WO2007129473A1 - Dérivé arylique bicyclique - Google Patents

Dérivé arylique bicyclique Download PDF

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Publication number
WO2007129473A1
WO2007129473A1 PCT/JP2007/000490 JP2007000490W WO2007129473A1 WO 2007129473 A1 WO2007129473 A1 WO 2007129473A1 JP 2007000490 W JP2007000490 W JP 2007000490W WO 2007129473 A1 WO2007129473 A1 WO 2007129473A1
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group
cycloalkyl
salt
solvate
compound according
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PCT/JP2007/000490
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Japanese (ja)
Inventor
Nobuo Machinaga
Toshiharu Yoshino
Takashi Suzuki
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Daiichi Sankyo Company, Limited
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Priority to TW096118806A priority Critical patent/TW200846342A/zh
Publication of WO2007129473A1 publication Critical patent/WO2007129473A1/fr

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a bicyclic aryl derivative compound which has sphingosine monophosphate receptor agonist activity and can be used as an immunosuppressant, and a pharmaceutical containing the same.
  • S 1 P The receptor for sphingosine mono 1-phosphate (hereinafter abbreviated as S 1 P) belongs to En dothelial D ifferentiation Gene (ED G) family, which is a G protein-related receptor, and S 1 P 1, S 1 P2, S 1 P 3, S 1 P 4 and S 1 P 5 consisting of 5 subtypes, also called EDG_1, EDG_5, EDG_3, EDG_6 and EDG_8, respectively .
  • ED G dothelial D ifferentiation Gene
  • FT Y720 [2-Amino-2- [2_ (4-octylphenyl) ethyl] _1,3_propanediol hydrochloride] having a sphingosine-like structure was known to have an immunosuppressive action (Patent Document 1).
  • FTY720 does not inhibit the production of cytodynamic ins such as I L_ 2 in i ⁇ ⁇ itro, but exhibits an immunosuppressive effect with a mechanism of action different from that of existing immunosuppressive agents FK 506 and cyclosporine. It was thought.
  • FTY720 was phosphorylated in vivo, acting as an S 1 P receptor agonist, and exhibiting an immunosuppressive effect by inducing blood phosphorus / ⁇ sphere reducing activity.
  • Non-patent document 1 FTY720 has been clinically tested for organ transplant rejection and multiple sclerosis, but it has been reported that bradycardia occurs as a side effect.
  • Non-patent document 2 Therefore, development of a new immunosuppressive agent that overcomes these problems and exhibits high effects is desired.
  • N_ (benzylmethyl) azetidine_3_carboxylic acid derivative having S 1 P 1 (EDG-1) receptor agonist action, N_ (benzofuranyl ester) (Til) aminopropionic acid derivatives and S 1 P 4 (EDG-6) receptor binding ability N_ (indolylmethyl) aminopropionic acid derivatives have been disclosed to exhibit immunosuppressive action ( Patent Documents 2 to 4) are demanding novel low-molecular-weight S 1 P receptor agonist ⁇ compounds that exhibit excellent effects, have few side effects, can be administered orally, and have long-lasting action.
  • Patent Document 1 International Publication No. 94Z008943 Panfrets
  • Patent Document 2 International Publication No. 2003/062252
  • Patent Document 3 International Publication No. 2005Z000833 Pamphlet
  • Patent Document 4 International Publication No. 2005Z020882
  • Non-patent literature 1 Sci e n c e, 296, 346-349 (2002)
  • An object of the present invention is to provide a novel compound having S 1 P receptor agonist activity, exhibiting an excellent effect as an immunosuppressive agent, and having few side effects and can be administered orally. To do.
  • the present inventors have found that a novel compound having a bicyclic aryl structure different from conventional compounds exhibits S 1 P receptor agonist activity.
  • the present invention has been found that it can be used as an immunosuppressive agent that continuously decreases the number of lymphocytes in mouse peripheral blood by oral administration in a mouse in vivo model and has few side effects such as bradycardia. Too o
  • n 1, 2, 3 or 4
  • R 1 represents a hydrogen atom or a C 1 -C 6 alkyl group
  • R 2 and R 2a are each independently a hydrogen atom or a C 1 to C 6 alkyl group, or R 2 and R 2a may be combined to form a methylene group or an ethylene group. ;
  • a r 1 is naphthalene, 1 H-indole, 1 H-pyro mouth [2, 3- b] pyridine, 1 H-pyro mouth [3, 2- b] pyridine, 1 H-pyro mouth [2, 3 -c]
  • Divalent groups derived from pyridine or benzofuran (these groups are each independently a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-C6 alkyl group, a halogeno C1- C6 alkyl group, C3-C6 cycloalkyl group, /, mouth Ceno-C3-C6 cycloalkyl group, C1-C6 alkoxy group and halogeno C1-C6 alkoxy group selected from 1 to And may have 3 groups as substituents;
  • Ar 2 is a phenyl group, a pyridyl group, a furyl group, a enyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, a 1 H-pyrazolyl group or a 1 H- [1,2,4] triazolyl group [these groups are Each independently a halogen atom, nitro group, cyano group, C1-C6 alkyl group, halogeno C1-C6 alkyl group, C1-C6 alkoxy C1-C6 alkyl group, C3-C6 cyclo Alkyl group, halogeno C3-C6 cycloalkyl group, (C3-C6 cycloalkyl) methyl group, C1-C6 alkoxy group, /, mouth geno C1-C6 alkoxy group, C3-C6 cyclo An alkyloxy group, (C3-C6 cycloalkyl
  • C1-C6 alkyl group, C3-C6 cycloalkyl group, /, mouth geno C3-C6 cycloalkyl group, (C3-C6 cycloalkyl) methyl group, C1-C6 alkoxy group 1 or 2 groups selected from the group consisting of C 3 to C 6 cycloalkyloxy groups and (C 3 to C 6 cycloalkyl) methyloxy groups may be substituted. It shows that 1 to 3 groups selected from the group consisting of may have as a substituent. ]. ]
  • the compound represented by these, its salt, or those solvates are provided.
