WO2005102332A1

WO2005102332A1 - Therapeutic agent for arthrosis deformans

Info

Publication number: WO2005102332A1
Application number: PCT/JP2005/007953
Authority: WO
Inventors: Hiroyuki Aono; Masaaki Murai
Original assignee: Santen Pharmaceutical Co., Ltd.
Priority date: 2004-04-27
Filing date: 2005-04-27
Publication date: 2005-11-03

Abstract

A compound which is suitable for use as a therapeutic agent for arthrosis deformans; 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 accelerating cartilage cell proliferation and inhibiting MMP-13 production, and is useful as a therapeutic agent for arthrosis deformans. 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

Osteoarthritis 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] Osteoarthritis is a disease that causes degeneration of local cartilage of a joint due to various causes, and eventually causes symptoms such as joint deformation accompanied by degeneration of a joint bone. It mainly occurs in the joints such as the ankle, knee, hip, cervical vertebra, spine, lumbar vertebra, shoulder joint, elbow joint, hand joint or small joints such as fingers. Osteoarthritis is caused by mechanical stress (repetitive loading, excessive movement, trauma, etc.) and wear or degeneration of cartilage due to aging, etc., which inhibits chondrocyte proliferation and matrix meta-oral proteinase. With increased production.

[0003] Articular cartilage functions as an excellent load buffer in a joint. Its composition also includes water (about 70%), collagen (mainly type II collagen, about 20%), proteodalican (about 10%) and chondrocyte strength. Proteodalican has high hydrophilicity because it has many negatively charged glycosaminoglycans and a core protein having a binding site with collagen. These substrates are synthesized and maintained by chondrocytes.

[0004] Matrix meta-oral proteinase 13 (MMP-13), also called collagenase 3, is frequently expressed in chondrocytes deep in articular cartilage. MMP-13 is an extracellular matrix (substrate) degrading enzyme specific for type I to type III collagen and gelatin. MMP-13 is highly specific for type II collagen, a major extracellular matrix of cartilage, plays an important role in cartilage metabolism, and plays a major role in cartilage degeneration in osteoarthritis It has been.

[0005] Here, cartilage degeneration refers to chondrocyte proliferation inhibition, reduction of chondrocyte matrix synthesis and qualitative change of cartilage matrix due to promotion of Z or matrix degradation, and cartilage fibrosis related to the repair reaction. It is generally considered to be a concept including

[0006] In the treatment of such osteoarthritis, non-steroidal anti-inflammatory drugs and adrenal Oral administration of cortical steroids has been performed. However, oral administration of non-steroidal anti-inflammatory analgesics does not go beyond the scope of coping therapy.Administration of corticosteroids has the risk of causing serious side effects, and the power of conventional OA It has been pointed out that the administration of steroids into the joint cavity, which is performed as a treatment, adversely affects the metabolism of chondrocytes and may cause rapid joint destruction (non-patent literature).

D o

[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 the perea 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: Torisu Takehiko, Joint Surgery, Vol. 21, 180-184, 2002

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 a compound suitable as a therapeutic agent for such osteoarthritis and to find a new pharmaceutical use of a known urea derivative.

Means for solving the problem

[0009] In view of the above, attention has been paid to a known perrea derivative (JP-A-2002-53555) represented by the following general formula [1], which has been reported to be useful as a medicament, and a search for a therapeutic agent for osteoarthritis has been conducted. As a result of these studies, these urea derivatives have the effect of promoting the growth of human chondrocytes and inhibiting the production of matrix meta-oral proteinase 13 (ΜΜΡ-13) from IL-1β-stimulated chondrocytes. The present inventors have found that the present invention is useful as a therapeutic agent for osteoarthritis, and have completed the present invention.

[0010] As a medicinal use of the perrea derivative, a use for treating autoimmune diseases such as rheumatoid arthritis is reported in JP-A-2002-53555. However, rheumatoid arthritis is a disease whose symptoms are similar to those of osteoarthritis. [0011] The major pathology of rheumatoid arthritis is inflammation and overgrowth of the synovium (synovitis) and concomitant deformation or destruction of the joint. On the other hand, in osteoarthritis, synovial hyperplasia is not observed or is slight, and synovitis in osteoarthritis is caused by the proinflammatory substance generated during the process of cartilage degeneration. It is said to be secondary. The destruction of cartilage in rheumatoid arthritis is mainly due to the invasion of cartilage by the overgrown synovium (pannus). In contrast, cartilage destruction in osteoarthritis is caused by mechanical stress (repetitive load, excessive exercise, trauma, etc.) and wear or degenerative degeneration of cartilage due to aging. The disease is considered a degenerative or degenerative lesion of the cartilage itself. Rheumatoid arthritis is an autoimmune disease, in which autoantibodies such as rheumatoid factor are detected in the blood and are accompanied by systemic symptoms such as an increase in CRP levels, whereas rheumatoid arthritis is associated with rheumatoid arthritis. Autoantibodies such as matoid factors are generally negative and CRP levels are usually normal. Osteoarthritis is distinguished from rheumatoid arthritis in many of these respects.

