WO2005102331A1 - Therapeutic agent for osteoporosis - Google Patents

Abstract

A compound which is suitable for use as a therapeutic agent for osteoporosis; and a new medicinal use of a known urea derivative. A compound having a structure represented by the general formula [1] or a salt thereof is highly effective in inhibiting osteoclast formation and is useful as an osteoporosis remedy. In the formula, A represents -(NR4)-, -(CR5R6)-, or -O-; B represents alkylene or alkenylene; R1, R2, R4, R5, and R6 each represents hydrogen, alkyl, alkenyl, adamantylalkyl, etc.; R3 represents aryl or an unsaturated heterocycle; and X represents oxygen or sulfur.

Description

 Specification

 Osteoporosis treatment

 Technical field

 [0001] The present invention relates to a perea derivative, an acid amide, and the like (hereinafter, these are collectively referred to as "perea derivatives").

) As an active ingredient.

 Background art

 [0002] Bone is constantly being remodeled (remodeled) by the balance between bone resorption and bone formation. In other words, 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. By maintaining a balance between the two, bone homeostasis is maintained.

 [0003] 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.

 [0004] 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-κB (RANKL), interleukin-1 (IL-1), and macrophage co-stimulatory factor (M-CSF) Etc. are known. As an ex vivo factor, for example, lipopolysaccharide (LPS) which is a cell component of Gram-negative bacteria is known.

 [0005] 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. Prostaglandin E (PGE

 3 2 2

And interleukin 1 (IL-1) and the like are known (Non-Patent Document 1).

[0006] Osteoclasts can be induced by a suitable stimulation of monocyte-macrophage progenitor cells. For example, formation can be induced by stimulating bone marrow cells with RANKL and M-CSF. In addition, the presence of 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.

3 2

 Thus, osteoclasts can be formed.

[0007] On the other hand, 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-α) 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

 Disclosure of the invention

 Problems to be solved by the invention

[0008] It is significant to search for suitable compounds as therapeutic agents for such osteoporosis and to find new pharmaceutical uses of known urea derivatives. Means for solving the problem

[0009] Accordingly, 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. . As a result, they have found that these perrea derivatives have an inhibitory effect on osteoclast formation and are useful as therapeutic agents for osteoporosis, and have completed the present invention.

[0010] 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.

 [Chemical 1]

, Ν

[0011] [式中、 Aは、―（NR⁴ )―、 - (CR⁵ R⁶ )—または— O—を示し; Bは鎖中に、 、 一 S—、 一 （NR⁷ ) 一、 一 CO—、 一 N =若しくは R 1 [1]

[0011] [wherein, A represents — (NR ⁴ ) —, — (CR ⁵ R ⁶ ) — or —O—; B represents, in the chain, one, one S—, one (NR ⁷ ) one, One CO—, one N = or

 [Formula 2]

CH-CH—

Represents an alkylene group or an alkenyl group which may contain a hydroxy group, an alkoxy group, a cycloalkyl group, a cycloalkyl group, an aryl group, a siloxy group or a saturated or unsaturated group. 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. Are halogen, hydroxy, amino, cycloalkyl, adamantyl, aryl, carboxyl, alkoxycarbonyl, aryloxy - group, Aminokarubo - group, Shiano group or a saturated or may be substituted by an unsaturated heterocycle; 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. , Acyl, alkoxyalkyl, alkoxycarbyl, alkylaminocarboxy, cycloalkyloxycarboxy, arylalkoxycarboxy, alkylsulfol, arylsulfonyl, halo Genoalkyloxycarbyl group, imidazolylcarbyl group, pyridylcarbol group, saturated or unsaturated heterocyclic ring, or an alkyl group substituted with a saturated or unsaturated heterocyclic ring . same as below. ]

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.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0014] Each group defined by the general formula [1] will be described in detail.

 [0015] Alkylene groups include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, otatamethylene, decamethylene, dodecamethylene, methylmethylene, ethylethylene, and dimethylethylene. A linear or branched alkylene group having 1 to 12 carbon atoms, such as a group, propylethylene group, isopropylethylene group, methyltrimethylene group and the like.

 [0016] 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.

 [0017] 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.

 [0018] 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. Represents a linear or branched alkoxy group having

[0019] 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.

[0020] 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.

[0021] Cycloalkyl group means cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclodecyl group, cyclododecyl A cycloalkyl group having 3 to 20 carbon atoms such as a group;

[0022] 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.

[0023] 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.

[0024] The siloxy group means a trialkylsilyloxy group, a dialkyl (aryl) silyloxy group

And silicon-containing organic groups such as an alkyl (diaryl) oxy group and a triarylsilyloxy group.

 [0025] Halogen atom means fluorine, chlorine, bromine and iodine.

 The term “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. When 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!

 [0027] Specific examples of the saturated heterocycle 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.

Specific examples of 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 benzothiazole, benzothiazole, chenobilizine, oxazolopyridine, thiazolopyridine and furopyridine. Further, the above unsaturated heterocyclic ring may be in a form partially containing a saturated bond.

 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. Further, the quaternary ammonium salt of the present invention is also included in the salts in the present invention. Further, when geometric isomers or optical isomers are present in the present conjugate, those isomers are also included in the scope of the present invention. In addition, the present conjugate may be in the form of a hydrate and a solvate.

[0030] Preferable examples of the present invention include the following (1) to (3).

(1) A compound or a salt thereof, in which each group defined by the general formula [1] is selected from the following groups, or has a combined power thereof.

1) R ³ : pyridine ring.

[0032] 2) 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.

[0033] 3) 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.

[0034] 4) at least one of Ri and R ^2: § Daman chill alkyl group.

(2) A compound or a salt thereof in which each group defined by the general formula [1] has the following basic ability:

A: (NR ⁴ ), one (CR ⁵ R ⁶ ) or O—;

B: One O, one S-,-(NR ⁷ )-, one CO, one N = or [Formula 3]

—— CH-CH—

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,

R ⁷ : a hydrogen atom or an alkyl group, x: = o or = s,

 n: an integer from l to 5.

Among these, those in which R ² is an adamantyl alkyl group and R ³ is a pyridine ring are more preferable.

 Further, a compound or a salt thereof, in which each group defined by the general formula [1] has the following basic power, is particularly preferable.

[0039] A:-(NR ⁴ ), one (CR ⁵ R ⁶ ) — or O—;

 B: S or

 [Formula 4]

CH-CH—

An alkylene group or an alkenylene group,

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,

 x: = o,

 n: an integer from l to 5.