  • the present invention also relates to a medicament comprising the above compound, a salt thereof or a solvate thereof as an active ingredient; S 1 P receptor agonist; an immunosuppressive agent; a rejection reaction to transplantation, an autoimmune disease, And a therapeutic agent for Z or allergic diseases and a preventive agent for Z or allergic diseases.
  • the present invention includes one or more selected from the above-mentioned compounds, salts thereof or solvates thereof, immunosuppressive agents, antibodies used for immunosuppression, rejection drugs, antibiotics and steroids.
  • the present invention also provides use of the above compound, a salt thereof, or a solvate thereof for the manufacture of a medicament.
  • the present invention provides a method for preventing and / or treating a disease involving an S 1 P receptor, which comprises administering an effective amount of the above compound, a salt thereof or a solvate thereof. is there.
  • the bicyclic aryl derivatives, salts thereof and solvates thereof provided by the present invention have S 1 P receptor agonist activity and are administered orally in a mouse in V i V o model to produce a peripheral mouse periphery.
  • pharmaceuticals such as immunosuppressants.
  • rejection of transplantation in mammals, particularly humans, autoimmune diseases, allergic diseases It is useful as an active ingredient for therapeutic agents and Z or prophylactic agents.
  • Oral administration Since the number of lymphocytes in the peripheral blood of mice was reduced, these drugs may be administered orally. Furthermore, these drugs have few side effects such as bradycardia seen in other S 1 P receptor agonists.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • C 1 -C 6 alkyl group refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
  • a methyl group, an ethyl group, an n_propyl group, an isopropyl group 1 Examples include _ethylpropyl group, 2,2-dimethylpropyl group, n_butyl group, isobutyl group, tert_butyl group, n-pentyl group, and n-hexyl group.
  • halogeno C 1 -C 6 alkyl group refers to the C 1 -C 6 alkyl group having a halogen atom as a substituent, and the number of halogen atoms may be one or two or more In the case of two or more, the types of each halogen atom may be the same or different. For example, chloromethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2_chloroethyl group, 2,2,2_trifluoroethyl group, 1,1,2,2-tetrafluoroethyl group and penta Fluoroethyl group and the like can be mentioned.
  • the "C1-C6 alkoxy group” represents a linear or branched alkyloxy group having 1 to 6 carbon atoms, and includes, for example, a methoxy group, an ethoxy group, an n_propoxy group, an iso Examples thereof include propoxy group, 1_ethylpropoxy group, 2,2-dimethylpropoxy group, n-butoxy group, isobutyloxy group, tert-butoxy group, n-pentyloxy group and n_hexyloxy group.
  • the “C 1 -C 6 alkoxy C 1 -C 6 alkyl group” refers to the C 1 -C 6 alkyl group having a C 1 -C 6 alkoxy group as a substituent. Examples thereof include a methoxymethyl group, an ethoxymethyl group, a 2-methoxystyl group, and a 2_ethoxycetyl group.
  • the “halogeno C 1 -C 6 alkoxy group” refers to the C 1 -C 6 alkoxy group having a halogen atom as a substituent, and the number of halogen atoms is one or two or more. The type of each halogen atom in the case of two or more may be the same or different.
  • Examples thereof include a fluoromethoxy group, a chloromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a pentafluoroethoxy group, and the like.
  • C3-C6 cycloalkyl group refers to a group consisting of a 3- to 6-membered saturated hydrocarbon ring, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. It is done.
  • ⁇ (C 3 -C 6 cycloalkyl) methyl group means a methyl group having the above C 3 -C 6 cycloalkyl group as a substituent, (cyclopropyl) methyl group, (cyclobutyl) methyl group , (Cyclopentyl) methyl group and (cyclohexyl) methyl group.
  • Halogeno C3-C6 cycloalkyl group refers to the C3-C6 cycloalkyl group having a halogen atom as a substituent, and includes 2_fluorocyclopropyl group, 2,2-difluorocyclopropyl group 3_fluorocyclobutyl group, 3,3-difluorocyclobutyl group, 4_fluorocyclohexyl group and 4,4-difluorocyclohexyl group.
  • C3-C6 cycloalkyloxy group refers to a 3- to 6-membered cycloalkyloxy group, for example, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group. Groups.
  • ⁇ (C 3 -C 6 cycloalkyl) methyloxy group means a methoxy group having the above-mentioned C 3 -C 6 cycloalkyl group as a substituent, (cyclopropyl) methyloxy group, (cyclobutyl) methyloxy group, (Cyclobenzoyl) methyloxy group and (cyclohexyl) methyloxy group.
  • n 1, 2, 3 or 4, and 1 is preferable.
  • R 1 in the general formula (I) represents a hydrogen atom or a C 1 to C 6 alkyl group, preferably a hydrogen atom, a methyl group, an ethyl group or a tert_butyl group.
  • R 2 and R 2a are each independently a hydrogen atom or a C 1 to C 6 alkyl group, or R 2 and R 2a may be integrated to form a methylene group or an ethylene group. It shows that.
  • R 2 and R 2a are each independently a hydrogen atom, a methyl group or an ethyl group, or preferably united to form a methylene group or an ethylene group, and R 2 and R 2a are both hydrogen atoms. It is more preferable to form a methylene group by integrating them.