[0012] Furthermore, there is a synovium in rheumatoid arthritis patients (Husby G et al., Journal of Autoimmunity Vol. 1, 363-371, 1988)! /, A large amount of tumor necrosis factor α (TNF-α) TNF plays a crucial role in the pathogenesis of rheumatoid arthritis because its presence is detected and TNF neutralization therapy is significantly effective (Nobuyuki Takasaka, Mebio, Vol. 20 No. 3, 30-35). It is shown to help. In contrast, in osteoarthritis, the presence of TNF-α is not detected in the synovium (Husby G et al., Vol. 1, 363-371, Journal of Autoimmunity 1988). On the other hand, focusing on the cartilage itself that caused arthritis, a large amount of TNF-a mRNA was detected in cartilage from rheumatoid arthritis patients, whereas the amount of TNF-a mRNA was detected in cartilage from osteoarthritis patients. In normal cartilage, TNF-a mRNA is not detected at all, that is, human cartilage has the potential to produce TNF-α. It has been reported that TNF-a is not produced in normal human cartilage. (Patel IR et al., Journal of immunology Vol. 160, 4570-4579, 1998).

[0013] As the pharmacological action of the urea derivative, which is an active ingredient in the present invention, TNF production inhibitory action is reported in JP-A-2002-53555. There is no direct connection.

[0014] The present invention relates to a compound represented by the following general formula [1] or a salt thereof (hereinafter, unless otherwise specified, " The present invention relates to a therapeutic agent for osteoarthritis, a chondrocyte proliferation promoter and a matrix meta-oral proteinase production inhibitor comprising the compound of the present invention as an active ingredient.

[Chemical 1]

[0015] [wherein, A represents — (NR ⁴ ) —, — (CR ⁵ R ⁶ ) — or —O—; B represents

, One S—, one (NR ⁷ ) one, one CO—, one N = or

[Formula 2]

CH-CH—

[0016] represents an alkylene group or an alkenylene group which may contain a hydroxyl group, an alkoxy group, a cycloalkyl group, an aryl group, a siloxy group or a saturated or unsaturated 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, may be substituted by Shiano group or a saturated or unsaturated heterocyclic ring; R ¹ and R ^2, R ² and R ^4, R ² tR ⁵ and R ² and R ⁶ 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; each amino group, hydroxy group and The hydrogen atom of the aminocarbon group is an alkyl group, a cycloalkyl group, an adamantyl group, an adamantylalkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxyalkyl group, an alkoxycarbyl group, or an alkylaminocarbol. Group, cycloalkyloxycarbyl group, arylalkoxycarbol group, alkylsulfol group, arylsulfonyl group, halogenoalkyloxycarbol group, imidazolylcarbyl group, pyridylcarbol group, It may be substituted with a saturated or unsaturated heterocyclic ring or an alkyl group substituted with a saturated or unsaturated heterocyclic ring. same as below. ]

This compound has an excellent cartilage growth-promoting action and an inhibitory action on the production of matrix-degrading enzymes from chondrocytes.

It is useful as a therapeutic agent for osteoarthritis.

BEST MODE FOR CARRYING OUT THE INVENTION

[0017] Each group defined by the general formula [1] will be described in detail.

[0018] The alkylene group includes a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, an otatamethylene group, a decamethylene group, a dodecamethylene group, a methylmethylene group, an ethylethylene group, 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.

[0019] The alkene-group means a biylene group, a probenylene group, a butylene group, a pentylene group, a hexene group, an otatelen 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.

[0020] An alkyl group is a methyl group, an ethyl group, a propyl group, a butyl group, a hexyl group, an octyl group, a decyl group, a dodecyl group, an isopropyl group, an isobutyl group, an isopentyl group, an isohexyl group, an isooctyl group, 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 term “alkoxy group” means 1 to 12 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexoxy, octyloxy, decyloxy, dodecyloxy, isopropoxy, and t-butoxy. Represents a linear or branched alkoxy group having [0022] The alkyl group is a straight-chain or branched group having 2 to 12 carbon atoms such as a bur group, an aryl group, a 3-butyl group, a 5-hexyl group and an isopropyl group. Represents an alkenyl group

[0023] The term "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.

[0024] The cycloalkyl group is a cycloalkyl having 3 to 20 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, and a cyclododecyl group. Represents a group.

[0025] The cycloalkenyl group refers to a cycloalkenyl group having 5 to 20 carbon atoms such as a cyclopentyl group, a cyclohexyl group, a cycloheptenyl group and the like.

[0026] 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.

