WO2009107736A1 - 線維化抑制剤 - Google Patents
線維化抑制剤 Download PDFInfo
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- WO2009107736A1 WO2009107736A1 PCT/JP2009/053582 JP2009053582W WO2009107736A1 WO 2009107736 A1 WO2009107736 A1 WO 2009107736A1 JP 2009053582 W JP2009053582 W JP 2009053582W WO 2009107736 A1 WO2009107736 A1 WO 2009107736A1
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
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- 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
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Definitions
- the present invention relates to a fibrosis inhibitor comprising a heterocyclic derivative represented by the following general formula (1) (hereinafter referred to as “the present heterocyclic derivative (1)”) or a pharmaceutically acceptable salt thereof as an active ingredient. It is about.
- R 1 and R 2 are the same or different and are each a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy
- R 3 and R 4 are the same or different and each represents a hydrogen atom or alkyl
- R 5 represents a hydrogen atom, an alkyl or a halogen atom
- Y represents N or N ⁇ O
- A represents NR 6 and R 6 represents a hydrogen atom, alky
- E represents phenylene or a single bond, or D and E together represent a divalent group represented by the following formula (3); [In the formula (3), u represents an integer of 0 to 2, and v represents 0 or 1. ] G represents O, S, SO or SO 2 ; Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl or a group represented by the following formula (4).
- R 7 is amino, monoalkylamino, dialkylamino, or hydroxy, or halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkyl Any one of the following 1) to 4) which may be substituted with 1 to 3 substituents selected from the group consisting of amino, dialkylamino, carboxy, cyano and nitro; 1) alkyl, 2) aryl, 3) Aryloxy, 4) A heterocyclic group. ]
- Fibrosis of an organ or the like is caused by excessive accumulation of extracellular matrix in the organ due to some cause such as invasion or damage. If the degree of damage to the organ or the like due to invasion or damage is minor, the repaired scar does not remain and the organ and the like recover normally. However, when the degree of damage to an organ or the like due to invasion or damage is large or persists, the fibrosis of the repair scar will damage the original function of the organ or the like. Furthermore, a vicious circle is formed in which new fibrosis occurs due to this, eventually leading to malfunction of organs and the like.
- Interstitial pneumonia (pulmonary fibrosis) is known as a disease caused by fibrosis of organs. Interstitial pneumonia causes inflammation of the alveolar wall for some reason, proliferation of fibroblasts in the interstitium, hardening of the lungs due to excessive deposition of collagen fibers, impaired gas exchange, and ultimately breathing It is a disease that leads to failure. Death occurs on average 3-5 years after onset. The detailed mechanism of the development of interstitial pneumonia has not yet been clarified, and there is no established treatment.
- ONO-1301 a prostaglandin I 2 (hereinafter referred to as “PGI 2 ”) receptor agonist
- PKI 2 a prostaglandin I 2 receptor agonist
- This heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof has already been reported to be useful as a PGI 2 receptor agonist in the treatment of pulmonary hypertension and obstructive arteriosclerosis (for example, (See Patent Document 1).
- the object of the present invention is mainly to provide a novel fibrosis inhibitor.
- the present heterocyclic derivative (1) has an effect of suppressing the proliferation of fibroblasts, thereby completing the present invention.
- Examples of the present invention include a fibrosis inhibitor containing the present heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
- R 1 and R 2 are the same or different and are phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, alkyl and alkoxy;
- R 3 and R 4 are the same or different and each represents a hydrogen atom or alkyl;
- R 5 is a hydrogen atom, Y is N,
- A is NR 6 ,
- R 6 is alkyl,
- D is alkylene
- E is a single bond,
- G O,
- Q is carboxy or a group represented by formula (4),
- R 7 is amino, monoalkylamino, dialkylamino, or hydroxy, or a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl Any one of the following 1) to 4) optionally substituted with 1 to 3 substituents selected from the group consisting of alkylsulfonyl, hydroxy, amino
- Compound A 2- ⁇ 4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy ⁇ acetic acid
- Compound B 2- ⁇ 4- [N— ( 5,6-Diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy ⁇ -N- (methylsulfonyl) acetamide
- alkyl in the present invention is a linear or branched one having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Examples include butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. In particular, those having 1 to 4 carbon atoms are preferred.
- Haloalkyl “Haloalkyl”, “arylalkyl”, “alkylthio”, “alkoxyalkyl”, “alkylsulfonyl”, “monoalkylamino”, “dialkylamino”, “monoalkylcarbazoyl” and “dialkylcarbamoyl” in the present invention
- Examples of the moiety include the same alkyl groups as those described above.
- alkoxy is a straight or branched chain having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- Examples include butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy and isohexyloxy. In particular, those having 1 to 4 carbon atoms are preferred.
- alkoxy moiety of “alkoxycarbonyl” and “alkoxyalkyl” in the present invention include the same as the above alkoxy.
- alkenyl is linear or branched having 2 to 6 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, Examples thereof include 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. In particular, those having 3 or 4 carbon atoms are preferred.
- cycloalkyl in the present invention include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, those having 5 to 7 carbon atoms are preferred.
- halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- aryl includes 6 to 10 carbon atoms, such as phenyl, 1-naphthyl and 2-naphthyl. In particular, phenyl is preferred.
- arylalkyl As the aryl moiety of “arylalkyl” and “aryloxy” in the present invention, the same aryl as the above aryl can be exemplified.
- alkylene in the present invention, linear or branched ones having 1 to 8 carbon atoms such as methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, tetramethylene, pentamethylene, Examples include hexamethylene, heptamethylene, and octamethylene. In particular, those having 3 to 6 carbon atoms are preferred, and those having 4 carbon atoms are particularly preferred.
- alkenylene in the present invention, linear or branched ones having 2 to 8 carbon atoms such as ethenylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 4-methyl-3-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene, 1-heptenylene, 2- Examples include heptenylene, 3-heptenylene, 4-heptenylene, 5-heptenylene, 6-heptenylene, 1-octenylene, 2-octenylene, 3-octenylene, 4-octenylene, 5-octenylene, 6-octenylene and 7-octenylene. .