  • a r 1 is naphthalene, 1 H-indole, 1 H-pyro mouth [2, 3-b] pyridine, 1 H-pyro mouth [3, 2-b] pyridine, 1 H-pyro mouth [ 2,3-c] Divalent groups derived from pyridine or benzofuran (these groups are each independently a halogen atom, a hydroxyl group, a cyan group, a nitro group, a C1-C6 alkyl group, a halogeno group).
  • C1-C6 alkyl group selected from the group consisting of C1-C6 alkyl group, C3-C6 cycloalkyl group, halogeno C3-C6 cycloalkyl group, C1-C6 alkoxy group and halogeno C1-C6 alkoxy group It may have ⁇ 3 groups as substituents.
  • Ar 2 is a phenyl group, a pyridyl group, a furyl group, a enyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, a 1 H_pyrazolyl group or a 1 H_ [1, 2, 4] triazolyl group [these groups Each independently represents a halogen atom, a diaryl group, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3- C 6 cycloalkyl group, /, oral geno C 3 -C 6 cycloalkyl group, (C 3 -C 6 cycloalkyl) methyl group, C 1 -C 6 alkoxy group, /, oral geno C 1 -C 6 alkoxy group , C3-C
  • R 3 i , R 3 j, R 3k and R 31 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, or a cyan group.
  • Nitro group, C1-C6 alkyl group, halogeno C1-C6 alkyl group, C3-C6 cycloalkyl group, /, oral geno C3-C6 cycloalkyl group, C1-C6 alkoxy group or halogeno C represents a 1 to C 6 alkoxy group;
  • R 4 a , R 4 b , R 4c and R 4 d each independently represent a hydrogen atom or a C 1 -C 6 alkyl group. ] The group represented by these can be mentioned.
  • a r 1 is more preferably a group represented by the formula (II_a), (II-b), (II-c) and (II_f).
  • a r 1 is represented by the following formulas (II_a_1), (II_b_1), (II-c-1) and (II_f_1) [0024] [Chemical 3]
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R3 k and R3 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-C6 alkyl group, A halogeno C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogeno C3-C6 cycloalkyl group, a C1-C6 alkoxy group or a halogeno C1-C6 alkoxy group;
  • a group represented by the following is more preferable.
  • a r 1 is further represented by the formula (II_a_1), (II_b_1) ), (II _c_ 1) or (II _ f _ 1)
  • Oh with a group represented by connexion, R 3a, R 3b, R 3c, R 3d, R 3 R 3f, R 3k and R 31 is a hydrogen atom
  • R 4a and R 4b are each independently a hydrogen atom or a methyl group.
  • a r 2 include the following formulas (III_a) to (III_i):
  • R 6 represents a hydrogen atom or a C 1 -C 6 alkyl group
  • R 7a and R 7b are each independently a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C6 cycloalkyl group, / , Mouth geno C 3 -C 6 cycloalkyl group, (C 3 -C 6 cycloalkyl) methyl group or phenyl group [this phenyl group is a halogen atom, cyano group, nitro group, C 1 -C 6 alkyl group, C 3- C 6 cycloalkyl group, /, mouth geno C 3 to C 6 cycloalkyl group, (C 3 to C 6 cycloalkyl) methyl group, C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkyloxy group and (C3-C6 cycloalkyl)
  • a r 2 is expressed by the following formula (I V_a) to (I V_d)
  • R 8 R 8d , R 8e and R 8 f are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, C1-C6 Alkoxy C1-C6 alkyl group, C3-C6 cycloalkyl Group, /, mouth geno C 3 -C 6 cycloalkyl group, (C 3 -C 6 cycloalkyl) methyl group, C 1 -C 6 alkoxy group, /, mouth geno C 1 -C 6 alkoxy group, C 3- C 6 cycloalkyloxy group or (C 3 -C 6 cycloalkyl) methyloxy group;
  • R 9a , R 9b , R 9c , R 9d , R 9 R 9 f , R 9g and R 9h are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C6 alkyl group, a C3- C 6 cycloalkyl group, /, mouth geno C 3 to C 6 cycloalkyl group, (C 3 to C 6 cycloalkyl) methyl group, C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkyloxy group or (C 3 -C6 cycloalkyl) Methyloxy group. ]
  • the group represented by these is more preferable.
  • a r 2 is a group represented by the formula (IV_a), (IV_b), (IV_c) or (IV_d), and is represented by the formula (IV_a), (IV_b) ), (I V_c) and
  • R 8a , R 8d , R 8e and R 8 f in (I Vd) are each independently a nitro group, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group and a C1-C6 Those which are any one group selected from the group consisting of alkoxy C1-C6 alkyl groups are preferred.
  • R 8a, R 8d , R 8e and R 8 f are each independently Shiano group, selected from halogeno C 1 -C6 alkyl and C 1 ⁇ C6 group consisting alkoxy C 1 through C 6 alkyl group Any one group is more preferable, and a halogeno C 1 -C 6 alkyl group is more preferable.
  • the halogen atom is preferably a fluorine atom
  • the mouthgeno C1-C6 alkyl group is particularly preferably a trifluoromethyl group.
  • Formula (I V_a) ⁇ (I V_d ) in R 9a, R 9b, R 9c , R 9d, R 9e, R 9 f, and R 9h is preferably a hydrogen atom.
  • R 1 in the general formula (I) is particularly preferably a hydrogen atom.
  • preferred compounds of the present invention include the following formulas (V-1) to (V-73): / vu / O 06 ooz-osfcld ⁇ - ⁇ - ⁇ AV ⁇ _ ⁇
  • an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid or formic acid, acetic acid or methanesulfonic acid, if desired. It can be made into a physiologically acceptable salt using an organic acid such as In addition, when the compound of the present invention represented by the general formula (I) has an acidic group such as a carboxyl group, it is generally possible to form a base addition salt.
