WO2006041015A1 - Dérivé d’aminoalcool, sel d’addition dudit dérivé, et agent immunosuppresseur - Google Patents

Dérivé d’aminoalcool, sel d’addition dudit dérivé, et agent immunosuppresseur Download PDF

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Publication number
WO2006041015A1
WO2006041015A1 PCT/JP2005/018560 JP2005018560W WO2006041015A1 WO 2006041015 A1 WO2006041015 A1 WO 2006041015A1 JP 2005018560 W JP2005018560 W JP 2005018560W WO 2006041015 A1 WO2006041015 A1 WO 2006041015A1
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group
general formula
immunosuppressive agent
carbon atoms
chemical
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PCT/JP2005/018560
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Japanese (ja)
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Yasushi Kohno
Naoki Ando
Kazuhiko Kuriyama
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Kyorin Pharmaceutical Co., Ltd.
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Publication of WO2006041015A1 publication Critical patent/WO2006041015A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton

Definitions

  • the present invention relates to an amino alcohol derivative useful as an immunosuppressant, an addition salt thereof, and a hydrate thereof.
  • Immunosuppressants are used to treat allergic diseases such as rheumatoid arthritis, nephritis, osteoarthritis, systemic lupus erythematosus, chronic inflammatory diseases such as Crohn's disease, chronic inflammatory diseases such as inflammatory bowel disease, asthma and dermatitis. It is used in many ways as a medicine. In particular, with the advancement of medical technology, in recent medical practice where many transplant operations for tissues and organs have been carried out, can rejection control after transplantation be controlled well? However, immunosuppressants play a very important role in this area as well.
  • the 2-amino-1,3-propanediol derivative as an immunosuppressant has the power disclosed in Patent Document 1 and Patent Document 2 and has a diarylsulfide group or a diaryl ether group, which is a feature of the present invention. It is known that amino alcohol derivatives have an excellent immunosuppressive effect. It wasn't.
  • Patent Document 3 Patent Document 4, Patent Document 5, Patent Document 6, and Patent Document 10 disclose that 2_amino-ethanol derivatives exhibit an immunosuppressive action. It is different.
  • an aminoalcohol derivative having a diarylsulfide group or a diarylether group which is structurally similar to the compound of the present application, is disclosed in Patent Document 7, Patent Document 8, and Patent Document 9, but the present application It does not include compounds having a substituent only at the para position of the terminal aryl group that is characteristic of the compound.
  • Patent Document 1 Pamphlet of WO94 / 08943
  • Patent Document 2 JP-A-9 2579602
  • Patent Document 3 Pamphlet of WO02 / 06268
  • Patent Document 4 Japanese Patent Laid-Open No. 2002-53575
  • Patent Document 5 Japanese Unexamined Patent Publication No. 2002-167382
  • Patent Document 6 Japanese Unexamined Patent Publication No. 2002-316985
  • Patent Document 7 WO03 / 029205 pamphlet
  • Patent Document 8 WO03 / 029184 pamphlet
  • Patent Document 9 WO04 / 026817 pamphlet
  • Patent Document 10 WO04 / 024673 pamphlet
  • the problem to be solved by the present invention is to provide an amino alcohol derivative having an excellent immunosuppressive action and few side effects.
  • the present inventors have found that the immunosuppressive agents known so far are structurally A novel alumino alcohol derivative having a diarylsulfide group or a diaryl ether group having a different valence, particularly a carbon chain containing an aminoamino unit at the para position of one of the aryl groups, and the other end
  • the present invention was completed by finding that a compound having a substituent at the para position of the side aryl group has a strong immunosuppressive action. That is, the present invention relates to
  • R is a halogen atom, a trifluoromethyl group, a hydroxy group, or a lower alkyl having 1 to 4 carbon atoms.
  • R represents a hydrogen atom, a halogen atom or a trifluoromethyl group
  • R is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkenyl group having 2 to 4 carbon atoms.
