Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D475/00—Heterocyclic compounds containing pteridine ring systems
  • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
  • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to a novel methotrexate derivative, more specifically, a novel methotrexate derivative useful as an antirheumatic agent.
• Methotrexate has long been used as a treatment for leukemia, but since 1951 Gubner et al. Reported its effectiveness in treating rheumatoid arthritis (RA) and psoriasis, it has been used as a treatment for RA. It has been used in Europe and the United States. More recently, a detailed study of dosage and administration has revealed that low-dose methotrexate therapy has relatively few side effects and excellent efficacy. However, since side effects such as liver damage and pulmonary fibrosis caused by taking methotrexate cannot be ignored, there is a demand for a drug with fewer side effects and excellent efficacy.
• the present inventors have conducted intensive studies for a more excellent compound as a therapeutic agent for rheumatism in methotrexate derivatives, and have reached the present invention.
• the present invention provides a compound represented by the following general formula (E):
• R t represents a lower alkyl group having 1 to 4 carbon atoms
• R z represents a lower alkyl group having 1 to 4 carbon atoms or a trifluoromethyl group
• R 3 represents a hydrogen atom
• R 4 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms
• R 5 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms
• R 5 represents a general formula C00R 6 (where R 6 represents a hydrogen atom
• a group represented by the group or the formula S0 3 H are represented by a lower alkyl group having a carbon number of 1 to 4)
• n represents an integer from 4 to ⁇ .
• R 7 represents a lower alkyl group having 1 to 4 carbon atoms
• R B represents a lower alkyl group having 1 to 4 hydrogen or C
• R 9 is the formula C00B lo (wherein R 10 is hydrogen represents an atomic also, you express a group or the formula S0 3 II represented by a lower alkyl group having 1 to 4 carbon atoms) groups, m is an integer of from 1 4.)
• R 12 V represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms
• R 12 V represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms
• R 13 represents a general formula C00R 1 Z (this this in R 12 represents a group represented by hydrogen or a carbon number of 1 indicates a 4 lower alkyl group), a group represented by or the formula S0 3 H, £ is an integer of from 1 4.) or Or general formula H 2 ) k C00Ri6
• R 15 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms
• k represents an integer of 2 or 3.
• the invention also relates to the use of these compounds as antirheumatic agents.
• Some of the antirheumatic agents of the present invention include known compounds. Specifically, 3′-methylaminopterin (Cancer Research Vol. 20, No. 10: 698-733, 1960) is available, but the use of this compound as an anti-rheumatic drug is not well known. Not been.
• Figure 1 and Figure 2 show the concentration of the test drug at each concentration. Indicates the uptake (ratio) of H-UdR.
• the compound of the present invention can be synthesized, for example, as follows (Method A) — ⁇ ,:.
• R ′ represents a lower alkyl group having 1 to 4 carbon atoms
• a ! Represents a protecting group
• X represents a halogen atom.
• R, R 2 , R 3 , R 4 R and n are the same as above.
• A represents a meaning
• a 2 represents a protecting group
• X represents a halogen atom.
• the reaction for obtaining the compound of the general formula (2) from the compound of the general formula (1) is carried out in the presence of sodium hydrogencarbonate, calcium carbonate, carbonated lime, or the like.
• METHANOL performed, water Eta Roh Lumpur, a mixed solvent such as water one propanol Lumpur, by the this reacting the halogen represented by a compound of formula X 2 in the general formula (1).
• the compound of the general formula (2) and acetic anhydride are reacted with toluene, benzene, xylene, dioxane, pyridin and the like. It is carried out by reacting in a solvent.
• the steps from obtaining the compound of the general formula (2) from the compound of the general formula (1) and obtaining the compound of the general formula (3) from the compound of the general formula (2) are reversed. You may.
• the compound of the general formula (3) and copper cyanide are used, for example, ⁇ -methylpyrrolidone, dimethylformamide, dimethylformamide
• a solvent such as thiacetoamide, dimethyl propylene urea, and hexamyl phosphoric triamide.
• the reaction for obtaining the compound of the general formula (5) from the compound of the general formula (4) is carried out by reacting the compound of the general formula (4) with 12 ⁇ -hydrochloric acid, 50% -sodium hydroxide aqueous solution and the like. This is done.
• the reaction for obtaining the compound of the general formula (?) From the compound of the general formula (5) and the compound of the general formula (6) is carried out by a reaction such as methanol or ethanol.
• the reaction is carried out in the presence of hydrochloric acid or sulfuric acid in the presence of alcohol.
