Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Reexamination Certificate
1999-04-08
2001-12-25
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
C514S121000, C558S160000, C544S337000
Reexamination Certificate
active
06333424
ABSTRACT:
BACKGROUND OF THE INVENTION
WO 96/40156 and WO 96/40190, each published Dec. 19, 1996, disclose therapeutic derivatives of diphosphonates. These compounds have the formula A—V′ and are obtained by reacting a diphosphonic acid compound with a pharmaceuticaly active entity. In these compounds of formula A—V′, A is the residue of a pharmaceutically active entity and V′ is the residue of the diphosphonic acid compound.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide novel pharmaceutically active compounds having improved utility for treating various diseases, especially diseases of the bones and teeth, Further objects are to provide new pharmaceutically active chemical entities for treating infectious diseases of bone and teeth, osteomyelitis, periodontal disease, urinary catheter-related infections, infectious urinary calculi, gastritis and peptic ulcers, and bone cancer. Another object is to provide intermediates for preparing these new chemical entities. Still another object is to provide methods for treating these diseases, and methods for preparing the pharmaceutically active agents. These and other objects of the present invention will be apparent from the following description.
SUMMARY OF THE INVENTION
Therapeutic agents having utility in achieving the foregoing objects of the invention are obtained with compounds prepared by reacting a 2,2-bis-(disubstituted-phosphoryl)-ethylsulfanyl-acetic acid compound with a pharmaceutically active chemical entity effective to treat the underlying disease.
DETAILED DESCRIPTION
The pharmaceutically active therapeutic agents of the present invention are compounds obtained by reacting a 2,2-bis-(disubstituted-phosphoryl)-ethylsulfanyl-acetic acid compound with a pharmaceutically active chemical entity effective to treat the underlying disease, i.e., an infectious disease of bone or teeth, osteomyelitis, periodontal disease, urinary catheter-related infections, infectious urinary calculi, gastritis and peptic ulcers, and bone cancer. The diphosphonate moiety causes the therapeutic agent to be attracted to, and to concentrate on, the surfaces of various salt crystals and the more complex forms of such crystals, such as hydroxyapatite, a major constituent of bone and the surface of dentition. Bacteria associated with these crystals are thereby exposed to an elevated concentration of the therapeutic agent, relative to the surrounding milieu. The therapeutic moiety is derived from a pharmaceutical that is pre-selected because of its recognized ability to treat the underlying disease state. The diphosphonate intermediates of the present invention can be prepared by reacting thioglycolic acid with a tetraester of ethylidene-diphosphonic acid, H
2
C═C(PO
3
R
2
)
2
, wherein the group R is an alkyl group of 1-10 carbons. The reaction product is the corresponding 2,2-bis-(di-substituted-phosphoryl)-ethylsulfanyl-acetic acid compound. The latter compound is then reacted with a pharmaceutically active compound of the formula A—NH
2
or A—COOCH
2
Cl wherein A is the residue of the pharmaceutically active compound, that is to say, it is the pharmaceutically active compound less the H or Cl atom lost in the coupling reaction with the 2,2-bis-(di-substituted-phosphoryl)-ethylsulfanyl-acetic acid compound. (If neither of the —NH
2
or —COOCH
2
Cl groups are present in the pharmaceutically active compound, they are introduced by using conventional chemical techniques known to those skilled in organic and medicinal chemistry fields). In the former case the resulting compound has the following formula
while in the latter case the chloro compound is replaced by the group
whereby the resulting compound has the formula
The above-illustrated compound is susceptible to in vivo and in vitro cleavage by the enzyme esterase whereby the starting pharmaceutically active compound is reconstituted.