 (3) A compound or a salt thereof in which each group defined by the general formula [1] has the following basic ability:

A: — (NR ⁴ ) —, — (CR ⁵ R ⁶ ) —or — O—;

B: O—, — S—,-(NR ⁷ ) —, — N = or

[Formula 5] CH-CH—

Wherein the 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, cycloalkyloxycarbol, arylalkoxycarbol, unsaturated heterocyclic ring, etc. Is substituted with alkyl group substitution unsaturated heterocyclic ring, I even ,,

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,

 x: = o or = s,

 n: an integer from l to 5.

[0043] Among these, the compounds having the following basic formulas or their compounds in which each group defined by the general formula [1] is Salts are more preferred.

A:-(NR ⁴ ) —or— (CR ⁵ R ⁶ ) —,

 B: an alkylene group or an alkenyl-group,

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,

 x: = o.

[0045] Further, among these, a 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.

 [0046] Further, a compound or a salt thereof in which each group defined by the general formula [1] has the following basic power is more preferable.

[0047] A:: — (NR ⁴ ) — or one (CR ⁵ R ⁶ ) —,

 B: an alkylene group or an alkenyl-group,

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,

 x: = o.

 [0048] The following compounds and salts thereof are the most preferred specific examples of the present compound.

[0049] 〇 1 [2— (1 adamantyl) ethyl] 1 Pentyl 3— [3— (4 pyridyl) pu pill]

 [Formula 6]

[2—（ 1 ァダマンチノレ）ェチル] 3— [3—（4 ピリジル）プロピル] 3 トリフルォロプロピル）ゥレア（ィ匕合物 2)

[2— (1 adamantinole) ethyl] 3— [3— (4 pyridyl) propyl] 3 trifluoropropyl) rare (2)

 [Formula 7]

[0051] 〇1 [2— (1-adamantyl) ethyl]

 Le) propyl] ゥ rea (compound 3)

[Formula 8]

[0052] 〇 1 [2- (1-adamantyl) ethyl] 1 [2- (N- (t-butoxycarbol) N-methylamino] ethyl] 3- [3- (4 pyridyl) propyl] プ ロ ピ ル rea Compound 4) [Chemical 9]

[0053] 〇 1 [3— (1 adamantine) propyl ”1 propyl 3— [3— (4 pyridyl) pu mouth pill]

 [Formula 10]

[0054] 〇1 ペンチルー 1 フエネチルー 3— [3—（4 ピリジル）プロピル]ゥレア（ィ匕合物 6 )

[0054] 〇1 pentyl-1 phenethyl-3- [3- (4 pyridyl) propyl] ゥ rare

 [Formula 11]

〇 1— [2— (1 adamantyl) ethyl ”3— [2 Methyl 3- (4 pyridyl) propyl] 1 Pentyl peria (Compound 7)

 [Formula 12]

[0056] 〇 1 [2- (1-adamantyl) ethyl] 1 [2— [N (t-butoxycarbol) N-methylamino] ethyl] -3 -— [2-methyl3- (4-pyridyl) propyl]ゥ Rare (8)

[Formula 13]

〇（Z)— 1— [2— (1—ァダマンチル）ェチル] 1 ペンチル

〇 (Z) — 1— [2— (1—adamantyl) ethyl] 1 Pentyl

Le) 2 probe] ゥ rare (compound 9)

[Formula 14]

〇 (Ε) —1— [2- (1-adamantinole) ethyl ”1 pentyl-3— [3- (4-pyridyl) 2-proberl] ゥ rea (compound 10)

0( + )-l-[2-(l-ァダマンチル）ェチル] 3— [ 2 メチル 3—（4 ピリジル )プロピル] 1 ペンチルゥレア（化合物 11)

0 (+) -l- [2- (l-adamantyl) ethyl] 3— [2-methyl 3- (4-pyridyl) propyl] 1 pentyl peria (compound 11)

 [Formula 16]

〇 1— [2— (1 adamantyl) ethyl] 3— [1—methyl-3- (4 pyridyl) propyl] 1 pentyl peria (compound 12)

[Formula 17]

〇（+ )—1 [2—（1 ァダマンチノレ）ェチル] -l-[2-[N-(t-ブトキシカノレボ -ル）—N—メチルァミノ]ェチル ]—3— [2—メチル—3— (4—ピリジル）プロピル]ゥ レア (化合物 13)

〇 (+)-1 [2- (1 adamanchinole) ethyl] -l- [2- [N- (t-butoxycanolebol-yl) -N-methylamino] ethyl] -3-3- [2-methyl-3- (4 —Pyridyl) propyl] ゥ rare (compound 13)

[Formula 18]

[0062] 〇5- (4 pyridyl) valeric acid N pentyl-N phenethylamide (distilled compound 14)

[0063] 〇5- (4 pyridyl) valeric acid N— [2- (1-adamantyl) ethyl] —N-pentylamide (Compound 15)

 [Formula 20]

[0064] N- [2- (1-Adamantyl) ethyl] 3- (4 pyridylmethylthio) propionate

 -N-Pentylamide (compound 16)

[Formula 21]

 〇 2- [2- (4-Pyridyl) ethylthio] acetic acid N— [2- (1-adamantyl) ethyl] N pentylamide (Compound 17)

 [Formula 22]

[0066] 6- (4 Pyridyl) caproic acid N- [2- (1-adamantyl) ethyl]

 Luamide (compound 18)

 [Formula 23]

[0067] The present compound can be produced, for example, by the method described in JP-A-2002-53555.

[0068] 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. [0069] 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. Using this experimental system, it was examined whether the present conjugated product suppressed osteoclast formation. As will be described in detail in the section on pharmacological tests below, it was found that 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.

 [0070] The present compound is more preferably effective for treating osteoporosis associated with enhanced osteoclast formation by RANKL, M-CSF, IL_1, PGE2, and LPS.

 [0071] The present compound is more preferably effective for treating osteoporosis associated with enhanced osteoclast formation by RANKL or M-CSF.

 [0072] 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.), and drug-induced osteoporosis (eg, osteoporosis caused by administration of steroids) (Kyoji Ikeda, Vol. 58, 2658-2663, The latest medicine, 2003).

[0074] 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).

 [0075] Osteoporosis associated with endocrine disease includes, for example, osteoporosis associated with hyperthyroidism. In 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). In 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. As a result, osteoblast formation and bone resorption through RANKL expression enhancement of osteoblasts and bone marrow stromal cells are promoted. In addition, hyperparathyroidism has also been shown to enhance osteoclast formation and bone resorption through increased RANKL production (Hiroyuki Koshiyama, Vol. 58, 2671-2679, 2003).

 [0076] As the drug-induced osteoporosis, for example, 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).

 [0077] The present compound is useful as a therapeutic agent for osteoporosis via these enhanced osteoclast formation.

[0078] 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. For example, 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.

