Classifications

• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
• • 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]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B55/00—Racemisation; Complete or partial inversion

Definitions

• the present invention relates to 2,2-dimethyl-3-alkylether-4-alkoxy-6- alkyl amino benzopyran derivatives, which effectively inhibit the production of PGE2 that is a prostaglandin-related receptor, or the pharmaceutically available salts thereof; and a PGE2 production inhibitor containing the same, and a pharmaceutical composition for treating inflammation related to PGE2 activity containing the same.
• the present inventors disclose in Korean Patent Application No. 2003- 37562, 2,2-dimethyl-3-ester-4-alkoxy-6-alkyl amino benzopyran and its preparation according to parallel synthesis on solid phase. More specifically, in the above application, 2,2-dimethyl-3-ester-4-alkoxy-6-alkyl amino benzopyran is effectively synthesized, using solid-phase combinational chemistry technology, and its medical use for preventing and treating brain nerves is disclosed.
• aminobenzopyran compound was designed having various hydrogen bond acceptors that can eliminate oxidative radicals, such as the above benzopyran compound having hydroxyl group, and various alkyl ether groups introduced at position 3; and was synthesized. Further, based on the fact that there has been no report that the compound inhibits the production of prostaglandin E2 (hereinafter called "PGE2"), animal tests were conducted with the prepared aminobenzopyran compound with various alkyl ethers introduced at position 3, using human-originated dermal cells and animals such as mice, and confirming that the compound has an excellent inflammation inhibition effect. Based on these findings, the present invention was completed.
• the present invention provides 2,2-dimethyl-3-alkylether-4-alkoxy-6- alkyl amino benzopyran derivatives or the pharmaceutically acceptable salts thereof.
• the present invention provides a PGE2 production inhibitor containing the 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkyl amino benzopyran derivatives or the pharmaceutically acceptable salts thereof, as an effective ingredient; and a use of the compound for preventing and treating the inflammation related to PGE2 activity.
• 2,2-dimethyl-3-alkylether-4-alkoxy-6- alkyl amino benzopyran derivatives or the pharmaceutically acceptable salts thereof are provided by the combinational chemistry technology on solid phase.
• PGE2 production inhibitors containing the above derivatives as an effective ingredient are provided, and further their use as a therapeutic for inflammation related to PGE2 activity is provided.
• the present invention provides 2,2-dimethyl-3-alkylether-4-alkoxy-6- alkyl amino benzopyran derivatives represented by the following formula (1) or the pharmaceutically available salts thereof: [Formula 1]
• R 1 and R 2 which are the same or different from each other, are selected from the group consisting of C]-Ci 0 linear, branched or cyclic alkyl, benzyl, substituted benzyl and penethyl; and
• R 3 is one selected from the group consisting of hydrogen atom, C]-C] 0 alkyl, C 2 -C] 0 alkenyl, C 2 -C] 0 alkynyl, benzyl, substituted benzyl and naphtylmethyl; in which the substituted benzyl is substituted with 1 to 4 substituents selected from the group consisting of halogen atom, nitro, C]-C] 0 alkyl, C]-C] 0 alkoxy and Ci-C] 0 haloalkyl.
• the 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkyl amino benzopyran derivatives according to the present invention comprise the racemic compound or the isomer thereof.
• R 1 and R 2 which are the same or different from each other, are selected from the group consisting OfC]-C 10 alkyl, benzyl, substituted benzyl, and penethyl; and R 3 is one selected from the group consisting of hydrogen atom, Cj-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, benzyl, substituted benzyl, and naphtylmethyl; in which the substituted benzyl is substituted with 1 to 4 substituents selected from the group consisting of halogen atom, nitro, C]-C 4 alkyl, Ci-C] 0 alkoxy and C]-C 4 haloalkyl.
• the present invention provides a PGE2 production inhibitor comprising as an effective ingredient the 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkyl amino benzopyran derivatives of the formula (1) or the pharmaceutically available salts thereof.
