• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    The present invention relates to a therapeutic agent and / or prophylactic agent for deformable arthrosis, containing as an active ingredient a hydroxamic acid derivative compound of formula (I), or a nontoxic salt thereof, having a matrix metalloproteinase inhibitory action: Formula I In the formula, R 1 represents a hydrogen atom, C 1-8 alkyl, C 1-8 alkyl substituted with -OR 2 , and R 2 represents H, C 1-8 alkyl, benzyl, C 1-8 alkoxy C 1-8 alkyl. .)
    公开号:KR20040019106A
    申请号:KR10-2004-7001682
    申请日:2002-08-05
    公开日:2004-03-04
    发明作者:마에다요시조；야마시타카즈노리；오가와코지
    申请人:오노 야꾸힝 고교 가부시키가이샤；
    IPC主号:
    专利说明:

    Deformative arthrosis treatment agent {REMEDIAL AGENT FOR ARTHROSIS DEFORMANS}
    [5] Matrix metalloproteinases (hereinafter abbreviated as MMP) are neutral metalloproteinases with zinc in the active center (hereinafter abbreviated as Zn 2+ ), and to date, more than 20 kinds of molecules with different primary structures. The species is confirmed. Specifically, interstitial collagenase (MMP-1), leukocyte collagenase (MMP-8), collagenase-3 (MMP-13), gelatinase A (MMP-2), gelatinase B (MMP-9), strromlycine 1 (MMP-3), strromlycine 2 (MMP-10), matrylysine (MMP-7), metalloelase (MMP-12), and the like.
    [6] Under the physiological situation, MMPs degrade collagen, laminin, proteoglycans, fibronectin, elastin, gelatin, etc., and thus act on growth and tissue remodeling of joint tissues, bone tissues, connective tissues, and the like. However, the destruction of various tissues in the condition is thought to be due to an increase in the expression or activity of the MMP due to the disruption of the regulatory function of the MMP. For example, it has been reported that MMP-1, 2, 3, 8, 9, 13 are highly expressed at the site of cartilage destruction in patients with deformable arthrosis, and that these MMPs are strongly involved in the decomposition of cartilage matrix. Progression, 182, 549-553 (1997); J. Clin. Invest., 84 , 678-685 (1989).
    [7] On the other hand, osteoarthritis (OA) is a disease that accounts for most of the joint pain seen in the elderly, and due to degenerative degeneration of articular cartilage, elasticity decreases, abrasion, cracks, etc. New bone formation is promoted, the articular cartilage is lost, and the bone is exposed to the joint surface, resulting in symptoms such as joint pain and fluid retention. Commonly affected joints include knees, crotch, spinal cord, elbows, shoulders, and fingers. In addition, the cause is often not clear. Non-steroidal analgesics and anti-inflammatory agents are used as the first selective medicines for the treatment, and joint injection therapy of hyaluronic acid preparations which enhance the lubricating function of the joint and also have anti-inflammatory action is also performed. However, these are only symptomatic therapy to date, and no fundamental treatment is established.
    [8] As a patent application that exemplifies deformable arthrosis in an adaptive disease of a compound having an MMP inhibitory action, there are, for example, GB2268934 specification and EP606046 specification. In addition, CGS-27023A (2 (R)-[N- (4-methoxyphenylsulfonyl) -N- (3-pyridylmethyl) amino] -3-methylbutanohydroxamic acid hydrochloride) which is an MMP inhibitor) Has been reported to be valid in rabbit OA models [Inflamm Res 44, Supplement 2, S117-S118, (1995)]. At present, however, there is no therapeutic agent and / or prophylactic agent for deformable arthrosis as a compound having an MMP inhibitory activity, and there are very few compounds having an MMP inhibitory activity that is being developed for them.
    [1] The present invention relates to a therapeutic agent for deformable arthrosis.
    [2] In particular, the present invention relates to a therapeutic and / or prophylactic agent for deformable arthrosis, which contains, as an active ingredient, a hydroxamic acid derivative compound of formula (I) having a matrix metalloproteinase inhibitory activity, or a non-toxic salt thereof:
    [3]
    [4] (In the formulas, all symbols represent the same meanings as described later.)