[0027] The siloxy group means a silicon-containing organic group such as a trialkylsilyloxy group, a dialkyl (aryl) silyloxy group, an alkyl (diaryl) oxy group, and a triarylsilyloxy group.

[0028] The halogen atom means fluorine, chlorine, bromine, or iodine.

[0029] The term "heterocycle" refers to a 5- to 20-membered saturated or unsaturated monocyclic or bicyclic heterocyclic ring containing 1 to 4 nitrogen atoms, oxygen atoms and sulfur atoms, for example. 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!

Specific examples of the saturated heterocyclic ring include pyrrolidine having a nitrogen atom in the ring, piperidine, Monocyclic heterocycles such as homopiperidine, piperazine, morpholine having a nitrogen atom and an oxygen atom in the ring, and thiomorpholine having a nitrogen atom and a sulfur atom in the ring, such as a benzene ring To form a bicyclic heterocyclic ring 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, benzimidazole , Naphthyridine, pyro-mouth pyridine, imidazopyridine, etc., bicyclic heterocycle such as furan having an oxygen atom in the ring, or bicyclic heterocycle such as benzofuran, etc., having a sulfur atom in the ring Monocyclic heterocycles such as thiophene or bicyclic heterocycles such as benzothiophene; monocyclic heterocycles such as oxazole, isooxazole, thiazole, isothiazole or benzoxazole having a nitrogen atom and an oxygen atom or a sulfur atom in the ring , Benzothiazole, chenoviridine, oxazolopyridine, And bicyclic complex rings such as azolopyridine and furopyridine. Further, the above unsaturated heterocyclic ring may be in a form partially containing a saturated bond.

[0032] 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, and 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.

[0033] 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 : a pyridine ring.

[0036] 2) At least one of R ^J , R ² , R ⁴ , R ⁵ and R ⁶ : an adamantylalkyl group, an adamantyloxyalkyl group, an adamantylaminoalkyl group or an adamantyla Minocarbylalkyl group.

[0037] 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.

[0038] 4) at least one of Ri and R ^2: § Daman chill alkyl group.

[0039] (2) A compound or a salt thereof in which each group defined by the general formula [1] has the following basic ability:

[0040] A:-(NR ⁴ ), one (CR ⁵ R ⁶ ) — or one O—;

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

[Formula 3]

CH-CH—

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 combine 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 : adamantylalkyl group, adamantyloxyalkyl group, adamantylamino An alkyl group or an adamantylaminocarboalkyl 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 adamantylalkyl 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.

A :—( NR ⁴ ) —, (CR ⁵ R ⁶ ) — or O—;

B: S or

[Formula 4]

CH-CH—

An alkylene group or an alkylene 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 power:

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

B: In the chain, — O—, — S—,-(NR ⁷ ) —, — N = or

[Formula 5]

CH-CH—

[0048] An alkylene group or alkenyl group which may contain, 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.

[0049] Among these, a compound or a salt thereof, in which each group defined by the general formula [1] has the following basicity, is more preferable.

[0050] A :—( NR ⁴ ) —or one (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.

[0051] 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.

[0052] Further, a compound or a salt thereof, in which each group defined by the general formula [1] has the following basis, is more preferable.

[0053] 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 Substituted with 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, a pyridin ring or a thiophene ring. Furthermore, the hydrogen atom of each amino group, hydroxy group and aminocarbyl group in R ¹ is an alkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxycarbyl group, a cycloalkyloxycarbyl group. , Substituted with an arylalkoxycarbo group,

R ² : a cycloalkyl group, a phenylalkyl group or a cycloalkylalkyl group,

R ³ : pyridine ring,

R ⁴ : hydrogen atom,

R ⁵ and R ⁶ : hydrogen atom,

x: = o.

[0054] The most preferred and specific examples of the present compound include the following compounds and salts thereof.

[0055] 〇 1 [2— (1 adamantinole) ethyl] 1 pentyl 3— [3— (4 pyridyl) p mouth pill] ゥ rea

[Formula 6]

[0056] 〇 1 1 [2— (1 adamantyl) ethyl ”

Le) propyl] ゥ rea (compound 2)

[Formula 7]

[0057] 〇 1 [2- (1-adamantyl) ethyl] 1 [2— [N— (t-butoxycarbol) N-methylamino] ethyl] 3— [3- (4 pyridyl) propyl] ゥ rea Compound 3) [Formula 8]

[0058] 〇 1 [3- (1-adamantinole) propyl] 1 propyl 3— [3- (4 pyridyl) fu mouth pill] ゥ rare (diagonal compound 4)

[Formula 9]

[0059] 〇1 pentyl-1 phenethyl-3— [3- (4 pyridyl) propyl] ゥ rare

[Formula 10]

〇 1— [2— (1 adamantyl) ethyl] 3— [2 Methyl 3- (4 pyridyl) propyl] 1 Pentyl peria (Compound 6)

[Formula 11]