- those having 3 to 6 carbon atoms are preferred, and those having 4 carbon atoms are preferred, and those
- heterocyclic group examples include the following (1) or (2).
- an atom or a sulfur atom such a nitrogen atom or sulfur atom may form an oxide.
- piperidino, piperazinyl, 3-methylpiperazin-1-yl, homopiperazinyl, monophorino, thiomonophorino, 1-pyrrolidinyl, 2-pyrrolidinyl, 2-tetrahydrofuranyl can be mentioned.
- the present heterocyclic derivative (1) can be synthesized by the method described in Patent Document 1 (International Publication No. 02/088084 pamphlet).
- the present heterocyclic derivative (1) can be used as a medicine as a free base or acid, but can also be used in the form of a medically acceptable salt by a known method.
- a salt of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, or hydrobromic acid, or acetic acid, List organic acid salts of tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, or camphorsulfonic acid Can do.
- alkali metal salts such as sodium salt and potassium salt
- alkaline earth metal salts such as calcium
- the present heterocyclic derivative (1) has geometric isomers (Z-form and E-form), and each geometric isomer and a mixture thereof are also included in the present heterocyclic derivative (1).
- some of the heterocyclic derivatives (1) have asymmetric carbons, but each optical isomer and their racemates are also included in the heterocyclic derivatives (1).
- the optical isomer is obtained from the racemate obtained as described above using its basicity and using an optically active acid (for example, tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid), It can be optically resolved by a known method, or can be produced using a previously prepared optically active compound as a raw material.
- the fibrosis inhibitor according to the present invention can be used, for example, for the treatment of the following diseases involving fibrosis of an organ or tissue.
- Kidney disease Tubular interstitial nephritis (2) Respiratory disease Interstitial pneumonia (pulmonary fibrosis) (3) Gastrointestinal disease Cirrhosis, chronic pancreatitis, Skills gastric cancer (4) Cardiovascular disease Myocardial fibrosis (5) Bone and joint disease Myelofibrosis, rheumatoid arthritis (6) Skin disease Scar after operation, burn scar, keloid , Hypertrophic scar, scleroderma (7) obstetrics disease uterine fibroids (8) urological diseases prostatic hypertrophy (9) other diseases Alzheimer's disease, sclerosing peritonitis, type I diabetes, postoperative organ adhesion
- the fibrosis inhibitor according to the present invention preferably contains the present heterocyclic derivative (1) in the range of 0.01 to 99.5% as it is or in a pharmaceutically acceptable non-toxic and inert carrier. Is contained in the range of 0.5 to 90%.
- the carrier examples include solid, semi-solid or liquid diluents, fillers, and other formulation aids. One or more of these can be used.
- the fibrosis inhibitor according to the present invention is a solid or liquid dosage unit, such as powder, capsule, tablet, dragee, granule, powder, suspension, liquid, syrup, elixir, lozenge and the like.
- a parenteral preparation such as an injection and a suppository can be used. It may be a sustained-release preparation.
- oral preparations such as tablets are particularly preferable.
- the powder can be produced by making the present heterocyclic derivative (1) fine.
- the powder can be produced by making the present heterocyclic derivative (1) fine and then mixing it with a finely divided pharmaceutical carrier such as edible carbohydrates such as starch and mannitol.
- a finely divided pharmaceutical carrier such as edible carbohydrates such as starch and mannitol.
- flavor, etc. can be added arbitrarily.
- Capsules are manufactured by first filling the powdered powdered powder or powder as described above into granules as described in the section of tablets, for example, into capsule shells such as gelatin capsules. can do.
- Lubricants and fluidizing agents such as colloidal silica, talc, magnesium stearate, calcium stearate and solid polyethylene glycol can be mixed in powder form and then filled. .
- disintegrators and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, calcium carbonate, sodium carbonate
- the fine powder of the present heterocyclic derivative (1) can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant and wrapped in a gelatin sheet to form a soft capsule.
- Tablets can be made by adding excipients to make a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and then tableting.
- a powder mixture can be produced by mixing a suitably powdered material with the diluent or base described above.
- a binder for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol
- a dissolution retardant for example, paraffin
- a resorbent for example, a quaternary salt
- An adsorbent for example, bentonite, kaolin or the like can be added.
- the powder mixture can first be moistened with a binder such as syrup, starch paste, gum arabic, cellulose solution or polymer solution, stirred and mixed, dried and pulverized into granules.
- a binder such as syrup, starch paste, gum arabic, cellulose solution or polymer solution
- stearic acid, stearate, talc, mineral oil or the like as a lubricant to the granules thus produced, it is possible to prevent them from adhering to each other.
- a tablet can also be manufactured by directly compressing after mixing this heterocyclic derivative (1) with a fluid inert carrier, without going through the granulation and slagging steps as described above. it can.
- Film tablets and sugar coatings can be applied to the tablets thus produced.
- a transparent or translucent protective coating made of a shellac hermetic coating, a coating of sugar or polymer material and a polishing coating made of wax can also be used.
- oral dosage forms such as solutions, syrups, troches, and elixirs may also be in dosage unit form so that a given amount contains a certain amount of the heterocyclic derivative (1).
- the syrup can be produced by dissolving the present heterocyclic derivative (1) in a suitable flavor aqueous solution.
- An elixir can be produced by using a non-toxic alcoholic carrier.
- the suspending agent can be produced by dispersing the present heterocyclic derivative (1) in a non-toxic carrier. If necessary, solubilizers and emulsifiers (for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (for example, peppermint oil, saccharin), etc. may be added. it can.
- solubilizers and emulsifiers for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
- preservatives for example, peppermint oil, saccharin, etc.
- a dosage unit formulation for oral administration can be microencapsulated.
- the formulation can also be extended in action time or sustained release by being coated or embedded in a polymer, wax or the like.
- the parenteral preparation can take the form of a liquid dose unit for subcutaneous, intramuscular or intravenous injection, for example, a solution or suspension.
- the parenteral preparation is prepared by suspending or dissolving a certain amount of the heterocyclic derivative (1) in a non-toxic liquid carrier suitable for injection purposes, for example, an aqueous or oily medium, and then suspending the suspension. Or it can manufacture by sterilizing a solution.