 [0079] The dose of the present compound can be appropriately selected depending on the condition, age, dosage form, etc. of the patient. In the case of an oral preparation, 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.

[0080] Examples of the preparation of the present compound and the results of pharmacological tests using the present compound are shown below.

However, these examples are for better understanding of the present invention, and do not limit the scope of the present invention.

[0081] Formulation Examples

 Examples of general preparations of the present danigata as oral preparations and injections are shown below.

[0082] 1) Prescription 1

 Tablets (in lOOmg)

 1 mg

 Lactose 66.4 mg

 Corn starch 20 mg

 Canoleboxy Mesinoresorenorosekanoreshimu 6 mg

 Hydroxypropinoresenololose 4 mg

 0.6 mg of magnesium stearate

 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.

[0083] 2) Prescription 2

 Capsule (in 150mg)

 5 mg

 Lactose 145 mg

A desired capsule can be obtained by appropriately changing the mixing ratio of the present danidol and lactose. [0084] 3) Prescription 3

 Injection (in 10ml)

 This compound 10-: LOO mg

 Sodium chloride 90 mg

 Sodium hydroxide suitable

 Hydrochloric acid

 Sterile purified water suitable

 By appropriately changing the mixing ratio of the present compound and the additive, a desired injection can be obtained.

[0085] Pharmacological test

 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.

(Preparation of Test Compound-Containing Liquid)

 Compounds 1 to 18 described above were each dissolved in DMSO, and the resulting solution having a concentration of 5 mM was diluted with a medium so that the final concentration in the culture solution was 1 μM, to prepare a test compound-containing solution.

 [0087] (Medium and Culture Conditions Used)

 For the cell culture, αMEM medium containing fetal calf serum (10%), penicillin G (lOOUZml) and streptomycin (100 gZml) was used. Culture conditions were 5% CO and 37 ° C.

 2

 (Culture of bone marrow cells)

Five hind limb femurs and tibias of ddY mice (male, 5 weeks old) were collected, and the bone marrow cavity was washed with αΜEM 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. One week later, 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.

 [0089] (TRAP staining)

 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.

 [0090] (Result evaluation)

 The osteoclast formation inhibition rate with respect to the control was calculated by the following equation.

 [0091] Osteoclast formation inhibition rate (%) = {1— (number of TRAP-positive cells in drug-added group) / (number of TRAP-positive cells in control group)} X 100

 Table 1 shows the results.

[Table 1] Compounds Osteoclast formation inhibition rate (%) Compounds Osteoclast formation inhibition rate (%) Compound 1 90.9 Compound 1 0 52.9 Compound 2 407 Compound 1 1 93.7 Compound 3 34.4 Compound 1 2 96.3 Compound 4 93.1 Compound 1 3 96.3 Compound 5 55.0 Compound 1 4 39.7 Compound 6 56.6 Compound 1 5 76.7 Compound 7 92.1 Compound 1 6 67.2 Compound 8 95.2 Compound 1 7 33.3 Compound 9 35.4 Compound 1 8 52.5 As is clear from Table 1, all test compounds were Inhibited osteoclast formation. No TRAP-positive cells were generated in the normal control group. From the results of the pharmacological tests, it is confirmed that the present compound exhibits an excellent inhibitory action on osteoclast formation and is useful as a therapeutic agent for osteoporosis.

Claims

The scope of the claims  An agent for treating osteoporosis, comprising a compound represented by the following general formula [1] or a salt thereof as an active ingredient.  [Chemical 1]

[Wherein, A represents-(NR ⁴ )--(CR ⁵ R ⁶ )-or-O-; B is in the chain S— NR ⁷ ) CO— N = or [Formula 2] CH-CH—

Represents an alkylene group or an alkenyl group, wherein the alkylene group and the alkenyl group are a hydroxy group, an alkoxy group, a cycloalkyl group, an aryl group, a siloxy group, or a saturated or unsaturated heterocyclic ring. R ¹ R ² R ⁴ R ⁵ and R ⁶ may be the same or different and are a hydrogen atom, an alkyl group, an alkyl group, A hydroxy group, an alkyl group, a cycloalkyl group, a cycloalkyl group, a hydroxy group, an acyl group or an amino group, wherein the alkyl group, alkenyl group, alkyl group, cycloalkyl group or cycloalkyl group is halogen. Atom, hydroxy group, amino group, cycloalkyl group, adamantyl group, aryl group, carboxyl group, alkoxycarbonyl group, aryloxycarbol group, amino R ¹ and R ² R ² and R ⁴ , R ² tR ⁵ and R ² and R ⁶ may be substituted with a saturated or unsaturated heterocyclic group, a cyano group or a saturated or unsaturated heterocyclic ring. 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 = S; 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, Aryl groups, arylalkyl groups, acyl groups, alkoxyalkyl groups, alkoxycarbyl groups, alkylaminocarbol groups, cycloalkyloxycarbyl groups, arylalkoxycarbol groups, alkylsulfol groups, Substituted with arylsulfonyl, halogenoalkyloxycarbyl, imidazolylcarbyl, pyridylcarbol, saturated or unsaturated heterocycle, or alkyl group substituted with saturated or unsaturated heterocycle It's been good. ] [2] The therapeutic agent for osteoporosis according to claim 1, wherein R ³ is a pyridine ring. [3] at least one of R ² , R ⁴ , R ⁵ and R ⁶ is an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminocarbonylalkyl group; 2. The therapeutic agent for osteoporosis according to claim 1, wherein: [4] At least one of R ¹ and R ^{2 is} a adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminocarboxyalkyl group. The therapeutic agent for osteoporosis according to the above. [5] The therapeutic agent for osteoporosis according to claim 1, wherein at least one of R ¹ and R ^{2 is} a adamantyl alkyl group. [6] A represents one (NR ⁴ ) one,-(CR ⁵ R ⁶ ) — or one O; B represents O, one S one, one (NR ⁷ ) one, CO, one N = Or  [Formula 3] CH-CH—