[0061] 0 (Ζ) -1- [2- (1-adamantyl) ethyl] 1 pentyl-3— [3- (4-pyridyl) 2prober] ゥ rea (compound 7)

[Formula 12]

0 (+)-l- [2- (l-adamantyl) ethyl] 3— [2-methyl 3- (4 pyridyl) propyl] 1 pentyl peria (compound 8)

[Formula 13]

〇 1— [2— (1 adamantyl) ethyl] 3— [1—Methyl-3- (4 pyridyl) propyl] 1 Pentyl peria (Compound 9)

[Formula 14]

〇 (+) 1 2— (1 adamantyl) ethyl] — 1— [2— [N— (t—butoxycanolevo) -R) -N-methylamino] ethyl] -3- (2-Methyl-3- (4-pyridyl) propyl] ゥ rare (Compound 10)

[Formula 15]

〇5— (4 Pyridyl) valeric acid N pentyl-N phenethylamide

[Formula 16]

〇3— (4 Pyridylmethylthio) propionic acid N— [2- (1-adamantyl) ethyl] -N-pentylamide (Compound 12)

〇 2— [2- (4 pyridyl) ethylthio] acetic acid N— [2- (1 adamantyl) ethyl] N pentylamide (Compound 13)

[Formula 18]

[0068] 6- (4 Pyridyl) caproic acid N- [2- (1-adamantyl) ethyl]

Luamide (compound 14)

[Formula 19]

[0069] The present compound can be produced, for example, by the method described in JP-A-2002-53555.

[0070] The present invention also relates to a method for treating osteoarthritis, which comprises administering an effective amount of the compound represented by the general formula [1] or a salt thereof to a patient.

[0071] 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 treatment for osteoarthritis.

[0072] A pharmacological test on the function of begu chondrocytes for examining the usefulness of the present compound was performed.

Although the details will be described in the section of pharmacological test described below, it was found that the present conjugated product promotes human chondrocyte proliferation. In addition, it has been reported that IL-1β is involved in the pathogenesis of osteoarthritis through increased production of 13-13, and from this viewpoint, the effect of the present compound was tested. It was found that the present compound has an excellent 13-13 production inhibitory effect. Was issued. From these points, the present compound was found to be useful as a therapeutic agent for osteoarthritis.

[0073] The osteoarthritis referred to in the present invention is a disease caused by various causes and resulting in degeneration of local cartilage of a joint. It is mainly expressed in joints such as the ankle, knee, hip, cervical vertebra, spine, lumbar vertebra, shoulder, elbow, and hand, or small joints such as the fingers. This osteoarthritis is caused by mechanical stress (repetitive load, excessive movement, trauma, etc.) and wear or degenerative degeneration of cartilage due to aging, etc., and inhibits chondrocyte proliferation and matrix meta-oral proteinase ( MMP), especially with increased production of MMP-13. Specific disorders include osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, cervical spondylopathy, osteoporosis, osteoarthritis of the lumbar, osteoarthritis of the shoulder, osteoarthritis of the shoulder, osteoarthritis of the elbow, Osteoarthritis of the osteoarthritis of the small joints such as the fingers or fingers.

[0074] 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. A binder such as calcium carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, a coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, and a film agent such as a gelatin film. Can be prepared.

[0075] 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 dose is usually 0.1 to 5000 mg, preferably 1 to 1000 mg per day. Alternatively, it may be administered in several divided doses.

[0076] Hereinafter, Formulation Examples of the present invention and the results of pharmacological tests using the present invention are illustrated, but these examples are for better understanding of the present invention. It is not intended to limit the range. [0077] Formulation Examples

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

[0078] 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 (eg, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the desired coated tablet (the following formulation) The same applies to tablets). Also, a desired tablet can be obtained by appropriately changing the amounts of the present compound and additives.

[0080] 2) Prescription 2

Capsule (in 150mg)

5 mg

Lactose 145 mg

[0081] A desired capsule can be obtained by appropriately changing the mixing ratio of the present danidol and lactose.

[0082] 3) Prescription 3

Injection (in 10ml)

This compound 100 mg

Sodium chloride 90 mg

Sodium hydroxide appropriate amount

Hydrochloric acid

Appropriate amount of sterilized purified water

[0083] A desired injection can be obtained by appropriately changing the mixing ratio of the present compound and additives. It comes out.

[0084] Pharmacological test

(Pharmacological test 1) Effect on proliferation of human chondrocytes

According to the method of Reboul P et al. (Journal of Clinical Investigation, 97; 2011-2019, 1996), normal human chondrocytes were cultured, and the effect of the present compound on chondrocyte proliferation under unstimulated conditions was examined.

(Preparation of Test Compound-Containing Liquid)

Compounds 1 to 14 described above were dissolved in DMSO, and the resulting 5 mM solution was diluted with culture medium to a final concentration of 3 M or 10 M in the culture medium to prepare a test compound-containing solution. did.