  • X represents ⁇ , S, SO or SO
  • n represents an integer of 1 to 4]
  • aminoamino derivative according to 1) a pharmacologically acceptable salt thereof and a hydrate thereof, characterized in that
  • R is a chlorine atom.
  • the compound represented by the general formula (1) is: (1) 2-Amino-2- [4- (4-Benzyloxyphenoxy) 1-2-cyclophenyl] propinole_ 1,3_propanediol,
  • R is a halogen atom, a trifluoromethyl group, a hydroxy group, or a lower alkyl having 1 to 4 carbon atoms.
  • R represents a hydrogen atom, a halogen atom or a trifluoromethyl group
  • R is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkenyl group having 2 to 4 carbon atoms.
  • X represents ⁇ , S, SO or SO
  • n represents an integer of 1 to 4]
  • An immunosuppressive agent comprising at least one of the amino alcohol derivative represented by the formula: [0020] 6)
  • the compound represented by the general formula (1) is a compound represented by the general formula (la)
  • An immunosuppressive agent characterized by comprising as an active ingredient at least one of the amino alcohol derivatives and pharmacologically acceptable salts and hydrates thereof according to 5), which are compounds represented by:
  • the immunosuppressive agent is a prophylactic or therapeutic agent for autoimmune diseases such as inflammatory bowel disease, systemic lupus erythematosus (SLE), and Crohn's disease. 5) or 6) Immunosuppressants,
  • the present invention relates to a novel amino alcohol derivative, in particular, a diarylsulfur having a carbon chain containing an amino alcohol unit at the para position of one aryl group and a substituent at the para position of the other aryl group.
  • idyadiaryl ether derivatives have a strong immunosuppressive action.
  • immunosuppressive compounds are used as preventive or therapeutic agents for rejection in S container transplantation and bone marrow transplantation, as well as prophylactic or therapeutic agents for autoimmune diseases such as inflammatory bowel disease, systemic lupus erythematosus, and Crohn's disease.
  • Rheumatoid arthritis It is useful as a prophylactic or therapeutic agent for psoriasis, a prophylactic or therapeutic agent for psoriasis or atopic dermatitis, and a prophylactic or therapeutic agent for tracheal asthma or hay fever.
  • the pharmacologically acceptable salt of the compound represented by the general formula (1) in the present invention includes hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, Examples include acid addition salts such as citrate and tartrate.
  • halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and represents “a lower alkyl group having 1 to 4 carbon atoms”
  • “Lower alkyl group” such as “1 to 4 lower alkoxy group” means, for example, straight chain or branched hydrocarbon having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, ptyl, t_butyl, etc. S.
  • “Lower alkenyl group having 2 to 4 carbon atoms” refers to a buyl group, an aryl group, a 1_propenyl group, an isopropenyl group, a 1-buturyl group, a 2-butyr group, a 2-methynolelinole group, and a 3-butenyl group. And hydrocarbons having 2 to 4 carbon atoms and having an unsaturated double bond.
  • the “optionally substituted phenyl group” and “optionally substituted phenoxy group” are halogens such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom at any position on the benzene ring.
  • Examples thereof include an atom, a trifluoromethyl group, a lower alkyl group having 1 to 4 carbon atoms, and a lower alkoxy group having!
  • Examples of the “aralkyl group” in the “aralkyl group” and “aralkyloxy group” include a benzyl group, a diphenylmethyl group, a phenethyl group, and a phenylpropyl group.
  • R is a hydrogen atom or a hydride.
  • the compound represented by can be produced, for example, by the route shown below.
  • R represents a lower alkyl group having 1 to 4 carbon atoms
  • Boc represents a t-butoxycarbonyl group.
  • Y represents a chlorine atom, a bromine atom or an iodine atom
  • R, R, X and n represent the same as those described above.
