Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1993-07-26
1995-11-14
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514 86, 514108, 514119, 514129, 562 12, 562 13, 548113, A61K 3166, A61K 3702, C07F 9572, C07F 938, C07F 940, C07F 965
Patent
active
054666821
DESCRIPTION:
BRIEF SUMMARY
This application is A371 of EP 92/00102 filed Jan. 20, 1992.
The present invention relates to compounds of general formula (I) ##STR2## wherein
A is a --(CH.sub.2)--.sub.n group with n comprised between 1 and 10;
R is an acyl residue from a known anti-inflammatory compound belonging in the class of salicylic, arylacetic, arylpropionic, anthranilic, 4,5-dihydroxy- or 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic, nicotinic acids.
Examples of known anti-inflammatory acids, the acyl residues of which form the R group, as defined in formula (I ], are reported hereinbelow: acid, diflunisal, fendosal; bumadizone, cinmetacin, clidanac, clometacin, clopirac, diclofenac, etodolac, fenclofenac, indobufen, indometacin, methiazinic acid, sulindac, tolmetin, zomepirac; flurbiprofen, ibuprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, protizinic acid, pineprofen, pirprofen, pranoprofen, suprofen, thiaprofenic acid; niflumic acid, lobenzarit, tolfenamic acid; 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acids: diacerhein, thiorhein.
Particularly preferred are the compounds of formula (I) wherein R is 2-acetoxybenzoyl, the residues from diflunisal, ibufenac, ibuprofen, naproxen, indometacin, diacerhein.
Most preferred compounds are those in which n is 3 or 5.
in case the residue R contains one or more chiral carbon atoms, the invention comprises the single enantiomers and the mixtures of racemates and of diastereoisomers thereof.
The invention also relates to the diphosphonic acid salts, the esters of both the phosphonic groups and the hydroxy group, with the proviso that they are pharmaceutically acceptable.
The compounds of formula (I) are prepared by the condensation of known anti-inflammatory compounds with known .omega.-aminoalkylene-1-hydroxy-1,1-diphosphonic acid derivatives already used in therapy due to their inhibiting action on bone resorption and antiurolithiasic action.
.omega.-Aminoalkylene-1-hydroxy-1,1-diphosphonic acids are described in Italian Patent Applications N. ITA230503 and ITA22295A8 and in German Patent Applications N. DE-OS 2,534,391 and DE-OS 3,540,150.
Alkyl-1-hydroxy-1,1-diphosphonic acid derivatives condensed with anti-inflammatory residues through a C--C bond are known from EP-A-84822.
The compounds of the invention, on the contrary, are characterized by an amido bond between the amino group of the .omega.-aminoalkylenehydroxydiphosphonic acid and the carboxy group of the anti-inflammatory compound.
Contrary to what could be assumed, the pharmacological properties of the compounds of formula (I) are not those typical of "pro-drugs" which can release "in vivo" the two components which independently carry on their therapeutical activities.
In fact, it has surprisingly been found that compounds (I) have a far higher anti-inflammatory activity than the activity which could be assigned to the "in vivo" release of a known RCOOH pharmacologically active acid. This is even more surprising because the aminoalkylhydroxydiphosphonic component is completely devoid of anti-inflammatory activity.
Compounds of formula (I) are prepared by reacting a compound of formula (II) ##STR3## wherein A has the above mentioned meaning, with a compound of formula RCOOH, wherein R is as defined above, or with a reactive derivative thereof (chloride, anhydride, imidazolide etc.).
The reaction is preferably carried out in an aqueous medium in the presence of alkali, using a reactive derivative of the carboxy group of the R molecule, such as the acid chloride.
The advantageous properties of the compounds of the invention make them useful in the therapy of muscle-skeletal disorders.
Therefore, the compounds of the invention will be used for the preparation of pharmaceutical compositions in admixture with suitable excipients and/or other drugs which can adjuvate the therapeutic action.
Examples of said pharmaceutical compositions comprise both solid and liquid oral formulations, optionally in sustained-release or gastro-resistant forms, injectable formulations, optionally in depot fo
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Mian Maurizio
Rosini Sergio
Higel Floyd D.
Istituto Gentili S.p.A.
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