[0086] (Media used and culture conditions)

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 and cell number measurement)

Commercially available normal human chondrocytes were cultured at passage number 3 to 5 and used. Cells detached by trypsin treatment were counted, diluted to a cell density of 2 × 10 ⁵ cells / ml, and seeded on a 96-well culture plate at 2 × 10 ⁴ cells / well. The next day after seeding, the medium was completely removed, and immediately replaced with a solution containing the test compound. After 48 hours, the absorbance at 450 nm (OD450) was measured using a commercially available cell count kit (Dojindo Laboratories) using the WST method according to the package insert.

[0088] (Result evaluation)

The cell growth promotion rate with respect to the control was calculated by the following formula.

[0089] Cell growth rate (%) = (absorbance of drug-added group) Z (absorbance of normal control group) X 100 These results are shown in Table 1.

[table 1] Compound concentration (JUM) Chondrocytes

Compound concentration (M) Chondrocyte proliferation (%) Proliferation (%) Compound 1 10 1 17.7 Compound 8 3 1 12.3 Compound 2 10 121.4 Compound 9 10 1 14.2 Compound 3 10 108.2 Compound 1 0 10 109.3 Compound 4 10 125.1 Compound 1 1 10 132.7 Compound 5 10 1 19.9 Compound 1 2 10 132.5 Compound 6 3 1 10.1 Compound 1 3 10 135.1 Compound 7 3 1 13.6 Compound 1 4 10 125.3

As is clear from Table 1, all test compounds promoted the proliferation of unstimulated normal human chondrocytes.

[0091] (Pharmacological test 2) Inhibitory effect of human chondrocytes on MMP-13 production

Human chondrocytes are known to produce MMP-13 upon IL-1 j8 stimulation, and MMP-13 is known to be involved in cartilage degeneration through collagen degradation (Reboul P et al. Journal of Clinical Investigation, 97; 2011-2019, 1996). It has recently been pointed out that IL-1j8 is involved in cartilage degeneration in osteoarthritis. Therefore, the effect of these compounds on IL-118-induced MMP-13 production in normal human chondrocytes was examined using a commercially available kit for measuring MMP-13 activity according to the method of Reboul P et al.

(Preparation of Test Compound-Containing Liquid)

Compounds 1 to 14 described above were each dissolved in DMSO, and the obtained solution having a concentration of 5 mM was diluted with a medium so that the final concentration in the culture solution was 10 M, to prepare a test compound-containing solution.

[0093] (Media used and culture conditions)

The medium and culture conditions used were the same as in pharmacological test 1.

[0094] (Culture and activity measurement)

Commercially available normal human chondrocytes (passage 3-5) cultured in the same manner as in pharmacological test 1 were detached by trypsin treatment, and the cells were counted and diluted to a cell density of 2 x 10 ⁵ cells / ml. Then, 1 × 10 ⁵ cells / well were seeded on a 24-well culture plate. The next day after the seeding, the medium was completely removed and immediately replaced with a solution containing the test compound. At that time, human recombinant IL-118 was added to all culture wells except the normal control to a final concentration of lOngZml. After 48 hours, collect the culture supernatant and use a commercially available MMP-13 activity measurement kit (Amersham 'Pharmacia). The activity of MMP-13 in the culture supernatant that had been subjected to the activity treatment was measured according to the package insert described in the above.

[0095] (Result evaluation)

The MMP-13 production inhibitory effect on the control was calculated by the following equation.

[0096] MMP-13 activity inhibitory activity (%) = {(MMP-13 activity in culture supernatant of control group)-(MMP-13 activity in culture supernatant of drug-added group)} / {(culture of control group MMP-13 activity in supernatant) (MMP-13 activity in culture supernatant of normal control group)} X 100

Table 2 shows the results.

[Table 2]

M M P- 13 MMP- 13

Compound Compound

Production suppression (%) Production suppression (%)

Compound 1 37.7 Compound 8 38.1

Compound 2 1 1.7 Compound 9 67.7

Compound 3 22.7 Compound 1 0 43.5

Compound 4 36.4 Compound 1 1 39.6

Compound 5 39.0 Compound 1 2 54.8

Compound 6 67.5 Compound 1 3 45.2

Compound 7 49.1 Compound 1 4 62.3

[0097] As is clear from Table 2, the test compounds V and S were also present in the culture supernatant of IL-1-stimulated chondrocytes.

It showed an inhibitory effect on MMP-13 activity.

[0098] From the results of the above pharmacological tests, the compound showed excellent chondrocyte proliferation promoting action and

It has an inhibitory effect on MMP-13 production and is confirmed to be useful as a therapeutic agent for osteoarthritis.

Claims

The scope of the claims

A therapeutic agent for osteoarthritis comprising a compound represented by the following general formula [1] or a salt thereof as an active ingredient.