- Non-toxic salts and salt solutions can be added to make the injection solution isotonic.
- stabilizers, preservatives, emulsifiers, and the like can be added.
- the suppository is obtained by dissolving the present heterocyclic derivative (1) in a low-melting-point water-soluble or insoluble solid such as polyethylene glycol, cocoa butter, semi-synthetic oil [for example, Witepsol (registered trademark)], higher esters ( For example, it can be produced by dissolving or suspending in myristyl palmitate ester) or a mixture thereof.
- a low-melting-point water-soluble or insoluble solid such as polyethylene glycol, cocoa butter, semi-synthetic oil [for example, Witepsol (registered trademark)], higher esters ( For example, it can be produced by dissolving or suspending in myristyl palmitate ester) or a mixture thereof.
- the dose of the fibrosis inhibitor according to the present invention varies depending on the patient's condition such as body weight and age, administration route, symptom level, etc.
- the amount is suitably in the range of 0.01 mg to 1000 mg per day, more preferably in the range of 0.1 mg to 100 mg. In some cases, this may be sufficient, or vice versa.
- it can be administered once to several times a day or at intervals of 1 day to several days.
- Test example 1 Test method Human lung fibroblasts (manufactured by Lonza Walkersville, hereinafter the same) are basal medium for human lung fibroblasts (manufactured by Lonza Walkersville, the same hereinafter) (hereinafter referred to as “basal medium”). Was cultured at 37 ° C. under 5% CO 2 using a growth medium supplemented with FGM-2 added factor set (manufactured by Lonza Walkersville, the same applies hereinafter). Human lung fibroblasts were seeded on 96-well plates at 1 ⁇ 10 3 cells / well and cultured overnight in a growth medium.
- the cells were washed once with 100 ⁇ L of phosphate buffered saline (manufactured by Nissui Pharmaceutical Co., Ltd., the same applies hereinafter), added with a basal medium, and cultured for 24 hours. Furthermore, it was washed once with 100 ⁇ L of phosphate buffered saline, and 80 ⁇ L / well of basal medium was added. 10 ⁇ L of 100 ⁇ M Compound A or Compound B solution was added to each well and cultured for 2 hours. The added chemical solution was prepared by previously dissolving Compound A or Compound B in dimethyl sulfoxide (DMSO) to prepare a 10 mM chemical solution, which was diluted 100 times with a basal medium.
- DMSO dimethyl sulfoxide
- DMSO diluted 100-fold with basal medium was used for the unstimulated control group and the control group.
- 10 ⁇ L of 100 ng / mL epidermal growth factor (EGF) (manufactured by PeproTech) solution was added to each well and cultured for 48 hours.
- a basal medium was used for the non-stimulated control group.
- the absorbance at 490 nm was measured using CellTiter 96, AQueous assay (manufactured by Promega) in order to examine the cell proliferation activity.
- a microplate reader (Benchmark, manufactured by Bio-Rad, the same applies hereinafter) was used for the measurement of absorbance.
- FIG. 1 human lung fibroblasts significantly increased their cell proliferation activity by EGF stimulation.
- the cells treated with Compound A and Compound B had significantly decreased cell proliferation activity compared to the control group.
- Test example 2 (1) Test method Human lung fibroblasts were cultured under a condition of 37 ° C. and 5% CO 2 using a growth medium. Human lung fibroblasts were seeded on a 96-well plate at 3 ⁇ 10 3 cells / well and cultured overnight in a growth medium. The cells were washed once with 100 ⁇ L of phosphate buffered saline, basal medium was added and cultured for 24 hours. Furthermore, it was washed once with 100 ⁇ L of phosphate buffered saline, and 80 ⁇ L / well of basal medium was added. 10 ⁇ L of 1 ⁇ M Compound A drug solution was added to each well and cultured for 2 hours.
- Compound A was dissolved in DMSO in advance to prepare a 1 mM chemical solution, which was diluted 100 times with a basal medium.
- DMSO diluted 100-fold with basal medium was used for the unstimulated control group and the control group.
- 10 ⁇ L of 100 ng / mL transforming growth factor- ⁇ (Transforming Growth Factor- ⁇ : TGF ⁇ ) (manufactured by CHEMICON) was added to each well and cultured for 48 hours.
- a basal medium was used for the non-stimulated control group. After culturing for 48 hours, in order to examine the cell proliferation activity, the absorbance at 490 nm was measured using the cell proliferation activity measuring reagent in the same manner as in Test Example 1.
- Test example 3 (1) Test method Human lung fibroblasts were seeded on a 96-well plate at 5 ⁇ 10 3 cells / well and cultured in a growth medium overnight as in Test Example 1. The cells were washed once with 100 ⁇ L of basal medium, 100 ⁇ L of basal medium was added, and cultured for 24 hours. Further, the plate was washed once with 100 ⁇ L of basal medium, and 80 ⁇ L / well of basal medium was added. To this well, 10 ⁇ L of 0.1, 1, 10 or 100 ⁇ M Compound A chemical solution was added to each well.
- medical solution used what melt
- 10 ⁇ L each of DMSO diluted 100-fold with basal medium was added.
- TGF ⁇ 1 Transforming Growth Factor ⁇ 1
- the medium was collected to measure the concentration of procollagen type I C-terminal peptide (PIP) in the medium, and 100 ⁇ L of basal medium was newly added, and 3- (4,5-dimethyl-2-thiazolyl) was added.
- PIP procollagen type I C-terminal peptide
- MTT -2,5-diphenyl-2H tetrazolium bromide
- Cell proliferation activity was measured by adding 10 ⁇ L of a 5 mg / mL MTT stock solution to each well and incubating for 4 hours, then adding 100 ⁇ L of 0.04 M hydrochloric acid isopropanol solution to each well, and absorbance at 595 nm using a microplate reader.