Other compounds of the present invention are illustrated by the formula A—X—Z wherein A is the residue of a pharmaceutically active compound, X is a linking group that is cleavable in vivo and in vitro by an endogenous enzyme, and Z is
wherein R is H or alkyl of from 1 to 10 carbons. An example of such an endogenous enzyme is esterase, in which case of esterase the cleavable group has the structural formula
The reaction between the pharmaceutically active compound and the 2,2-bis-(di-substituted-phosphoryl)-ethylsulfanyl-acetic acid compound takes place under well-known conventional and standard conditions for reactions of this type. An illustration of these reaction conditions is shown in Example 2. Additional illustrations are shown in the two published disclosures mentioned above, WO 96/40156 and WO 96/40190.
The 2,2-bis-(di-substituted-phosphoryl)-ethylsulfanyl-acetic acid compounds of the present invention are prepared by reacting thioglycolic acid with a tetra-substituted ethylidene diphosphonate compound wherein the alkyl group has from 1 to 10 carbon atoms. The reaction preferably takes place in a polar solvent, such as a halogenated hydrocarbon, e.g., dichloromethane, for a period of from about 1 or 2 hours to about 20 hours at a temperature of from about 10° C. to about 30° C. Compounds wherein R is H are obtained by reacting any of the foregoing compounds wherein R is alkyl with bromotrimethyl silane, then with water. The reaction is preferably carried out in a polar solvent, preferably dry, such as a halogenated hydrocarbon, a specific example of which is dichloromethane, at about room temperature followed by addition of water.
Compounds of the present invention have been shown to bind in a saturable way to a slurry of rat tibia and to show activity against microorganisms. Other tests have shown that the binding increases with time and that the bound compound can be removed from the bone slurry by exposure to CaCl
2
. Taken together these tests demonstrate that the compounds of the present invention bind to and are retained by calcium sites in bone and, further, inactivate bacteria.
The compounds of the present invention are intended for treatment of a member of a mammalian species, e.g., dogs, mice, primates and humans, and normally are administered orally but also can be administered by other routes, for example, parenterally or by injection. In general, these compounds can be used at a dosage amount that is in the range of from about 10% to about 1000%, preferably from about 25% to about 750%, and most preferably from about 50% to about 500% that at which the pharmaceutically active component itself is used. The compounds of the present invention are used in the form of various pharmaceutical preparations such as tablets, capsules, granules, syrups and the like which are well known in the art, and which can be prepared by methods known per se using suitable diiuents, bindings, disintegrators, coating agents and the like. Other preparations suitable for injection or parenteral use also can be prepared by techniques known in the art.
Other non-pharmaceutical compounds are obtained in similar manner by replacing the pharmaceutically active compound with an insecticide, fungicide, poison for vermin, and the like.
Examples of useful pharmaceutically active chemical entities suitable for reaction with the 2,2-bis-(di-substituted-phosphoryl)-ethylsulfamyl-acetic acid compounds of the present invention include, without intending to be limited thereby:
an aminoglycoside such as amikacin (U.S. Pat. No. 3,781,268), ampramycin (U.S. Pat. No. 3,691,279), arbekacin (U.S. Pat. No. 4,107,424), bambermycin (U.S. Pat. No. 3,674,866), butirosin (U.S. Pat. No. 3,541,078), dibekacin (German patent 2,135,191), dihydrostreptomycin (U.S. Pat. No. 2,498,574), fortimycin A (U.S. Pat. No. 3,976,768) and fortimycin B (Japan Kokai 75 145,588), gentamicin (U.S. Pat. Nos. 3,091,572 and 3,136,704), isepamicin (Belgian patent 818,431), kanamycin (U.S. Pat. No. 2,931,798), micronomicin (German patent 2,326,781), neomycin (2,799,620), neomycin undecylenate (U.S. Pat. No. 3,022,286), netilmicin (German patent 2,437,160), paromomycin (U.S. P
Hartmann John F.
Herczegh Pal
Hornyak Miklos
Kovacs Arpad
Sztaricskai Ferenc J.
Eliza Nor Biopharmaceuticals, Inc.
Higel Floyd D.
Perrella D. J.
Sackey Benjamin
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