WO2005102331A1 - Agent thérapeutique pour ostéoporose - Google Patents

Agent thérapeutique pour ostéoporose Download PDF

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Publication number
WO2005102331A1
WO2005102331A1 PCT/JP2005/007952 JP2005007952W WO2005102331A1 WO 2005102331 A1 WO2005102331 A1 WO 2005102331A1 JP 2005007952 W JP2005007952 W JP 2005007952W WO 2005102331 A1 WO2005102331 A1 WO 2005102331A1
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group
osteoporosis
alkyl
alkyl group
cycloalkyl
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PCT/JP2005/007952
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English (en)
Japanese (ja)
Inventor
Hiroyuki Aono
Masaaki Murai
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Santen Pharmaceutical Co., Ltd.
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Publication of WO2005102331A1 publication Critical patent/WO2005102331A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to a perea derivative, an acid amide, and the like (hereinafter, these are collectively referred to as "perea derivatives").
  • Bone is constantly being remodeled (remodeled) by the balance between bone resorption and bone formation.
  • osteoblasts which are responsible for bone formation, create new bone tissue in bone resorption pits created by bone resorption, which is responsible for bone resorption, and are constantly remodeled.
  • bone homeostasis is maintained.
  • Osteoporosis is a disease in which bone remodeling causes ataxia for some reason, bone mineral content is lost, and bone becomes weak. In osteoporosis, remodeling dysfunction is due to enhanced bone resorption or reduced bone formation.
  • Enhanced bone resorption is caused by enhanced osteoclast formation or enhanced osteoclast function.
  • Factors that promote osteoclast formation include in vivo factors such as Receptor Activator of NF- ⁇ B (RANKL), interleukin-1 (IL-1), and macrophage co-stimulatory factor (M-CSF) Etc. are known.
  • RNKL Receptor Activator of NF- ⁇ B
  • IL-1 interleukin-1
  • M-CSF macrophage co-stimulatory factor
  • LPS lipopolysaccharide
  • RANKL promotes osteoclast formation and promotes bone resorption by enhancing osteoclast function. It is known that osteoclast formation via osteoblasts or stromal cells is also mediated by RANKIN.
  • Activated vitamin D, parathyroid hormone (PTH), and the like are factors that promote RANKL expression in osteoblasts and stromal cells.
  • PTH parathyroid hormone
  • PGE Prostaglandin E
  • Non-Patent Document 1 Interleukin 1 (IL-1) and the like are known.
  • Osteoclasts can be induced by a suitable stimulation of monocyte-macrophage progenitor cells.
  • formation can be induced by stimulating bone marrow cells with RANKL and M-CSF.
  • cells that support osteoclast formation such as osteoblasts and stromal cells, and the presence of monocyte-macrophage progenitor cells coexist, and appropriate stimulation, ie, activation Stimulation of vitamin D, PGE, PTH, parathyroid hormone-related peptides, steroids, etc.
  • osteoclasts can be formed.
  • the urea derivative which is an active ingredient in the present invention is a known compound, and is disclosed in Patent Document 1 together with a production method thereof.
  • Patent Document 1 describes that this urea derivative has an inhibitory effect on tumor necrosis factor a (TNF- ⁇ ) production and is useful as a therapeutic drug for autoimmune diseases such as rheumatoid arthritis (RA).
  • Patent Document 2 describes that it is useful as an angiogenesis inhibitor.
  • Non-patent document 1 Yasushi Kobayashi et al., The Latest Medicine, Vol. 58, 2631—2639, 2003
  • Patent Document 1 Japanese Patent Application Laid-Open No. 2002-53555
  • Patent Document 2 Japanese Patent Application Laid-Open No. 2003-226686
  • the present inventors focused on a known urea derivative represented by the following general formula [1] (JP-A-2002-53555), which is reported to be useful as a medicament, and conducted a search for a therapeutic agent for osteoporosis. .
  • these perrea derivatives have an inhibitory effect on osteoclast formation and are useful as therapeutic agents for osteoporosis, and have completed the present invention.
  • the present invention relates to a therapeutic agent for osteoporosis and an osteoclast formation inhibitor containing, as an active ingredient, a compound represented by the following general formula [1] or a salt thereof (hereinafter, referred to as "the present compound” unless otherwise specified): is there.
  • R 1 , R 2 , R 4 , R 5 and R 6 may be the same or different and may be substituted with a hydrogen atom, an alkyl group, or a heterocyclic ring; Group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkyl group, a hydroxy group, an acyl group or an amino group, and the alkyl group, the alkenyl group, the alkyl group, the cycloalkyl group or the cycloalkyl group.
