Bone resorption inhibition/osteogenesis promotion pharmaceutical

Details Bone resorption inhibition/osteogenesis promotion pharmaceutical Bone resorption inhibition/osteogenesis promotion pharmaceutical

1995-08-29

1997-12-16

Criares, Theodore J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

3,10-dihydroxy-2-naphthacene carboxamide or derivative doai

A61K 3165

Patent

active

056985428

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a pharmaceutical composition 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 in 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 in the bones, but they have neither a bone resorption inhibition function nor an ossification function. Only U.S. Pat. No. 4,925,833 describes that tetracycline promotes the synthesis of bone proteins in the experiments at the cell level. Though synthesis of bone proteins is necessary for osteogenesis, the synthesis of bone proteins alone cannot promote osteogenesis.
Materials which have an osteogenesis promotion function and which can be used as the prophylactics and remedies for bone diseases are not yet known.
Accordingly, the present invention contemplates to provide a remedy for bone diseases which can provide a bone resorption inhibition function as well as osteogenesis function, preferably synergistically, and can concentrate in the bones.


DISCLOSURE OF THE INVENTION

The inventors of the present invention have conducted various studies to solve the problems described above and have found that the compounds which are obtained by causing a covalent bond between a tetracycline type antibiotic and asteroid type hormone such as estrogen, by a linker, has an osteogenesis function in addition to a bone resorption inhibition function and moreover, can concentrate in the bones, and have thus completed the present invention.
Accordingly, an active component of the present invention is represented 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

FIGS. 1A-1D are photographs showing the result of Experiment No. 3.
FIGS. 2A-2D are photographs showing the result of Experiment No. 3.
FIGS. 3A-3D are photographs showing the result of Experiment No. 3.
FIGS. 1A to 3D show the results when the same experiment is repeatedly carried out three time

REFERENCES:
patent: 4925833 (1990-05-01), McNamara et al.
M.W. Orme et al., "Synthesis of .beta.-Estradiol-3-Benzoate-17-(Succinyl-12A-Tetracycline): A Potential Bone-Seeking Estrogen", Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 11, Jun. 1994, pp. 1375-1380.

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