• the reaction may be performed in the presence of thionyl chloride in alcohol.
• the alkyl group represented by R ′ in the formula is preferably a methyl group, an ethyl group, and the like.
• the reaction for obtaining the compound of the formula (9) is carried out by dissolving the compound of the formula (7) in a solvent such as pyridine or in the presence of sodium hydride, and adding tetrahydrofuran, dimethylformamide, This is carried out by suspending in dimethoxetane, dioxane, toluene, or the like, adding the compound of the general formula (8), and stirring.
• a solvent such as pyridine or in the presence of sodium hydride
• tetrahydrofuran, dimethylformamide This is carried out by suspending in dimethoxetane, dioxane, toluene, or the like, adding the compound of the general formula (8), and stirring.
• the protecting group represented by A 1 in the formula include a P-toluenesulfonyl group, a benzyloxycarbonyl group, an acetyl group and the like.
• the compound of the general formula (9) can be obtained by reacting the compound of the general formula (9) with, for example, anhydrous dimethylformamide or tetrahydrofuran. , Dimethoxane, dioxane, etc., and then, under ice-cooling, for example, adding sodium hydrogen hydride and stirring at 10 to 120 ° C., preferably at room temperature. ), And the mixture is stirred at room temperature to 120, preferably at room temperature.
• the reaction for obtaining the compound of the general formula (12) from the compound of the general formula (11) is carried out by converting the compound of the general formula (11) into a solvent such as methanol, ethanol, tetrahydrofuran, or the like.
• the reaction is carried out at 10 to 100 ° C., preferably at room temperature, in the presence of an aqueous sodium hydroxide solution or the like.
• Reaction for obtaining a compound of the general formula (13) from a compound of the general formula (12) Is carried out by suspending the compound of the general formula (12) in an acid halogenating agent such as thionyl chloride, oxalyl chloride and the like, and stirring at room temperature in the presence of a catalytic amount of dimethylformamide and the like. .
• an acid halogenating agent such as thionyl chloride, oxalyl chloride and the like
• the reaction for obtaining the compound of the general formula (15) from the compound of the general formula (13) and the compound of the general formula (14) is carried out by dissolving the compound of the general formula (13) in a solvent such as dichloromethane. At room temperature in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, sodium bicarbonate in addition to an aqueous solution of the compound of the general formula (14) under ice or water cooling. This is done by stirring.
• the reaction for obtaining the compound of the general formula (16) from the compound of the general formula (15) is carried out by adding the compound of the general formula (15) to a solution of anisol diphenol or the like in a hydrogen bromide / acetic acid solution, 'C ⁇ 60, preferably by stirring at room temperature.
• a 1 is a carboxy group
• the reaction for obtaining the compound of the general formula (16) from the compound of the general formula (15) is carried out by converting the compound of the general formula (15) to methanol or ethanol.
• the reaction may be carried out by dissolving in a solvent such as acetic acid and acetic acid, adding palladium monocarbon, and then stirring at room temperature in a hydrogen atmosphere.
• the reaction for obtaining the compound of the general formula (18) from the compound of the general formula (16) and the compound of the general formula (17) is performed by converting the compound of the general formula (16) and the compound of the general formula (17) to dimethyl acetate In a solvent such as dimethylformamide, stirring is carried out at 0 to 100, preferably at 50 to 60.
• stirring is carried out at 0 to 100, preferably at 50 to 60.
• R 4 is a hydrogen atom
• the reaction for obtaining the compound of the general formula (20) from the compound of the general formula (5) and the compound of the general formula (19) is performed by the reaction of the compound of the general formula (5) and the compound of the general formula (19).
• the suspension is allowed to react at 0 to 100'C, preferably at room temperature.
• the protecting group represented by A 2 includes a trifluoroacetyl group, an acetyl group and the like.
• the reaction for obtaining the compound of the general formula (22) from the compound of the general formula (20) and the compound of the general formula (21) is performed by adding an aqueous solution of the compound of the general formula (20) and the compound of the general formula (21) to water. Add potassium oxide and add 0 ⁇
• the reaction for obtaining the compound of the general formula (23) from the compound of the general formula (22) is carried out by reacting the compound of the general formula (22) with a hydration power or sodium hydroxide in water.
• the compound of the above general formula (11) may be used instead of the compound of the general formula (22).
• the compound of (17) is stirred in a solvent such as dimethyl acetate amide at 0 ⁇ (: up to 100 ° C., preferably at 40 to 55 ° C.). .