  • step A In the presence of a base (step A). -Do
  • the reaction uses methanol, ethanol, 1,4-dioxane, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF), etc. as a reaction solvent, sodium hydride, potassium hydride,
  • DMSO dimethyl sulfoxide
  • DMF N-dimethylformamide
  • THF tetrahydrofuran
  • the reaction can be carried out at a reaction temperature of 0 ° C. to heating under reflux, preferably 80 ° C. to 100 ° C.
  • step A-2 Can be produced by reducing the compound represented by the general formula (3) (step A-2).
  • reaction is carried out using an alkylborane such as borane (BH) or 9-borabicyclo [3.3.1] nonane (9-BBN).
  • alkylborane such as borane (BH) or 9-borabicyclo [3.3.1] nonane (9-BBN).
  • Metal hydride complex compounds such as lithium aluminum hydride (UA1H), preferably borohydride
  • Lithium lithium LiBH is used, and THF, ethanol, methanol, etc. are used as the reaction solvent.
  • the reaction temperature may be -78 ° C to under reflux with heating, preferably at room temperature.
  • the compound represented by the general formula (lb) in the synthesis route A can be produced by acidolysis of the compound represented by the general formula (4) (step A-3).
  • the reaction may be carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or an organic such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • the reaction can be carried out in a mixed solution with a solvent and the reaction temperature can be from 0 ° C to room temperature.
  • the compound represented by can also be produced by the following synthetic route.
  • the reaction uses methanol, ethanol, 1,4-dioxane, DMS0, DMF, THF, etc. as a reaction solvent, in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, etc.
  • the reaction temperature may be 0 ° C to heating under reflux, preferably 80 ° C to 100 ° C.
  • step B-2 Can be produced by reducing the compound represented by the general formula (7) (step B-2).
  • the reaction may be alkyl borane derivatives such as BH and 9-BBN, iBu A1H, NaBH, LiAlH, etc.
  • reaction temperature is -78 ° C to under reflux, preferably at room temperature That power S.
  • M represents a carbon atom or a key atom
  • R, R, Boc and n are as described above
  • the compound represented by general formula (12) is a compound represented by the general formula (12).
  • R represents a lower alkyl group having 1 to 4 carbon atoms, and R is as described above.
  • R represents a chlorine atom or a trifluoromethanesulfoxyloxy group
  • step B_3 It can be produced by reacting a compound represented by 7 4 ways] (step B_3).
  • the reaction with the compound represented by the general formula (12) or the general formula (13) may be carried out in the presence of a Lewis acid such as zinc chloride or camphorsulfonic acid, p-toluenesulfonic acid, pyridinium p- In the presence of a catalyst such as toluene sulfonate, no solvent or DMF, THF, methyl chloride
  • a Lewis acid such as zinc chloride or camphorsulfonic acid, p-toluenesulfonic acid, pyridinium p-
  • a catalyst such as toluene sulfonate, no solvent or DMF, THF, methyl chloride
  • the reaction temperature can be from room temperature to 100 ° C.
  • reaction with the general formula (14) is carried out using triethinoleamine, pyridine, 2,6-lutidine, imidazole, black mouth form, and acetonitrile, and the reaction temperature is 0 ° C to 100 °. Can be done in C.
  • the reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon, etc., in a solvent such as ethanol, methanol, THF, DMF, ethyl acetate, etc. under normal pressure to pressure. Under a hydrogen pressure of room temperature to 100 ° C.
  • a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon, etc.
  • reaction is carried out using methylene chloride as a reaction solvent in the presence of a base such as triethylamine. It is preferable that copper acetate is allowed to act at ordinary temperature in the presence or absence of molecular mouth and molecular weight.
  • the compound represented by the general formula (lc) is produced by acid-decomposing the compound represented by the general formula (11) or by acid-decomposing after desilylation. (Step B-6).
  • the reaction is carried out in an inorganic acid or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, certain methanol, ethanol, THF, 1,4-dioxane, ethyl acetate, etc.