    [44] 1 shows various doses of N-hydroxy-5-hydroxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide (Compound (II)) twice daily. It is a graph which shows the effect of suppressing the erosion area of the femur at the time.
    [9] Disclosure of the Invention
    [10] As described above, there is a desire to provide a therapeutic agent and / or a prophylactic agent for deformable arthrosis, and it is expected to use MMP inhibitors as the therapeutic and / or prophylactic agents. However, it is natural that not all of the known MMP inhibitors are effective for deformable arthrosis, and the present situation has not been reached in reality.
    [11] Under the circumstances described above, the present inventors conducted a thorough study and found for the first time that the hydroxamic acid derivative compound of the general formula (I), or a nontoxic salt thereof, is effective for deformable arthrosis, and completed the present invention.
    [12] That is, the present invention relates to a therapeutic agent and / or a preventive agent for deformable arthrosis containing as an active ingredient a hydroxamic acid derivative compound of formula (I), or a nontoxic salt thereof:
    [13] Formula I
    [14]
    [15] Wherein R 1 represents a hydrogen atom, C 1-8 alkyl, or C 1-8 alkyl substituted with -OR 2 , and R 2 represents a hydrogen atom, C 1-8 alkyl, benzyl, or C 1-8 alkoxy substituted C1-8 alkyl, except N-hydroxy-5-ethoxymethyloxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide.)
    [16] Hydroxamic acid derivatives of the general formula (I) are compounds having an MMP inhibitory effect and are the compounds described in the specification of WO99 / 19296.
    [17] As described herein, aminobutanoic acid derivatives comprising a compound of formula (I) have an MMP inhibitory action and therefore, rheumatism, osteoarthritis, pathological bone resorption, osteoporosis, periodontal disease, interstitial nephritis, arteriosclerosis, emphysema, Liver cirrhosis, corneal injury, disease of metastasis infiltration or proliferation of cancer cells, autoimmune diseases (Crohn's disease, Siegren's disease, etc.), diseases caused by vascular outflow or infiltration of leukocyte cells, angiogenesis, multiple sclerosis, aortic aneurysm, uterus It is described as being effective in endometriosis or the like. However, there is no description that the compound of formula (I) is effective for deformable arthrosis.
    [18] It is known that there is a relationship between MMP and osteoarthritis (OA). However, according to the inventors' confirmation of several MMP inhibitors to the rabbit lateral meniscus partial ablation model being evaluated as an actual OA condition model, the compound of formula (I) showed effectiveness.
    [19] details
    [20] In general formula (I) which represents the compound used by this invention, C1-8 alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group, and isomers thereof.
    [21] In the formula (I), -OR 2 is a C1~8 alkyl substituted is a -OR 2 is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl substituted, octyl and the isomers thereof.
    [22] In formula (I), C1-8 alkyl substituted with C1-8 alkoxy group is selected from methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy group and isomers thereof One group to be substituted is substituted methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl groups and isomers thereof.
    [23] In formula (I), a symbol
    [24]
    [25] Is a bond representing an isomer or a mixture thereof due to the presence of an asymmetric carbon, specifically, a sign indicating that the bond is bound to the front side of the ground.
    [26]
    [27] Symbol indicating that it is engaged with the back side of the ground
    [28]
    [29] Or mixtures thereof.
    [30] In the present invention, unless otherwise mentioned, the isomers include all of them. For example, the alkyl group and the alkoxy group include straight chain and branched chain. In addition, isomers (R, S, α, β, enantiomers, diastereomers) due to the presence of asymmetric carbons, optically active agents (D, L, d, l) having optical sensitization, and chromatographic separation Polar bodies (high polar bodies, low polar bodies), equilibrium compounds, mixtures of any proportion thereof, and racemic mixtures are all included in the present invention.
    [31] In general formula (I), although the group which R <1> represents is all preferable, More preferably, they are C1-4 alkyl which substituted one hydrogen atom, C1-4 alkyl, or -OR <2> .
    [32] In the general formula (I), all of the groups represented by R 2 are preferable, but more preferably C 1-4 alkyl substituted with one hydrogen atom, C 1-4 alkyl, benzyl, or C 1-4 alkoxy.
