Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1996-09-25
1997-12-16
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514120, 514 79, 514 88, 514 95, 514 89, 514 99, 514 90, 514101, 514 94, 514 92, 562 20, 558156, 558158, 546 21, 546 22, 546 24, 544232, 544243, 548112, 548412, 549 5, 549218, 540542, A61K 3166, C07F 938, C07F 940
Patent
active
056985410
DESCRIPTION:
BRIEF SUMMARY
This is the U.S. National Stage application of PCT/EP95/01062 filed Mar. 22, 1995, published as WO 95/26358 on Oct. 5, 1995.
The present invention concerns new 2,4-diphosphono-glutaric acid derivatives, processes for their production and pharmaceutical agents containing these substances.
The hexaethyl ester of 2,4-diphosphonoglutaric acid is described in "Angew. Chemie" 92, 43 (1983) and Can. J. Chem. 60, 840 (1982); J. Org. Chem. 25, 1232 (1960) mentions 2,4-diphosphono-3-phenylglutaric acid hexaethyl ester, however, a pharmacological action of these compounds is not known.
It was now found that 2,4-diphosphonoglutaric acids substituted in the 2 position have an excellent effect on calcium metabolism and are therefore suitable for the broad treatment of disorders of calcium metabolism.
They can be used particularly well in situations where bone synthesis and degradation is disturbed i.e. they are suitable for the treatment of diseases of the skeletal system such as e.g. osteoporosis, Morbus Paget, Morbus Bechterew, paradontoses among others.
Due to these properties they can, however, also be used in the therapy of urolithiasis and to prevent heterotopic ossifications. Furthermore, through their influence on calcium metabolism, they form a basis for the treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis. Due to their extremely good affinity to bone mineral, 2,4-diphosphonoglutaric acid and its derivatives are also extremely well-suited to transport pharmacologically active compounds directly to the bones.
The present invention concerns compounds of the general formula I ##STR2## in which R denotes lower alkyl which can be substituted if desired by hydroxy, alkoxy, amino, dialkylamino, alkylmercapto, alkylsulfinyl, alkanesulfonyl, cycloalkyl, aryl or by a heterocyclic ring, or it denotes lower alkenyl, cycloalkyl, cycloalkenyl, aryl or a heterocyclic ring and lower alkyl, cycloalkyl, aryl or arylmethyl,
In all cases lower alkyl is intended to represent a straight-chained or branched C.sub.1 -C.sub.6 alkyl group such as e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl, in particular methyl, ethyl, isopropyl, butyl and hexyl. Lower alkenyl denotes unsaturated residues with 3-6 carbon atoms such as e.g. allyl, but-2-enyl, hexa-2,4-dienyl, but above all allyl.
Cycloalkyl denotes a 3- to 7-membered ring such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring, preferably a cyclopentyl and cyclohexyl ring.
Cycloalkenyl is intended to represent an unsaturated 5-7 ring such as a cyclopentenyl, cyclohexenyl and cycloheptenyl ring.
Alkoxy is understood as residues such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy or pentoxy residue, in particular a methoxy, ethoxy, isopropoxy and butoxy residue.
Dialkylamino is intended to represent an amino group with two equal or different C.sub.1 -C.sub.5 alkyl residues such as e.g. dimethylamino, methylpropylamino, methylpentyl-amino, diethylamino or dipropylamino and above all dimethylamino, methylpropylamino and methylpentylamino.
Alkylmercapto, alkylsulfinyl and alkanesulfonyl are preferably understood to mean methylmercapto, methylsulfinyl and methanesulfonyl respectively.
Aryl denotes a phenyl or naphthyl residue which can be substituted once or several times, if desired, by lower alkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, alkylmercapto, alkylsulfinyl, alkanesulfonyl, carboxamido which can be substituted once or twice by lower alkyl, or by carboxyl, alkoxycarbonyl or cyano.
A heterocyclic ring is understood to be a 5- to 7-membered, saturated or unsaturated ring such as e.g. a pyrrolidine, piperidine, azepine, tetrahydrofuran, tetrahydropyran, morpholine, dioxan, furan, thiophene, pyridine, pyrazole, imidazole, thiazole, oxazole, pyrimidine or pyrazine ring, preferably a pyrrolidine, piperidine, morpholine, furan, thiophene, pyridine and imidazole ring, wherein the ring system can be substituted once or several times by halogen, lower alkyl or alkoxy.
Halogen is intended to represent fluor
REFERENCES:
patent: 3933944 (1976-01-01), Moreau
CA95:70845, 1983 Abst of "Diethyl Ester of 2,4 bis(diethoxyphosphinyl) pimelic acid" Petrov Zhiobshich Chem. and English translation of article from Plen Pub Corp. 1983.
Bauss Frieder
Esswein Angelika
Tsaklakidis Christos
Zimmermann Gerd
Boehringer Mannheim GmbH
Ivy C. Warren
Vollano Jean F.
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