Nitrogen-containing heterocyclic compound

Abstract

As a result of an effort made by us for the purpose of developing a therapeutic agent having a bone formation-stimulating effect by promoting the functions of osteoblasts, the present inventors discovered that a certain nitrogen-containing heterocyclic compound exhibits a potent bone formation-stimulating effect on the osteoblast and thus can serve as an excellent prophylactic or therapeutic agent against a metabolic bone disease, whereby establishing the present invention. Thus, the present invention provides a 3,6-disubstituted 1,2,4-triazolo[4,3-b]pyridazine compound or a pharmaceutically acceptable salt thereof as well as a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable carrier, especially a bone-forming agent.

Description

TECHNICAL FIELD [0001] The present invention relates to a nitrogen-containing heterocyclic compound having an ability of stimulating bone formation in an osteoblast or a pharmaceutically acceptable salt thereof. BACKGROUND ART [0002] A normal bone metabolism involves an equilibrium between the level of bone resorption by osteoclasts and the level of bone formation by osteoblasts, by which a homeostasis is maintained. A metabolic bone disease is considered to be developed once such a balance between the bone resorption and the bone formation is lost. This disease includes osteoporosis, osteitis fibrosa (hyperparathyroidism), osteomalacia and Paget's disease which affects the parameters of systemic bone metabolism. The osteoporosis is observed frequently in postmenoposal women or old men, and causes a pain such as a lumbar pain and a bone fracture, and is seriously problematic especially in older patients whose bone fracture readily leads to a systemic weakness and a dementia. For the...

AI Technical Summary

Benefits of technology

[0067] As a result of the administration of the invention compounds, significant increases in osteoid thickness and bone formation rate were observed, exhibiting excellent bone formation-stimulating effects of the invention compounds.

[0068] A pharmaceutical composition containing an invention compound (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier can be prepared by an ordinary method using one or more of a compound represented by the formula (I) or pharmaceutically acceptable salt thereof together with a pharmaceutical carrier, excipient and other additives employed usually in a formulation. The administration can be conducted in various dosage forms orally as a tablet, pill, capsule, granule, powder, liquid, inhalation formulation and the like, or parenterally as an injection formulation such as an intravenous injection, intramuscular injection and the like, as well as a suppositories, percutaneous liquid formulations, ointments, percutaneous patches and the like.

[0069] A solid composition for an invention oral administration may be a tablet, powder, granule and the like. In such a solid composition, one or more active substance is mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate and the like. The composition may contain additives other than the inert diluent as customary in the art, including a lubricant such as magnesium stearate, a disintegrant such as calcium fibrinoglycolate, a stabilizer, a dissolution aid such as glutamic acid or aspartic acid. A tablet or pill may be sugar-coated if necessary with sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate and the like or covered with a gastric or enteric film coating.

[0070] A liquid composition for an oral administration contains a pharmaceutically acceptable emulsifier, solubilizer, suspending agent, syrup, elixir and the like, together with an ordinarily employed inert diluent such as a purified water and ethanol. Such a composition may contain, in addition to an inert diluent, other auxiliary agents such as a humectant, suspending agent, as well as a sweetener, flavor, fragrance and preservative.

[0071] An injection formulation for a parenteral administration includes an aseptic aqueous or non-aqueous solution, suspension and emulsion. Such an aqueous solution and suspension may contain a distilled water for injection or a physiological saline. A non-aqueous solution and suspension may contain propylene glycol, polyethylene glycol, a vegetable oil such as an olive oil, an alcohol such as ethanol, as well as Polysorbate 80 (trade name) and the like. Such a composition may also contain auxiliary agents such as a preservative, humectant, emulsifier, dispersing agent, dissolution aid (for example, glutamic acid, aspartic acid) and the like. Any of these materials can be made aseptic by filtration through a filter retaining bacteria, incorporation of a sterilizing agent or irradiation. Any of these material can be formulated as an aseptic solid composition which is to be reconstituted just before use with an aseptic water or aseptic solvent for injection.

[0072] In a usual oral administration, the daily dose is about 0.001 to 10 mg / kg body weight, preferably 0.01 to 5 mg / kg, which may be given at once, or twice to four times in portions. When given intravenously, the daily dose is about 0.0001 to 1 mg / kg body weight, which may be given at once, or several times in portions. The dosage may vary depending on the symptom, age, sex and the like of each individual patient. EXAMPLES

Problems solved by technology

The osteoporosis is observed frequently in postmenoposal women or old men, and causes a pain such as a lumbar pain and a bone fracture, and is seriously problematic especially in older patients whose bone fracture readily leads to a systemic weakness and a dementia.

However, most of these therapeutic agents do not exhibit marked bone formation-stimulating effect, although they were reported to have a bone resorption-inhibiting effect.

Nevertheless, their clinical utility is unknown.

However, any of these references and patent specifications does not contain any disclosure or suggestion of an osteogenesis-promoting effect.

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