    [33] Particularly preferred R 1 in the present specification includes hydrogen atom, methyl, ethyl, methoxymethyl, ethoxymethyl, ethoxyethyl, benzyloxymethyl, methoxymethoxymethyl, and methoxyethoxymethyl.
    [34] As a specific compound used for this invention,
    [35] N-hydroxy-5-hydroxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide,
    [36] N-hydroxy-5-methoxymethyloxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide,
    [37] N-hydroxy-5-ethoxymethyloxy-2 (R) -methyl-4 (R)-(4-phenoxybenzoyl) aminopentanamide,
    [38] N-hydroxy-5-ethoxymethyloxy-2 (R) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide,
    [39] N-hydroxy-5-benzyloxymethyloxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide, or
    [40] N-hydroxy-5- (2-methoxyethoxy) methyloxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide and its nontoxic salts are mentioned.
    [41] You may use the compound used for this invention in the form of the following nontoxic salts. The salt is preferably a non-toxic water soluble salt.
    [42] Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, Salts of cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-glucamine, etc.). have. The compound or non-toxic salt thereof used in the present invention may be converted into a hydrate by a known method.
    [43] Compounds of formula (I) may be prepared by the methods described in the specification WO 99/19296.
    [45] The effectiveness of the compound of the present invention on deformable arthrosis has been demonstrated, for example, by the following rabbit lateral meniscus partial ablation model experiment.
    [46] [Experimental method]
    [47] After preliminary breeding of rabbits (magnetic Kbs: NZW (Healthy) rabbits) for 1 week, meniscus resection was performed by the following method.
    [48] The rabbit was administered with ceracal 2% injection (0.05 ml / kg) subcutaneously, and neembutal injection (20 mg / kg) was administered intravenously in the marginal vein, and anesthetized. The right knee was disinfected with iodine tincture diluted 5 times with distilled water. As needed, 2% of xylocaine injection solution was added dropwise to the incision, and local anesthesia was performed.
    [49] Next, the epithelium and arthrosis of the outer side of the knee of the right Fuji were dissected at 90 ° to the patellar ligament, the lateral lateral ligaments were cut off, and then the seed bone ligaments were cut off. At this time, bosmine injection was dripped and hemostasis was carried out. The tissue combined with the tissue in front of the lateral meniscus was taken with forceps, the meniscus was pulled forward, and the center 1/3 was excised. The sulcus was washed with physiological saline solution, and the synovial membrane and articular cap were closed. In addition, the near layer and the outer skin were also sutured.
    [50] After surgery, crystalline penicillin G potassium (5000 U / animal) and streptomycin sulfate (100 mg / animal) were injected intramuscularly in the left Fuji to prevent infection. It is raised until dissecting on day 7 after surgery, and during that time, N-hydroxy-5-hydroxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl of formula (II) Aminopentanamide (compound (II)) was administered twice daily at doses of 1, 3 and 10 mg / kg, respectively:
    [51]
    [52] Neembutal injections (40 mg / kg) were administered intravenously in the marginal vein and anesthetized. After that, the animals were bleeded and the right knee joint portion was taken out. The knee joint was dissected to extract the femur and tibia. The femur and tibia were preserved at room temperature in 10% neutral buffered formalin. After the collection of the whole sample was completed, the femur and tibia head were masked. The erosion area was measured using a stereo microscope.
    [53] In the statistical treatment method, the comparison of the cartilage erosion area between the control group and the test compound-administered group was performed by Williams' multiple comparison (EXSAS, Ver 5.00). The result is shown in FIG.
    [54] The experimental model is capable of inducing cartilage destruction that is severe in deformable arthrosis in humans and is generally recognized as an OA model. In this model, the compound of formula (I) was found to exhibit high effectiveness. Therefore, it can be judged that the compound of formula (I) is effective for deformable arthrosis.
    [55] [toxicity]
    [56] The toxicity of the compound of formula (I) is very low and can be judged to be sufficiently safe for use as a medicine. For example, the lowest lethal dose in a single oral administration of Compound (II) to rats was at least 2000 mg / kg.
