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WO1998048807A1 - Inhibiteurs de la synthese de l'hyaluronate - Google Patents

Inhibiteurs de la synthese de l'hyaluronate Download PDF

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Publication number
WO1998048807A1
WO1998048807A1 PCT/JP1998/001793 JP9801793W WO9848807A1 WO 1998048807 A1 WO1998048807 A1 WO 1998048807A1 JP 9801793 W JP9801793 W JP 9801793W WO 9848807 A1 WO9848807 A1 WO 9848807A1
Authority
WO
WIPO (PCT)
Prior art keywords
hyaluronic acid
vesnarinone
cells
acid
production
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1998/001793
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English (en)
Japanese (ja)
Inventor
Noboru Ueki
Kazuya Higashino
Tomohiro Taguchi
Masayuki Takahashi
Masakazu Adachi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Priority to AU68543/98A priority Critical patent/AU6854398A/en
Publication of WO1998048807A1 publication Critical patent/WO1998048807A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention relates to a hyaluronic acid synthesis inhibitor containing a specific carbostyril derivative as an active ingredient.
  • Extracellular matrix is composed of extracellular matrix components such as hyaluronic acid, laminin, and type IV collagen. It is known that various site cytokines are involved in fibrosis from overexpression of the extracellular matrix component to fibril formation. These site forces and the substrate components themselves are complex and interrelated and control the fibrosis.
  • liver inflammation progresses, some cells in the liver, such as hyaluronic acid, such as Ito cells and fibroblasts, Production is enhanced and blood hyaluronic acid levels increase.
  • hyaluronic acid such as Ito cells and fibroblasts
  • Other chronic inflammatory diseases such as inflammation in other organs such as lung and kidney and rheumatoid arthritis, have been shown to activate fibroblasts and increase hyaluronan production .
  • an object of the present invention is to research and develop the above-mentioned anti-fibrotic agents required in the art, and in particular, to specifically inhibit the synthesis of hyaluronic acid, one of the extracellular matrix components, To provide new drugs that can be converted.
  • the inventors of the present invention have conducted intensive studies for the above purpose, and as a result, have found that the carbostilyl derivative represented by the following general formula (1) and a salt thereof have a desired hyaluronic acid synthesis inhibitory action. And found. The present invention has been completed based on this finding.
  • a hyaluronan synthesis inhibitor comprising at least one therapeutically effective amount selected from a carbostyryl derivative represented by the following general formula (1) and a salt thereof together with a pharmaceutical carrier.
  • R represents a benzoyl group which may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms on a phenyl ring.
  • the carbon-carbon bond between the 3rd and 4th positions of the carbostyrinole skeleton indicates a single bond or a double bond.
  • the above-mentioned hyaluronic acid synthesis inhibitor in particular, wherein the carbostyril derivative is 6- [41- (3,4-dimethoxybenzoyl) -11-piperazinyl] -13,4-dihydrocarbostyril or a salt thereof C ) a carbostyril derivative represented by the above general formula (1) as an active ingredient in the hyaluronic acid synthesis inhibitor of the present invention;
  • the salts thereof, and their production methods are described in, for example, Japanese Patent Publication No. 1143477.
  • the publication also states that the carbostyril derivative is useful as a cardiotonic agent.
  • carbostyril derivative has the ability to regulate apoptosis and the ability to induce cell differentiation, and is capable of adapting to various diseases based on these actions.
  • S for example, W093 / 09 It is taught in No. 2 bulletin.
  • the action of inhibiting the synthesis of hyaluronic acid according to the present invention is not related to the known actions described for the above-mentioned carbostyril derivatives, and, of course, cannot be predicted from these known actions.
  • the agent of the present invention based on its inhibitory action on hyaluronic acid synthesis, is useful for the prevention, treatment and treatment of various fibrotic diseases and conditions caused by overproduction of hyaluronic acid.
  • the agent of the present invention can exert the action of inhibiting the synthesis of hyaluronic acid by inhibiting the gene expression (mRNA amount) of the enzyme in addition to the direct inhibition of hyaluronan synthase.