  • R 1 and R 2, R 2, R 2 and R 5 and R 2 and R 6 are saturated Or R 3 represents an aryl group or an unsaturated heterocyclic ring; R 7 represents a hydrogen atom or an alkyl group; X represents OO or SS; n Represents an integer of 1 to 5; the hydrogen atom of each of the above amino, hydroxy and aminocarbon groups is an alkyl group, a cycloalkyl group, an adamantyl group, an adamantyl alkyl group, an aryl group, an arylalkyl group.
  • the invention's effect [0013]
  • the present compound exhibits an excellent inhibitory action on osteoclast formation, and is useful as a therapeutic agent for osteoporosis.
  • Alkylene groups include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, otatamethylene, decamethylene, dodecamethylene, methylmethylene, ethylethylene, and dimethylethylene.
  • the alkylene group is a biylene group, a probenylene group, a butylene group, a pentylene group, a hexylene group, an otatelenene group, a butanediylidene group, a methylproylene group.
  • a straight-chain or branched alkylene group having at least one double bond such as a group and having 2 to 12 carbon atoms.
  • Alkyl groups include methyl, ethyl, propyl, butyl, hexyl, octyl, decyl, dodecyl, isopropyl, isobutyl, isopentyl, isohexyl, isooctyl, It represents a linear or branched alkyl group having 1 to 12 carbon atoms such as a t-butyl group and a 3,3-dimethylbutyl group.
  • the alkoxy group means 1 to 12 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a hexoxy group, an octyloxy group, a decyloxy group, a dodecyloxy group, an isopropoxy group and a t-butoxy group.
  • the alkenyl group refers to a linear or branched alkenyl group having 2 to 12 carbon atoms such as a vinyl group, an aryl group, a 3-butenyl group, a 5-hexenyl group and an isopropyl group.
  • the alkynyl group refers to a straight-chain or branched alkyl group having 2 to 12 carbon atoms such as an ethur group, a propynyl group, and a butynyl group.
  • Cycloalkyl group means cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclodecyl group, cyclododecyl
  • the cycloalkenyl group refers to a cycloalkenyl group having 5 to 20 carbon atoms such as a cyclopentyl group, a cyclohexyl group, and a cycloheptenyl group.
  • the aryl group represents an aromatic hydrocarbon ring such as a phenyl group or a naphthyl group, which may have one or more substituents, for example, an alkyl group, a cycloalkyl group, Examples include a carboxy group, an amino group, a hydroxy group, an aminoalkyl group, a hydroxyalkyl group, a nitro group, a cyano group, a halogen atom, and an alkyloxy group.
  • the siloxy group means a trialkylsilyloxy group, a dialkyl (aryl) silyloxy group
  • silicon-containing organic groups such as an alkyl (diaryl) oxy group and a triarylsilyloxy group.
  • Halogen atom means fluorine, chlorine, bromine and iodine.
  • heterocycle refers to, for example, a 5- to 20-membered saturated or unsaturated monocyclic or bicyclic heterocyclic ring containing 1 to 4 nitrogen atoms, oxygen atoms, and sulfur atoms.
  • the heterocyclic group may have one or more substituents, and examples of the substituent include an alkyl group, a cycloalkyl group, a carboxy group, an amino group, a hydroxy group, an aminoalkyl group, and a hydroxyalkyl group. , A nitro group, a cyano group, a halogen atom, an alkyloxy group, an aryl group, an arylalkyl group, and a saturated or unsaturated heterocyclic ring.
  • the above-mentioned heterocyclic ring has a nitrogen atom or a sulfur atom in the ring, those atoms are oxidized to be in the form of N-oxide, S-oxide or the like!
  • saturated heterocycle examples include pyrrolidine, piperidine, homopiperidine, piperazine having a nitrogen atom in the ring, morpholine having a nitrogen atom and an oxygen atom in the ring, nitrogen and sulfur.
  • Monocyclic heterocycles such as thiomorpholine having an atom in the ring may be mentioned, and these may be condensed with a benzene ring or the like to form a bicyclic heterocycle such as tetrahydroquinoline or tetrahydroisoquinoline.