    [57] [Application to Drugs]
    [58] Hydroxyamic acid derivatives of formula (I), or non-toxic salts thereof, having inhibitory activity against matrix metalloproteinases, such as gelatinases, strolisine or collagenase, etc., used in the present invention are particularly effective in animals including humans, in particular It is useful for the treatment and / or prevention of deformable arthrosis in humans.
    [59] Compounds of formula (I) or non-toxic salts thereof,
    [60] 1) complement and / or enhance the prophylactic and / or therapeutic effect of the compound,
    [61] 2) improving the dynamics and absorption of the compound, reducing the dose,
    [62] And / or
    [63] 3) In order to reduce the side effects of the compound, it may be administered as a combination in combination with other drugs.
    [64] The combination of the compound of the formula (I) and the other medicament may be administered in the form of a compounding agent containing a positive component in one formulation, or may be administered as a separate formulation. Administration of this separate formulation includes simultaneous administration and timed administration. In addition, administration by the time difference may administer a compound of Formula (I) first, and may administer another agent later, another agent may be administered first, and the compound of Formula (I) may be administered later. Each administration method may be same or different.
    [65] The disease which exhibits a prophylactic and / or therapeutic effect by the said combination agent is not specifically limited, What is necessary is just a disease which complements and / or enhances the prophylactic and / or therapeutic effect of the compound of general formula (I).
    [66] Other agents for supplementing and / or enhancing the prophylactic and / or therapeutic effects of the compound of formula (I) against modified arthrosis include, for example, nonsteroidal anti-inflammatory drugs, steroids, immunosuppressants, anti-inflammatory enzymes, cartilage protectants, T Cell inhibitors, TNFα inhibitors, prostaglandin synthase inhibitors, IL-6 inhibitors, interferon γ agonists, IL-1 inhibitors, prostaglandins, phosphodiesterase 4 inhibitors, and the like.
    [67] As nonsteroidal anti-inflammatory drugs, for example, lion pyrine, sodium salicylate, aspirin, aspirin-dialuminate formulation, diflunisal, indomethacin, suprofen, upenamate, dimethylisopropylazulene, bupesa film, fel Binac, Diclofenac, Tolmetin Sodium, Clinolyl, Fenbufen, Naphmethone, Proglumetacin, Indomethacinpanesyl, Acemetasin, Maleic Proglumetacin, Anfenac Sodium, Mopezolac, Etodolac, Ibuprofen Ibuprofenpiconol, naproxen, flurbiprofen, flurbiprofenaxetyl, ketoprofen, phenopropenecalcium, thiapropene, oxaprozin, pranopropene, roxofene sodium, alumin Noprofen, zaltoprofen, mefenamic acid, aluminum mefenamate, tolpenamic acid, flocfenin, ketophenylbutazone, oxyphenbutazone, pyrocampam, tenoxycam, anpyrocampam, napageln ointment, pyrisol , Tiramides, salts Tinolidine, emorfazone, sulfirin, migrenin, saridon, cedes G, amiphyloN, sorbone, pyrine cold medicine, acetaminophen, phenacetin, mesylic acid dimethazine, citride formulation, bipyrin Systemic cold medicines;
    [68] As a steroid agent, for example, as a topical drug, propionate clobetasol, tifluoroacetate, fluorinide, furancarboxylic acid metazone, dipropionate beta metazone, butyric acid beta metazone, valeric acid beta metazone, and difluflu Redate, Pdesonide, valeric acid diflucoltron, amcinonide, halsinoid, dexamethasone, propionate dexamethasone, valeric acid dexamethasone, acetate dexamethasone, acetic acid hydrocortisone, butyric acid hydrocoltizone , Butyric acid propionate, hydrocortisone, depropionate, propionate, pledononizolone valeric acid, fluorinone acetonide, beclometazone propionate, triamcinolone acetonide, pivalate flumetazone, propionate alclometazone, butyrate clobeta Zone, a pledonzolone, peclomethasone propionate, a fluxy cholide, etc. are mentioned.
    [69] Examples of oral medicines and injections include: Coltisone Acetate, Hydrocortisone, Hydrocortisone Phosphate, Sodium Succinate Hydrocortisone Sodium, Fluorocoltisone Acetate, Fledonizolone, Pledonizuzolone Acetate, Plethyonizolone Sodium Sulfate, Butyl Acetate Zolone, pledononizolone sodium phosphate, halopledon acetate, methyl pledonzolone, methyl pledononizolone acetate, methyl pledononizolone sodium triamcinolone, triamcinolone acetate, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, Sodium dexamethasone phosphate, dexamethasone palmitate, paramesa acetate, beta metazone, and the like.