  • the reaction temperature is 0 ° C to room temperature.
  • M in the general formula (10) is a key atom
  • THF, DMF 1,4_dioxane or the like is used as a solvent
  • potassium fluoride, cesium fluoride, tetraptyl ammonium fluoride are used.
  • R represents a t-butyldimethylsilyl group or a methoxymethyl group
  • R, Boc and n are as defined above
  • the reaction may be carried out in the presence of an organic base such as triethylamine or diisopropylethylamine, using DMF, THF, or methylene chloride as a reaction solvent at a reaction temperature of 0 ° C to room temperature. I'll do it.
  • an organic base such as triethylamine or diisopropylethylamine
  • the compound represented by general formula (9 ′) can be produced by hydrogenolysis of the compound represented by the general formula (9 ′) (step B-4 ′).
  • the reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon, etc., in a solvent such as ethanol, methanol, THF, DMF, ethyl acetate, etc. under normal pressure to pressure. Under a hydrogen pressure of room temperature to 100 ° C.
  • a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon, etc.
  • Step B-5 ′ It can be produced by reacting the compound represented by the general formula (15) in the presence of the compound represented by the following formula and copper acetate (Step B-5 ′).
  • copper acetate is allowed to act at ordinary temperature in the presence of a base such as triethylamine, using methylene chloride or black mouth form as a reaction solvent, and in the presence or absence of molecular sieves. It is preferable.
  • the compound represented by the general formula (lc ') is produced by acid-decomposing the compound represented by the general formula (11') or by acidolysis after desilylation. (Step B-6 ').
  • the reaction is carried out in an inorganic acid or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, certain methanol, ethanol, THF, 1,4-dioxane, ethyl acetate, etc.
  • the reaction temperature is 0 ° C to room temperature.
  • step C_l Can be produced by hydrogenolysis of the resulting compound (step C_l).
  • the reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon, etc. in a solvent such as ethanol, methanol, THF, DMF, ethyl acetate, etc. under normal pressure to pressurized pressure. Under a hydrogen pressure of room temperature to 100 ° C.
  • a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon, etc.
  • a solvent such as ethanol, methanol, THF, DMF, ethyl acetate, etc.
  • copper acetate is allowed to act at normal temperature in the presence of a base such as triethylamine, using methylene chloride or black mouth form as a reaction solvent, and in the presence or absence of molecular sieves. It is preferable.
  • step C_3 Can be produced by reducing the compound represented by the general formula (17) (step C_3).
  • Reactions include alkylborane derivatives such as BH and 9-BBN, iBu A1H, NaBH, LiAlH, etc.
  • the reaction temperature is from ⁇ 78 ° C. to heating under reflux, preferably at room temperature.
  • the compound represented by the general formula (1d) can be produced by acidolysis of the compound represented by the general formula (18) (step C-4). .
  • the reaction may be carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, certain alcohol, methanol, ethanol, THF, 1,4-dioxane, ethyl acetate, etc.
  • the reaction temperature is 0 ° C to room temperature.
  • R is a lower alkyl group having 1 to 4 carbon atoms or carbon
  • R represents a lower alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms.
  • the reaction uses methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, etc. as a reaction solvent, in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, etc.
  • the reaction temperature may be 0 ° C to heating under reflux, preferably 80 ° C to 100 ° C.
  • the reaction uses methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, etc. as a reaction solvent, in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, etc.
  • the reaction temperature may be 0 ° C to heating under reflux, preferably 80 ° C to 100 ° C.
  • the reaction uses methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, etc. as a reaction solvent, in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, etc.
  • the reaction temperature can be 0 ° C to under reflux with heating, preferably 80 ° C to 100 ° C.
  • the reaction was carried out using methanol, ethanol, 1,4 dioxane, DMF, DMSO, etc. as the reaction solvent in the presence of a base such as sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or lithium hydroxide aqueous solution, and the reaction temperature was It can be carried out at 0 ° C to heating under reflux. Further, it is preferable to use potassium hydroxide in an ethanol solvent at 50 ° C.