  • the unsaturated heterocyclic ring include monocyclic heterocyclic rings such as pyrrole, pyridine, pyrazole, imidazole, pyrazine, pyridazine and pyrimidine having a nitrogen atom in the ring, or indole, quinoline, isoquinoline and benzimidazole , Naphthyridine, pyro-mouth pyridine, imidazopyridine and other bicyclic heterocycles, and monocyclic such as furan having an oxygen atom in the ring Heterocycle or bicyclic heterocycle such as benzofuran; monocyclic heterocycle such as thiophene having a sulfur atom in the ring; or bicyclic heterocycle such as benzothiophene; nitrogen atom and oxygen atom or sulfur atom in the ring And monocyclic heterocycles such as oxazole, isooxazole, thiazole and isothiazole, or bicyclic complex rings such as benzothi
  • the salts in the present invention are not particularly limited as long as they are pharmaceutically acceptable salts, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, succinic acid, sake Examples thereof include salts with organic acids such as sulfuric acid, and salts with alkali metals or alkaline earth metals such as sodium, potassium, and calcium.
  • the quaternary ammonium salt of the present invention is also included in the salts in the present invention.
  • geometric isomers or optical isomers are present in the present conjugate, those isomers are also included in the scope of the present invention.
  • the present conjugate may be in the form of a hydrate and a solvate.
  • Preferable examples of the present invention include the following (1) to (3).
  • R 3 pyridine ring.
  • R J at least one of R 2, R 4, R 5 and R 6: ⁇ Daman chill alkyl group, ⁇ Damman chill O alkoxyalkyl group, ⁇ Damman chill ⁇ amino alkyl group or Adamanchirua Minokarubo -Alkyl group.
  • Ri and R 2 at least one of Ri and R 2: ⁇ Daman chill alkyl group, Adamanchiruoki Shiarukiru group, ⁇ Damman chill ⁇ amino alkyl group or ⁇ Dammann chill ⁇ amino carbo - Rua Norekinore group.
  • A (NR 4 ), one (CR 5 R 6 ) or O—;
  • An alkylene group or an alkenyl group which may contain ((CH 2 ) n ), wherein the alkylene group is substituted with a hydroxy group, an alkoxy group, an aryl group, a siloxy group or a saturated or unsaturated heterocyclic ring; May be combined with A to form a saturated heterocyclic ring,
  • R 1 is a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkyl group, a hydroxy group or an amino group, wherein the alkyl group, the alkyl group, the alkyl group Group, cycloalkyl group or cycloalkyl group includes a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbyl group, an alkylaminocarbol group, an adamantyl group, an aryl group.
  • a hydrogen atom of each amino group, hydroxy group and aminocarbonyl group in R 1 which may be substituted with an oxycarbol group, a cyano group or a saturated or unsaturated heterocyclic ring is an alkyl group, a cycloalkyl group, Aryl group, arylalkyl group, acyl group, alkoxycarbol group, cycloalkyloxycarbol group, arylalkoxycar - group, Harogenoaruki Ruokishikarubo - group, imidazolylmethyl carbo - group, substituted by an alkyl group substituted with an unsaturated heterocyclic ring or unsaturated heterocyclic ring, even if I ,
  • R 2 an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminocarbonalkyl group;
  • R 3 unsaturated heterocyclic ring
  • R 4 a hydrogen atom, an alkyl group, an adamantyl alkyl group, a carboxyalkyl group, an alkoxycarbyl group, an alkoxycarbalkyl group, an amino group, an alkylamino group, an acylamino group or an alkoxycarbamino group;
  • R 5 and R 6 are the same or different and are a hydrogen atom, an alkyl group, an amino group or an alkoxycarbolamino group,
  • n an integer from l to 5.
  • R 2 is an adamantyl alkyl group and R 3 is a pyridine ring are more preferable.
  • R 1 is an alkyl group or an alkyl group, wherein the alkyl group may be substituted with a halogen atom or an amino group, and the amino group may be an alkyl group, an acyl group, an arylalkyloxycarbol group. May be substituted with a cycloalkyloxycarbol group or an alkoxycarbol group,
  • R 2 an adamantyl alkyl group
  • R 3 pyridine ring
  • R 4 hydrogen atom
  • R 5 and R 6 hydrogen atom
  • n an integer from l to 5.
  • alkylene group may be substituted with a hydroxy group, an alkoxy group, an aryl group or a saturated or unsaturated heterocyclic ring, And may form a saturated heterocyclic ring by combining with A.