- Test example 4 (1) Test method Human lung fibroblasts were seeded on a 24-well plate at 1 ⁇ 10 5 cells / well and cultured overnight in a growth medium in the same manner as in Test Example 1. The cells were washed once with 500 ⁇ L of basal medium, 500 ⁇ L of basal medium was added, and cultured for 24 hours. Furthermore, it was washed once with 500 ⁇ L of basal medium, and 400 ⁇ L / well of basal medium was added. Here, 50 ⁇ L of 1, 10 or 100 ⁇ M Compound A chemical prepared in the same manner as in Test Example 3 was added to each well. As a non-stimulated control group and a control group, 50 ⁇ L of DMSO diluted 100-fold with a basal medium was added.
- SV Total RNA Isolation System Invitrogen
- real-time quantitative PCR was used to perform type I collagen ⁇ 1 chain (COL1 ⁇ 1), type I collagen ⁇ 2 chain (COL1 ⁇ 2), ⁇ smooth muscle actin (ACTA), TGF ⁇ 1 and glyceraldehyde 3-phosphate dehydrogenase.
- Test Example 5 Rat renal stromal cells (NRF49F cells) were seeded at 1 ⁇ 10 4 cells / well in a 96-well plate, and 10% fetal bovine serum (manufactured by JRH Bioscience, the same applies hereinafter) containing Minimum Essential Medium (MEM). The culture was performed overnight at 37 ° C. and 5% CO 2 using a culture medium: manufactured by Nippon Pharmaceutical Co., Ltd. The plate was washed once with a MEM medium not containing fetal calf serum (hereinafter referred to as “serum-free MEM medium”), and 100 ⁇ L of serum-free MEM medium was added and cultured for 24 hours.
- MEM medium MEM medium not containing fetal calf serum
- cell proliferation activity was measured by the MTT method in the same manner as in Test Example 3. Discussion of this test was performed using a value (cell proliferation level) expressed as a relative value where the average value of the absorbance of the unstimulated control group was 1.
- Test Example 6 (1) Test method Human skin fibroblasts (manufactured by Kurabo Industries Co., Ltd., the same shall apply hereinafter) were seeded on 96-well plates at 5 ⁇ 10 3 cells / well, and Dulbecco's Modified Eagle's containing 10% fetal bovine serum. Using Medium (DMEM medium) (manufactured by Nippon Pharmaceutical Co., Ltd., the same shall apply hereinafter), the cells were cultured overnight under conditions of 37 ° C. and 5% CO 2 .
- DMEM medium Manufactured by Nippon Pharmaceutical Co., Ltd., the same shall apply hereinafter
- serum-free DMEM medium Human skin fibroblasts were washed once with DMEM medium not containing fetal bovine serum (hereinafter referred to as “serum-free DMEM medium”), and 100 ⁇ L of serum-free DMEM medium was added and cultured for 24 hours. Further, the plate was washed once with serum-free DMEM medium, and 80 ⁇ L / well of serum-free DMEM medium was added. 10 ⁇ L of 0.1, 1, 10 or 100 ⁇ M Compound A chemical prepared in the same manner as in Test Example 3 was added to each well. For the non-stimulated control group and the control group, 10 ⁇ L of DMSO diluted 100-fold with serum-free DMEM medium was added and cultured.
- FIG. 1 shows the cell growth inhibitory effect of Compound A and Compound B in human lung fibroblasts stimulated with EGF.
- the vertical axis represents absorbance.
- FIG. 2 shows the cell growth inhibitory effect of Compound A in human lung fibroblasts stimulated with TGF ⁇ .
- the vertical axis represents absorbance.
- FIG. 3 shows the collagen production inhibitory effect of Compound A in human lung fibroblasts stimulated with TGF ⁇ 1.
- the vertical axis represents a value calculated as a relative value obtained by correcting the measured PIP concentration value by the cell proliferation activity value (absorbance) and taking the average value of the unstimulated control group as 1.
- FIG. 4 shows the mRNA expression inhibitory effect of COL1 ⁇ 1 in human lung fibroblasts stimulated with TGF ⁇ 1.
- the vertical axis represents a relative value with the average value of the non-stimulated control group taken as 1 after correcting the expression level of COL1 ⁇ 1 mRNA with the expression level of GAPDH mRNA.
- FIG. 5 shows the mRNA expression inhibitory effect of COL1 ⁇ 2 in human lung fibroblasts stimulated with TGF ⁇ 1.
- the vertical axis represents a relative value with the expression level of COL1 ⁇ 2 mRNA corrected by the expression level of GAPDH mRNA and the average value of the unstimulated control group as 1.
- FIG. 6 shows the effect of suppressing ACTA mRNA expression in human lung fibroblasts stimulated with TGF ⁇ 1.
- the vertical axis represents the relative value with the average value of the non-stimulated control group taken as 1 after correcting the expression level of ACTA mRNA with the expression level of GAPDH mRNA.
- FIG. 7 shows the TGF ⁇ 1 mRNA expression inhibitory effect of Compound A in human lung fibroblasts stimulated with TGF ⁇ 1.
- the vertical axis represents the relative value with the expression value of TGF ⁇ 1 mRNA corrected by the expression amount of GAPDH mRNA and the average value of the unstimulated control group as 1.
- FIG. 8 shows the cytostatic effect of Compound A on rat kidney stromal cells stimulated with PDGFBB.
- the vertical axis represents a relative value with the average value of absorbance of the unstimulated control group being 1.
- FIG. 9 shows the collagen production inhibitory effect of Compound A in human skin fibroblasts stimulated with TGF ⁇ 1.
- the vertical axis represents a value calculated as a relative value obtained by correcting the measured PIP concentration value by the cell proliferation activity value (absorbance) and taking the average value of the unstimulated control group as 1.