  • a base such as sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or lithium hydroxide aqueous solution
  • the compound represented by 20) can be produced by rearranging the Curtius (Step D 15).
  • a general method for converting a carboxyl group into a strong rubamate can be used, for example, a method using chloroethyl carbonate and NaN, or preferably diphenyl phosphate azide.
  • Reactions include alkylborane derivatives such as BH and 9-BBN, iBu A1H, NaBH, LiAlH, etc.
  • the reaction temperature is from ⁇ 78 ° C. to heating under reflux, preferably at room temperature.
  • the compound represented by the general formula (le) in the synthesis route D can be produced by acid-decomposing or alkali-hydrolyzing the compound represented by the general formula (22) (step D). — 7).
  • the reaction may be carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or an organic compound such as methanol, ethanol, THF, 1,4 dioxane, or ethyl acetate. It can be applied in a mixed solution with a solvent, and the reaction temperature can be from 0 ° C to room temperature. Alternatively, methanol, ethanol, 1,4-dioxane, DMS ⁇ , DMF, THF, etc.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid
  • an organic compound such as methanol, ethanol, THF, 1,4 dioxane, or ethyl acetate. It can be applied in a mixed solution with a solvent, and the reaction temperature can be from 0 ° C to room temperature.
  • reaction solvents are used as reaction solvents, and in the presence of a base such as aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous lithium hydroxide, etc., the reaction temperature is The reaction can be carried out at 0 ° C. to heating under reflux, preferably at 80 to 100 ° C.
  • a base such as aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous lithium hydroxide, etc.
  • a compound in which X is SO or SO is a compound in which the corresponding X is S.
  • the reaction uses 1,4-dioxane, DMSO, DMF, THF, methylene chloride, black mouth form, etc. as the reaction solvent, and potassium permanganate, methacro mouth perbenzoic acid, hydrogen peroxide water as the oxidizing agent. Can be carried out at 0 ° C. to under reflux with heating, preferably at room temperature.
  • the target product was obtained as a pale yellow powder by reacting the compound of Reference Example 1 in the same manner as in Reference Example 3.
  • Example 5 (1.23 g) in toluene (40 mL) and tetrakistriphenylphosphine palladium (179 mg), phenylboric acid (452 mg) in ethanol (5 mL), 2 mol / L_Na CO aqueous solution (8.7 mL)
  • Reference Example 13 was reduced with NaBH under ice-cooling, and alcohol was used as in Reference Example 9.
  • the target product was obtained as a pale yellow oil.
  • Example 8 (147 mg) was dissolved in methanol (3 mL), 10% HCt AcOEt (3 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was concentrated to obtain the desired product (119 mg) as a colorless amorphous.
  • arylozide (5.21 mL) was added and stirred for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and then saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (hexane:
  • Example 29 To a solution of Example 29 (1.22 g) in benzene (15.0 mL) were added triethylamine (0.42 mL) and diphenyl phosphate azide (550 x L), and the mixture was heated to reflux for 40 minutes. The mixture was returned to room temperature, a methanol (15 mL) solution and sodium methoxide (251 mg) were added, and the mixture was heated to reflux for 1.5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate.
  • lithium borohydride (281 mg, 12.90 mmol) was added to a solution of Example 30 (1.43 g) in tetrahydrofuran (15 mL), ethanol (0.75 mL) was added dropwise, and the mixture was stirred for 3 hr. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (hexane
  • Example 31 To a solution of Example 31 (1.10 g) in dimethyl sulfoxide (14 mL) was added 5 moL / L_potassium hydroxide aqueous solution (14 mL) and ImoL / L-lithium hydroxide aqueous solution (7 mL), and 100 ° Heating stirring at C for 17 hours Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (aminated silica,
  • Example 32 (50 mg) was dissolved in a 10% hydrochloric acid methanol solution, and after 30 minutes, the solvent was distilled off to obtain the desired product (53.8 mg) as a colorless amorphous substance.