• the compound of the general formula (24) is prepared by adding the compound of the general formula (24) to dimethylformamide in the presence of cyanididodicyclohexylcarbodiimide and 1-hydroxybenzotriazole. , Dimethyl acetate, N-methylpyrrolidinone, etc., to prepare the active ester and mixed acid anhydride, respectively, and then add the compound of the general formula (14). 2 0 0 and preferably 10. It is performed by stirring at C ⁇ 80.
• triethylamine is added to the compound of the general formula (24), and then isobutyl chloroformate is added to the compound in a solvent such as dimethylformamide, dimethylacetamide, or N-methylpyrrolidinone.
• a solvent such as dimethylformamide, dimethylacetamide, or N-methylpyrrolidinone.
• Stir add the compound of the general formula (14), and stir at 100 ° C. to 50 ⁇ (:, preferably 110 ° !: to 0.
• Particularly R When 4 is a hydrogen atom, an aqueous solution of 1N-sodium hydroxide in a solvent such as methanol or ethanol is further added, and the solution is added at 0 ° C. to 60 ° C., preferably. Is stirred at room temperature to obtain the desired product.
• the reaction for obtaining the compound of the general formula (26) from the compound of the general formula (25) is carried out by refluxing the compound of the general formula (25) in acetic anhydride.
• the reaction for obtaining a compound of general formula (27) from the compound of general formula (26) is performed, for example, the acetic acid solution of the compound of general formula (26) by the general formula X 2 by the this reacting halogen to be shown.
• the compound of the general formula (27) and copper cyanide are reacted, for example, with ⁇ -methylpiperidinone, dimethylformamide
• the reaction can be carried out in a solvent such as dimethyl acetate amide, dimethyl propylene urea, hexylmethyl phospholipid amide, or the like, at a temperature of 100 to 250, preferably 200.
• the reaction for obtaining the compound of the general formula (29) from the compound of the general formula (28) is carried out by reacting the compound of the general formula (28) with concentrated hydrochloric acid or a 50% aqueous solution of sodium hydroxide. .
• the reaction for obtaining the compound of the general formula (31) from the compound of the general formula (29) and the compound of the general formula (30) is carried out, for example, by adding the compound of the general formula (29) and ether to an aqueous sodium hydroxide solution. After that, the reaction is carried out by adding an ether solution of the compound of the general formula (30).
• the protecting group represented by A 3 for example, P - toluenesulfonyl group, benzyl O propoxycarbonyl group, Asechiru group and the like.
• the compound of the general formula (31) is suspended in an acid halogenating agent such as thionyl chloride or oxalyl chloride, and a catalytic amount of dimethylforma is used. This is carried out by stirring at room temperature in the presence of a medium.
• an acid halogenating agent such as thionyl chloride or oxalyl chloride
• the reaction for obtaining the compound of the general formula (34) from the compound of the general formula (32) and the compound of the general formula (33) is performed by dissolving the compound of the general formula (32) in a solvent such as dichloromethane.
• An aqueous solution of the compound of 33) is added, and the mixture is stirred at room temperature in the co-presence of an inorganic base such as sodium carbonate, sodium hydroxide or sodium hydrogen carbonate.
• a compound of the general formula (34) is added to a solution of anisol difunoyl or the like in a hydrogen bromide / acetic acid solution, It is carried out by stirring at 10'C to 60'C, preferably at room temperature.
• the reaction for obtaining the compound of the general formula (35) from the compound of the general formula (34) is performed by converting the compound of the general formula (34) to methanol or It may be performed by dissolving in a solvent such as ethanol or acetic acid, adding palladium-carbon, and then stirring at room temperature in a hydrogen atmosphere.
• the compound of (17) is stirred in a solvent such as dimethyl acetate and dimethylformamide at 0 '(: up to 100'C, preferably at 50 to 60 ° C.
• a solvent such as dimethyl acetate and dimethylformamide
• R 12 and when R 14 is a hydrogen atom is methanol or ethanol in al, te preparative La arsenide Dorofura 1 N-hydroxide Na Application Benefits um aqueous solvent such as emissions addition, 0 'Celsius to 6 0 And, preferably, stirring with 3-5 to obtain the desired product.
• the reaction for obtaining the compound of the general formula (37) from the compound of the general formula (36) is carried out by dissolving the compound of the general formula (36) in a solvent such as an aqueous sodium hydrogencarbonate solution.
• a solvent such as an aqueous sodium hydrogencarbonate solution.
• the mixture is stirred in the presence of an aqueous solution of lithium or the like, or the compound of general formula (36) is suspended in dioxane or the like and stirred in the presence of dichlorosicianobenzoquinone, or a solution of manganese acetate (II) in acetic acid. This is performed by adding the compound of the general formula (36) and stirring.