  • hyaluronic acid is a component of the cell wall of group A streptococci, and the massive production of non-antigenic hyaluronic acid is a factor that can escape immune defenses when the aforementioned cocci enter the living body.
  • agent of the present invention is useful as a pharmaceutical tool in studies of the role of hyaluronan in cell or tissue function.
  • Each group represented by the general formula (1) is more specifically as follows. That is, examples of the linear or branched alkoxy group having 1 to 6 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentinoreoxy, and hexyloxy. And the like.
  • Benzyl groups having 1 to 3 straight-chain or branched alkoxy groups having 1 to 6 carbon atoms as substituents on the phenyl ring include, for example, benzoyl, 2-methyl Toxic benzoinole, 3—Methoxy benzoinole, 4-Methoxy benzoinole ⁇ , 2—Ethoxy benzoinole, 3—Ethoxybenzyl, 4-Ethoxybenzoyl, 3—Isopropoxy benzoinole, 4—Butoxybenzol Examples include inole, 2-pentynoleoxybenzoyl, 3-hexyloxybenzoyl, 3,4-dimethoxybenzoyl, 2,5-dimethoxybenzoyl, and 3,4,5-trimethoxybenzoyl. .
  • carbostyryl derivatives as active ingredients in the present invention, particularly preferred are, for example, 6— [4—
  • vesnarinone (3,4-Dimethoxybenzoyl) -1-piperazinyl) — 3,4—Dihydrocarbostilil (hereinafter referred to as “vesnarinone”).
  • the above-mentioned salts of the carbostyril derivatives include pharmaceutically acceptable acid addition salts formed using ordinary acids.
  • Specific examples of the acidic compound that forms the salt include inorganic acids such as sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid, and hydrobromic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, and lymic acid.
  • examples thereof include organic acids such as carboxylic acid, tartaric acid, citric acid, succinic acid, ethanesulfonic acid, p-toluenesulfonic acid, and benzoic acid.
  • the carbostilyl derivative of the general formula (1) or a salt thereof, which is an active ingredient of the drug of the present invention is usually used in the form of a general pharmaceutical preparation.
  • a preparation is prepared using commonly used diluents or excipients such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant.
  • diluents or excipients such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant.
  • Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment. Representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.).
  • those conventionally known in the field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaoli.
  • Excipients such as carbohydrate, crystalline cellulose, and caicic acid, water, ethanol, propanol, single syrup, sugar solution of sugar, starch solution, gelatin solution, carboxymethyl senorelose, seraq, methinoresenorelose, Binders such as calcium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, powdered agar, powdered laminaran, powdered sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester
  • disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc.
  • absorption promoters such as sodium chloride, sodium raurylsulfate, monoglyceride stearate, starch and lactose Agents, dis
  • the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets, or multi-layer tablets.
  • a wide variety of carriers conventionally known in this field can be used as carriers, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc.
  • binders such as gum arabic, powdered tragacanth, gelatin and ethanol, and disintegrants such as laminaran agar can be exemplified.
  • a wide variety of carriers known in the art can be used, such as polyethylene glycol, cocoa butter, higher alcohol, higher alcohol esters, gelatin, Semi-synthetic dalyceride can be mentioned.
  • the liquid preparations and suspensions are preferably sterilized and isotonic with blood. When formed into the form of these liquid preparations, emulsions and suspensions, they are rarely used.
  • various types commonly used in this field can be used, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostear oleanoleanole, polyoxylated isostearyl alcohol, and polystyrene.
  • Oxyethylene sorbitan fatty acid esters and the like can be mentioned.
  • a sufficient amount of salt, glucose, glycerin, etc., for preparing an isotonic solution may be included in the pharmaceutical preparation, and ordinary dissolution aids, buffers, and painless Conversion You may add an agent.
  • the hyaluronic acid synthesis inhibitor of the present invention may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals as necessary.
  • the amount of the compound to be contained as an active ingredient in the preparation of the present invention is not particularly limited, and is appropriately selected from a wide range. Usually, it is suitable to be in the range of about 1 to 70% by weight, preferably about 1 to 30% by weight in the whole composition.