  • test compound was intraperitoneally administered once a day for a total of 4 times daily, from the day of stimulation cell injection to 3 days later.
  • a solvent having the same composition as that used for the preparation of the test compound was administered. Table 5 shows.
  • the inhibition rate was calculated using the following formula.
  • the compound of the present invention represented by the general formula (1) is used in an animal experiment model. The effectiveness of was confirmed.
  • the present invention provides a novel amino alcohol derivative, particularly a carbon chain containing an amino alcohol unit at the para position of one aryl group, and a substituent at the para position of the other aryl group.
  • dialyl sulfydya dialyl ether derivatives have a strong immunosuppressive action.
  • Compounds having such immunosuppressive action are drugs for preventing or treating rejection in organ transplantation and bone marrow transplantation, drugs for preventing or treating autoimmune diseases such as inflammatory bowel disease, systemic lupus erythematosus, and Crohn's disease.
  • prophylactic or therapeutic agent for rheumatoid arthritis, a prophylactic or therapeutic agent for psoriasis or atopic dermatitis, and a prophylactic or therapeutic agent for bronchial asthma or hay fever.

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  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention décrit un dérivé d’aminoalcool présentant un excellent effet immunosuppresseur, et peu d'effets secondaires. La présente invention décrit plus spécifiquement un dérivé d’aminoalcool de formule générale (1) suivante : (1) (les exemples précis de dérivés d’aminoalcool peuvent inclure le 2-amino-2-[4-(4-benzyloxyphénoxy)-2-chlorophényl]propyl-1,3-propanediol).
PCT/JP2005/018560 2004-10-12 2005-10-06 Dérivé d’aminoalcool, sel d’addition dudit dérivé, et agent immunosuppresseur WO2006041015A1 (fr)

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WO2008018447A1 (fr) 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Dérivé d'aminoalcool et immunodépresseur le contenant en tant que principe actif
WO2008018427A1 (fr) 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Dérivé d'ester de l'acide aminophosphorique et modulateur du récepteur s1p contenant ledit dérivé en tant que principe actif
WO2008099781A1 (fr) * 2007-02-13 2008-08-21 Kyorin Pharmaceutical Co., Ltd. Agent thérapeutique ou prophylactique pour une maladie démyélinisante comprenant un dérivé d'amino alcool comme ingrédient actif
WO2009099174A1 (fr) * 2008-02-07 2009-08-13 Kyorin Pharmaceutical Co., Ltd. Agent thérapeutique ou agent préventif pour maladie inflammatoire des intestins contenant un dérivé d'alcool aminé comme composant actif
WO2009142195A1 (fr) * 2008-05-20 2009-11-26 杏林製薬株式会社 Agent d’induction/d’entretien de rémission
US7781617B2 (en) 2004-07-16 2010-08-24 Kyorin Pharmaceutical Co., Ltd Effective use method of medicaments and method of preventing expression of side effect
US7795472B2 (en) 2004-10-12 2010-09-14 Kyorin Pharmaceutical Co., Ltd. Process for producing 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride and hydrates thereof, and intermediates in the production thereof