• the reaction of obtaining a compound of the general formula (38) from a compound of the general formula (29) and a compound of the general formula (17) comprises the reaction of the compound of the general formula (29) and the compound of the general formula (17). It is carried out by stirring in a solvent such as dimethyl acetate amide at 0 to 100 ° C., preferably at 40 to 55 ° C.
• the reaction for obtaining the compound of the general formula (36) from the compound of the general formula (38) and the compound of the general formula (33) is carried out by subjecting the compound of the general formula (38) to jetting. After stirring in a solvent such as dimethylformamide, dimethylacetamide, or N-methylvinylidinone in the presence of cyanidyl diacid dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, the general The reaction is carried out by adding the compound of the formula (33) and stirring the mixture at 0 ° C. to 200 ° C., preferably at 10 ° C. to 80 ° C.
• a solvent such as dimethylformamide, dimethylacetamide, or N-methylvinylidinone
• triethylamine is added to the compound of the general formula (38), and then isobutyl chloroformate is added, followed by stirring in a solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, and the like. Then, the compound of the general formula (33) is added, and the mixture is stirred at 120 to 50, preferably at —10 ⁇ (: to 0. Particularly when R 1 Z is a hydrogen atom. Further, a 1N aqueous solution of sodium hydroxide in a solvent such as methanol or the like is added thereto, and the mixture is stirred at 0 to 60, preferably at room temperature, to obtain the desired product.
• a solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, and the like.
• the reaction for obtaining the compound of the formula (40) from the compound of the formula (39) is carried out by suspending the compound of the formula (39) in an acid halogenating agent such as thionyl chloride, oxalyl chloride, and the like. This is performed by stirring at room temperature in the presence of dimethylformamide.
• an acid halogenating agent such as thionyl chloride, oxalyl chloride, and the like. This is performed by stirring at room temperature in the presence of dimethylformamide.
• the reaction for obtaining the compound of the general formula (42) from the compound of the general formula (41) from the compound of the general formula (41) is carried out by dissolving the compound of the general formula (40) in a solvent such as dichloromethane. The compound is added, and the mixture is stirred at room temperature in the presence of water and an inorganic base such as potassium carbonate, sodium hydroxide, sodium hydrogen carbonate, or the like.
• the reaction for obtaining the compound of the general formula (43) from the compound of the general formula (42) is performed by dissolving the compound of the general formula (42) in a solvent such as acetic acid, adding zinc powder under cooling forever, and stirring at room temperature. Performed by In addition, this reaction is carried out by using iron powder in ethanol-hydrochloric acid, or using hydrogen, methanol and ethanol in tetrahydrofuran, and using hydrogen and hydrogen in a hydrogen atmosphere. It may be carried out by performing lower catalytic reduction.
• the compound of the general formula (43) and the compound of the general formula (47) are preferably 0 to 100 in a solvent such as dimethyl acetate and dimethyl formamide. Is carried out by stirring at 50 to 60 bar.
• examples of the halogen atom represented by X include chlorine and bromine.
• R 15 and R 16 is a hydrogen atom, further main Tano Lumpur or ethanol, te preparative La inhibit mud off la 1 N-hydroxide Na Application Benefits um aqueous solvent such as emissions added
• the desired product is obtained by stirring at 0 to 60 ° C, preferably at 20 to 30 °.
• the compound represented by the general formula ( ⁇ ) obtained by the present invention has an anti-rheumatic effect. This effect was confirmed by examining the following experimental example, “the effect of suppressing lymphocyte proliferation using human peripheral blood”.
• FIG. 1 shows the percentage that the U d R 1 0 0% uptake of.
• FIG. 1 shows the percentage that the U d R 1 0 0% uptake of.
• FIG. 2 and FIG. 3 it was confirmed that the compound of the present invention had a superior lymphocyte proliferation inhibitory action (anti-rheumatic action) than the control compound.
• the compound of Reference Example 4 (700 mg) was added to a 30% solution of hydrogen bromide-acetic acid (7) containing anisol (700 mg), and the mixture was stirred at room temperature for 4 hours. Next, ether was added to the reaction solution, and a red-brown oily substance precipitated. After removing most of the ether layer, the oily substance was suspended in chloroform. This suspension was washed with a saturated sodium hydrogen carbonate solution, and the organic layer was separated. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure to obtain the desired product (360 mg).