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Abstract
Description
式(1)中、R1、R2は、同一又は異なって、ハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる1~3個の置換基で置換されていてもよいアリールを表し;
R3、R4は、同一又は異なって、水素原子又はアルキルを表し;
R5は水素原子、アルキル又はハロゲン原子を表し;
YはN又はN→Oを表し;
AはNR6を表し、R6は水素原子、アルキル、アルケニル又はシクロアルキルを表し;
Dはヒドロキシで置換されていてもよいアルキレン又はアルケニレンを表すか、又はAとDとが一緒になって、次の式(2)で表される二価の基を表し;
[式(2)中、rは0~2の整数を表し、qは2又は3を表し、tは0~4の整数をそれぞれ表す。]
Eは、フェニレン又は単結合を表すか、又はDとEとが一緒になって、次の式(3)で表される二価の基を表し;
[式(3)中、uは0~2の整数を表し、vは0又は1を表す。]
Gは、O、S、SO又はSO2を表し;
Qは、カルボキシ、アルコキシカルボニル、テトラゾリル、カルバモイル、モノアルキルカルバモイル、ジアルキルカルバモイル又は次の式(4)で表される基を表す。
[式(4)中、R7は、アミノ、モノアルキルアミノ、ジアルキルアミノ、若しくはヒドロキシ、又はハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる1~3個の置換基で置換されていてもよい下記1)~4)のいずれかの基を表す;
1)アルキル、
2)アリール、
3)アリールオキシ、
4)複素環基。]
R1、R2が、同一又は異なって、ハロゲン原子、アルキル及びアルコキシからなる群から選ばれる1~3個の置換基で置換されていてもよいフェニルであり、
R3、R4が、同一又は異なって、水素原子又はアルキルであり、
R5が水素原子であり、
YがNであり、
AがNR6であり、R6がアルキルであり、
Dがアルキレンであり、
Eが単結合であり、
GがOであり、
Qが、カルボキシ又は式(4)で表される基であり、R7が、アミノ、モノアルキルアミノ、ジアルキルアミノ、若しくはヒドロキシ、又はハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる1~3個の置換基で置換されていてもよい下記1)~4)のいずれかの基である化合物が好ましい。
1)アルキル、
2)アリール、
3)アリールオキシ、
4)複素環基
2-{4-[N-(5,6-ジフェニルピラジン-2-イル)-N-イソプロピルアミノ]ブチルオキシ}酢酸(以下、「化合物A」という。)、及び
2-{4-[N-(5,6-ジフェニルピラジン-2-イル)-N-イソプロピルアミノ]ブチルオキシ}-N-(メチルスルホニル)アセトアミド(以下、「化合物B」という)
が好ましい。
(1)窒素原子、酸素原子及び硫黄原子から選択される1~4個までのヘテロ原子を有する5又は6員の芳香環基、又はそれらのベンゼン縮合環であって、かかる環構成原子が窒素原子又は硫黄原子の場合、かかる窒素原子、硫黄原子はオキシドを形成していてもよい。例えば、1-ピロリル、2-ピロリル、3-ピロリル、3-インドリル、2-フラニル、3-フラニル、3-ベンゾフラニル、2-チエニル、3-チエニル、3-ベンゾチエニル、1,3-オキサゾール-2-イル、4-イソオキサゾリル、2-チアゾリル、5-チアゾリル、2-ベンゾチアゾリル、1-イミダゾリル、2-イミダゾリル、4-イミダゾリル、2-ベンズイミダゾリル、1H-1,2,4-トリアゾール-1-イル、1H-テトラゾール-5-イル、2H-テトラゾール-5-イル、2-ピリジル、3-ピリジル、4-ピリジル、3-ピラゾリル、2-ピリミジニル、4-ピリミジニル、2-ピラジニル、1,3,5-トリアジン-2-イルを挙げることができる。
(2)環構成原子として、窒素原子、酸素原子又は硫黄原子を、同一又は異なって、1~4個含んでいてもよい、4~8員環の飽和環基、又はそれらのベンゼン縮合環基であって、環構成原子が窒素原子又は硫黄原子の場合、かかる窒素原子、硫黄原子はオキシドを形成していてもよい。例えば、ピペリジノ、ピペラジニル、3-メチルピペラジン-1-イル、ホモピペラジニル、モノホリノ、チオモノホリノ、1-ピロリジニル、2-ピロリジニル、2-テトラヒドロフラニルを挙げることができる。
本複素環誘導体(1)が塩基性を示す場合の「塩」としては、例えば、塩酸、硫酸、硝酸、リン酸、フッ化水素酸、若しくは臭化水素酸の無機酸の塩、又は酢酸、酒石酸、乳酸、クエン酸、フマール酸、マレイン酸、コハク酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、ナフタレンスルホン酸、若しくはカンファースルホン酸の有機酸の塩を挙げることができる。
本複素環誘導体(1)が酸性を示す場合の「塩」としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、又はカルシウム塩等のアルカリ土類金属塩を挙げることができる。
(1)腎臓疾患
尿細管間質性腎炎
(2)呼吸器疾患
間質性肺炎(肺線維症)
(3)消化器疾患
肝硬変、慢性膵炎、スキルス胃癌
(4)心血管疾患
心筋線維症
(5)骨・関節疾患
骨髄線維症、関節リウマチ
(6)皮膚疾患
手術後の瘢痕、熱傷性瘢痕、ケロイド、肥厚性瘢痕、強皮症
(7)産科疾患
子宮筋腫
(8)泌尿器疾患
前立腺肥大症
(9)その他の疾患
アルツハイマー病、硬化性腹膜炎、I型糖尿病、手術後臓器癒着
粉末混合物は、適当に粉末化された物質を上述の希釈剤やベースと混合することにより製造することができる。必要に応じて、結合剤(例えば、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシプロピルメチルセルロース、ゼラチン、ポリビニルピロリドン、ポリビニルアルコール)、溶解遅延化剤(例えば、パラフィン)、再吸収剤(例えば、四級塩)、吸着剤(例えばベントナイト、カオリン)等を添加することができる。
粉末混合物は、まず結合剤、例えば、シロップ、澱粉糊、アラビアゴム、セルロース溶液又は高分子物質溶液で湿らせ、攪拌混合し、これを乾燥、粉砕して顆粒とすることができる。このように粉末を顆粒化する代わりに、まず打錠機にかけた後、得られる不完全な形態のスラグを破砕して顆粒にすることも可能である。このようにして作られる顆粒に、滑沢剤としてステアリン酸、ステアリン酸塩、タルク、ミネラルオイル等を添加することにより、互いに付着することを防ぐことができる。