  • the method of administration of the preparation of the present invention is not particularly limited, and is determined according to various preparation forms, the age and sex of the patient, other conditions, and the degree of the disease.
  • a pharmaceutical preparation in the form of an injection can be administered by intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal administration and the like. It can be administered intravenously as needed, mixed with normal replacement fluids such as glucose and amino acids.
  • the preparation of the present invention in a solid form such as tablets, pills, granules, capsules and the like or a liquid form for oral administration can be administered orally or enterally. Suppositories can be administered rectally.
  • the dose of the preparation of the present invention can be appropriately selected from a wide range, and is not particularly limited.
  • the carbostyryl derivative of the general formula (1) (and its salt) is generally selected from the range of about 0.5 to 3 Omg per 1 kg of adult body weight per day.
  • the active ingredient in the dosage unit form Suitably, it is contained in an amount of 100 to 100 mg.
  • the preparation of the present invention can be administered once a day or divided into three to four times a day.
  • the preparation of the present invention has an inhibitory action on the production of hyaluronan synthase and an inhibitory action on the activity of the enzyme. Based on the inhibitory action on hyaluronan synthase, an overproduction of hyaluronic acid is performed. It is useful for prevention and treatment or treatment of various fibrotic diseases or conditions caused by the above. Specific examples of these applications include, for example, chronic hepatitis, fibrosis associated with chronic inflammatory diseases in various organs such as liver, lungs and kidneys, connective tissue diseases such as collagen disease, and cancer cells. Proliferation and transfer, group A streptococcal infection, and the like can be exemplified.
  • FIG. 1 is a photograph instead of a drawing showing the results of R T —PCR performed in accordance with pharmacological test example 1 (2-1).
  • - Figures 2 and 3 are photographs replacing the figures showing the results of RT-PCR performed under stimulus of site cytokines in accordance with pharmacological test example 1 (2-1).
  • the above mixture is sieved through a No. 60 screen and wet granulated with an alcoholic solution containing polyvinylpyrrolidone, Canolevovac 1500 and Calvovoux 600. Was. Add alcohol, if necessary, to make the powder into a paper mass. Corn starch was added and mixing continued until uniform particles were formed. It was passed through a No. 10 screen, placed in a tray, and dried in an oven at 100 ° C. for 12 to L: 4 hours. The dried particles are sieved with a No. 16 screen, dried sodium lauryl sulfate and dried magnesium stearate are added, mixed, and compressed to the desired shape using a tableting machine. Formed.
  • Recombinant human TNF-ct (Genzyme), recombinant human TGF- (Earth Pharmaceutical Co., Ltd.) and recombinant human IL-1a (Genzyme) were used as cytokines. All of them were stored frozen at 180 ° C until use.
  • Human embryo-derived fibroblast cell line MR C-5 cells [liver, 36, 3 (1995)] is a D-MEM medium containing 10% fetal bovine serum (JRH BIOSCIENCES) (Nikken Biomedical Science Research). ) And cultured at 37 ° C in the presence of 5% C ⁇ 2 .
  • this medium is referred to as “growth medium”.
  • hyaluronic acid is abbreviated as “HA” (the same applies hereinafter).
  • HA production indicates the amount of hyaluronic acid produced in 1 ml of the culture supernatant
  • HA production inhibition rate indicates the hyaluronic acid production of the control group (without adding vesnarinone). The ratio of the suppression by vesnarinone with respect to that of
  • Table 1 shows that vesnarinone did not inhibit the growth of MRC-5 cells.
  • vesnarinone reduced the production of hyaluronic acid in a dose-dependent manner. Statistically compared to the control group, vesnarinone showed significantly stronger suppression at all doses (38, 76 and 152 ⁇ M) at ⁇ ⁇ 0.01 (two-tailed Dunnett test) This was confirmed.
  • Table 2 shows the results of an examination of the same effect of vesnarinone on MRC-5 cells under the stimulation of cytokine.