  • the physiologically acceptable salt may be either an organic salt or an inorganic salt, and suitable examples thereof include alkali metals such as lithium salts, sodium salts and potassium salts, alkali salts such as magnesium salts and calcium salts.
  • Earth metal salt ammonium salt, ⁇ ethylamine salt, cyclohexylamine salt, piperazine salt, piperidine salt, morpholine salt, N, N'-dimethylethylenediammine salt, N-methyldarcamamine salt or squirrel salt (Hydroxymethyl) aminomethane salt and the like can be mentioned.
  • the compound represented by the general formula (I) or a salt thereof of the present invention may exist as a free form or a solvate.
  • the solvate is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include hydrates and ethanol solvates.
  • a nitrogen atom is present in the compound of the present invention represented by the general formula (I), it may be an N-oxide. These solvates and N-oxides are also included in the scope of the present invention.
  • the compound of the present invention represented by the general formula (I) or a salt thereof includes a geometric isomer such as a cis isomer or a trans isomer, a d isomer, an I isomer, etc.
  • a geometric isomer such as a cis isomer or a trans isomer
  • a d isomer such as a d isomer
  • an I isomer such as optical isomers
  • the compound of the present invention includes all stereoisomers and a mixture of these isomers in any ratio unless otherwise limited. is there.
  • the compound of the present invention, a salt thereof, or a solvate thereof exists as a prodrug.
  • prodrugs include compounds in which the carboxyl group of the compound represented by the general formula (I) is esterified or amidated.
  • the compound represented by the general formula (I) and its production intermediate can be produced by utilizing various known reactions described below.
  • the functional group may be protected with an appropriate protecting group at the stage of the raw material or intermediate.
  • Examples of such functional groups include a hydroxyl group, a carboxyl group, an amino group, a carbonyl group, etc.
  • the types of protecting groups and the conditions for the introduction and removal of these protecting groups are described in Examples.
  • G roupsin Organic Synthesis T-W. G reenand PG Wuts, Jonn Wiley & Sons, Inc., New York, 1 991
  • T-W. G reenand PG Wuts Jonn Wiley & Sons, Inc., New York, 1 991
  • the compound (I) of the present invention can be produced, for example, by the following [Production Method 1] or [Production Method 2].
  • R 1 a represents a lower alkyl group
  • W 1 represents a hydroxyl group or a leaving group
  • n A r KA r 2 R 2 and R 2a represent the same as those in the general formula (I). . ]
  • the ester derivative (la) in the compound (I) of the present invention is converted to the compound (3) by the etherification reaction of the compound (1) and the phenol derivative (2), and then the compound (3) is reduced to produce an alcohol.
  • the derivative (4) can be produced by conducting a reductive amination reaction with an amine compound (6) or a salt thereof after being led to a real aldehyde derivative (5) by an oxidation reaction.
  • the carboxylic acid derivative (Ib) can be produced by subjecting the ester derivative (Ia) to alkali or acid hydrolysis.
  • the above ester derivative (Ia) can also be produced by the following [Production Method 2].
  • W 2 represents a leaving group
  • n A r ⁇ A r 2 R 1 R 2 and R 2a represent the same as above.
  • the ester derivative (I a ) is converted into the compound (7) by converting the hydroxyl group of the alcohol derivative (4) to a leaving group W 2 and then subjected to a nucleophilic substitution reaction with the amine body (6). Can be manufactured.
  • W 1 represents a hydroxyl group or a leaving group
  • n, A r ⁇ 1> 2 and 13 represent the same as described above.
  • the compound (3) can be produced by an etherification reaction in which the alcohol derivative (1) and the phenol derivative (2) are treated with a azo reagent and a phosphine compound (Mitsunobu reaction).
  • a azo reagent include azodicarboxylic acid ethyl ester, azodicarboxylic acid diisopropyl ester, 1,1 ′ _ (azodicarbonyl) dipiperidine, and 1,1′-azobis ( ⁇ , ⁇ -dimethylformamide).
  • the amount of the azo reagent used is preferably in the range of equimolar to 1.2 molar relative to the phenol derivative (2).
  • Examples of the phosphine compound include triphenylphosphine, tri- ⁇ _butylphosphine, and trimethylphosphine.
  • the amount of the phosphine compound used is preferably in the range of equimolar to 1.3 molar times with respect to the phenol derivative (2).
  • Solvents include ether solvents such as tetrahydrofuran and jetyl ether, aprotic polar solvents such as acetonitrile, hydrocarbon solvents such as toluene and benzene, and halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane. A solvent is preferred.
  • the reaction temperature is in the range of 0 ° C to the boiling point of the solvent, and preferably in the range of 0 to 80 ° C.
  • the reaction time is usually about 1 to 24 hours.
  • W 1 is a leaving group
  • Compound (3) can also be produced by alkylating phenol derivative (2) with compound (1) in the presence of a base.
  • the leaving group W 1 of the compound (1) is preferably a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a benzenesulfonyloxy group, or the like.
  • bases include alkali metal hydroxides such as sodium hydroxide, lithium hydroxide, lithium hydroxide and the like, and hydrogens of alkali metal such as hydrogenated sodium and hydrogenated lithium.
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate.
  • the amount of the base used is preferably in the range of equimolar to 1.5 molar times with respect to the compound (1).
  • the solvent include aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and acetonitrile, and ether solvents such as tetrahydrofuran and jetyl ether.
  • the reaction temperature is in the range of _20 ° C to the boiling point of the solvent, and preferably in the range of 0 to 150 ° C.
  • the reaction time is usually about 1 to 48 hours.