    [70] Examples of inhalants include propionate beclomethasone, propionate fluticasone, budesonide, flunisonide, triamcinolone, ST-126P, ciclesonide, dexamethasonepalmitionate, mometazonefrancarbonate, and platherone sulfo Nate, deplaza coat, methylpledonizolone reputanate, methylpledonizolone sodium succinate, etc. are mentioned.
    [71] Examples of cartilage protective agents include sodium hyaluronate, glucosamine, chondroitin sulfate, and polysulfate glucosaminoglycan.
    [72] The mass ratio of the compound of formula (I) to other drugs is not particularly limited. Another agent may be administered in combination of any two or more thereof.
    [73] In addition, other medicaments that complement and / or enhance the prophylactic and / or therapeutic effects of the compounds of formula (I) include those not only discovered to date but also found in the future based on the above mechanisms.
    [74] In order to use the compound of the formula (I) or a combination of the compound of the formula (I) and another medicament for the above-mentioned purposes, it is usually administered systemically or topically in oral or parenteral form.
    [75] Dosages vary depending on age, weight, symptoms, therapeutic effect, method of administration, treatment time and the like, but are usually orally administered once a day or several times per adult in the range of 1 ng to 100 mg once per adult, or per adult , Parenteral administration from once daily to several times in the range of 0.1 ng to 10 mg at a time, or sustained intravenously in the range of 1 to 24 hours per day.
    [76] Of course, as mentioned above, since a dosage varies with various conditions, an amount smaller than the said dosage may be sufficient, and the administration may be required beyond the range.
    [77] When administering a compound of formula (I), or a combination of a compound of formula (I) and another medicament, internal solids, oral solutions for oral administration, and injections, external preparations, suppositories, eye drops for parenteral administration , Inhalants and the like.
    [78] Internal solids for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules.
    [79] In such internal solids, one or more active substances may be used as is, or as excipients (lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, polyvinylpyrrolidone, metasilicate alu). Magnesium phosphate), a disintegrating agent (calcium cellulose glycolate, etc.), a lubricant (magnesium stearate, etc.), a stabilizer, a dissolution aid (glutamic acid, aspartic acid, etc.), and the like, and are formulated according to a conventional method. Moreover, it may coat with a coating agent (white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and may coat with two or more layers. Also included are capsules of absorbable materials, such as gelatin.
    [80] Oral solution for oral administration includes pharmaceutically acceptable homemade, suspension, emulsion, syrup, elixirs and the like. In such liquids, one or more active substances are dissolved, suspended or emulsified in commonly used diluents (purified water, ethanol or a mixture thereof). This liquid may also contain a humectant, a suspending agent, an emulsifier, a sweetener, a flavoring agent, a fragrance, a preservative, a buffer, and the like.
    [81] Formulations of external preparations for parenteral administration include, for example, ointments, gels, creams, poultices, patches, linings, sprays, inhalants, sprays, eye drops, and nasal drops. These comprise one or more active substances and are prepared by known methods or by the formulations which are commonly used.
    [82] Ointments are prepared by known or commonly used prescriptions. For example, one or more active substances are prepared by softening or melting the base. The ointment is selected from those known or commonly used. For example, higher fatty acids or higher fatty acid esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (waxy, whale) Wax, ceresin, etc.), surfactant (polyoxyethylene alkyl ether phosphate ester, etc.), higher alcohol (cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oil (dimethyl polysiloxane, etc.), hydrocarbons (hydrophilic petrolatum, White petrolatum, refined lanolin, liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils (castor oil, olive oil, sesame oil, telepin oil, etc.), animal oil ( Mink oil, egg yolk oil, squalane, squalene and the like), water, an absorption accelerator, a dermatitis inhibitor, or a mixture of two or more thereof. It may also contain a moisturizer, preservative, stabilizer, antioxidant, flavoring agent, and the like.