また、錠剤は、上述のように顆粒化やスラグ化の工程を経ることなく、本複素環誘導体(1)を流動性の不活性担体と混合した後に直接打錠することによっても製造することができる。
こうして製造された錠剤にフィルムコーティングや糖衣を施すことができる。シェラックの密閉被膜からなる透明又は半透明の保護被覆、糖や高分子材料の被覆及びワックスよりなる磨上被覆をも用いることができる。
(1)試験方法
ヒト肺線維芽細胞(Lonza Walkersville社製。以下同じ。)は、ヒト肺線維芽細胞用基礎培地(Lonza Walkersville社製。以下同じ。)(以下、「基礎培地」という。)にFGM-2添加因子セット(Lonza Walkersville社製。以下同じ。)を加えた増殖用培地を用いて、37℃、5%CO2条件下で培養した。ヒト肺線維芽細胞を96wellプレートに1×103cells/wellで播種し、増殖用培地で一晩培養した。
当該細胞を100μLのリン酸緩衝生理食塩水(日水製薬社製。以下同じ。)で1回洗浄し、基礎培地を加え24時間培養した。更に、100μLのリン酸緩衝生理食塩水にて1回洗浄し、80μL/wellの基礎培地を加えた。ここに100μMの化合物A又は化合物Bの薬液を各wellに10μLずつ添加し、2時間培養した。なお、加えた薬液は、化合物A又は化合物Bを予めジメチルスルホキシド(DMSO)に溶解して、10mMの薬液を調製し、これを基礎培地で100倍に希釈したものを用いた。無刺激対照群及び対照群に対しては、DMSOを基礎培地で100倍希釈したものを用いた。
ここに100ng/mLの上皮成長因子(Epidermal Growth Factor:EGF)(PeproTech社製)溶液を各wellに10μLずつ添加し、48時間培養した。なお、無刺激対照群に対しては、基礎培地を用いた。
48時間培養後、細胞増殖活性を調べるために、CellTiter 96、AQueousアッセイ(Promega社製)を用いて、490nmにおける吸光度を測定した。吸光度の測定にはマイクロプレートリーダー(Benchmark、Bio-Rad社製。以下同じ。)を用いた。
(2)結果
図1に示すように、ヒト肺線維芽細胞は、EGF刺激により細胞増殖活性が有意に増加した。一方、化合物A及び化合物Bを処理した細胞は、対照群と比べて、細胞増殖活性が有意に減少した。
(1)試験方法
ヒト肺線維芽細胞は、増殖用培地を用いて、37℃、5%CO2条件下で培養した。ヒト肺線維芽細胞を96wellプレートに3×103cells/wellで播種し、増殖用培地で一晩培養した。
当該細胞を100μLのリン酸緩衝生理食塩水で1回洗浄し、基礎培地を加え24時間培養した。更に、100μLのリン酸緩衝生理食塩水にて1回洗浄し、80μL/wellの基礎培地を加えた。ここに1μMの化合物Aの薬液を各wellに10μLずつ添加し、2時間培養した。なお、加えた薬液は、化合物Aを予めDMSOに溶解して、1mMの薬液を調製し、これを基礎培地で100倍に希釈したものを用いた。無刺激対照群及び対照群に対しては、DMSOを基礎培地で100倍希釈したものを用いた。
ここに100ng/mLのトランスフォーミング増殖因子-α(Transforming Growth Factor-α:TGFα)(CHEMICON社製)溶液を各wellに10μLずつ添加し、48時間培養した。なお、無刺激対照群に対しては、基礎培地を用いた。
48時間培養後、細胞増殖活性を調べるために、試験例1と同様に細胞増殖活性測定試薬を用いて、490nmにおける吸光度を測定した。吸光度の測定にはマイクロプレートリーダーを用いた。
(2)結果
図2に示すように、ヒト肺線維芽細胞は、TGFα刺激により細胞増殖活性が有意に増加した。一方、化合物Aを処理した細胞は、対照群と比べて、細胞増殖活性が有意に減少した。
(1)試験方法
ヒト肺線維芽細胞は96wellプレートに5×103cells/wellで播種し、試験例1と同様に増殖用培地で一晩培養した。当該細胞を100μLの基礎培地で1回洗浄し、100μLの基礎培地を加え24時間培養した。更に、100μLの基礎培地にて1回洗浄し、80μL/wellの基礎培地を加えた。ここに0.1、1、10又は100μMの化合物Aの薬液を各wellに10μLずつ添加した。なお薬液は、化合物Aを予めDMSOに溶解して、10μM、100μM、1mM及び10mM濃度に調製し、これらを基礎培地で100倍に希釈したものを用いた。また無刺激対照群及び対照群として、DMSOを基礎培地で100倍希釈したものを10μLずつ添加した。2時間培養後に、100ng/mLのトランスフォーミング増殖因子β1(Transforming Growth Factor β1:TGFβ1)(PeproTech社製。以下同じ。)溶液を10μLずつ、また無刺激対照群に対しては基礎培地を10μLずつ添加した。48時間培養後に培地中のプロコラーゲンI型C末端ペプチド(PIP)濃度を測定するために培地を回収し、新たに100μLの基礎培地を加え、3-(4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H tetrazolium bromide (MTT)(ナカライテスク社製)を用いて、細胞増殖活性を測定した。細胞増殖活性の測定は、5mg/mLのMTTストック溶液を各wellに10μLずつ添加し、4時間培養した後、各wellに0.04M塩酸イソプロパノール溶液を100μLずつ加え、マイクロプレートリーダーで595nmにおける吸光度(参照波長655nm)を測定した。48時間培養後の培地中PIP濃度は、Procollagen Type I C-peptide(PIP) EIA Kit(Takara社製。以下同じ。)を用いて、添付の手順書に従い測定した。本試験の考察は、PIP濃度測定値を細胞増殖活性値(吸光度)で補正し、無刺激対照群の平均値を1とした相対値として算出した値(コラーゲン産生の指標)を用いて行った。
(2)結果
図3に示すように、ヒト肺線維芽細胞は、TGFβ1刺激によりコラーゲン産生が有意に増加した。一方、化合物Aを処理した細胞は、対照群と比べてコラーゲン産生が有意に減少した。
(1)試験方法