Represents an alkylene group or an alkenyl group, and the alkylene group may be substituted with a hydroxy group, an alkoxy group, an aryl group, a siloxy group, or a saturated or unsaturated heterocyclic ring. And R ¹ may 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, a hydroxy group or an amino group, wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group or cycloalkyl group is a halogen atom, hydroxy group, amino group, cycloalkyl group, aryl group, carboxyl group , An alkoxycarbyl group, an alkylaminocarbyl group, an adamantyl group, an aryloxycarbol group, a cyano group, or each of the above amino groups which may be substituted with a saturated or unsaturated heterocycle. Hydrogen atoms of hydroxy, amino and carboxy groups are alkyl, cycloalkyl, aryl, arylalkyl, acyl, alkoxycarbyl, cycloalkyloxycarbyl, aryl Alkoxy carboxy, halogenoalkyloxy carb, imidazolyl carbyl, unsaturated heterocyclic Or R ² is an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylamino group. R ³ represents an unsaturated heterocyclic ring; R ⁴ represents a hydrogen atom, an alkyl group, an adamantyl alkyl group, a carboxyalkyl group, an alkoxycarbyl group, an alkoxycarbylalkyl group R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, an alkyl group, an amino group or an alkoxycarbonylamino group; R represents an amino group, an alkylamino group, an acylamino group or an alkoxycarbonylamino group; ^The agent for treating osteoporosis according to claim 1, wherein ⁷ represents a hydrogen atom or an alkyl group; represents OO or = S; and n represents an integer of 15. [7] The therapeutic agent for osteoporosis according to claim 6, wherein R ² represents an adamantyl alkyl group, and R ³ represents a pyridine ring. [8] A represents one (NR ⁴ ) CR ⁵ R ⁶ ) — or one O—; B represents one S— or [Formula 4]

And R ¹ represents an alkyl group or an alkenyl group, and the alkyl group may be substituted with a halogen atom or an amino group. Yogu Furthermore the Amino group is an alkyl group, Ashiru group, § reel alkyl O propoxycarbonyl - group, a cycloalkyl O propoxycarbonyl - group or an alkoxycarbonyl - may be substituted with Le group; R ² is Adaman indicates Chiruarukiru group; R ³ represents a pyridine ring; R ⁴ represents hydrogen atom; R ⁵ and R ⁶ represents a hydrogen atom; indicates the = O; n is請represents an integer of 1 to 5 7. The therapeutic agent for osteoporosis according to claim 6. A represents one (NR ⁴ ) —, one (CR ⁵ R ⁶ ) one or one O—; B represents one O—, one S one, one (NR ⁷ ) one, one N = or  [Formula 5] CH-CH—

Represents an alkylene group or an alkylene group, and the alkylene group is bonded to A which may be substituted with a hydroxy group, an alkoxy group, an aryl group or a saturated or unsaturated heterocyclic ring. R ¹ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkyl group, a cycloalkyl group, a cycloalkyl group, a hydroxy group or an amino group; Group, alkyl group, alkyl group, cycloalkyl group or cycloalkenyl group is a halogen atom, hydroxy group, amino group, cycloalkyl group, aryl group, carboxyl group, alkoxycarbyl group, aryloxy group. Each of the above amino groups, hydroxy groups and the like which may be substituted with a carboxy group, an aminocarboyl group, a cyano group or a saturated or unsaturated heterocyclic ring And the hydrogen atom of the aminocarbonyl group is an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxycarbyl group, a cycloalkyloxycarbyl group, an arylalkoxycarbonyl group, an unsaturated group. R ² may be an alkyl group, an alkenyl group, a cycloalkyl group, a cycloalkylalkyl group or an arylalkyl group; R ³ represents a pyridine ring; R ⁴ represents a hydrogen atom, an alkyl group, an adamantyl alkyl group, a carboxyalkyl group, an alkoxycarbylalkyl group, an amino group, an alkylamino group, an acylamino group or an alkoxycarbonyl group. R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or an alkyl group; R ⁷ represents a hydrogen atom or an alkyl group; represents OO or SS; n is an integer of 1 to 5 2. The therapeutic agent for osteoporosis according to claim 1, which shows: [10] A force-(NR ⁴ ) — or one (CR ⁵ R ⁶ ) —; B represents an alkylene group or an alkenyl group; R ¹ represents an alkyl group or an alkenyl group; The alkyl group may be substituted with a halogen atom, an amino group, a cycloalkyl group, an aryl group, an imidazole group or a pyridine ring, and the amino group may be an alkyl group, an acyl group, an alkoxycarbyl group, a cycloalkyl group. R ² may be an alkyl group, an alkaryl group or an arylalkyl group; R ³ may be a pyridine ring; R ⁴ may be substituted with a xycarbyl group or an arylalkoxycarbonyl group; 10. The therapeutic agent for osteoporosis according to claim 9, wherein R ⁵ and R ^{6 each} represent a hydrogen atom; [11] The therapeutic agent for osteoporosis according to claim 10, wherein R ¹ represents an alkyl group, and R ² represents an alkyl group or an arylalkyl group. [12] A force-represents (NR ⁴ ) — or one (CR ⁵ R ⁶ ) —; B represents an alkylene group or an alkenyl group; R ¹ is an alkyl group, an alkenyl 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 aryloxycarbyl group, an aminocarbol group, or a pyridine ring. Or a hydrogen atom of each of the above-mentioned amino groups, hydroxy groups and aminocarbonyl groups which may be substituted by a thiophene ring is an alkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxycarbol group, cycloalkyl O alkoxy Cal ball - group, § reel alkoxycarbonyl - may be substituted with Le group; R ² represents a cycloalkyl group or a cycloalkyl group; R ³ is pyrid Shows a ring; R ⁴ represents a hydrogen atom; R ⁵ and R ⁶ represents a hydrogen atom; osteoporosis Osamu療剤of claim 9 showing the X is = 0.  [13] 1 [2— (1 adamantyl) ethyl] 1 Pentyl 3— [3— (4 pyridyl) propyl] ゥ rea, 1 [2— (1 adamantinole) ethyl] 3— [3— (4 pyridyl) propyl] — 1— (3,3,3-trifluoropropyl) ゥ rea, 1 [2— (1-adamantyl) ethyl] 1 2 butyr) 3— [3- (4 pyridyl) propyl] ゥ rea,  1 [2— (1 adamantyl) ethyl] 1 [2— [N— (t—butoxycarbol) N—methylamino] ethyl] —3— [3— (4-pyridyl) propyl] ゥ rea,  1 [3— (1 adamantinole) propyl] 1 propyl 3— [3— (4 pyridyl) pu pill]  1-pentyl- 1-phenethyl 3- [3- (4-pyridyl) propyl] ゥ rea,  1— [2— (1 adamantyl) ethyl] 3— [2 Methyl 3— (4 pyridyl) propyl] —1—pentyl perylene,  1 [2— (1 adamantyl) ethyl] 1 [2— [N— (t—butoxycarbol) N-methylamino] ethyl] 3— [2 methyl 3- (4 pyridyl) propyl] ゥ rea, (Z) 1 [2— (1 adamantyl) ethyl] 1 Pentyl 3— [3— (4 pyridyl) 2-probel] ゥ rea,  (E) 1 [2— (1 adamantine) ethyl] 1 pentyl 3— [3— (4 pyridyl) 2-probe] ゥ rea,  (+) — 1 [2- (1 adamantyl) ethyl] 3— [2-methyl-3- (4 pyridyl) propyl]-1—pentinouredia,  1— [2— (1 adamantyl) ethyl] 3— [1—Methyl-3— (4 pyridyl) propyl] —1—pentyl perylene,  (+)-1-[2- (1-adamantyl) ethyl]-l-[2- [N- (t-butoxycarbol) -N-methylamino] ethyl] -3-3- [2-methyl-3- (4-pyridyl) propyl] urea,  5— (4 pyridyl) valeric acid N pentyl N phenethylamide,  5— (4 pyridyl) valeric acid N— [2- (1-adamantyl) ethyl] —N—pentylamide,  3- (4-pyridylmethylthio) propionic acid N- [2- (1 adamantyl) ethyl] N-pentynoleamide, 2— [2- (4 pyridyl) ethylthio] acetic acid N— [2- (1 adamantyl) ethyl] N pentylamide and  6— (4 pyridyl) caproic acid N— [2- (1-adamantyl) ethyl] —N—pentylamide  A therapeutic agent for osteoporosis, comprising as an active ingredient a compound selected from the group consisting of or a salt thereof.  [14] The therapeutic agent for osteoporosis according to any one of claims 1 to 13, wherein the osteoporosis is osteoporosis accompanied by promotion of osteoclast formation. 15. The therapeutic agent for osteoporosis according to claim 14, wherein the osteoporosis is primary osteoporosis. 16. The therapeutic agent for osteoporosis according to claim 15, wherein the primary osteoporosis is postmenopausal osteoporosis, senile osteoporosis, or gestational osteoporosis. 17. The therapeutic agent for osteoporosis according to claim 14, wherein the osteoporosis is secondary osteoporosis. [18] The therapeutic agent for osteoporosis according to claim 17, wherein the secondary osteoporosis is osteoporosis associated with endocrine disease.  19. The therapeutic agent for osteoporosis according to claim 18, wherein the osteoporosis associated with endocrine disease is osteoporosis associated with hyperthyroidism, osteoporosis associated with Cushing's syndrome, and osteoporosis associated with hyperparathyroidism. [20] The therapeutic agent for osteoporosis according to claim 17, wherein the secondary osteoporosis is drug-induced osteoporosis. 21. The therapeutic agent for osteoporosis according to claim 20, wherein the drug-induced osteoporosis is osteoporosis associated with administration of a steroid.  [22] An osteoclast formation inhibitor comprising the compound represented by the general formula [1] according to claim 1 or a salt thereof as an active ingredient. [23] A method for treating osteoporosis, comprising administering to a patient an effective amount of a compound represented by the following general formula [1] or a salt thereof.  [Formula 6] , Ν R 1 [1]