  • Cytokine stimulation (TNF-a 250 units Zml IL-1 lOngZml or TGF- / 3 15 ng / ml) was performed 96 hours after seeding of MRC-5 cells, and vesnarinone (152 ⁇ l) was used. I) was tested for its effect.
  • Table 2 “Control” indicates a group not stimulated with site power in and without vesnarinone. From Table 2, it can be seen that the increase in the amount of HA produced by stimulation with TNF-aIL-1 and TGF-] 31 was suppressed by the addition of vesnarinone in all cases. These were 75%, 46% and 57%, respectively. Based on the above, vesnarinone significantly reduced the production of hyaluronic acid in a dose-dependent manner in the MRC-5 cell line under both unstimulated and stimulated site force-in. I understood this.
  • Figure 1 is a photograph replacing the drawing showing the results of the RT-PCR.
  • lanes 1, 6, 7, and 12 are molecular weight size markers, and the DNA fragment of the lowest band is shown. The size is 564 bp (indicated by the arrow).
  • Lanes 2, 3, 4, and 5 are the results of G3PDH as an internal standard.
  • Lane 8 shows the results of RT-PCR using RNA from MRC-5 cells cultured without vesnarinone (control).
  • the hyaluronan synthase band is the size
  • Lanes 9, 10, and 11 are vesnarinones of 3, 8, 76 and
  • the figure shows that vesnarinone dose-dependently suppressed the mRNA amount of hyaluronan synthase located in the 54 ⁇ 8 bp band, and suppressed the gene expression of the enzyme. You can see that there is.
  • Fig. 1 results of the same test on MRC-5 cells stimulated with sitekines were performed in the same manner as in Fig. 1; Fig. 2 (TNF-a severe or IL-1 ⁇ stimulation) and Fig. 3 (TGF- / 3 1 Stimulation).
  • cytokine stimulation (TNF- ⁇ 250 units / ml, IL-1 ⁇ lOngZml or TGF- / 315ng / ml) was performed simultaneously with the treatment with vesnarinone (152 / M).
  • lanes 1 and 8 show molecular weight size markers
  • lanes 2 unstimulated site force stimulation
  • 4 IL-1a stimulation
  • 6 TNF- ⁇ stimulation
  • Lanes 3 no site force stimulation
  • 5 IL-1 ⁇ stimulation
  • 7 TNF- ⁇ stimulation
  • lanes 1, 6 and 7 show the molecular weight markers for lane 2 (unstimulated site force in) and 4
  • TGF-] 31 stimulation was a control group without vesnarinone, and lanes 3 (no stimulation with site force) and 5 (TGF-1 stimulation) were tests with vesnarinone. In the group, lanes 8, 9, 10 and 11 all show the results of G3PDH.
  • vesnarinone does not affect the amount. Vesnarinone also showed a tendency to suppress the increase in the amount of hyaluronan synthase mRNA caused by TNF-c stimulation. Similarly, as shown in FIG. 3, vesnarinone tends to suppress the increase in the amount of hyaluronan synthase mRNA caused by the stimulation of TGF-] 31, which indicates that TNF- ⁇ Same as You can see that it is level.
  • MR C -. 5 Cells 6 X 1 0 4 was in a concentration of cells Zm 1 are suspended in growth culture ground, 1 Culture de Mesh diameter 1 5 O mm 8 X 1 0 6 cells // 3 0 ml growth medium and sowing in cormorants'll be, were cultured at 3 7 ° C, 5% C_ ⁇ 2. Three days after the culture, the test substance was added, and the cells were further cultured for 48 hours.
  • a buffer solution (25 mM Hepes (pH 7.2), 5 mM DDT, 15 mM gCl 2 ) was applied to the pellet thus obtained, and the solution was passed through a 23 G syringe needle three times. Used.
  • hyaluronidase (Amano Pharmaceutical) 10 ⁇ 1 (10TSU) was added, and the mixture was further incubated in a water bath at 37 ° C for 60 minutes.
  • the amount of UDP— [ 14C ] GLcUA was calculated by the difference between the control of the control and the sample treated with Streptomyces hyaluronidase.
