Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/18—Halogen atoms or nitro radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to novel quinoline ester derivatives, pharmaceutically acceptable salts thereof, solvates thereof, methods for preparing the same, and osteoprotegerin (OPG) secretagogues, for the prevention and treatment of metabolic bone diseases, comprising the same as an active ingredient.
• OPG osteoprotegerin
• Osteoporosis is the most common metabolic bone disease. It is a disease of progressive bone loss associated with an increased risk of fractures under even slight amounts of stress. Osteoporosis occurs when proteins, calcium and phosphate are resorbed back into the body from the bones, leaving pores in the bones. In patients with osteoporosis, the bone marrow cavity is expanded as the level of calcium, a mineral determining the physical strength of bone tissues, deceases for various reasons, such as heredity, diet, hormonal change, exercise, living habits, etc. Osteoporotic bones are more at risk of fracture, remarkably decreasing the quality of life. Particularly, women over the age of 30 start to gradually decrease in bone mineral density.
• Osteoporosis occurs in all persons irrespective of age and gender, but frequently in women at the time of menopause. The occurrence frequency also increases with age. Recently, the number of patients with osteoporosis has tended to increase geometrically over the world as the average human lifespan has increased. There is a need for medicines effective in the prevention and treatment of osteoporosis. The gradual increase in the aged population and the concern over quality of life are expanding the market for osteoporosis drugs. According to research by the WHO, it is reported that 30% of post-menopausal women in America suffer from osteoporosis, and 54% show osteopenia. About 26 million Americans are at risk of osteoporotic bone fracture. The number of patients with osteoporosis is expected to increase by 2% every year in the U.
• osteoporotic vertebral fracture occurs in 27% of American women over the age of 65 and in 21% of Danish women over the age of 70. Reports from the WHO and the NIH disclose that the number of persons over the age of 60 will amount to about 25% of the total population in the 21 st century, and therefore there is a need to study geriatric diseases extensively. Typically, osteoporosis is not therapeutically treated until a fracture occurs, in the hip or the vertebra.
• BMD- bone mineral density
• Osteoporosis drugs currently in use can be classified into bone resorption inhibitors and osteogenesis stimulators.
• Exemplified by estrogen, selective estrogen receptor modulators (SERMs), bisphosphonate and calcitonin, bone resorption inhibitors * are adapted for regulating the production and activity of osteoclasts.
• Fluorine agents and parathyroid hormones (PTH) are used as osteogenesis promoters.
• Osteoporosis drugs are also classified into hormones, such as estrogen, calcitonin and parathyroid hormone (PTH), and non-hormones, such as fluorine agent, and bisphosphonates.
• hormones such as estrogen, calcitonin and parathyroid hormone (PTH)
• PTH parathyroid hormone
• non-hormones such as fluorine agent, and bisphosphonates.
• bisphosphonates which stand first in the world market of osteoporosis drugs.
• etidronate, pamidronate, alendronate (Merck), risedronate (Hoffman La-Roche), zoledronate (Novartis, EP. No. 275821), ibandronate (Hoffman La-Roche, U. S. Pat. No. 4942157), and minodronate (YM-529, EP. No. 354806) are commercially available, or are undergoing clinical testing.
• bisphosphonate osteoporosis medicines suffer from disadvantages in that they must be ingested before meals, produce side effects, such as esophagitis and esophageal perforation, and have a low absorption rate.
• A is hydrogen or Ci-Ci 0 haloalkyl, with preference for hydrogen, bromoethyl, bromopropyl or bromobutyl; R, X and Z are as defined above; and the heterocyclic compound of step 2 (V- H) is a hydrogenate of the V defined in Chemical Formula 1).
• the base used in step 2 is triethylamine, sodium hydroxide, or potassium carbonate.
• the metabolic bone diseases include osteoporosis and osteoarthritis.
• the solution was cooled to room temperature and then washed with an aqueous 5% sodium hydroxide solution (300 ml) and water (300 ml).
• the organic layer thus formed was dried over anhydrous magnesium sulfate and concentrated in vacuum, followed by recrystallization of the concentrate to afford the object compound (115 g, 83%).
• the resulting reaction solution was cooled to room temperature and washed with an aqueous 5% sodium hydroxide solution (50 ml) and the organic layer thus formed was dried over anhydrous magnesium sulfate and concentrated in a vacuum.