• the PGE2 production inhibitor comprises as an effective ingredient the racemic compound or the isomer of the 2,2-dimethyl-3-alkylether-4-alkoxy-6- alkyl amino benzopyran derivatives.
• the present invention provides a pharmaceutical composition for treating the inflammation related to PGE2 activity, comprising as an effective ingredient the 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkylamino benzopyran derivatives of the formula (1) or the pharmaceutically available salt thereof.
• the pharmaceutical composition for treating the inflammation related to PGE2 activity comprises as an effective ingredient the racemic compound or the isomer of the 2,2-dimethy 1-3 -alley lether-4-alkoxy-6-alkyl amino benzopyran derivatives.
• the 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkyl amino benzopyran derivatives of the above formula (1) can be obtained by combinational chemistry synthesis technology using solid-phase combinational chemistry technology.
• reaction scheme 1 The process for preparing the 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkyl amino benzopyran derivatives of the above formula (1), using combinational chemistry technology, may be exemplified by the following reaction scheme 1 : [Reaction scheme 1]
• R 1 , R 2 and R 3 are as defined in the above, and ® is a polymer support selected from the group consisting of polystyrene-divinyl benzene, methacrylic acid-dimethylacrylamide and hydroxyl methacrylic acid.
• reaction scheme 1 comprises the steps of: Selectively introducing alkyl substituent to nitrogen atom of the benzopyran of the formula (2), to prepare N-alkyl substituted carbamate resin of the formula (3);
• 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran resin of the formula(4) and 2,2-dimethyl-3-alkylether-4-alkoxy-6- alkyl amino benzopyran resin of the formula (5), which are the reaction intermediates, are optical isomers, thus, if desired, each of the isomer compounds can be separated. Since the combinational chemistry technology in order to effectively prepare the above amino benzopyran derivatives using parallel synthesis on the solid-phase is described in Korean Laid-Open Publication No. 2003-37668, the details of the preparation of the above 2,2-dimethyl-3-alkylether-4-alkoxy- 6-alkyl amino benzopyran derivatives is omitted.
• a PGE2 production inhibitor comprising as an effective ingredient the 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkyl amino benzopyran derivatives of the formula (1) or the pharmaceutically available salt thereof is provided.
• a pharmaceutical composition for treating inflammation disease related to PGE2 activity comprising as an effective ingredient the 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkyl amino benzopyran derivatives of the formula (1) or the pharmaceutically available salt thereof, is provided.
• the 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkyl amino benzopyran derivatives of the formula (1) are optical isomer compounds, thus each isomer can be separated by the conventional method.
• chiral carbon is present in the 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkyl amino benzopyran derivatives of the formula (1) at positions 3 and 4, their racemic compounds can be separated using the conventional method.
• the PGE2 production inhibitor and the pharmaceutical composition according to the present invention may contain the isomer compounds or the racemic compounds of the 2,2-dimethyl-3-alkylether-4- alkoxy-6-alkyl amino benzopyran derivatives.
• the pharmaceutically available salt according to the present invention may be prepared by the conventional method in the art, for example, pharmaceutically available salt of the inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium acid sulfate, phosphoric acid and carbonic acid; salt of the organic acid such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid or acetylsalicylic acid (aspirin); metallic salt formed from the reaction with alkali metal ion such as sodium or potassium ion; or salt formed from the reaction with ammonium ion.
• pharmaceutically available salt of the inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium acid sulfate, phosphoric acid and carbonic acid
• salt of the organic acid such as formic acid, acetic acid, oxalic acid