  • the enzyme activity was evaluated as a specific activity (pmol / h / mg protein) based on the amount of glucuronic acid transferred from UDP- [ 14 C] dalcuronic acid per time and protein amount.
  • Vesnarinone was added during the cell culture described above (coexistence for 48 hours) and / or added during enzyme activity measurement (added to the enzyme reaction solution). More direct inhibition of the enzyme activity was tested.
  • Table 3 shows the results of testing the effect of vesnarinone on the production (activity) of hyaluronic acid synthase in MRC-5 cells stimulated with TGF- ⁇ 1.
  • TGF-] 31 (5 ng / ml) was added simultaneously with vesnarinone. In each addition group, no difference was observed in the amount of protein, the number of cells immediately before cell collection, and the cell morphology (the same applies hereinafter).
  • reaction solution represented as “reaction solution” in the table
  • inhibition rate 40% a direct inhibitory effect on hyaluronan synthase
  • reaction solution pretreatment with vesnarinone for 48 hours and addition of vesnarinone to the enzyme reaction solution: The reaction was indicated as “reaction solution”), and the inhibition rate of the enzyme activity was 74%, indicating that this combination had a significantly stronger inhibitory effect than the individual use alone (two-sided t test).
  • vesnarinone suppresses the production of hyaluronic acid by inhibiting the gene expression of hyaluronan synthase and directly inhibiting the activity of the enzyme. It is.
  • a hyaluronan synthesis inhibitor comprising a carbostyril derivative represented by the general formula (1) and a compound represented by the formula (1) or a salt thereof as an active ingredient. It is particularly useful for the prevention and treatment of various fibrotic diseases or conditions caused by overproduction.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des inhibiteurs de la synthèse de l'hyaluronate contenant une quantité efficace d'au moins un composé choisi parmi des dérivés de carbostyryle représentés par la formule générale (I), et de ses sels, et des excipients pharmaceutiquement acceptables. Dans cette formule, R représente benzoyle possédant éventuellement sur le cycle phénylique 1 à 3 groupes alcoxy C1-6 linéaires ou ramifiés, et la liaison carbone-carbone entre les positions 3 et 4 du squelette carbostyryle est une liaison simple ou double. Ces préparations sont utiles pour traiter diverses affections et pathologies fibroïdes provoquées par la production excessive d'acide hyaluronique.
PCT/JP1998/001793 1997-04-25 1998-04-16 Inhibiteurs de la synthese de l'hyaluronate Ceased WO1998048807A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68543/98A AU6854398A (en) 1997-04-25 1998-04-16 Hyaluronate synthesis inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/123132 1997-04-25
JP12313297 1997-04-25

Publications (1)

Publication Number Publication Date
WO1998048807A1 true WO1998048807A1 (fr) 1998-11-05

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PCT/JP1998/001793 Ceased WO1998048807A1 (fr) 1997-04-25 1998-04-16 Inhibiteurs de la synthese de l'hyaluronate

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000902A1 (fr) * 1991-07-03 1993-01-21 Otsuka Pharmaceutical Co., Ltd. Regulateur d'apoptose
WO1993011769A1 (fr) * 1991-12-10 1993-06-24 Otsuka Pharmaceutical Co., Ltd Agent anticancereux
WO1994004504A1 (fr) * 1992-08-19 1994-03-03 Otsuka Pharmaceutical Co., Ltd. Regulateur d'apoptose
JPH0733664A (ja) * 1993-07-26 1995-02-03 Otsuka Pharmaceut Co Ltd 平滑筋細胞増殖抑制剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000902A1 (fr) * 1991-07-03 1993-01-21 Otsuka Pharmaceutical Co., Ltd. Regulateur d'apoptose
WO1993011769A1 (fr) * 1991-12-10 1993-06-24 Otsuka Pharmaceutical Co., Ltd Agent anticancereux
WO1994004504A1 (fr) * 1992-08-19 1994-03-03 Otsuka Pharmaceutical Co., Ltd. Regulateur d'apoptose
JPH0733664A (ja) * 1993-07-26 1995-02-03 Otsuka Pharmaceut Co Ltd 平滑筋細胞増殖抑制剤

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