Wherein A represents — (NR ⁴ ) —, — (CR ⁵ R ⁶ ) — or —O—; B represents —O—, one S—, one (NR ⁷ ) one, One CO—, one N = or [Formula 7] CH-CH—

Represents an alkylene group or an alkenyl group, wherein the alkylene group and the alkenyl group are a hydroxy group, an alkoxy group, a cycloalkyl group, an aryl group, a siloxy group, or a saturated or unsaturated heterocyclic ring. R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ may be the same or different and are a hydrogen atom, an alkyl 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; Is a halogen atom, hydroxy group, amino group, cycloalkyl group, adamantyl group, aryl group, carboxyl group, alkoxycarbonyl group, aryloxycarbol R ¹ and R ² , R ² and R ⁴ , R ² tR ⁵ and R ² and R ⁶ may be substituted with a group, an aminocarboyl group, a cyano group or a saturated or unsaturated heterocyclic ring. 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 is an unsaturated heterocyclic ring; Represents an integer of 1 to 5; the hydrogen atom of each of the above amino, hydroxy and aminocarbyl groups is an alkyl group, a cycloalkyl group, an adamantyl group, an adamantylalkyl group, an aryl group, an arylalkyl group, Acyl, alkoxyalkyl, alkoxycarbyl, alkylaminocarbol, cycloalkyloxycarbol, arylalkoxycarbol, alkylsulfol, arylsulfonyl, halogeno It may be substituted with an alkyloxycarbyl group, imidazolylcarbyl group, pyridylcarbol group, saturated or unsaturated heterocyclic ring, or an alkyl group substituted with a saturated or unsaturated heterocyclic ring. ,. ] 24. The method according to claim 23, wherein R ³ is a pyridine ring. [25] At least one of R ² , R ⁴ , R ⁵ and R ⁶ is an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminocarbonylalkyl group 24. The method according to claim 23. [26] at least one of R ¹ and R ^{2 is} an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminocarboxyalkyl group; The method of treatment as described. [27] The method according to claim 23, wherein at least one of R ¹ and R ^{2 is} an adamantyl alkyl group. [28] A represents one (NR ⁴ ) —,-(CR ⁵ R ⁶ ) — or one O; B represents O, one S one, one (NR ⁷ ) one, CO, one N = Or  [Formula 8] CH-CH—

Represents an alkylene group or an alkenyl group, and the alkylene group may be substituted with a hydroxy group, an alkoxy group, an aryl group, a siloxy group, or a saturated or unsaturated heterocyclic ring. And R ¹ may form a saturated heterocyclic ring; R ¹ represents 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. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group or cycloalkenyl group may be a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbyl group, an alkyl group. It may be substituted with a luminocarbyl group, an adamantyl group, an aryloxycarbyl group, a cyano group or a saturated or unsaturated heterocyclic ring. The hydrogen atom of each amino group, hydroxy group and aminocarboxy group described is an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxycarbyl group, a cycloalkyloxycarboxy group. -Aryl group, arylalkoxycarbonyl group, halogenoalkyloxycarbyl group, imidazolylcarbyl group, unsaturated heterocyclic ring or unsaturated heterocyclic ring R represents an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminoalkyl group; R may be a substituted alkyl group; ³ represents an unsaturated heterocyclic ring; R ⁴ represents a hydrogen atom, an alkyl group, an adamantylalkyl group, a carboxyalkyl group, an alkoxycarbyl group, an alkoxycarbylalkyl group, an amino group, an alkylamino group, an acylamino group R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, an alkyl group, an amino group or an alkoxycarbonylamino group; R ⁷ represents a hydrogen atom or an alkyl group; The method according to claim 23, wherein represents = O or = S; and n represents an integer of 1 to 5. 29. The method according to claim 28, wherein R ² represents an adamantyl alkyl group, and R ³ represents a pyridine ring. [30] A represents — (NR ⁴ ) —, one (CR ⁵ R ⁶ ) — or O; B represents S— or [Formula 9]