• the pH was adjusted to 3.7 with 1 N hydrochloric acid, and the mixture was left in a refrigerator for 2 hours.
• the deposited precipitate was collected by filtration to obtain the desired product (180 mg).
• the solvent was distilled off under reduced pressure to obtain a colorless oily substance (830nig). Then, to the obtained residue (830mg), 30% hydrogen bromide monoacetic acid (10) and anisol (830mg) were added. Was added and the mixture was stirred at room temperature for 3 hours. After the reaction, a large amount of ether was added to the reaction solution, and a dark brown oily substance precipitated. After removing most of the ether layer, the oily substance was suspended in a mouth-mouth form, and the suspension was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product (360 nig).
• the mixture was poured into an aqueous solution of oxygen and extracted with black-mouthed form. After drying the mouth form layer with magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was applied to silica gel chromatography chromatography, and the solvent was eluted with chloroform.
• the compound of Reference Example 9 (9.5 g) was added to a 30% hydrogen bromide-acetic acid (100) solution containing anisol (9.5 g), and the mixture was stirred at room temperature for 4 hours. Next, a large amount of ether was added to the reaction solution, and a red-brown oily substance precipitated. After removing most of the ether layer, the oil was suspended in ⁇ -form. The suspension was washed with a saturated aqueous solution of sodium hydrogencarbonate and extracted with close-form. The mouth form layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product (4.0 g).
• 6-bromomethyl_2,4—diaminobuteridin hydrobromide isopropanol adduct (3.8 g) and 4-methylamino-3-one Tilbenzoic acid (4.8 g) was suspended in dimethyl acetate (50 ⁇ ), stirred at 40 ° C for 4 days, and then stirred at 55 ° C for 2 days.
• the desired product (3.3 g) was obtained.
• the dichloromethane layer was separated, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated aqueous solution of sodium chloride in that order, and dried over sodium sulfate.
• the solvent was distilled off under reduced pressure to obtain the desired product (2.14 g).
• Example 10 The compound of Example 10 (0.59 g) was added to ethanol (40 « ⁇ ) and THF.
• the reaction solution was poured into dilute hydrochloric acid, neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the obtained brown precipitate was collected by filtration.
• the insoluble material was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure.
• the obtained residue was dissolved in methanol (50), 1N aqueous sodium hydroxide solution (20) was added, and the mixture was stirred at 60 rpm for 1 hour. After methanol was distilled off under reduced pressure, insolubles were collected by filtration. Under ice cooling, the pH was adjusted to 4 using 1 N hydrochloric acid.
• the target fraction was concentrated to dryness under reduced pressure and dissolved in methanol (2).
• 1N aqueous sodium hydroxide solution (0.4) was added under ice-cooling and nitrogen atmosphere. The mixture was stirred for 5 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in water, the insolubles were removed by filtration, and the pH was adjusted to 3.5 using 1 N hydrochloric acid. The yellow precipitate was collected by filtration, washed with a small amount of water, and dried in vacuo.
• the compound of Reference Example 28 (3.3 g) was added to an aqueous solution of sodium hydroxide (0.84 g) under a nitrogen atmosphere, ether (60) was added, and the mixture was cooled with ice. Then, an aqueous solution (15) of sodium hydroxide (3.3 g) and an ether solution of benzyloxycarbonyl chloride (6.8) were simultaneously added dropwise, and the mixture was stirred at room temperature for 4 hours. . The one-layer was separated, the aqueous layer was washed with ether, and adjusted to pH 1-2 with 3N hydrochloric acid under ice-cooling. The resulting crystals were filtered by suction, washed with water, and dried by heating to obtain the desired product (5.3 g).
• the target product (3.9 nig) was sampled under the conditions of flow rate: 2.5 / min, column temperature: room temperature, detection wavelength: 303 nm, and injection volume of 200.
• the compound of Reference Example 32 (10. Og) was dissolved in acetic acid (160), and zinc powder (18 g) was slowly added under ice-cooling. After stirring at room temperature for 2 hours, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated solution was dissolved in a black mouth form (200) and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product (7.8 g).
• the compound of Reference Example 34 (5.9 g) was dissolved in acetic acid (100), Under cooling, zinc powder (ll g) was added slowly. After stirring at room temperature for 2 hours, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated solution was dissolved in a porcine (100) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product (7.8 g).
• the desired product (760 mg) was obtained using a mixed solvent of the following:
• methotrexate derivative of the present invention exhibits a superior lymphocyte proliferation inhibitory action as compared with conventionally known compounds, and is therefore extremely useful as a therapeutic agent for rheumatism.

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