are the same or different, are hydrogen or C.sub.1 -C.sub.4 alkyl;
A is hydrogen, halogen (chlorine, bromine or iodine), hydroxy, straight or branched C.sub.1 -C.sub.12 alkyl;
B is a covalent bond, a straight or branched C.sub.1 -C.sub.8 alkylene chain, an 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, B forms: ##STR2## b) heterocyclic rings of formulae if R.sub.3 is absent and together with the adjacent nitrogen atom ##STR3## c) an ortho, meta or para substituted aralkyl of formula ##STR4##
X is O, S, N--CH.sub.3 ;
m is zero or the integer 1 or 2;
m.sub.1 is the integer 1, 2, 3 or 4;
n and n.sub.1 are an integer from 1 to 5; p is zero or the integer 1; 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;
R.sub.4 and R.sub.5, together with the ##STR5## group to which they are linked, are the residue from a D or L amino acid; q is zero or 1.
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, piperidine, pyridine, picoline, dicyclohexylamine; organic acid addition salts, such as: formate, acetate, trifluoroacetate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate salts; inorganic acid addition salts, such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate salts; or with amino acids, such as asparnate, glutamate, lysine or arginine salts.
C.sub.1 -C.sub.
REFERENCES:
patent: 4567169 (1986-01-01), Lavielle et al.
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.
Livi Valeria
Menta Ernesto
Spinelli Silvano
Tognella Sergio
Boehringer Mannheim Italia S.p.A.
Dees Jos,e G.
Frazier Barbara S.
LandOfFree
Gem-diphosphonic acid nitrosocarbamoyl derivatives, a process fo does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Gem-diphosphonic acid nitrosocarbamoyl derivatives, a process fo, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Gem-diphosphonic acid nitrosocarbamoyl derivatives, a process fo will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2182986