And R ¹ represents an alkyl group or an alkenyl group, and the alkyl group may be substituted with a halogen atom or an amino group. The amino group may be substituted with an alkyl group, an acyl group, an arylalkyloxycarbyl group, a cycloalkyloxycarbol group or an alkoxycarbol group; R ² represents an adamantylalkyl group. shown; R ³ represents a pyridine ring; R ⁴ represents hydrogen atom; R ⁵ and R ⁶ represents a hydrogen atom; indicates the = O; n is請Motomeko 28, wherein an integer of 1 to 5 Treatment method. A represents one (NR ⁴ ) —, one (CR ⁵ R ⁶ ) one or one O; and B represents one O, one S one, one (NR ⁷ ) one, one N = or [Formula 10] CH-CH—

Represents an alkylene group or an alkylene group, and the alkylene group is bonded to A which may be substituted with a hydroxy group, an alkoxy group, an aryl group or a saturated or unsaturated heterocyclic ring. R ¹ may be 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 alkenyl group, the alkyl group, the cycloalkyl group or the cycloalkenyl group is , A halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbyl group, an aryloxycarbol group, an aminocarbol group, a cyano group or a saturated or unsaturated heterocyclic ring The hydrogen atom of each of the above amino groups, hydroxy groups and aminocarbonyl groups which may be substituted with an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxycarbyl group, Cycloalkyloxycarbyl group, arylalkoxy group, carbonyl group, unsaturated heterocycle or unsaturated heterocycle It may be replacement by conversion alkyl group; R ² is an alkyl group, Aruke - group, a cycloalkyl group, a cycloalkyl Ruarukiru group or § reel alkyl group; R ³ represents a pyridine ring; R ⁴ Represents a hydrogen atom, an alkyl group, an adamantylalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an amino group, an alkylamino group, an acylamino group or an alkoxycarbonylamino group; R ⁵ and R ⁶ are the same or different represents a hydrogen atom or an alkyl group; R ⁷ represents a hydrogen atom or an alkyl group; is = O or = indicates S; n is a method of treatment of claim 23, wherein an integer of 1-5. A represents -force (NR ⁴ ) — or one (CR ⁵ R ⁶ ) —; B represents an alkylene group or an alkenyl group; R ¹ represents an alkyl group or an alkenyl group; It may be substituted with a halogen atom, an amino group, a cycloalkyl group, an aryl group, an imidazole group or a pyridine ring, and the amino group may be an alkyl group, an acyl group, an alkoxycarbyl group, a cycloalkyloxycarboxy group. Substituted with an aryl group or an arylalkoxycarbonyl group. R ² represents an alkyl group, an alkenyl group or an arylalkyl group; represents a pyridine ring; R ⁴ represents a hydrogen atom; R ⁵ and R ⁶ represent a hydrogen atom; 32. The treatment method according to claim 31, which represents O. [33] The method according to claim 32, wherein R ¹ represents an alkyl group, and R ² represents an alkyl group or an arylalkyl group. [34] A force-represents (NR ⁴ ) — or one (CR ⁵ R ⁶ ) —; B represents an alkylene group or an alkenyl group; R ¹ is an alkyl group, an alkenyl 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 aryloxycarbyl group, an aminocarbol group, or a pyridine ring. Or a hydrogen atom of each of the above-mentioned amino groups, hydroxy groups and aminocarbonyl groups which may be substituted by a thiophene ring is an alkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxycarbol group, cycloalkyl O alkoxy Cal ball - group, § reel alkoxycarbonyl - may be substituted with Le group; R ² represents a cycloalkyl group or a cycloalkyl group; R ³ is pyrid Shows a ring; R ⁴ represents a hydrogen atom; R ⁵ and R ⁶ represents a hydrogen atom; a method of treatment of claim 31, wherein X indicates a is = 0.  [35] 1 [2- (1 adamantyl) ethyl] 1 Pentyl-3— [3- (4 pyridyl) propyl] ル rea,  1 [2— (1 adamantinole) ethyl] 3— [3— (4 pyridyl) propyl] — 1— (3,3,3-trifluoropropyl) ゥ rea,  1 [2— (1-adamantyl) ethyl] 1 2 butyr) 3— [3- (4 pyridyl) propyl] ゥ rea,  1 [2— (1 adamantyl) ethyl] 1 [2— [N— (t—butoxycarbol) N—methylamino] ethyl] —3 [3— (4—pyridyl) propyl] ゥ rea,  1 [3— (1 adamantinole) propyl] 1 propyl 3— [3— (4 pyridyl) pu pill] 1-pentyl- 1-phenethyl 3 -— [3- (4-pyridyl) propyl] ゥ rea, 1— [2- (1 adamantyl) ethyl] 3— [2 methyl 3- (4 pyridyl) propyl] —1-pentylperyl, 1 [2— (1 adamantyl) ethyl] 1 [2— [N— (t—butoxycarbol) N-methylamino] ethyl] 3— [2 methyl 3- (4 pyridyl) propyl] ゥ rea, (Z) 1 [2— (1 adamantyl) ethyl] 1 Pentyl 3— [3— (4 pyridyl) 2-probel] ゥ rea,  (E) 1 [2— (1 adamantine) ethyl] 1 pentyl 3— [3— (4 pyridyl) 2-probe] ゥ rea,  (+) — 1 [2- (1 adamantyl) ethyl] 3— [2-methyl-3- (4 pyridyl) propyl]-1—pentinouredia,  1— [2— (1 adamantyl) ethyl] 3— [1—Methyl-3— (4 pyridyl) propyl] —1—pentyl perylene,  (+)-1-[2- (1-adamantyl) ethyl]-l-[2- [N- (t-butoxycarbol) -N-methylamino] ethyl] -3-3- [2-methyl-3- (4-pyridyl) propyl] urea,  5— (4 pyridyl) valeric acid N pentyl N phenethylamide,  5— (4 pyridyl) valeric acid N— [2- (1-adamantyl) ethyl] —N—pentylamide,  3- (4-pyridylmethylthio) propionic acid N- [2- (1 adamantyl) ethyl] N-pentynoleamide,  2- [2- (4-pyridyl) ethylthio] acetic acid N- [2- (1-adamantyl) ethyl] N pentylamide and  6- (4-pyridyl) caproic acid N- [2- (1-adamantyl) ethyl] -N-pentylamide  A method for treating osteoporosis, comprising administering to a patient an effective amount of a compound selected from the group consisting of the following or a salt thereof. [36] The method according to any one of claims 23 to 35, wherein the osteoporosis is osteoporosis accompanied by promotion of osteoclast formation. 37. The method according to claim 36, wherein the osteoporosis is primary osteoporosis. [38] Primary osteoporosis is postmenopausal osteoporosis, senile osteoporosis, or post-pregnancy osteoporosis 38. The treatment method according to claim 37, wherein 39. The method according to claim 36, wherein the osteoporosis is secondary osteoporosis. [40] The method according to claim 39, wherein the secondary osteoporosis is osteoporosis associated with endocrine disease. 41. The method according to claim 40, wherein the osteoporosis associated with an endocrine disease is osteoporosis associated with hyperthyroidism, osteoporosis associated with Cushing's syndrome, or osteoporosis associated with hyperparathyroidism.  42. The method according to claim 39, wherein the secondary osteoporosis is drug-induced osteoporosis. 43. The method according to claim 42, wherein the drug-induced osteoporosis is osteoporosis associated with administration of a steroid.  [44] A method for suppressing osteoclast formation, which comprises administering to a patient an effective amount of the compound represented by the general formula [1] according to claim 23 or a salt thereof. [45] Use of a compound represented by the following general formula [1] or a salt thereof for the manufacture of a therapeutic agent for osteoporosis.  [Formula 11] , B, Wherein A represents — (NR ⁴ ) —, — (CR ⁵ R °) — or —O—; B represents —O—, one S—, one (NR ⁷ ) one, One CO—, one N = or  [Formula 12] CH-CH—