  • Compound (1) is commercially available or can be produced by the method shown below.
  • the compound (1_1) in which W 1 is a hydroxyl group is an ester
  • compound (1_2) in which ⁇ T is a leaving group is obtained from an alcohol form (1-1) based on a conventional method using a hydroxyl group as an alkylsulfonyloxy group or arylsulfonyloxy group. Or a leaving group W 1 a such as a halogen atom.
  • the above compound (8) is commercially available or can be produced according to the methods listed in the following (a) to (j).
  • a compound in which W1 in compound (1) is a chlorine atom, a bromine atom or an iodine atom
  • (1-3) can also be produced by the following method.
  • W 3 represents a chlorine atom, a bromine atom or an iodine atom
  • Ar 2 represents the same as described above.
  • Compound (1-3) is compounded with Compound (9) such as chlorine, bromine, sulfuryl chloride, N_ bromosuccinimide, N-chlorosuccinimide, N-odosuccinimide or dichlorite tert-butyl. It can be produced by carrying out a halogenation reaction using a halogenating reagent. This halogenation reaction can also be carried out under light irradiation or in the presence of a catalyst such as perbenzoic acid.
  • Reference materials for halogenation reactions include: Experimental Chemistry Course (4th edition, Vo on 1 9. Edited by The Chemical Society of Japan, Maruzen Co., Ltd.) Can be mentioned.
  • R 3b have the general formula (I) and shows the same, R 1 a represents those same as above.
  • the compound (2-1) is commercially available, for example by the method of Gao, Y. et al. (J. Med. Chem. 200 1, 44, 2869-2878.) Or D awson, M. I. (J. Med. Chem. 2004, 47, 35 1 8-3536.).
  • R 3c, R 3d and R 4a shows what the same as the general formula (I), R 1 a have the same meanings as before SL.
  • Compound (2_2) is commercially available, for example, as described by Coowar, D. et al. (J. Med. Chem. 2004, 47, 6270-6282., Bashford, KE et al. ( J. C hem. Soc., Perkin Tran s. 1, 2002, 1 672- 1 687.). Hiroya, K. et al. (J. Org. C h em., 2004 , 69, 1 1 26- 1 1 3 6.) or E zuquerra, J. et al. (J. Or. Chem. 1 996, 61, 5804-58 1 2.) it can.
  • R 3e , R 3 f and R 4b represent the same as in the general formula (I), and R 1 a represents the same as the above. ]
  • Compound (2-3) can be prepared, for example, by the method of Mo I ina, P. et al. (J. Org. C chem. 2003, 68, 489-499.) Or the method of BI ench, T. et al. (WO 05Z000849 No. gazette).
  • R 3 g, R 3h and R 4b represent the same as in the general formula (I), and R 1 a represents the same as the above. ]
  • Compound (2-4) is produced, for example, by applying the method of Fry dman, B. et al. (J. Org. Chem. 1 968, 33 (1 0), 3762-3766.). be able to.
  • R 3 i , R 3 j and R 4c represent the same as in the general formula (I), and R 1 a represents the same as the above. ]
  • Compound (2-5) can be prepared, for example, by the method of F r y dman n, B. et al.
  • Compound (2-6) is commercially available or is available, for example, from Ko I asa, T. et al. Method (J. Med. Chem. 2000, 43, 690-705.), La nitte, G. et al. (Eurr. J Med Med. C he m. — Ch em. T her. , 1 986, 21 (5), 379—383.), Pie, PA et al. (J. Med. Ch em. 2004, 47, 87 1-887.) Or A readi, A (Synthesis, 1 986, 9, 7 49-751.).
  • the alcohol derivative (4) shown in [Production Method 1] can be produced by the following method.
  • the alcohol derivative (4) can be produced by reducing the compound (3) according to a known method.
  • the aldehyde derivative (5) shown in [Production Method 1] can be produced by the following method.
  • Aldehyde derivatives (5) are, for example, the above alcohol derivatives (4), diacids It can be produced by oxidizing with manganese oxide.
  • the amount of mangan dioxide used can be in the range of equimolar to 20 times mol, preferably in the range of equimolar to 1.5 times mol with respect to the alcohol derivative (4).
  • As the reaction solvent hydrocarbon solvents such as toluene, benzene and hexane, ether solvents such as jetyl ether, halogenated hydrocarbon solvents such as chloroform and carbon tetrachloride are preferable.
  • the reaction temperature can be carried out in the range of 0 ° C. to the boiling point of the solvent, preferably in the range of room temperature to the boiling point of the solvent.
  • the reaction time is usually about 4 to 48 hours.
  • the aldehyde derivative (5) can also be produced by the oxidation methods shown in the following (r) to (u).
  • the ester derivative (la) is a reductive amino acid obtained by treating an aldehyde derivative (5) with an amine compound (6) or a salt thereof (for example, hydrochloride) that can be produced commercially or by a known method in the presence of a reducing agent. It can be produced by carrying out a chemical reaction.
  • a reducing agent used in this reaction sodium triacetoxyborohydride or sodium cyanoborohydride is preferable, and as a reference, the method of Gordon, D. et al. (Bioor g. Med. C he m. L etters, 1 995, 5 (1), 47 -50.) Or the method of Ke IIey, JL et al. (J. Med. Chem. 1 990, 33 (7), 1 9 1 0-1 9 1 4.).
  • Compound (7) used in [Production Method 2] can be produced by the following method.
  • n, A r KA r 2 and W 2 are the same as described above.
  • Compound (7) can be produced by converting the hydroxyl group of alcohol derivative (4) to a leaving group such as an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen.
  • a leaving group such as an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen.