A

R 1

[1]

X

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

[Formula 2]

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 = 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 osteoarthritis 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 osteoarthritis 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 osteoarthritis according to the above.

[5] The therapeutic agent for osteoarthritis according to claim 1, wherein at least one of R ¹ and R ^{2 is} an 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]

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 therapeutic agent for osteoarthritis according to claim 1, wherein ⁷ represents a hydrogen atom or an alkyl group; represents = O or = S; and n represents an integer of 15.

[7] The therapeutic agent for osteoarthritis 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]

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. 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 osteoarthritis 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 osteoarthritis 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 osteoarthritis according to claim 9, wherein R ⁵ and R ^{6 each} represent a hydrogen atom;

[11] The therapeutic agent for osteoarthritis 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; osteoarthritis therapeutic agent according to claim 9, wherein indicating the X is = 0; R ⁴ represents a hydrogen atom; R ⁵ and R ⁶ represents a hydrogen atom.

[13] 1 [2— (1 adamantyl) ethyl] 1 Pentyl 3— [3— (4 pyridyl) propyl] ゥ rea,

1- [2— (1-adamantyl) ethyl] 1-1-1 (2 butyr) -1 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,

(Z) 1 [2— (1 adamantyl) ethyl] 1 Pentyl 3— [3— (4 pyridyl) 2-probel] 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,

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 osteoarthritis comprising a compound selected from the group consisting of or a salt thereof as an active ingredient.

The osteoarthritis is osteoarthritis accompanied by suppression of chondrocyte proliferation or osteoarthritis accompanied by enhanced production of matrix meta-oral proteinase from chondrocytes. 2. The therapeutic agent for osteoarthritis according to item 1. [15] The therapeutic agent for osteoarthritis according to any one of claims 1 to 13, wherein the osteoarthritis is osteoarthritis associated with mechanical stress or aging osteoarthritis.

16. The therapeutic agent for osteoarthritis according to claim 15, wherein the mechanical stress is a repetitive load, excessive exercise, or trauma.

[17] osteoarthritis is osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, cervical osteoarthritis, osteoarthritis, lumbar osteoarthritis, osteoarthritis of the shoulder, osteoarthritis of the elbow 14. The therapeutic agent for osteoarthritis according to any one of claims 1 to 13, wherein the agent is osteoarthritis, osteoarthritis of the wrist joint or small joint such as a finger.

[18] A chondrocyte proliferation promoter comprising the compound represented by the general formula [1] according to claim 1 or a salt thereof as an active ingredient.

[19] A matrix meta-oral proteinase production inhibitor comprising a compound represented by the general formula [1] according to claim 1 or a salt thereof as an active ingredient.

[20] The matrix metaoral proteinase 13 is the matrix metaoral proteinase 13

9. The matrix meta-oral proteinase production inhibitor according to 9 above.

[21] A method for treating osteoarthritis, which comprises administering an effective amount of a compound represented by the following general formula [1] or a salt thereof to a patient.

[Formula 6]

[1]

Wherein A represents — (NR ⁴ ) —, — (CR ⁵ R ⁶ ) — or —O; B represents O—, one S, one (NR ⁷ ) one, CO, one N = or

[Chemical 7] One CH-CH—

(CH ₂ ) _n 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 a phenyloxycarbonyl group, an imidazolylcarbonyl group, a pyridylcarbyl group, a saturated or unsaturated heterocyclic ring, or an alkyl group substituted with a saturated or unsaturated heterocyclic ring. ,. ]

[22] The treatment method according to claim 21, wherein R ³ is a pyridine ring.

[23] 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; 22. The treatment method according to claim 21.

[24] 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.

[25] The method according to claim 21, wherein at least one of R ¹ and R ^{2 is} an adamantyl alkyl group. Method of treatment.

[26] 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 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 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 22. The method according to claim 21, wherein X represents = O or = S; and n represents an integer of 1 to 5.

27. The method according to claim 26, wherein R ² represents an adamantyl alkyl group, and R ³ represents a pyridine ring.

[28] A represents one (NR ⁴ ) —, one (CR ⁵ R ⁶ ) — or one O; B represents one S or one in the chain

—— CH—CH—, an alkylene group or an alkenyl group which may contain (CH ₂ ) _n ); R ¹ represents an alkyl group or an alkenyl group, and the alkyl group is a halogen atom or The amino group may be substituted with an alkyl group, an acyl group, an arylalkyloxycarbol group, a cycloalkyloxycarbol group or an alkoxycarbol group. R ² represents an adamantyl alkyl group; R ³ represents a pyridine ring; R ⁴ represents a hydrogen atom; R ⁵ and R ⁶ represent a hydrogen atom; 28. The treatment method according to claim 26, wherein represents an integer of 1 to 5.