    [83] Gels are prepared by known or commonly used prescriptions. For example, one or more active materials are prepared by melting the base. The gel base is selected from those known or commonly used. For example, lower alcohols (ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, etc.), neutralizing agents (triethanolamine, diisopropanolamine, etc.), surfactants (mono) Polyethylene glycol stearate and the like), gum, water, absorption accelerator, dermatitis inhibitor, or a mixture of two or more thereof. Moreover, you may contain the preservative, antioxidant, a flavoring agent, etc.
    [84] Creams are prepared by known or commonly used prescriptions. For example, one or more active substances are prepared by melting or emulsifying in a base. The cream base is selected from those known or commonly used. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers (polyoxyethylene alkyl ethers) , Fatty acid esters, etc.), water, an absorption accelerator, and a dermatitis inhibitor, or a mixture of two or more thereof. Moreover, you may contain the preservative, antioxidant, a flavoring agent, etc.
    [85] Poultices are prepared by known or commonly used prescriptions. For example, it is prepared by melting one or more active materials into a base and then applying them totally onto the support as a combination. The foaming agent is selected from those known or commonly used. For example, thickeners (polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium, magnesium, etc.) Selected from water, dissolution aids, tackifiers, and dermatitis inhibitors, or a mixture of two or more thereof. Moreover, you may contain the preservative, antioxidant, a flavoring agent, etc.
    [86] The patch is prepared by a known or commonly used prescription. For example, one or more active materials are melted into a base and prepared by spreading on the support. The base for patch is selected from those known or commonly used. For example, one selected from polymer bases, fats and oils, higher fatty acids, tackifiers, and dermatitis inhibitors may be used alone or in combination of two or more thereof. Moreover, you may contain the preservative, antioxidant, a flavoring agent, etc.
    [87] The linen agent is prepared by a known or commonly used prescription. For example, one or more actives are prepared by dissolving, suspending or emulsifying one or more selected from water, alcohols (ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soaps, emulsifiers, suspending agents and the like. . Moreover, you may contain the preservative, antioxidant, a flavoring agent, etc.
    [88] Sprays, inhalants, and sprays may contain, in addition to the diluents generally used, stabilizers, such as sodium hydrogen sulfite, and buffers that impart isotonicity, such as isotonic agents, such as sodium chloride, sodium citrate, or citric acid. Methods of making sprays are described, for example, in detail in US Pat. Nos. 2,868,691 and 3,095,355.
    [89] Injections for parenteral administration include solid injections used by dissolving or suspending them in solutions, suspensions, emulsions and solvents. Injections are used by dissolving, suspending or emulsifying one or more active substances in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and the like and combinations thereof are used. Injectables may also contain stabilizers, dissolution aids (glutamic acid, aspartic acid, Polysorbate 80®, etc.), suspending agents, emulsifying agents, analgesics, buffers, preservatives, and the like. They are either sterilized in the final process or prepared by aseptic manipulation. Aseptic solids, such as lyophilized products, may also be prepared and dissolved in sterile or sterile distilled water or other solvents prior to their use.
    [90] Inhalants for parenteral administration include aerosols, powders for inhalation, or liquids for inhalation, and the inhalation liquids may be dissolved or suspended in water or other suitable medium for use.
    [91] These inhalants are manufactured according to a known method.
    [92] For example, in the case of inhalation solutions, preservatives (benzalkonium chloride, parabens, etc.), colorants, buffering agents (sodium phosphate, sodium acetate, etc.), isotonic agents (sodium chloride, concentrated glycerin, etc.), thickeners (carboxyvinyl polymers, etc.), absorption A promoter and the like are appropriately selected and prepared as necessary.
    [93] For inhaled powders, lubricants (stearic acid and salts thereof), binders (starch, dextrin, etc.), excipients (lactose, cellulose, etc.), colorants, preservatives (benzalkonium chloride, parabens, etc.), absorption accelerators, etc. are required. It selects suitably according to the preparation.
    [94] When administering a liquid for inhalation, a nebulizer (atomizer, nebulizer) is usually used, and when a powder for inhalation is administered, a powder inhaler is usually used.
    [95] Other compositions for parenteral administration include one or more active substances, include suppositories for rectal administration prescribed by conventional methods, pessaries for vaginal administration, and the like.