  • References for conversion reactions to leaving groups include experimental chemistry Lectures (4th edition, Vo to 1. 9. Chemical Society of Japan, Maruzen Co., Ltd.) “Organic synthesis I: Hydrocarbons ⁇ Halogen compounds, P 438 to P 446 and P 465 to 470” can be mentioned.
  • Compound (Ia) shown in [Production Method 2] can be produced by the following method.
  • n, A r 1 , A r 2 , R 1 a , R 2 , R 2a and W 2 are the same as described above.
  • Compound (Ia) is a nucleophilic substitution reaction of compound (7) with amine (6) or a salt thereof (for example, hydrochloride) that can be produced commercially or by a known method in the presence of a base.
  • Bases used include organic amine bases such as ⁇ ethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4_ (N, N-dimethylamino) pyridine, or inorganic bases such as potassium carbonate and cesium carbonate.
  • the amount of the base used may be in the range of 1 to 30 equivalents, preferably in the range of 1 to 10 equivalents, relative to the compound (I a).
  • the reaction solvent is preferably a halogenated hydrocarbon solvent such as methyllene, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran, and an aprotic polar solvent such as acetonitrile or N, N-dimethylformamide.
  • the reaction temperature is in the range of -20 ° C to the boiling point of the solvent, preferably in the range of room temperature to 80 ° C.
  • the reaction time is usually about 1 to 48 hours. References for this reaction include, for example, the method of Z hao, H.
  • the compound of the present invention produced as shown in [Production Method 1] to [Production Method 2_2] is produced by a known method such as extraction, precipitation, fractionation, chromatography, fractionation. It can be isolated and purified by recrystallization, recrystallization, etc.
  • optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) and column chromatography that recrystallize with an appropriate salt.
  • S 1 P receptor agonis is useful as an immunosuppressant.
  • the compound of the present invention represented by the general formula (I), a salt thereof, and a solvate thereof have a strong agonism effect on S 1 P receptors (particularly S 1 P 1 receptors). Therefore, it is useful as an active ingredient of immunosuppressants, and is useful as a therapeutic agent for transplantation rejection, autoimmune diseases, allergic diseases, etc. in mammals, particularly rabbits, and as an active ingredient of Z or preventive agents. .
  • the compounds of the present invention, salts thereof, and solvates thereof can be administered orally because they continuously decreased the number of lymphocytes in mouse peripheral blood by oral administration in a mouse in vivo model. It can be used as an active ingredient of a medicine such as an immunosuppressive agent.
  • these drugs have few side effects such as bradycardia seen in other S 1 P receptor agonists.
  • rejection for transplantation means liver, kidney, heart, lung, small intestine, skin, cornea, bone, fetal tissue, bone marrow cell, hematopoietic stem cell, peripheral blood stem cell, umbilical cord blood stem cell, islet cell, liver
  • transplants such as cells, nerve cells, and intestinal epithelial cells
  • chronic rejection that occurs after that, and graft-versus-host disease.
  • autoimmune diseases include collagen disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, nephrotic syndrome, lupus nephritis, Syugren's syndrome, scleroderma, polymyositis, psoriasis, inflammatory bowel Disease, Crohn's disease, mixed connective tissue disease, primary myxedema, Addison's disease, aplastic anemia, autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune diabetes, uveitis, anti-receptor Disease, myasthenia gravis, thyroid poisoning, thyroiditis, Hashimoto's disease, etc.
  • Examples of allergic diseases include atopic dermatitis, asthma, rhinitis, conjunctivitis, and hay fever.
  • the compound of the present invention represented by the general formula (I), a salt thereof, or a solvate thereof is administered to a mammal (particularly baboon), it can be administered systemically or locally, orally or locally. Can be administered parenterally.
  • the medicament of the present invention can be prepared by selecting an appropriate form according to the administration method and preparing various preparations usually used.
  • oral pharmaceutical forms include tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, syrups, elixirs, and the like.
  • the preparation of such forms of pharmaceuticals includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, preservatives that are commonly used as additives. , Using antioxidants, coloring agents, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffers, diluents, wetting agents, etc. It can be carried out.
  • the parenteral pharmaceutical forms include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, Examples include inhalants.
  • the preparation of such forms of pharmaceuticals involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution, which are commonly used as additives
  • the medicament of the present invention comprises a compound represented by the general formula (I), a salt thereof, or a solvate thereof, an immunosuppressant, an antibody used for immunosuppression, a therapeutic agent for rejection, an antibiotic, and It may be a pharmaceutical comprising a combination of one or more selected from steroid drugs.
  • This pharmaceutical is administered as a concomitant drug by combining the compound of the present invention represented by the general formula (I), a salt thereof, or a solvate thereof and one or more of other drugs.
  • the combination of the compound of the present invention represented by the general formula (I), a salt thereof, or a solvate thereof and another drug is a combination of both components in one preparation. It may be an agent or may be administered as a separate preparation.
  • each preparation When administered separately, each preparation may be administered at the same time or may be administered after a time lag. In addition, the administration method of each preparation may be the same or different.
  • These drugs are selected from the compound represented by the general formula (I), a salt thereof, or a solvate thereof, and an immunosuppressant, an antibody used for antiimmune, a rejection drug, an antibiotic, and a steroid drug. It may be a kit that combines other drugs such as one or more
  • immunosuppressive agents include, for example, cyclosporine, tacrolimus (FK 506), azathioprine, mizoribine, methotrexer ⁇ , mofethyl enolic acid , Cyclophosphamide, sirolimus, everolimus, prednisolone, methylprednisolone, orthoclone OKT 3, anti-human lymphocyte globulin, deoxycis pargarine, and the like.