EP2359821A1 (fr) * 2004-11-29 2011-08-24 Novartis AG Posologie d'un agoniste du recepteur s1p
US8048928B2 (en) 2005-10-07 2011-11-01 Kyorin Pharmaceutical Co., Ltd. Therapeutic agent for treating liver disease containing 2-amino-1,3-propanediol derivative as active ingredient, and method for treating liver disease
US8318811B2 (en) 2006-02-06 2012-11-27 Kyorin Pharmaceutical Co., Ltd. Method for treating an inflammatory bowel disease using 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediol or a salt thereof
CN102863345A (zh) * 2011-07-06 2013-01-09 中国医学科学院药物研究所 胺基丙二醇类衍生物、其制备方法和其药物组合物与用途
US20130172297A1 (en) * 2010-05-06 2013-07-04 Novartis Ag Treatment of Autoimmune Diseases
US20130210924A1 (en) * 2010-05-06 2013-08-15 Novartis Ag Dosage Regimen of Diaryl Sulfide Derivatives
CN104844486A (zh) * 2014-02-17 2015-08-19 中国医学科学院药物研究所 胺基丙二醇类衍生物、其制备方法和其药物组合物与用途
WO2016013225A1 (fr) * 2014-07-24 2016-01-28 杏林製薬株式会社 Procédé de fabrication de dérivé de diphénylsulfure, et intermédiaire de production
US10251867B2 (en) 2008-03-17 2019-04-09 Actelion Pharmaceuticals Ltd. Dosing regimen for a selective S1P1 receptor agonist

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WO2002094770A2 (fr) * 2001-05-24 2002-11-28 Fujisawa Pharmaceutical Co., Ltd. Derives d'amino-alcool

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US7781617B2 (en) 2004-07-16 2010-08-24 Kyorin Pharmaceutical Co., Ltd Effective use method of medicaments and method of preventing expression of side effect
US7807854B2 (en) 2004-07-16 2010-10-05 Kyorin Pharmaceutical Co., Ltd. Effective use method of medicaments and method of preventing expression of side effect
JP4792400B2 (ja) * 2004-10-12 2011-10-12 杏林製薬株式会社 ２−アミノ−２−［２−［４−（３−ベンジルオキシフェニルチオ）−２−クロロフェニル］エチル］−１，３−プロパンジオール塩酸塩又はその水和物の製造方法及びその製造中間体
US7795472B2 (en) 2004-10-12 2010-09-14 Kyorin Pharmaceutical Co., Ltd. Process for producing 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride and hydrates thereof, and intermediates in the production thereof
EP2359821A1 (fr) * 2004-11-29 2011-08-24 Novartis AG Posologie d'un agoniste du recepteur s1p
US8048928B2 (en) 2005-10-07 2011-11-01 Kyorin Pharmaceutical Co., Ltd. Therapeutic agent for treating liver disease containing 2-amino-1,3-propanediol derivative as active ingredient, and method for treating liver disease
US8318811B2 (en) 2006-02-06 2012-11-27 Kyorin Pharmaceutical Co., Ltd. Method for treating an inflammatory bowel disease using 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediol or a salt thereof
JP5188972B2 (ja) * 2006-08-08 2013-04-24 杏林製薬株式会社 アミノリン酸エステル誘導体及びそれらを有効成分とするｓ１ｐ受容体調節剤
WO2008018427A1 (fr) 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Dérivé d'ester de l'acide aminophosphorique et modulateur du récepteur s1p contenant ledit dérivé en tant que principe actif
EP2058317A4 (fr) * 2006-08-08 2011-06-29 Kyorin Seiyaku Kk Dérivé d'ester de l'acide aminophosphorique et modulateur de récepteur s1p contenant le dit dérivé en tant que principe actif
CN101506145B (zh) * 2006-08-08 2013-05-29 杏林制药株式会社 氨基醇衍生物以及将它们作为有效成分的免疫抑制剂