[29] 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 10]

—— CH—CH— (Although containing (CH ₂ ) _n , represents an alkylene group or an alkylene group, and the alkylene group is 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; Group, a hydroxy group or an amino group; the alkyl group, the alkyl group, the alkyl group, the cycloalkyl Groups or cycloalkenyl groups include 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, a cyano group or a saturated group; Or a hydrogen atom of each of the above amino groups, hydroxy groups and aminocarbonyl groups which may be substituted with an unsaturated heterocyclic ring is an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, an acyl group, R ² may be substituted with an alkoxycarbonyl group, a cycloalkyloxycarbyl group, an arylalkoxycarbonyl group, an unsaturated heterocyclic ring or an alkyl group substituted with an unsaturated heterocyclic ring; There alkyl group, Aruke - group, a cycloalkyl group, an cycloalkyl Ruarukiru group or § reel alkyl group; R ³ is Shows the lysine ring; R ⁴ is hydrogen atom, an alkyl group, § Damman chill alkyl group, carboxyalkyl group, Arukokishikaru ball - shows Ruarukiru group, an amino group, an alkylamino group, an Ashiruamino group or Arukokishikaru Boniruamino group; R 22. The same or different ⁵ and R ⁶ represent a hydrogen atom or an alkyl group; R ⁷ represents a hydrogen atom or an alkyl group; represents OO or SS; and n represents an integer of 1-5. Treatment method.

[30] 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 represents an alkyl group, an alkenyl group or an arylalkyl group; may represent a pyridine ring; R ⁴ represents a hydrogen atom 30. The method according to claim 29, wherein R ⁵ and R ⁶ represent a hydrogen atom;

[31] The treatment method according to claim 30, wherein R ¹ represents an alkyl group, and R ² represents an alkyl group or an arylalkyl group.

[32] 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 aminocarboyl group. And hydrogen atoms of each of the above-mentioned amino groups, hydroxy groups and aminocarbonyl groups which may be substituted with a phenyl group, a pyridine ring or a thiophene ring are an alkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxy group. R ² may be a cycloalkyl group or a cycloalkylalkyl group; R ³ may be a pyridine ring. 30. The therapeutic method according to claim 29, wherein R ⁴ represents a hydrogen atom; R ⁵ and R ⁶ represent a hydrogen atom; and X represents = 0.

1— [2— (1 adamantyl) ethyl] 1 Pentyl—3— [3— (4 pyridyl) propyl] 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,

5— (4 pyridyl) valeric acid N pentyl N phenethylamide,

N- [2- (1 adamantyl) ethyl] 3- (4-pyridylmethylthio) propionate N-pentynoleamide,

6— (4 pyridyl) caproic acid N— [2- (1-adamantyl) ethyl] —N—pentylamide

A method for treating osteoarthritis, which comprises administering to a patient an effective amount of a compound or a salt thereof selected from the group consisting of:

[34] The method of claim 2, wherein the osteoarthritis is osteoarthritis accompanied by suppression of chondrocyte proliferation or osteoarthritis accompanied by enhanced production of matrix meta-oral proteinase from chondrocytes.

The treatment method according to any one of 1 to 33.

35. The method according to any one of claims 21 to 33, wherein the osteoarthritis is osteoarthritis associated with mechanical stress or aging osteoarthritis.

36. The method according to claim 35, wherein the mechanical stress is a repetitive load, excessive exercise, or trauma.

[37] osteoarthritis is osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, cervical osteoarthritis, osteoarthritis, lumbar osteoarthritis, osteoarthritis of the shoulder, osteoarthritis of the elbow The treatment method according to any one of claims 21 to 33, wherein the method is osteoarthritis, osteoarthritis of the wrist joint, or osteoarthritis of a small joint such as a finger.

[38] A method for promoting chondrocyte proliferation, comprising administering to a patient an effective amount of the compound represented by the general formula [1] according to claim 21 or a salt thereof.

[39] A method for suppressing the production of matrix meta-oral proteinase, comprising administering to a patient an effective amount of the compound represented by the general formula [1] or a salt thereof according to claim 21.

[40] The claim wherein the matrix meta-oral proteinase is matrix meta-oral proteinase 13

39. The suppression method according to 39.

[41] Use of a compound represented by the following general formula [1] or a salt thereof for the manufacture of a therapeutic agent for osteoarthritis.

[Formula 11]

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 12]

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 R ⁵ and R ² and R ⁶ may be substituted or substituted with a group, an aminocarbyl 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 group, alkoxyalkyl group, alkoxycarbol group, alkylaminocarbol group, cycloalkyl Xycarbyl, arylalkoxycarbyl, alkylsulfol, arylsulfonyl, halogenoalkyloxycarbyl, imidazolylcarbyl, pyridylcarbol, saturated or unsaturated It may be substituted with a heterocyclic ring or an alkyl group substituted with a saturated or unsaturated heterocyclic ring. ]

[42] The use according to claim 41, wherein R ³ is a pyridine ring.