    [96] Formulation Example 1
    [97] Each of the following components were mixed in a conventional manner, followed by tableting to obtain 100 tablets containing 50 mg of the active ingredient in one tablet.
    [98] N-hydroxy-5-hydroxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl)
    [99] Aminopentanamide ... 5.0 g
    [100] Carboxymethyl cellulose calcium (disintegrant) 0.2 g
    [101] Magnesium stearate (lubricant) 0.1 g
    [102] Microcrystalline cellulose0.1 g
    [103] Formulation Example 2
    [104] After mixing the following components in a conventional manner, the solution is sterilized by a conventional method, filled in 5 ml of ampoules, and lyophilized by a conventional method, and the ampoule 100 containing 20 mg of the active ingredient in one ampoule. Got a dog.
    [105] N-hydroxy-5-hydroxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl)
    [106] Aminopentanamide2.0 g
    [107] 20 g of mannitol
    [108] 500 ml of distilled water
    权利要求:
    Claims (4)
    [1" claim-type="Currently amended] A therapeutic and / or prophylactic agent for deformable arthrosis, comprising as an active ingredient a hydroxamic acid derivative compound of formula (I):
    Formula I

    Wherein R 1 represents a hydrogen atom, C 1-8 alkyl, or C 1-8 alkyl substituted with -OR 2 , and R 2 represents a hydrogen atom, C 1-8 alkyl, benzyl, or C 1-8 alkoxy substituted C1-8 alkyl, except N-hydroxy-5-ethoxymethyloxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide.)
    [2" claim-type="Currently amended] 2. The compound of claim 1, wherein R 1 is a hydrogen atom, C 1-4 alkyl, or C 1-4 alkyl substituted with one of —OR 2 , and R 2 is a hydrogen atom, C 1-4 alkyl, benzyl, or C 1-4 alkoxy A therapeutic agent and / or prophylactic agent for deformable arthrosis, comprising as an active ingredient a hydroxamic acid derivative compound having one substituted C1-4 alkyl or a nontoxic salt thereof.
    [3" claim-type="Currently amended] The hydroxamic acid derivative compound according to claim 2, wherein R 1 is a hydrogen atom, methyl, ethyl, methoxymethyl, ethoxymethyl, ethoxyethyl, benzyloxymethyl, methoxymethoxymethyl, methoxyethoxymethyl, Or a therapeutic and / or prophylactic agent for deformable arthrosis containing the nontoxic salt thereof as an active ingredient.
    [4" claim-type="Currently amended] The compound of claim 1, wherein the compound is
    (1) N-hydroxy-5-hydroxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide,
    (2) N-hydroxy-5-methoxymethyloxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide,
    (3) N-hydroxy-5-ethoxymethyloxy-2 (R) -methyl-4 (R)-(4-phenoxybenzoyl) aminopentanamide,
    (4) N-hydroxy-5-ethoxymethyloxy-2 (R) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide,
    (5) N-hydroxy-5-benzyloxymethyloxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide, or
    (6) N-hydroxy-5- (2-methoxyethoxy) methyloxy-2 (S) -methyl-4 (S)-(4-phenoxybenzoyl) aminopentanamide, or a non-toxic salt thereof Agents and / or prophylactic agents for osteoarthritis.
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    同族专利:
    公开号 | 公开日
    CA2456965A1|2003-02-20|
    US20040198831A1|2004-10-07|
    EP1421934A4|2006-03-29|
    WO2003013494A1|2003-02-20|
    EP1421934A1|2004-05-26|
    JPWO2003013494A1|2004-11-25|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-08-06|Priority to JP2001237345
    2001-08-06|Priority to JPJP-P-2001-00237345
    2002-08-05|Application filed by 오노 야꾸힝 고교 가부시키가이샤
    2002-08-05|Priority to PCT/JP2002/007961
    2004-03-04|Publication of KR20040019106A
    优先权:
    申请号 | 申请日 | 专利标题
    JP2001237345|2001-08-06|
    JPJP-P-2001-00237345|2001-08-06|
    PCT/JP2002/007961|WO2003013494A1|2001-08-06|2002-08-05|Remedial agent for arthrosis deformans|
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