Bone resorption inhibition/osteogenesis promotion compound

Details Bone resorption inhibition/osteogenesis promotion compound Bone resorption inhibition/osteogenesis promotion compound

1995-03-01

1998-06-02

Ford, John M.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

540112, 540113, 540107, C07D29504

Patent

active

057602140

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to compounds having novel bone resorption inhibition/osteogenesis promotion functions.


BACKGROUND ART

Normal retention of bones is accomplished by the balance of bone resorption and osteogenesis, and when bone resorption is promoted, bone components are dissolved and decrease, resulting in bone diseases such as osteoporosis. It is known that sex hormones such as estrogen have the function of suppressing bone resorption, and are therefore used as prophylactics and remedies for osteoporosis in Europe and America. Nonetheless, it has not yet been confirmed that these hormones concentrate on the bones, and the possibility of carcinogenesis resulting from single administration of these hormones cannot be denied.
On the other hand, tetracycline type antibiotics have a property such that they concentrate on the bones, but they have neither the bone resorption inhibition function nor the ossification function. Only U.S. Pat. No. 4,925,833 describes that tetracycline promotes the synthesis of bone proteins in the experiments of a cell level. Though the synthesis of the bone proteins is necessary for osteogenesis, the synthesis of the bone proteins alone cannot promote osteogenesis.
Materials which have the osteogenesis promotion function and which can be used as the prophylactics and remedies for bone diseases have not yet been known to this date.
Accordingly, the present invention contemplates to provide a remedy for bone diseases, which has a bone resorption inhibition function as well as osteogenesis function, preferably synergistically, and can concentrate on the bones.


DISCLOSURE OF THE INVENTION

The inventors of the present invention have conducted various studies so as to solve the problems described above and have found out that the compounds which are obtained by causing covalent bond between a tetracycline type antibiotic and a steroid type hormone such as estrogen by a linker has an osteogenesis function in addition to a bone resorption inhibition function and moreover, can concentrate on the bones, and have thus completed the present invention.
Accordingly, the present invention provides a bone resorption inhibitor/osteogenesis promoter expressed by the formula (I): ##STR2## (where R.sub.1 is hydrogen or a hydroxyl group, R.sub.2 is hydrogen or a hydroxyl group, R.sub.3 is hydrogen or a methyl group and R.sub.4 is hydrogen, halogen or a dimethylamino group); (III), (IV) or (V): ##STR3## (where n is 0 to 4, and --X-- is a direct bond, --O-- or --NH--); and Z is a monovalent group formed by removing hydrogen or a hydroxyl group from a compound represented by the following formula (VI): ##STR4## (where R.sub.1 ' is HO-- or O.dbd.; R.sub.2 ' is a hydrogen atom or a methyl group; R.sub.3 ' is a hydrogen atom, a phenyl group or a substituted phenyl group; R.sub.4 ' is a methyl group or an ethyl group; R.sub.5 ' is a hydroxyl group, a ketone group or an acetyl group; R.sub.6 ' is hydrogen, a hydroxyl group, a methyl group, an ethynyl group or a prophynyl group; or R.sub.5 ' and R.sub.6 ' together form .dbd.O; R.sub.7 ' is hydrogen, a hydroxyl group or .dbd.O; or R.sub.6 ' and R.sub.7 ' are together bonded to oxygens of a 2,2-dioxypropyl group, and symbol ... represents a single bond or a double bond), whereby this bond group exists at the 2-position, 3-position, 4-position, 6-position, 7-position or 17-position, or at the phenyl group bonded to the 11-position, (1) of the formula (II) and (2) of the formulas (III) to (V) are directly connected, and (3) of the formulas (III) to (V) and any of the bond groups of the formula (VI) are directly bonded!.
In the formula (II) described above, the halogen is, for example, fluorine, chlorine, bromine or iodine, and is preferably chlorine.


BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph showing the result of Experiment No. 3.
FIG. 2 is a photograph showing the result of Experiment No. 3.
FIG. 3 is a photograph showing the result of Experiment No. 3.
FIGS. 1 to 3 show the results when the same experiment is repeate

REFERENCES:
patent: 4925833 (1990-05-01), McNamara
patent: 5183815 (1993-02-01), Saari et al.

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