  • tacrolimus FK 506
  • azathioprine mizoribine
  • methotrexer ⁇ mofethyl enolic acid
  • Cyclophosphamide sirolimus, everolimus, prednisolone, methylprednisolone, orthoclone OKT 3, anti-human lymphocyte globulin, deoxycis pargarine, and the like.
  • Antibiotics include, for example, cefuroxime sodium, meropenem trihydrate, netilmycin sulfate, sisomycin, ceftibutene, ⁇ 1— 1 8 0 6, IB— 3 6 7, ⁇ bramycin, PA— 1 4 20, doxorubicin, astromycin sulfate, ceftametopipoxil hydrochloride, and the like.
  • Examples of steroidal drugs include clobetasol propionate, diflorazone acetate, fluocinonide, mometasone furanate, and betapropionate dipropionate.
  • the dose of the compound of the present invention represented by the general formula (I), a salt thereof, or a solvate thereof varies depending on symptoms, age, body weight, the type of drug administered in combination, the dose, and the like. However, it is usually in the range of 0.0 1 mg to 100 O mg per adult adult in terms of Compound (I), systemically or locally, once or several times daily, orally or non- It is preferably administered orally or continuously administered intravenously in the range of 1 to 24 hours per day.
  • Infrared spectrum was measured by KB “tablet method or ATR method using Hitachi 270-30 spectrometer or Horiba FT-720 (ST Japan Durascope (Diamon dZKRS_5)). Elemental analysis was performed with Perkin—Elmer CHNSZ O 2400 II The mass spectrometer was J EO LJ MS-AX 505W (EI, CI).
  • EDC 1_Ethyl_3_ (3-Dimethylaminopropyl) carpositimide hydrochloride
  • F o u n d C, 60. 1 1; H, 4. 26; N, 2. 69.
  • F o u n d C, 60. 08; H, 4. 39; C I, 6. 67; F, 1 1. 1 0; N, 7. 85.
  • aqueous layer was extracted with ethyl acetate (50 ml). Together The extract was washed with a saturated aqueous ammonium chloride solution (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (Biotage 40M) to obtain the title compound (673 mg).
  • DM-solution (5 ml) of 5-hydroxymono 1_methyl_ 1 H-indole_2_carboxylic acid ethyl ester (21 9 mg) was mixed with 4-chloromethyl biphenyl-2-carbonitol (273 mg ) And potassium carbonate (207 mg), and stirred for 3 days at 50 ° C. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (Yamazen Hi-Flash column L) to obtain the title compound (344 mg).
  • Lithium borohydride 50. Omg was added to a solution of 2_trifluoromethylbiphenyl mono-4-carboxylate methyl ester (21 5mg) in THF (10ml) at room temperature.
  • the reaction mixture was heated to reflux with stirring for 15 hours, After cooling to room temperature, water (30 ml) and 1 N aqueous hydrochloric acid solution (30 ml) were added, and the mixture was extracted with ethyl acetate (2 x 30 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the resulting residue was purified using silica gel flash column chromatography (Biotage 25M) to obtain the title compound (1 82 mg).
  • F o n d C, 64. 81; H, 4. 97; F, 1 1. 09; N, 5. 6 5.
  • F o u n d C, 60. 43; H, 4. 07; F, 1 1. 44; N, 2. 7 1; S, 6. 51.
  • 6-Hydroxybenzofuran_2_carboxylic acid methyl ester 50 Omg in a DMF (30 ml) solution was charged with 5_chloromethyl-1,3_phenyl-1,2_trifluoromethylthiophene (860mg) and potassium carbonate (40Omg). In addition, the mixture was stirred at 50 ° C for 3 hours. The reaction mixture was cooled to room temperature, saturated brine was added, and the mixture was extracted 3 times with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (98 Omg). MS (ES I) mZz: 433 (M + H) +.
  • 3_cyan_4 cyclohexylbenzoic acid methyl ester (566mg) in a solution of THF (6. Oml), methanol (3.0ml) and 1N sodium hydroxide aqueous solution (3.0m) l) was added at room temperature. After stirring at room temperature for 3 days, water (5. Oml) was added to the reaction solution, pH was adjusted to 3 with 1N hydrochloric acid, and black mouth form (10ml) was added to separate the layers. The aqueous layer was extracted with black mouth form (3 X 7.5 ml), the extracts were combined, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the title compound (483 mg).
  • the filtrate of the benzoic acid derivative was gradually added to a suspension of sodium borohydride (520 mg) in ethanol (5 Oml) in another Kolben at 0 ° C. After stirring at 0 ° C for 1 hour, 1 N hydrochloric acid was gradually added to adjust the pH to 4. Ethyl acetate (1 Om I) was added to the reaction solution for liquid separation, and the aqueous layer was extracted with ethyl acetate (3 ⁇ 5 Om I). The combined extracts were dried over anhydrous sodium sulfate, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (Biotage 4 OS) to give the title compound
  • the target PCR product was purified and treated with b l u n t i n g k i n at i o n (B K L K i t: Takara Bio), and pUC 1 1 8ZHIc I I—B A P (Takara / Io) and I i gat i o n 3 ⁇ 4r were performed. After introducing L i ga t i ong mi x. Into E. coli DH5 (TOYOBO) and selecting a positive clone by PCR, a plasmid incorporating HA_Gqi5 DNA was obtained.
  • the HA_Gq i 5 gene integrated into P UC 1 1 8 was excised with restriction enzymes and purified. After the preparation, expression plasmid pc DN A3.1H Hygro (+) (Invitrogen) and ligation were performed. Next, after introducing into E. coli DH5 and selecting a positive clone, an HA_Gqi5 expression plasmid was obtained.