• the concentrate was purified through silica gel column chromatography to afford the object compound (7.1 g, 77%).
• the organic layer thus formed was separated, dried over anhydrous magnesium sulfate, and concentrated in a vacuum, followed by purification through silica gel column chromatography to afford the object compound (1.0 g, 52%).
• the extract was dried over anhydrous magnesium sulfate and concentrated in a vacuum, followed by the recrystallization of the concentrate in a mixture of ethylacetate and hexane to afford the object cocmpound (0.34 g, 73%).
• the concentrate was re-dissolved in toluene (30 ml) and mixed with morpholinoethyl resorcinol (0.57 g), tetrabutylammonium bromide(0.41 g) and sodium hydroxide(0.3 g), and reflux was conducted for 4 hrs.
• the reaction solution was cooled to room temperature and subjected to extraction with ethyl acetate.
• the extract was dried over anhydrous magnesium sulfate and concentrated in a vacuum, followed by purification through silica gel column chromatography to afford the object compound (1.3 g, 79%).
• the ovary was detected along the uterus, with caution taken not to injure the main organs, such as the diaphragm, the liver, etc.
• the ovary was ligated with sutures and incised. After the ovariectomy, the organs were repositioned within the abdominal cavity and the abdominal wall was closed layer by layer with sutures. Cefazolin (50 ml/mg) was injected in order to prevent infection.
• BMD was analyzed in the form of relative pre- and post-ovariectomy values.
• a T-test (SigmaPlot 2000, version 6.0) was performed to test the statistical significance (PO.05).
• mice After being etherized, female rats, each measuring about 250 g, having a catheter inserted into the femoral vein and artery thereof, were intravenously injected with the compound of Example 6 or 7 at a dose of 5 mg/kg for 1 min.
• the blood was sampled in an amount of 0.3 ml from the femoral artery at each time point corresponding to 0, 5 min, 10 min, 15 min, 1 hr, 2 hr, 4 hr, 6 hr, 9 hr and 12 hr after the injection, in order to measure the level of the compound of Example 6 or 7 in the blood.
• the blood samples Immediately after they were taken, the blood samples were placed in an ice bath for 30 min. Then, the sera obtained through centrifugation at 3,000 rpm for 10 min were placed in a -2O 0 C freezer before use.
• Examples 6 and 7 were analyzed in an HPLC system (Shimadzu LC-IOAD).
• Each of the compounds of Examples 6 and 7 was dissolved at a concentration of 1 mg/ml in methanol to form a stock solution. This stock solution was sequentially diluted in methanol to form a series of standard solutions in concentrations of 40, 20, 10, 2, 1 and 0.5 ⁇ g/ml.
• Calibration concentrations were constructed at 0.05, 0.1, 0.2,' 1, 2 and 4 ⁇ g/ml.
• 100 ⁇ l of blank serum was mixed with 10 ⁇ l of each standard solution (40, 20, 10, 2, 1 and 0.5 ⁇ g/ml) and then with 250 ⁇ l of acetonitrile, followed by centrifugation for 10 min.
• the resulting supernatant (300 ⁇ l) was dried by evaporation in a nitrogen atmosphere and reconstituted with 50 ⁇ l of methanol. 20 ⁇ l of the reconstituted solution was subjected to HPLC analysis.
• the average blood levels of the compounds of Examples 6 and 7 were plotted for distribution phase and post-distribution phase on a semilog scale against time after they were intravenously injected at a dose of 5 mg/kg into female rats. Each pharmacokinetic parameter was evaluated in a non-compartment open model using a WinNonlin program.
• the compounds according to the present invention may be formulated in various forms according to the intended purpose.
• Formulations containing the compounds of Examples 6, 7, 13 and 16 as effective ingredients are illustrated in the following examples, but are not construed to limit the scope of the invention.
• the ingredients were well mixed and loaded in a total amount of 400 mg per capsule into hard gelatin capsules. Other advantageous ingredients, in place of or in addition to vitamin C, may be used.
• the formulations may be prepared in various oral dosage forms, such as tablets, granules, powders, microcapsules, drinks, suspensions, emulsions, syrup, other liquids, etc. using typical methods.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2006
  • 2006-04-06 KR KR1020060031655A patent/KR100878443B1/ko not_active IP Right Cessation
• 2007
  • 2007-04-05 WO PCT/KR2007/001678 patent/WO2007114672A1/en active Application Filing

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