Represents an alkylene group or an alkylene group; The alkene group may be substituted with a hydroxy group, an alkoxy group, a cycloalkyl group, an aryl group, a siloxy group or a saturated or unsaturated heterocycle, and may be combined with A to form a saturated heterocycle. R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ may be the same or different and are each a hydrogen atom, an alkyl group, an alkenyl group, an alkyl group, a cycloalkyl group, a cycloalkyl group, a hydroxy group, An alkyl group, an alkenyl group, an alkyl group, a cycloalkyl group or a cycloalkyl group, such as a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an adamantyl group, an aryl group, or a carboxyl group; Group, an alkoxycarbonyl group, an aryloxycarbyl group, an aminocarbol group, a cyano group or a saturated or unsaturated heterocyclic ring. At best; R ¹ and R ^2, R ² and R ^4, R ² tR ⁵ and R ² and R ⁶ are saturated or may form a heterocyclic ring unsaturation; of R ³ is Ariru group or an unsaturated R ⁷ represents a hydrogen atom or an alkyl group; X represents OO or = S; n represents an integer of 1 to 5; each of the above-mentioned amino, hydroxy and aminocarbol groups Hydrogen atoms are alkyl, cycloalkyl, adamantyl, adamantylalkyl, aryl, arylalkyl, acyl, alkoxyalkyl, alkoxycarbyl, alkylaminocarbol, cycloalkyl Oxycarbyl group, arylalkoxycarbyl group, alkylsulfol group, arylsulfonyl group, halogenoalkyloxycarbol group, imidazolylcarbyl group, pyridylcarbol group, saturated Or an alkyl group substituted with an unsaturated heterocyclic ring or a saturated or unsaturated heterocyclic ring. ] [46] The use according to claim 45, wherein R ³ is a pyridine ring. [47] At least one of R ² , R ⁴ , R ⁵ and R ⁶ is an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminocarbonylalkyl group 46. The use according to claim 45. 48. The method according to claim 45, wherein at least one of R ¹ and R ^{2 is} an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group, or an adamantylaminocarbonalkyl group. Use of the description. [49] The use according to claim 45, wherein at least one of R ¹ and R ^{2 is} an adamantyl alkyl group. [50] A represents — (NR ⁴ ) —, — (CR ⁵ R ⁶ ) or —O; B represents one, one (NR ⁷ ) one, CO, one N = or  [Formula 13] CH-CH—

Represents an alkylene group or an alkenyl group, and the alkylene group may be substituted with a hydroxy group, an alkoxy group, an aryl group, a siloxy group, or a saturated or unsaturated heterocyclic ring. And R ¹ may form a saturated heterocyclic ring; R ¹ represents 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. The alkyl group, alkenyl group, alkynyl group, cycloalkyl group or cycloalkenyl group may be a halogen atom, a hydroxy group, an amino group, a cycloalkyl group, an aryl group, a carboxyl group, an alkoxycarbyl group, an alkyl group. It may be substituted with a luminocarbyl group, an adamantyl group, an aryloxycarbyl group, a cyano group or a saturated or unsaturated heterocyclic ring. The hydrogen atoms of the amino, hydroxy and aminocarboyl groups described are alkyl, cycloalkyl, aryl, arylalkyl, acyl, alkoxycarboyl, cycloalkyloxycarbo. -Alkyl group, arylalkoxycarbonyl group, halogenoalkyloxycarbyl group, imidazolylcarbyl group, unsaturated heterocycle or an alkyl group substituted with an unsaturated heterocycle. R ² represents an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantylaminopropylalkyl group; and R ³ represents an unsaturated heterocyclic ring. It is shown; R ⁴ is a hydrogen atom, an alkyl group, § Damman chill alkyl group, carboxyalkyl group, alkoxycarbonyl - group, § Rukokishikarubo - Ruarukiru group, an amino group Alkylamino group, an Ashiruamino group or § alkoxycarbonyl § amino group; R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, § alkyl group, an amino group or an alkoxycarbonyl § amino group; R ⁷ is a hydrogen atom Or represents an alkyl group; represents = O or = S; n represents an integer of 1 to 5. Use of. [51] The use according to claim 50, wherein R ² represents an adamantyl alkyl group, and R ³ represents a pyridine ring. [52] A represents one (NR ⁴ ) —, one (CR ⁵ R ⁶ ) — or one O; B represents one S or one in the chain —— CH-CH—

And R ¹ represents an alkyl group or an alkenyl group, and the alkyl group may be substituted with a halogen atom or an amino group. The amino group may be substituted with an alkyl group, an acyl group, an arylalkyloxycarbyl group, a cycloalkyloxycarbol group or an alkoxycarbol group; R ² represents an adamantylalkyl group. shown; R ³ represents a pyridine ring; R ⁴ represents hydrogen atom; R ⁵ and R ⁶ represents a hydrogen atom; indicates the = O; n is請Motomeko 50, wherein an integer of 1 to 5 Use of. [53] A represents one (NR ⁴ ) —,-(CR ⁵ R ⁶ ) — or one O; B represents O, one S one, one (NR ⁷ ) one, N = or  [Formula 15] —— CH-CH—