[43] 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 42. Use according to claim 41.

[44] The 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.

[45] The use according to claim 41, wherein at least one of R ¹ and R ^{2 is} an adamantyl alkyl group.

[46] 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 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. Laminocarbyl, adamantyl, aryloxycarbyl, cyano or May be substituted with a saturated or unsaturated heterocyclic ring, and the hydrogen atom of each of the above amino groups, hydroxy groups and aminocarbyl groups may be an alkyl group, a cycloalkyl group, an aryl group or an aryl group. An alkyl group, an acyl group, an alkoxycarbol group, a cycloalkyloxycarbol group, an arylalkoxycarbol group, a halogenoalkyloxycarbyl group, an imidazolylcarbyl group, an unsaturated heterocyclic ring or R ² may be substituted with an alkyl group substituted with an unsaturated heterocyclic ring; R ² represents an adamantyl alkyl group, an adamantyl oxyalkyl group, an adamantyl amino alkyl group or an adamantyl amino group; Lupo - Ruarukiru represents a group; R ³ represents a heterocyclic unsaturated ring; R ⁴ is a hydrogen atom, an alkyl group, § Damman chill alkyl group, carboxyalkyl group, alkoxy Rubo - group, § Rukokishikarubo - Ruarukiru group, an amino group, an 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 42. The use according to claim 41, wherein R ⁷ represents a hydrogen atom or an alkyl group; X represents = 0 or = S; and n represents an integer of 15.

[47] The use according to claim 46, wherein R ² represents an adamantylalkyl group, and R ³ represents a pyridine ring. [48] A represents — (NR ⁴ ) CR ⁵ R ⁶ ) — or O; S—or in the chain

[Formula 14]

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. It is shown; R ³ represents a pyridine ring; R ⁴ represents hydrogen atom; R ⁵ and R ⁶ represents a hydrogen atom; indicates the = O;請which n represents an integer of 1 5 Use according to claim 46.

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

[Formula 15]

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 alkoxycarbonylamino group. It is shown; R ⁵ and R ⁶ represent the same or different and each represents a hydrogen atom or an alkyl group; R ⁷ is a hydrogen atom or Use according to claim 41, wherein n is an integer from 1 to 5; indicates the = O or = S; an alkyl group.

A represents -force (NR ⁴ ) — or one (CR ⁵ R ⁶ ) —B represents an alkylene group or R ¹ represents an alkyl group or an alkyl group, and 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; The amino group may be substituted with an alkyl group, an acyl group, an alkoxycarbyl group, a cycloalkyloxycarbyl group or an arylalkoxycarbol group; R ² represents an alkyl group, an alkaryl group; 50 shows a pyridine ring; R ⁴ represents a hydrogen atom; R ⁵ and R ⁶ represent a hydrogen atom; and represents = O.

[51] The use according to claim 50, wherein R ¹ represents an alkyl group, and R ² represents an alkyl group or an arylalkyl group.

[52] 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; use of claim 49 wherein indicating the is = O.

[53] for the manufacture of a therapeutic agent for osteoarthritis,

1 [2— (1-adamantyl) ethyl] 1 2 butyr) 3— [3- (4 pyridyl) propyl] ゥ rea,

1 [3— (1 adamantinole) propyl] 1 propyl 3— [3— (4 pyridyl) pu pill] ゥ rea, 1-pentyl- 1-phenethyl 3- [3- (4-pyridyl) propyl] ゥ rea,

5— (4 pyridyl) valeric acid N pentyl N phenethylamide,

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:

[54] The osteoarthritis is osteoarthritis accompanied by suppression of chondrocyte proliferation or osteoarthritis accompanied by enhanced production of matrix metaoral proteinase from chondrocytes.

Use according to any of 1-53.

[55] The use according to any one of claims 41 to 53, wherein the osteoarthritis is osteoarthritis associated with mechanical stress or aging osteoarthritis.

[56] The use according to claim 55, wherein the mechanical stress is repetitive load, excessive movement or trauma.

[57] osteoarthritis is osteoarthritis, osteoarthritis of the knee, osteoarthritis of the hip, cervical osteoarthritis, osteoarthritis, lumbar osteoarthritis, osteoarthritis of the shoulder, osteoarthritis Arthrosis, deformity 54. The use according to any one of claims 41 to 53, which is for wrist joint disease or osteoarthritis of a small joint such as a finger.

[58] Use of the compound represented by the general formula [1] or a salt thereof according to claim 41 for the manufacture of a chondrocyte proliferation promoter.

[59] Use of the compound represented by the general formula [1] or a salt thereof according to claim 41 for the production of a matrix meta-mouth proteinase production inhibitor.

[60] The claim wherein the matrix meta-oral proteinase is matrix meta-oral proteinase 13

Use according to 59.