ヒト肺線維芽細胞は24wellプレートに1×105cells/wellで播種し、試験例1と同様に増殖用培地で一晩培養した。当該細胞を500μLの基礎培地で1回洗浄し、500μLの基礎培地を加え24時間培養した。更に、500μLの基礎培地にて1回洗浄し、400μL/wellの基礎培地を加えた。ここに試験例3と同様の方法で調製した1、10又は100μMの化合物Aの薬液を各wellに50μLずつ添加した。また無刺激対照群及び対照群として、DMSOを基礎培地で100倍希釈したものを50μLずつ添加した。2時間培養後に100ng/mLのTGFβ1溶液を各wellに50μLずつ添加し、また無刺激対照群に対しては基礎培地を50μLずつ添加した。24時間培養後、SV Total RNA Isolation System(Invitrogen社製)を用いてRNAを抽出し、SuperScriptIII(Invitrogen社製)を用いてRNAから1st strand cDNAを合成した。こうして作製したcDNAを鋳型として、リアルタイム定量PCR法により、I型コラーゲンα1鎖(COL1α1)、I型コラーゲンα2鎖(COL1α2)、α平滑筋アクチン(ACTA)、TGFβ1及びグリセルアルデヒド3-リン酸デヒドロゲナーゼ(GAPDH)のmRNA発現量を測定した。リアルタイム定量PCRはPlatinum SYBR Green qPCR Super-Mix-UDG with ROX(Invitrogen社製)及び各遺伝子に特異的なプライマーを使用し、Platinum SYBR Green qPCR Super-Mix-UDG with ROX添付の手順書に従い、ABI PRISM 7000(Applied Biosystems社)を用いて行った。本試験の考察は、各遺伝子のmRNAの発現量をGAPDHのmRNA発現量で補正し、無刺激対照群の平均値を1とする相対値として算出した値(mRNA発現レベル)を用いて行った。
(2)結果
図4~7に示すように、ヒト肺線維芽細胞はTGFβ1刺激により各mRNA発現レベルが増加した。一方、化合物Aを処理した細胞は、対照群と比べて、各mRNAレベルが減少した。
(1)試験方法
ラット腎間質細胞(NRF49F細胞)は、96wellプレートに1×104cells/well播種し、10%牛胎児血清(JRH Bioscience社製。以下同じ)を含むMinimum Essential Medium(MEM培地:日本製薬社製。以下同じ。)を用いて、37℃、5%CO2条件下で一晩培養した。牛胎児血清を含まないMEM培地(以下、「無血清MEM培地」という。)で1回洗浄し、100μLの無血清MEM培地を加え24時間培養した。更に、無血清MEM培地にて1回洗浄した後、無血清MEM培地を80μL/well加えた。ここに試験例1と同様の方法で調製した、100μMの化合物Aの薬液を各wellに10μLずつ添加した。また無刺激対照群及び対照群に対しては、DMSOを無血清MEM培地で100倍希釈したものを10μLずつ添加した。2時間培養後に100ng/mLの血小板由来成長因子(Platelet-Derived Growth Factor-BB:PDGFBB)(Sigma社製)溶液を各wellに10μLずつ、また無刺激対照群は無血清MEM培地を10μLずつ添加し培養した。48時間培養後に、試験例3と同様にMTT法により細胞増殖活性(吸光度)を測定した。本試験の考察は、無刺激対照群の吸光度の平均値を1とする相対値で表した値(細胞増殖レベル)を用いて行った。
(2)結果
図8に示すように、ラット腎間質細胞は、PDGFBB刺激により細胞増殖レベルが有意に増加した。一方、化合物Aを処理した細胞は、対照群と比べて、細胞増殖レベルが有意に減少した。
(1)試験方法
ヒト皮膚線維芽細胞(クラボウ社製。以下同じ。)は、96wellプレートに5×103cells/wellで播種し、10%の牛胎児血清を含むDulbecco’s Modified Eagle’s Medium(DMEM培地)(日本製薬社製。以下同じ。)を用いて、37℃、5%CO2条件下で一晩培養した。ヒト皮膚線維芽細胞を牛胎児血清を含まないDMEM培地(以下、「無血清DMEM培地」という。)で1回洗浄し、100μLの無血清DMEM培地を加え24時間培養した。更に無血清DMEM培地にて1回洗浄し、80μL/wellの無血清DMEM培地を加えた。ここに試験例3と同様の方法で調製した0.1、1、10又は100μMの化合物Aの薬液を各wellに10μLずつ添加した。また無刺激対照群及び対照群に対しては、DMSOを無血清DMEM培地で100倍希釈したものを10μLずつ添加し培養した。2時間培養後に100ng/mLのTGFβ1溶液を各wellに10μLずつ添加し、無刺激対照群に対しては無血清MEM培地を10μLずつ添加した。48時間培養後に試験例3と同様にMTT法により細胞増殖活性(吸光度)と、培地中のPIP濃度を測定した。本試験の考察は、PIP濃度測定値を細胞増殖活性値(吸光度)で補正し、無刺激対照群の平均値を1とした相対値として算出した値(コラーゲン産生の指標)を用いて行った。
(2)結果
図9に示すように、ヒト皮膚線維芽細胞は、TGFβ1刺激によりコラーゲン産生が有意に増加した。一方、化合物Aを処理した細胞は、対照群と比べて、コラーゲン産生が有意に減少した。
Claims (7)
- 次の一般式(1)で表される複素環誘導体又はその医薬上許容される塩を有効成分として含有する線維化抑制剤;
式(1)中、R1、R2は、同一又は異なって、ハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる1~3個の置換基で置換されていてもよいアリールを表し;
R3、R4は、同一又は異なって、水素原子又はアルキルを表し;
R5は水素原子、アルキル又はハロゲン原子を表し;
YはN又はN→Oを表し;
AはNR6を表し、R6は水素原子、アルキル、アルケニル又はシクロアルキルを表し;
Dはヒドロキシで置換されていてもよいアルキレン又はアルケニレンを表すか、又はAとDとが一緒になって、次の式(2)で表される二価の基を表し;
[式(2)中、rは0~2の整数を表し、qは2又は3を表し、tは0~4の整数をそれぞれ表す。]
Eは、フェニレン又は単結合を表すか、又はDとEとが一緒になって、次の式(3)で表される二価の基を表し;
[式(3)中、uは0~2の整数を表し、vは0又は1を表す。]
Gは、O、S、SO又はSO2を表し;
Qは、カルボキシ、アルコキシカルボニル、テトラゾリル、カルバモイル、モノアルキルカルバモイル、ジアルキルカルバモイル又は次の式(4)で表される基を表す。
[式(4)中、R7は、アミノ、モノアルキルアミノ、ジアルキルアミノ、若しくはヒドロキシ、又はハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる1~3個の置換基で置換されていてもよい下記1)~4)のいずれかの基を表す;
1)アルキル、
2)アリール、
3)アリールオキシ、
4)複素環基。] - 複素環誘導体(1)において、R1、R2が、同一又は異なって、ハロゲン原子、アルキル及びアルコキシからなる群から選ばれる1~3個の置換基で置換されていてもよいフェニルであり、
