Phosphonic acid compounds, their production and use

Details Phosphonic acid compounds, their production and use Phosphonic acid compounds, their production and use

1995-08-11

1998-02-10

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

558 83, 558177, 558190, A01N 5716, A61K 3166, C07F 944

Patent

active

057169446

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP95/01328 filed Jul. 3, 1995.
1. Technical Field
The invention relates to a phosphonic acid derivative, or salt thereof, that stimulates osteogenesis (bone formation), a method of its production, and a use thereof.
2. Background Art
Osteoporosis is a pathologic state or disease involving some symptoms or risks due to quantitative bone reduction exceeding a certain degree. Major symptoms are spinal kyphosis, and fractures of thoracic vertebrae (dorsolumbar bones), lumber vertebral, femoral necks, distal ends of radius, ribs, proximal ends of humeri, and others. In normal bone tissue, bone destruction occurs constantly, but there is a good balance between bone formation and resorption; osteoblasts and osteoclasts play key roles in bone formation and bone resorption, respectively. Upon deterioration of this balance, bone resorption surpasses bone formation, resulting in onset of osteoporosis associated with quantitative bone reduction. Traditionally, bone resorption inhibitory agents such as estrogens, calcitonin and bisphosphonates have been used to prevent and treat osteoporosis. However, these bone resorption inhibitors fail to have a satisfactory effect in some cases, due to subject limitations or uncertain efficacy. There is therefore need of a new osteogenesis stimulator that positively increases once-decreased bone mass as a prophylactic/therapeutic drug for osteoporosis.
European Patent Publication EP-524023-A1 describes an osteogenesis promoter represented by the formula: ##STR2## Japanese Patent Unexamined Publication Nos. 232880/1991 and 364179/1992 disclose a 3,4-dihydro-2-benzothiopyran-1-carboxamide derivative and a 1,2,4,5-tetrahydro-3-benzothiepin-2-carboxamide derivative as therapeutic drugs for osteoporosis.
Japanese Patent Unexamined Publication Nos. 230570/1989 and 232864/1991 disclose a 3,4-dihydronaphthalene-2-carboxamide derivative and a 2,3-dihydro-1-benzothiepin-4-carboxamide derivative. However, no carboxamide derivatives are known to have a substitutional phenyl group containing phosphonic acid as an N-substituent.


DISCLOSURE OF INVENTION

The invention provides a phosphonic acid derivative that promotes osteogenesis, a method of its production, and an osteogenesis promoter containing it as an active ingredient.
The present inventors sought to develop a more commonly applicable drug showing direct action on the bone to promote osteogenesis, and found that a phosphonic acid derivative represented by the formula (I) below activates osteoblast function, which is associated directly with osteogenesis promotion, to promote calcification. The inventors made further investigations based on this finding, and developed the present invention.
Accordingly, the present invention relates to: ##STR3## wherein ring A is a benzene ring that may be substituted; Y is a divalent group as a constituent member of ring B forming a 5- to 8-membered ring; Q.sub.1 is a group of the formula: ##STR4## wherein X is a bond or a divalent group; R.sup.1 and R.sup.2, identical or different, are hydrogen or a lower alkyl group, or may be combined together to form a ring; Q.sub.2 is hydrogen, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted; the group of the formula --CON(Q.sub.1)(Q.sub.2) is connected to the a- or b-position carbon atom, or a salt thereof, Y is a divalent group as a constituent member of ring B forming a 5- to 7-membered ring, ##STR5## wherein E' is a divalent aromatic hydrocarbon group; W' is a bond or an alkylene group; R.sup.1 and R.sup.2, identical or different, are hydrogen or a lower alkyl group, or may be combined together to form a ring, group is a divalent monocyclic aromatic hydrocarbon group, hydrocarbon group is a phenylene group, lower alkyl group, atoms, together to form --Z-- wherein Z represents a carbon chain of a chain length of 2 to 4 atoms that may have at least one side chain, alkyl, --(CH.sub.2).sub.2 --, --CON(Q.sub.1)(Q.sub.2) is connected to the a-position carbon atom, group or an aromatic hydroc

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