Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-14
2002-07-30
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S122000
Reexamination Certificate
active
06426353
ABSTRACT:
BACKGROUND OF THE INVENTION
U.S. Pat. No. 6,017,926 (issued Jan. 25, 2000) discloses compounds of structural formula (1):
which include the two enantiomeric forms at the C-3 position (marked with *) of the propionic acid side-chain.
These compounds are antagonists of the integrin receptor &agr;v&bgr;3 and are therefore useful for inhibiting bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammatory arthritis, cancer, and metastatic tumor growth. They are particularly useful for inhibiting bone resorption and for the treatment and prevention of osteoporosis.
SUMMARY OF THE INVENTION
The present invention relates to novel derivatives of 3-(6-methoxy-pyridin-3-yl)-3-{2-oxo-3-[3-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl}-propionic acid (1), methods for their preparation, pharmaceutical compositions containing such compounds, and methods for using these compounds as &agr;v&bgr;3 integrin receptor antagonists. These derivatives are formed by metabolic conversion of the compounds of formula (1).
Because of their activity as &agr;v&bgr;3 integrin receptor antagonists, the compounds of the present invention are useful, inter alia, for inhibiting bone resorption and for the treatment and prevention of osteoporosis.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention, there are provided compounds of structural formula (I):
wherein at least one of R
1
, R
2
, and R
3
is hydroxy or oxo;
and the individual stereoisomers thereof, or a pharmaceutically acceptable thereof.
One class of this embodiment of the present invention is directed to compounds of structural formula (II):
and the individual stereoisomers thereof;
or a pharmaceutically acceptable salt thereof.
A subclass of this class is directed to compounds of structural formula (III):
and the individual stereoisomers thereof at the hydroxylated C-5 position (marked with **) of the tetrahydro-[1,8]naphthyridine ring;
or a pharmaceutically acceptable salt thereof.
A second class of this embodiment of the present invention is directed to compounds of structural formula (IV):
and the individual stereoisomers thereof;
or a pharmaceutically acceptable salt thereof.
A subclass of this class is directed to compounds of structural formula (V):
and the individual stereoisomers thereof at the hydroxylated C-7 position (marked with **) of the tetrahydro-[1,8]naphthyridine ring;
or a pharmaceutically acceptable salt thereof.
A third class of this embodiment of the present invention is directed to compounds of structural formula (VI):
and the individual stereoisomers thereof; or a pharmaceutically acceptable salt thereof.
A subclass of this class of this is directed to compounds of structural formula (VII):
and the individual stereoisomers thereof at the hydroxylated benzylic position (marked with **) of the tetrahydro-[1,8]naphthyridine ring;
or a pharmaceutically acceptable salt thereof.
A fourth class of this embodiment of the present invention is directed to compounds of structural formula (VIII):
and the individual stereoisomers thereof; or a pharmaceutically acceptable salt thereof.
A subclass of this class is directed to the compound of structural formula (IX):
or a pharmaceutically acceptable salt thereof.
A second embodiment of the present invention is directed to compounds of structural formula (X):
and the individual stereoisomers thereof; or a pharmaceutically acceptable salt thereof.
A class of this embodiment is directed to the compound of structural formula (XI):
or a pharmaceutically acceptable salt thereof.
A third embodiment of the present invention is directed to compounds of structural formula (XII):
and the individual stereoisomers thereof; or a pharmaceutically acceptable salt thereof.
A class of this embodiment is directed to the compound of structural formula (XII):
or a pharmaceutically acceptable salt thereof.
In a further embodiment of the compounds of the present invention, there are provided bis-hydroxylated derivatives of structural formulae XIV-XVI:
and the individual stereoisomers thereof,
or a pharmaceutically acceptable salt thereof.
For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Salts of basic compounds encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
The compounds of the present invention can have chiral centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers, with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers or diastereomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers.
Compounds of the present invention may be separated into enantiomeric pairs of diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate or a mixture thereof. The pair of enantiomers (racemic mixture) thus obtained may be resolved into single enantiomers by conventional means, for example, by the use of an optically active acid as a resolving agent, or by HPLC using a chiral stationary phase. Alternatively, any stereoisomer of a compound of the present invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention.
The term “therapeutically effective amount” shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human
Arison Byron H.
Cui Donghui
Duggan Mark E.
Fang Xiaojun
Halczenko Wasyl
Dentz Bernard
Durette Philippe L.
Merck & Co. , Inc.
Winokur Melvin
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