  • R 1 is a hydrogen atom, an alkyl group, an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkyl group, a hydroxy group or an amino group, wherein the alkyl group, the alkyl group, the alkyl group Group, cycloalkyl group or cycloalkyl group includes a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbyl group, an aryloxycarbonyl group, an aminocarbonyl group,
  • the hydrogen atom of each amino group, hydroxy group and aminocarbyl group of R 1 which may be substituted by a cyano group or a saturated or unsaturated heterocyclic ring is an alkyl group, a cycloalkyl group, an aryl group, Arylalkyl, acyl, alkoxycarbyl, cycloalky
  • R 2 an alkyl group, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group or an arylalkyl group,
  • R 3 pyridine ring
  • R 4 a hydrogen atom, an alkyl group, an adamantylalkyl group, a carboxyalkyl group, an alkoxycarbylalkyl group, an amino group, an alkylamino group, an acylamino group or an alkoxycarbolamino group,
  • R 5 and R 6 the same or different and a hydrogen atom or an alkyl group
  • R 7 a hydrogen atom or an alkyl group
  • n an integer from l to 5.
  • R 1 is an alkyl group or an alkyl group, which may be substituted with a halogen atom, an amino group, a cycloalkyl group, an aryl group, an imidazole group, or a pyridine ring; It may be substituted with an alkyl group, an acyl group, an alkoxycarbyl group, a cycloalkyloxycarbyl group or an arylalkoxycarbol group;
  • R 2 alkyl group, alkyl group or arylalkyl group
  • R 3 pyridine ring
  • R 4 hydrogen atom
  • R 5 and R 6 hydrogen atom
  • R 1 is an alkyl group having 3 or more carbon atoms, compounds or salts thereof R 2 was or alkyl group is ⁇ reel alkyl group is particularly preferred.
  • A : — (NR 4 ) — or one (CR 5 R 6 ) —,
  • R 1 is an alkyl group, an alkyl group or a cycloalkyl group, wherein the alkyl group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbyl group, an aryl group.
  • Okishikarubo - group, Aminokarubo - group, pyridine down ring or Chiofen ring at each Amino groups in Yogu more R 1 may be substituted, hydroxy group and Aminokarubo - hydrogen atom
  • Le group is an alkyl group, Ariru Group, an arylalkyl group, an acyl group, an alkoxycarbyl group, a cycloalkyloxycarbyl group, or an arylalkoxycarbyl group.
  • R 2 cycloalkyl group, phenylalkyl group or cycloalkylalkyl group
  • R 3 pyridine ring
  • R 4 hydrogen atom
  • R 5 and R 6 hydrogen atom
  • the present compound can be produced, for example, by the method described in JP-A-2002-53555.
  • the present invention also relates to a method for treating osteoporosis, which comprises administering an effective amount of the compound represented by the general formula [1] or a salt thereof to a patient.
  • the present invention further relates to the use of the compound represented by the general formula [1] or a salt thereof for the manufacture of a therapeutic agent for osteoporosis.
  • a pharmacological test was conducted on the formation of osteoclasts from bone marrow cells to examine the usefulness of this compound. Osteoclasts are cells that play a central role in enhancing bone resorption in osteoporosis, as described below. An experimental system that stimulates bone marrow cells with RANKL and M-CSF is frequently used to induce osteoclasts.
  • the present conjugated product suppressed osteoclast formation.
  • the present conjugate inhibited the formation of osteoclasts from bone marrow cells induced by M-CSF and RANKL. From this, it has been found that the present compound is useful as a therapeutic agent for osteoporosis, preferably a therapeutic agent for osteoporosis accompanied by enhanced osteoclast formation.
  • the present compound is more preferably effective for treating osteoporosis associated with enhanced osteoclast formation by RANKL, M-CSF, IL_1, PGE2, and LPS.
  • the present compound is more preferably effective for treating osteoporosis associated with enhanced osteoclast formation by RANKL or M-CSF.
  • the present compound is most preferably effective for the treatment of osteoporosis associated with enhanced osteoclastogenesis by RANKL and M-CSF.
  • the pathology of osteoporosis is roughly classified into primary osteoporosis and secondary (secondary) osteoporosis.
  • Primary osteoporosis includes postmenopausal osteoporosis, senile osteoporosis, post-pregnancy osteoporosis, etc.
  • Osteoporosis associated with the syndrome osteoporosis associated with hyperparathyroidism, etc.
  • drug-induced osteoporosis eg, osteoporosis caused by administration of steroids
  • Bone resorption in postmenopausal osteoporosis is enhanced by estrogen deficiency due to the end of menstruation (menopause), which increases RANKL production from osteoblasts and bone marrow stromal cells via mediators such as IL1 and PGE2. It has been shown that osteoclast formation and bone resorption are enhanced (Kyoji Ikeda, New Medicine 58, 2658-2663, 2003).