EP2058317A1 (fr) * 2006-08-08 2009-05-13 Kyorin Pharmaceutical Co., Ltd. Dérivé d'ester de l'acide aminophosphorique et modulateur de récepteur s1p contenant le dit dérivé en tant que principe actif
KR101339976B1 (ko) 2006-08-08 2013-12-10 교린 세이야꾸 가부시키 가이샤 아미노인산에스테르 유도체 및 그들을 유효성분으로 하는 ｓ1ｐ 수용체 조절제
US8232319B2 (en) 2006-08-08 2012-07-31 Kyorin Pharmaceutical Co., Ltd. Amino phosphate derivative and S1P receptor modulator having same as an active ingredient
US8273748B2 (en) 2006-08-08 2012-09-25 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivative and immunosuppresive agent having same as an active ingredient
WO2008018447A1 (fr) 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Dérivé d'aminoalcool et immunodépresseur le contenant en tant que principe actif
CN101501049B (zh) * 2006-08-08 2013-04-24 杏林制药株式会社 氨基磷酸酯衍生物以及将它们作为有效成分的s1p受体调节剂
WO2008099781A1 (fr) * 2007-02-13 2008-08-21 Kyorin Pharmaceutical Co., Ltd. Agent thérapeutique ou prophylactique pour une maladie démyélinisante comprenant un dérivé d'amino alcool comme ingrédient actif
JP5452237B2 (ja) * 2008-02-07 2014-03-26 杏林製薬株式会社 アミノアルコール誘導体を有効成分とする炎症性腸疾患の治療剤又は予防剤
US8476305B2 (en) 2008-02-07 2013-07-02 Kyorin Pharmaceutical Co., Ltd. Therapeutic agent or prophylactic agent for inflammatory bowel disease comprising amino alcohol derivative as active ingredient
WO2009099174A1 (fr) * 2008-02-07 2009-08-13 Kyorin Pharmaceutical Co., Ltd. Agent thérapeutique ou agent préventif pour maladie inflammatoire des intestins contenant un dérivé d'alcool aminé comme composant actif
US10660880B2 (en) 2008-03-17 2020-05-26 Actelion Pharmaceuticals Ltd Dosing regimen for a selective S1P1 agonist
US10251867B2 (en) 2008-03-17 2019-04-09 Actelion Pharmaceuticals Ltd. Dosing regimen for a selective S1P1 receptor agonist
RU2505288C2 (ru) * 2008-05-20 2014-01-27 Киорин Фармасьютикал Ко., Лтд. Средства поддержания индуцированной ремиссии
JPWO2009142195A1 (ja) * 2008-05-20 2011-09-29 杏林製薬株式会社 寛解導入維持剤
WO2009142195A1 (fr) * 2008-05-20 2009-11-26 杏林製薬株式会社 Agent d’induction/d’entretien de rémission
US20130172297A1 (en) * 2010-05-06 2013-07-04 Novartis Ag Treatment of Autoimmune Diseases
US20130210924A1 (en) * 2010-05-06 2013-08-15 Novartis Ag Dosage Regimen of Diaryl Sulfide Derivatives
CN103702973A (zh) * 2011-07-06 2014-04-02 中国医学科学院药物研究所 胺基丙二醇类衍生物、其制备方法和其药物组合物与用途
JP2014523887A (ja) * 2011-07-06 2014-09-18 中国医学科学院薬物研究所 アミノプロパンジオール誘導体、準備、および医薬品組成物および用途
CN103702973B (zh) * 2011-07-06 2016-01-20 北京协和制药二厂 胺基丙二醇类衍生物、其制备方法和其药物组合物与用途
WO2013004190A1 (fr) * 2011-07-06 2013-01-10 中国医学科学院药物研究所 Dérivés amino-propylène-glycol, procédé de préparation, composition pharmaceutique et utilisation correspondante
CN102863345A (zh) * 2011-07-06 2013-01-09 中国医学科学院药物研究所 胺基丙二醇类衍生物、其制备方法和其药物组合物与用途
CN104844486A (zh) * 2014-02-17 2015-08-19 中国医学科学院药物研究所 胺基丙二醇类衍生物、其制备方法和其药物组合物与用途
CN104844486B (zh) * 2014-02-17 2018-10-30 中国医学科学院药物研究所 胺基丙二醇类衍生物、其制备方法和其药物组合物与用途
WO2016013225A1 (fr) * 2014-07-24 2016-01-28 杏林製薬株式会社 Procédé de fabrication de dérivé de diphénylsulfure, et intermédiaire de production

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