  • HA_Gq i 5 expression plasmid obtained in (2) into the CHO-K 1 cell using Fugene 6 (Roche Diagnostics) reagent, and select cells using hygromycin. went. Cells were cloned twice, and HA_Gqi5-expressing CHO cells were selected by Western plotting using anti-HA antibodies.
  • the human S 1 P 1 (EDG-1) gene (265, No. 1 6, 9308-931 3, 1 990) was inserted into UC 1 1 8 After digestion with a restriction enzyme and purification, expression plasmid pc DNA3.1 Z IcHisA (In Vitrogen) and Iigation were performed. Next, after introducing into E. coli DH5 and selecting a positive clone, a human S1P1 (EDG-1) expression plasmid was obtained.
  • the H A_G qi 5 expressing CHO cells obtained in (3) were added to Fugene 6 (Roche ⁇ Diagnostic Co., Ltd.)
  • An S 1 P 1 (EDG-1) expression plasmid was introduced using a reagent, and cells were selected using G418. Cells were cloned twice, and cells whose intracellular calcium was increased by S 1 P stimulation were selected.
  • G qi 5 protein-expressing C HO cells transfected with human S 1 P 1 (EDG-1) obtained in (6) above are placed in a black bottom transparent 96-well plate.
  • test compounds were evaluated.
  • a suspension or solution administration solution was prepared using MC (methylcellulose) solution (concentration at which 0.2 m I was orally administered per 20 g of mouse body weight).
  • test substance Four hours after oral administration of the test substance, blood was collected (0.5 ml) from the posterior vena cava using EDT A as an anticoagulant under ether anesthesia. The number of lymphocytes in the peripheral blood was determined with the integrated hematology analyzer ADV IA 120 (Bayer Medical). The pharmacological action of the test drug is based on the control (solvent administration) group. The effect was judged by the ratio TZC ( ⁇ / ⁇ ) of the average peripheral blood lymphocyte count in the test drug administration group.
  • TZC (%) (mean peripheral blood lymphocyte count in the test drug group) (average peripheral blood lymphocyte count in the solvent group) X 1 00
  • the compound of the present invention had agonis activity against the S 1 P 1 receptor, and its strength was equivalent to that of Compound 1 (compound described in WO 2003 062252 Pamphlet).
  • the compound of the present invention showed an effect of decreasing the number of lymphocytes in peripheral blood by oral administration.
  • Compound 1 (compound described in International Publication No. 2003Z062252 Panfrez®) was administered at a dose of 0.3 mgZkg, and the effect of reducing peripheral blood lymphocyte counts was the reference value (average peripheral blood lymphocyte count in the vehicle administration group) ) Of 52.0%.
  • the compound of the present invention shows a low value of 12.26 to 23.1% of the reference value by oral administration of 0.3 mgZkg, and the peripheral blood lymphocyte count reduction effect exceeds that of Compound 1.
  • the compound of the present invention decreased the number of lymphocytes in peripheral blood by oral administration, and its effectiveness persisted even after 24 hours.
  • Compound 1 (compound described in International Publication No. 2003Z062252 Panfrez®) showed efficacy after 4 hours of oral administration of 1 mgZkg and 3 mgZkg as shown in Table 2, but 24 hours Later, the effect of reducing the number of lymphocytes in peripheral blood disappeared, and it recovered to the reference value (average peripheral blood lymphocyte count in the solvent-administered group). On the other hand, even after 24 hours, the compound of the present invention showed a low value of 10.1 to 27.3% of the reference value by oral administration of 1 mgZkg, and Z or 3 mgZkg, and maintained its efficacy.
  • the bicyclic allyl derivative of the present invention has high S 1 P receptor agonis ⁇ ⁇ activity, and is excellent in oral absorption and persistence. Therefore, rejection of transplantation, autoimmune diseases, treatment of allergic diseases It is an orally administrable drug that can be used as an agent and Z or a prophylactic agent, and has extremely high clinical usefulness.

Abstract

La présente invention concerne un nouveau composé à activité agoniste vis-à-vis du récepteur S1P, qui peut agir avec toutes les fonctionnalités d'un immunosuppresseur, qui présente peu d'effets secondaires néfastes et qui peut être administré par voie orale. La présente invention concerne spécifiquement un agoniste du récepteur S1P comprenant un composé de formule générale (I), l'un de ses sels, ou un solvate du composé ou du sel au titre de principe actif. (I) où n représente 1, 2, 3 ou 4 ; R1 représente un atome d'hydrogène ou un groupement alkyle en C1-C6 ; R2 et R2a représentent indépendamment un atome d'hydrogène ou un groupement alkyle en C1-C6, ou forment ensemble un groupement méthylène ou un groupement éthylène ; Ar1 représente un groupement divalent dérivé du naphtalène, du 1H-indole, de la 1H-pyrrolopyridine ou du benzofuranne ; et Ar2 représente un groupement phényle éventuellement substitué, un groupement thiényle éventuellement substitué, un groupement 1H-pyrazolyle éventuellement substitué, ou similaires.
PCT/JP2007/000490 2006-05-09 2007-05-09 Dérivé arylique bicyclique WO2007129473A1 (fr)

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WO2010002820A1 (fr) * 2008-06-30 2010-01-07 Allergan, Inc. Aza-indoles et composés apparentés ayant une activité biologique antagoniste des récepteurs de la sphingosine-1-phosphate (s1p)
US8536339B2 (en) 2008-06-30 2013-09-17 Allergan, Inc. AZA-indoles and related compounds having sphingosine-1-phosphate (S1P) receptor antagonist biological activity
US8012992B2 (en) 2008-06-30 2011-09-06 Allergan, Inc. Aza-indoles and related compounds having sphingosine-1-phosphate (S1P) receptor antagonist biological activity
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