  • the mechanism of bone resorption enhancement in senile osteoporosis was conventionally thought to be a decrease in bone formation due to aging.In recent years, however, it has been attributed to a decrease in bone formation and a lack of calcium due to a decrease in calcium availability. Reactively increase blood calcium levels, increase blood levels of PTH, Has been shown to enhance osteoclast formation and bone resorption through increased RANKL production (Kyoharu Ikeda, Vol. 58, 2658-2663, 2003).
  • Osteoporosis associated with endocrine disease includes, for example, osteoporosis associated with hyperthyroidism.
  • hyperthyroidism increased thyroid function has been shown to increase thyroid hormone production, resulting in increased osteoclastogenesis and bone resorption through increased RANKL production from osteoblasts ( Hiroyuki Koshiyama, New Medicine 58, 2671 2679, 2003).
  • osteoporosis associated with Cushing's syndrome an endocrine disease in which the production of the endogenous steroid dalcocorticoid is increased, excessive amounts of steroids suppress bone formation through osteoblast-suppressing action and simultaneously suppress PTH secretion.
  • osteoblast formation and bone resorption through RANKL expression enhancement of osteoblasts and bone marrow stromal cells are promoted.
  • hyperparathyroidism has also been shown to enhance osteoclast formation and bone resorption through increased RANKL production (Hiroyuki Koshiyama, Vol. 58, 2671-2679, 2003).
  • osteoporosis caused by administration of a steroid agent is typical. It is common in patients who receive steroids for long-term continuous administration. The mechanism is similar to the bone resorption in Cushing's syndrome, which is that excessive steroids increase osteoclast formation through increased RANKL production and bone resorption (Shizuki Suzuki et al., New Medicine 58, 2664-2670) , 2003).
  • the present compound is useful as a therapeutic agent for osteoporosis via these enhanced osteoclast formation.
  • the compound of the present invention can be administered parenterally or orally.
  • Dosage forms include tablets, capsules, granules, powders, injections, patches and the like.
  • Methods for formulating the compound according to the present invention are described in JP-A-2002-53555 and JP-A-2003-226686.
  • the formulation is not limited to these methods, and a formulation can be obtained using a commonly used technique.
  • oral preparations such as tablets, capsules, granules, powders and the like include bulking agents such as lactose, crystalline cellulose, starch, vegetable oil, lubricating agents such as magnesium stearate, talc, hydroxypropylcellulose, polyvinylpyrrolidone, etc.
  • Disintegrators such as calcium carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, Coating agents such as macrogol and silicone resin, film agents such as gelatin film, etc. can be prepared by heating as needed.
  • the dose of the present compound can be appropriately selected depending on the condition, age, dosage form, etc. of the patient.
  • the dosage is usually 0.1 to 5000 mg, preferably 1 to 1000 mg per day. Alternatively, it may be administered in several divided doses.
  • the tablets of the above formulation are coated with 2 mg of a coating agent (for example, ordinary coating agents such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the target coated tablet (the tablets of the following formulation are also available). the same). Also, a desired tablet can be obtained by appropriately changing the amounts of the present compound and additives.
  • a coating agent for example, ordinary coating agents such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.
  • a desired capsule can be obtained by appropriately changing the mixing ratio of the present danidol and lactose. [0084] 3) Prescription 3
  • Bone marrow contains progenitor cells of osteoclasts, and it is known that when M-CSF and RAN KL act on bone marrow cells, they are divided into osteoclasts. Tartrate-resistant acid phosphatase (TRAP) activity is widely used as an indicator of osteoclast formation. Osteoclasts when primary cultured mouse bone marrow cells are stimulated with RANKL and M-CSF, a system commonly used to evaluate osteoclast formation (eg, Yamada T et al: Blood 101; 2227-2234, 2003) The effect of this compound on cell formation was examined.
  • T et al Blood 101; 2227-2234, 2003
  • ⁇ MEM medium containing fetal calf serum (10%), penicillin G (lOOUZml) and streptomycin (100 gZml) was used. Culture conditions were 5% CO and 37 ° C.
  • ddY mice Five hind limb femurs and tibias of ddY mice (male, 5 weeks old) were collected, and the bone marrow cavity was washed with ⁇ EM to obtain bone marrow cells.
  • the bone marrow cells were suspended in the culture medium to 1 ⁇ 10 6 Zml, and 5 ⁇ 10 4 cells were seeded on a 12-well culture plate.