• the pharmaceutical composition of the present invention can be formulated into conventional formulations in the art, for example, oral formulation such as tablet, capsule, troche, drink or emulsion, or non-oral formulation, by adding the conventional non-toxic, pharmaceutically available carrier, supplement and excipient thereto.
• oral formulation such as tablet, capsule, troche, drink or emulsion, or non-oral formulation
• the administration dose of the compound of the present invention to the human body may depend on a subject's age, weight, sex, administration type, health state and disease state. On the basis of an adult whose weight is 70 kg, the dose is 0.01-1,000 mg/ml, and can be administered one to several times per day according to the judgment of a doctor or pharmacist.
• Step 1 N-Methylation of 2,2-dimethyl-3,4-dihvdro-6-amino benzopyran carbamate resin (formula (2))
• Carbamate resin in the form of benzopyren of the formula (2) (200.00 mg, 0.12 mmol) was added to dimethylsulfoxide (DMSO)(3 ml), and stirred for 10 minutes at room temperature, then IM of lithium-t-butoxide (LiOtBu; 0.36 ml, 0.36 mmol) dissolved in THF) was added thereto, and shaken for 20 minutes at the same temparature. Iodomethane (MeI; 0.051 ml, 0.36 mmol) was added thereto and shaken for 15 hours at 35°C for reaction.
• N-methyl substituted carbamate resin of the formula (3-1) was filtered, and washed repeatedly with DMF, DCM, DCM/MeOH and MeOH to obtain N-methyl substituted carbamate resin of the formula (3-1) as a light-brown solid (ATR-FTIR; N-methylation carbamate: 1700 cm "1 ).
• Step 4 Eliminated reaction of 2,2-dimethyl-3-benzylether-4-methoxy- 6- methyl amino benzopyran carbamate resin (formula (5-1))
• Resin of the formula (5-1) (200 mg) was added to dichloromethane (5 ml), and thereto trifluoroacetic acid (TFA, 1 ml) was added and the mixture shaken for 3 hours. After reaction, the reaction mixture was filtered and washed repeatedly with DCM and MeOH. The combined filtrate was concentrated in vacuo. Thereto, ethyl acetate (3 ml) was added, and filtered to strong anion exchange (SAX) resin to remove residual TFA..
• SAX strong anion exchange
• the inflammation inhibition test is to determine the extent to which the 2-2-dimethyl-3-alkylether-4-alkoxy-6-alkyl amino benzopyran derivatives prepared in the above examples 1-101 lower the level of PGE2 at cell level, which is the index of the inflammation.
• TPA (12-O-tetradecanoylphobol-13- acetate), which is the oncogene used in this example, is the material which infiltrates leucocyte at epidermis and dermis, inducing inflammation, and thereby inducing tumor through epidermal proliferation, pursuant to the application concentration and time, as in the case of local administration to a mouse.
• NHF normal human fibroblast, 5 x 10 5 /plate
• test materials that are expected to be inflammation inhibition agents, with 5 different concentrations in which the highest concentration is set to 500 nM, and with the common ratio set to 10, and then was cultivated for 30 minutes at 37°C, 5% CO 2 .
• the cell was then treated with TPA for 18 hours, and the cultured medium supernatant was obtained and PGE2 ELISA assay performed.
• the inflammation inhibition effect was compared using the IC 50 value, which is the concentration required to reduce the level of PGE2 in the test material- treated group to 50% of the PGE2 level prepared by TPA in the untreated group.
• the inflammation inhibition ratio shows 100% in all of the test groups, and the excellent PGE2 synthesis inhibition effect was confirmed by its IC 50 result. Therefore, the 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkyl amino benzopyran derivatives can be used as novel therapeutics for inflammation disease related to PGE2 activity.
• Injection agent containing 100 mg of the compound of the formula (1), as an effective ingredient, 180 mg of mannitol, 26 mg of Na 2 HPO 4 * 12H 2 O and 2,974 mg of distilled water was prepared.

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Citations (4)

• 2005
  • 2005-05-28 KR KR1020050045294A patent/KR100673974B1/ko active IP Right Grant
• 2006
  • 2006-05-26 CN CNA2006800187736A patent/CN101184745A/zh active Pending
  • 2006-05-26 WO PCT/KR2006/002023 patent/WO2007001119A1/en active Application Filing
  • 2006-05-26 JP JP2008513383A patent/JP2008542262A/ja not_active Withdrawn

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