Ureido derivatives of naphthalenephosphonic acids

Details Ureido derivatives of naphthalenephosphonic acids Ureido derivatives of naphthalenephosphonic acids

1995-10-30

1997-12-23

Morris, Patricia L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

548112, A61K 31675, C07F 9572

Patent

active

057007888

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP95/0444, filed Feb. 8, 1995.
The present invention relates to new ureido derivatives of naphthalenephosphonic acids, to a process for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
In international application PCT/EP91/00014 ureido derivatives of poly-4-amino-2-carboxy-1-methyl-pyrrole compounds are disclosed.
Now we have found that new naphthalenephosphonic acid derivatives and a narrow selected class of new naphthalenephosphonic acids falling within the scope of the general formula of PCT/EP91/00014, but therein not specifically disclosed, are endowed with valuable biological properties.
Accordingly, subject of the present invention are new ureido derivatives of naphthalenephosphonic acids having the following formula (I) ##STR2## wherein each of m and n, which are the same, is an integer of 1 to 4; each of p and q, which are the same, is an integer of 1 to 3; and each of the R groups, which are the same, is a free or esterified phosphonic acid group; and the pharmaceutically acceptable salts thereof.
The free, salified or esterified phosphono (HO).sub.2 PO-groups may be on either or both the phenyl moieties of the naphthalene group.
The substituted naphthyl groups are preferably 1-, 2-, 3- or 4-naphthyl groups, typically 3- or 4-naphthyl groups. When the naphthyl groups are substituted by three free, esterified or salified phosphonic acid groups, the phosphonic acid substituents are preferably in the 1-, 5- and 7-, 2-, 5- and 6- or 2-, 5- and 7-positions. When they are substituted by 2 free, esterified or salified acid groups, the phosphonic acid substituents are preferably in the 1- and 5-, 1- and 6-, 1- and 7- or 5- and 7-positions. When they are substituted by one free, esterified or salified acid group, the phosphonic acid substituent is preferably in the 1-, 3-, 5- or 6-position. The invention also includes within its scope all the possible isomers, stereoisomers and their mixtures and the metabolites and the metabolic precursors or bio-precursors of the compounds of formula (I). As already said, the invention includes within its scope also the esters and the pharmaceutically acceptable salts of the acids of formula (I).
Only one or both of the two acidic functions of each phosphone (HO).sub.2 PO-group can be salified and/or esterified.
In the salts of the invention preferably only one of the two acidic functions of each phosphono group is in a salified form, whereas in the esters of the invention both of the two acidic functions of each phosphono group are preferably in an esterified form.
Esters of the acids of formula (I) are for instance alkyl and aryl-alkyl esters, having a branched or straight alkyl chain. C.sub.1 -C.sub.6 alkyl and phenyl-C.sub.1 -C.sub.6 alkyl esters, typically methyl, ethyl, propyl, isopropyl, butyl, benzyl and phenylethyl esters, are more preferred.
Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, N-methylglucamine, triethyl-amine, triethanolamine, dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, N-ethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine, .beta.-phenethylamine, N-benzyl-.beta.-phenethyl-amine, N-benzyl-N,N-dimethylamine and the other acceptable organic amines. Sodium and potassium salts are preferred.
As stated above, the present invention also includes within its scope pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different formula to formula (I) above but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
Preferred compounds of formula (I) are the compounds wherein each of m and n is 2; each of p and q is 2; and each of the R groups, which are the same, is a free or a C.sub.1 -C.sub..sub.6 alkyl- or phenyl-C.sub.1 -C.sub.6 alkyl-es

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