  • M—CSF and RAN KL was added to the final concentrations of lOngZml and lOOngZml, respectively, and a test compound-containing solution (final concentration of IngZml of the i-conjugate) was further added.
  • TRAP staining was performed by the following method to examine the ability to induce osteoclast differentiation. The test compound was not added to the control group, and none of M-CSF, RANKL, and the test compound were added to the normal control group.
  • TRAP staining was performed according to the method of Udagawa et al. (Endocrinology 125: 1805-1813, 1989).
  • the TRAP stain was prepared by dissolving Naphtol AS-MX phosphoric Acid (5 mg) and Fast Red Violet LB salt (25 mg) in 0.5 ml of N, N-dimethylformamide, and adding 50 mM sodium tartrate '0.1 M sodium acetate buffer (pH 5.0) was prepared by mixing 50 ml. After removing the cultured cell viability medium and fixing the cells with PBS containing 10% formalin, an appropriate amount of TRAP staining solution was heated and stained at room temperature for 10 to 15 minutes. After washing and drying, the number of TRAP-positive cells was counted in any two fields under a microscope, and the average was taken as the number of TRAP-positive cells.
  • the osteoclast formation inhibition rate with respect to the control was calculated by the following equation.
  • Osteoclast formation inhibition rate (%) ⁇ 1— (number of TRAP-positive cells in drug-added group) / (number of TRAP-positive cells in control group) ⁇ X 100

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Abstract

Un composé qui convient pour une utilisation comme agent thérapeutique pour l'ostéoporose ; une nouvelle utilisation médicinale d'un dérivé connu de l'urée. Un composé ayant une structure représentée par la formule générale [1] ou un sel de celui-ci est hautement efficace pour inhiber la formation d'ostéoclaste et il est utile comme remède contre l'ostéoporose. Dans la formule, A représente -(NR4)-, -(CR5R6)- ou -O- ; B représente de l'alkylène ou de l'alkenylène ; R1, R2, R4, R5 et R6 représentent chacun de l'hydrogène, de l'alkyle, de l'alkényle, de l'adamantylalkyle, etc. ; R3 représente de l'aryle ou un hétérocycle insaturé ; X représente de l'oxygène ou du soufre.
PCT/JP2005/007952 2004-04-27 2005-04-27 Agent thérapeutique pour ostéoporose WO2005102331A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008074384A1 (fr) 2006-12-21 2008-06-26 Merck Patent Gmbh Dérivés de 2-adamantyle-butyramide en tant qu'inhibiteurs sélectifs de 11βêta-hsd1
US8686006B2 (en) 2008-10-22 2014-04-01 Santen Pharmaceutical Co., Ltd. Pharmaceutical composition for improving intestinal absorption
WO2018230713A1 (fr) 2017-06-16 2018-12-20 学校法人同志社 Composés ayant une activité inhibitrice de caspase, agent pharmaceutique les contenant pour le traitement ou la prévention des symptômes, troubles ou maladies de l'endothélium cornéen, et application dudit agent pharmaceutique
US11433090B2 (en) 2017-06-16 2022-09-06 The Doshisha mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof

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Publication number Priority date Publication date Assignee Title
JP2002053555A (ja) * 2000-05-31 2002-02-19 Santen Pharmaceut Co Ltd ＴＮＦ−α産生阻害物質
JP2003063993A (ja) * 2001-06-11 2003-03-05 Takeda Chem Ind Ltd 医薬組成物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002053555A (ja) * 2000-05-31 2002-02-19 Santen Pharmaceut Co Ltd ＴＮＦ−α産生阻害物質
JP2003063993A (ja) * 2001-06-11 2003-03-05 Takeda Chem Ind Ltd 医薬組成物

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008074384A1 (fr) 2006-12-21 2008-06-26 Merck Patent Gmbh Dérivés de 2-adamantyle-butyramide en tant qu'inhibiteurs sélectifs de 11βêta-hsd1
US8686006B2 (en) 2008-10-22 2014-04-01 Santen Pharmaceutical Co., Ltd. Pharmaceutical composition for improving intestinal absorption
WO2018230713A1 (fr) 2017-06-16 2018-12-20 学校法人同志社 Composés ayant une activité inhibitrice de caspase, agent pharmaceutique les contenant pour le traitement ou la prévention des symptômes, troubles ou maladies de l'endothélium cornéen, et application dudit agent pharmaceutique
US11433090B2 (en) 2017-06-16 2022-09-06 The Doshisha mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof

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