R3、R4が、同一又は異なって、水素原子又はアルキルであり、
R5が水素原子であり、
YがNであり、
AがNR6であり、R6がアルキルであり、
Dがアルキレンであり、
Eが単結合であり、
GがOであり、
Qが、カルボキシ又は式(4)で表される基であり、R7が、アミノ、モノアルキルアミノ、ジアルキルアミノ、若しくはヒドロキシ、又はハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる1~3個の置換基で置換されていてもよい下記1)~4)のいずれかの基である、請求項1に記載の線維化抑制剤。
1)アルキル、
2)アリール、
3)アリールオキシ、
4)複素環基 - 尿細管間質性腎炎、間質性肺炎、肝硬変、慢性膵炎、スキルス胃癌、心筋線維症、骨髄線維症、関節リウマチ、手術後の瘢痕、熱傷性瘢痕、ケロイド、肥厚性瘢痕、強皮症、子宮筋腫、前立腺肥大症、アルツハイマー病、硬化性腹膜炎、I型糖尿病及び手術後臓器癒着からなる群より選択される疾患を治療するための請求項1又は2のいずれかに記載の線維化抑制剤。
- 間質性肺炎を治療するための請求項1又は2のいずれかに記載の線維化抑制剤。
- 2-{4-[N-(5,6-ジフェニルピラジン-2-イル)-N-イソプロピルアミノ]ブチルオキシ}酢酸、2-{4-[N-(5,6-ジフェニルピラジン-2-イル)-N-イソプロピルアミノ]ブチルオキシ}-N-(メチルスルホニル)アセトアミド又はその医薬上許容される塩を有効成分として含有する線維化抑制剤。
- 尿細管間質性腎炎、間質性肺炎、肝硬変、慢性膵炎、スキルス胃癌、心筋線維症、骨髄線維症、関節リウマチ、手術後の瘢痕、熱傷性瘢痕、ケロイド、肥厚性瘢痕、強皮症、子宮筋腫、前立腺肥大症、アルツハイマー病、硬化性腹膜炎、I型糖尿病及び手術後臓器癒着からなる群より選択される疾患を治療するための請求項5に記載の線維化抑制剤。
- 間質性肺炎を治療するための請求項5に記載の線維化抑制剤。
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- 2009-02-26 US US12/919,885 patent/US8729086B2/en not_active Ceased
- 2009-02-26 CN CN201510089864.XA patent/CN104761509A/zh active Pending
- 2009-02-26 DK DK09714302.8T patent/DK2246336T3/da active
- 2009-02-26 HU HUE09714302A patent/HUE050786T2/hu unknown
- 2009-02-26 ES ES09714302T patent/ES2817557T3/es active Active
- 2009-02-26 AU AU2009218115A patent/AU2009218115B2/en active Active
- 2009-02-26 JP JP2010500744A patent/JP5522030B2/ja active Active
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US8791122B2 (en) | 2009-06-26 | 2014-07-29 | Nippon Shinyaku Co., Ltd. | Form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and method for producing the same |
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KR20170024165A (ko) | 2009-06-26 | 2017-03-06 | 니뽄 신야쿠 가부시키가이샤 | 결정 |
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Also Published As
Publication number | Publication date |
---|---|
RU2497525C2 (ru) | 2013-11-10 |
BRPI0908491A2 (pt) | 2015-08-11 |
DK2246336T3 (da) | 2020-07-20 |
US20110015211A1 (en) | 2011-01-20 |
LT2246336T (lt) | 2020-08-25 |
US20140221397A1 (en) | 2014-08-07 |
US8729086B2 (en) | 2014-05-20 |
US8889693B2 (en) | 2014-11-18 |
CY1123308T1 (el) | 2021-12-31 |
KR20100135726A (ko) | 2010-12-27 |
AU2009218115A1 (en) | 2009-09-03 |
CA2716554A1 (en) | 2009-09-03 |
ES2817557T3 (es) | 2021-04-07 |
RU2010139644A (ru) | 2012-04-10 |
MX2010008745A (es) | 2010-08-30 |
CN104761509A (zh) | 2015-07-08 |
PL2246336T3 (pl) | 2020-12-14 |
AU2009218115B2 (en) | 2013-05-30 |
CN101959868A (zh) | 2011-01-26 |
HRP20201352T1 (hr) | 2020-11-27 |
CA2716554C (en) | 2017-01-10 |
PT2246336T (pt) | 2020-07-29 |
SI2246336T1 (sl) | 2020-09-30 |
JPWO2009107736A1 (ja) | 2011-07-07 |
EP2246336B1 (en) | 2020-07-01 |
JP5522030B2 (ja) | 2014-06-18 |
USRE46364E1 (en) | 2017-04-11 |
KR101581059B1 (ko) | 2015-12-30 |
EP2246336A4 (en) | 2011-12-21 |
HUE050786T2 (hu) | 2021-01-28 |
EP2246336A1 (en) | 2010-11-03 |
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