Represents an alkylene group or an alkylene group, and the alkylene group is bonded to A which may be substituted with a hydroxy group, an alkoxy group, an aryl group or a saturated or unsaturated heterocyclic ring. R ¹ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkyl group, a cycloalkyl group, a cycloalkyl group, a hydroxy group or an amino group; Group, alkyl group, alkyl group, cycloalkyl group or cycloalkenyl group is a halogen atom, a hydroxy group, an amino group, a cycloalkyl group. Or a substituted or unsubstituted aryl group, aryl group, carboxyl group, alkoxycarbyl group, aryloxycarbyl group, aminocarbol group, cyano group or a saturated or unsaturated heterocycle. The hydrogen atom of each amino, hydroxy and aminocarbonyl group is an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxycarbyl group, a cycloalkyloxycarbyl group, an aryl group. R ² may be substituted with an alkyl group, an alkenyl group, a cycloalkyl group, a cycloalkylalkyl group or an alkoxy group, which may be substituted with a carbonyl group, an unsaturated heterocyclic ring or an alkyl group substituted with an unsaturated heterocyclic ring. R ³ represents a pyridine ring; R ⁴ represents a hydrogen atom, an alkyl group, an adamantyl alkyl group, a carboxyalkyl group; R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or an alkyl group; R ⁷ represents a hydrogen atom; a kill group, an alkoxycarbalkyl group, an amino group, an alkylamino group, an acylamino group or an alkoxycarbonylamino group; 46. The use according to claim 45, wherein = represents an O or = S; and n represents an integer of 1 to 5. [54] A force-represents (NR ⁴ ) — or one (CR ⁵ R ⁶ ) —; B represents an alkylene group or an alkenyl group; R ¹ represents an alkyl group or an alkenyl group; The alkyl group may be substituted with a halogen atom, an amino group, a cycloalkyl group, an aryl group, an imidazole group or a pyridine ring, and the amino group may be an alkyl group, an acyl group, an alkoxycarbyl group, a cycloalkyl group. R ² may be an alkyl group, an alkaryl group or an arylalkyl group; R ³ may be a pyridine ring; R ⁴ may be substituted with a xycarbyl group or an arylalkoxycarbonyl group; represents a hydrogen atom; R ⁵ and R ⁶ represents a hydrogen atom; use of claim 53 wherein indicating the is = O. [55] The use according to claim 54, wherein R ¹ represents an alkyl group, and R ² represents an alkyl group or an arylalkyl group. [56] A force-(NR ⁴ ) — or one (CR ⁵ R ⁶ ) —; B represents an alkylene group or an alkenyl group; R ¹ is an alkyl group, an alkenyl 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 aryloxycarbyl group, an aminocarbol group, or a pyridine ring. Or each amino group described above which may be substituted with a thiophene ring. The hydrogen atoms of the amino, hydroxy and aminocarbonyl groups are alkyl, aryl, arylalkyl, acyl, alkoxycarbyl, cycloalkyloxycarbyl, arylalkoxycarbyl R ² represents a cycloalkyl group or a cycloalkylalkyl group; R ³ represents a pyridine ring; R ⁴ represents a hydrogen atom; R ⁵ and R ⁶ represent a hydrogen atom; 54. The use according to claim 53, wherein indicates 0.  For the manufacture of a therapeutic agent for osteoporosis,  1— [2— (1 adamantyl) ethyl] 1 Pentyl—3— [3— (4 pyridyl) propyl] ゥ rea,  1 [2— (1 adamantinole) ethyl] 3— [3— (4 pyridyl) propyl] — 1— (3,3,3-trifluoropropyl) ゥ rea,  1 [2— (1-adamantyl) ethyl] 1 2 butyr) 3— [3- (4 pyridyl) propyl] ゥ rea,  1 [2— (1 adamantyl) ethyl] 1 [2— [N— (t—butoxycarbol) N—methylamino] ethyl] —3— [3— (4-pyridyl) propyl] ゥ rea,  1 [3— (1 adamantinole) propyl] 1 propyl 3— [3— (4 pyridyl) pu pill]  1-pentyl- 1-phenethyl 3- [3- (4-pyridyl) propyl] ゥ rea,  1— [2— (1 adamantyl) ethyl] 3— [2 Methyl 3— (4 pyridyl) propyl] —1—pentyl perylene,  1 [2— (1 adamantyl) ethyl] 1 [2— [N— (t—butoxycarbol) N-methylamino] ethyl] 3— [2 methyl 3- (4 pyridyl) propyl] ゥ rea, (Z) 1 [2— (1 adamantyl) ethyl] 1 Pentyl 3— [3— (4 pyridyl) 2-probel] ゥ rea,  (E) 1 [2— (1 adamantine) ethyl] 1 pentyl 3— [3— (4 pyridyl) 2-probe] ゥ rea,  (+) — 1 [2- (1 adamantyl) ethyl] 3— [2-methyl-3- (4 pyridyl) propyl]-1—pentinouredia, 1— [2— (1 adamantyl) ethyl] 3— [1—Methyl-3— (4 pyridyl) propyl 1]-Pentyl ゥ rare,  (+)-1-[2- (1-adamantyl) ethyl]-l-[2- [N- (t-butoxycarbol) -N-methylamino] ethyl] -3-3- [2-methyl-3- (4-pyridyl) propyl] urea,  5— (4 pyridyl) valeric acid N pentyl N phenethylamide,  5— (4 pyridyl) valeric acid N— [2- (1-adamantyl) ethyl] —N—pentylamide,  3- (4-pyridylmethylthio) propionic acid N- [2- (1 adamantyl) ethyl] N-pentynoleamide,  2- [2- (4-pyridyl) ethylthio] acetic acid N- [2- (1-adamantyl) ethyl] N pentylamide and  6- (4-pyridyl) caproic acid N- [2- (1-adamantyl) ethyl] -N-pentylamide  Use of a compound or a salt thereof selected from the group consisting of: [58] The use according to any one of claims 45 to 57, wherein the osteoporosis is osteoporosis accompanied by promotion of osteoclast formation.  [59] The use according to claim 58, wherein the osteoporosis is primary osteoporosis.  [60] The use according to claim 59, wherein the primary osteoporosis is post-menopausal osteoporosis, senile osteoporosis or post-pregnancy osteoporosis. [61] The use according to claim 58, wherein the osteoporosis is secondary osteoporosis. 62. The use according to claim 61, wherein the secondary osteoporosis is osteoporosis associated with endocrine disease. 63. The use according to claim 62, wherein the osteoporosis associated with an endocrine disease is osteoporosis associated with hyperthyroidism, osteoporosis associated with Cushing's syndrome, and osteoporosis associated with hyperparathyroidism.  [64] The use according to claim 61, wherein the secondary osteoporosis is drug-induced osteoporosis. [65] The use according to [64], wherein the drug-induced osteoporosis is osteoporosis associated with administration of a steroid. [66] The compound represented by the general formula [1] according to claim 45, for producing an osteoclast formation inhibitor. Use of the compound or its salts _c