JPH11279129A - Fluoroamino acid derivative - Google Patents
Fluoroamino acid derivativeInfo
- Publication number
- JPH11279129A JPH11279129A JP11019137A JP1913799A JPH11279129A JP H11279129 A JPH11279129 A JP H11279129A JP 11019137 A JP11019137 A JP 11019137A JP 1913799 A JP1913799 A JP 1913799A JP H11279129 A JPH11279129 A JP H11279129A
- Authority
- JP
- Japan
- Prior art keywords
- hexane
- compound
- formula
- acid
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002253 acid Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims description 33
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000003514 metabotropic receptor agonist Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- DIWVNJFXRKZAGI-FJNNMDBYSA-N (1s,2s,3s,5r,6s)-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound C1[C@H](F)[C@@](N)(C(O)=O)[C@@H]2[C@@H](C(O)=O)[C@H]12 DIWVNJFXRKZAGI-FJNNMDBYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 7
- 230000007062 hydrolysis Effects 0.000 abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 7
- 150000002576 ketones Chemical group 0.000 abstract description 6
- 208000012902 Nervous system disease Diseases 0.000 abstract description 5
- 208000025966 Neurological disease Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 208000020016 psychiatric disease Diseases 0.000 abstract description 5
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- 201000010099 disease Diseases 0.000 abstract description 4
- 206010013663 drug dependence Diseases 0.000 abstract description 4
- 201000000980 schizophrenia Diseases 0.000 abstract description 4
- 208000011117 substance-related disease Diseases 0.000 abstract description 4
- ANUFAWHRSIJTHW-UHFFFAOYSA-N 2-methylheptanedioic acid Chemical compound OC(=O)C(C)CCCCC(O)=O ANUFAWHRSIJTHW-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006150 Bucherer-Bergs reaction Methods 0.000 abstract description 3
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 abstract description 3
- 229940091173 hydantoin Drugs 0.000 abstract description 3
- 238000003682 fluorination reaction Methods 0.000 abstract description 2
- 230000003449 preventive effect Effects 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- WTXWGJHLNCVWJH-UHFFFAOYSA-N ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate Chemical compound C1CC(=O)C2C(C(=O)OCC)C21 WTXWGJHLNCVWJH-UHFFFAOYSA-N 0.000 abstract 1
- 239000003823 glutamate receptor agonist Substances 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- -1 ketone compound Chemical class 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000013078 crystal Substances 0.000 description 17
- 150000003862 amino acid derivatives Chemical class 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000001819 mass spectrum Methods 0.000 description 13
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 10
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000011737 fluorine Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 7
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- BPLRJDHINIIWSN-UHFFFAOYSA-N ethyl 3-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate Chemical compound C1C(F)C(=O)C2C(C(=O)OCC)C21 BPLRJDHINIIWSN-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 238000007429 general method Methods 0.000 description 6
- 238000004255 ion exchange chromatography Methods 0.000 description 6
- DIWVNJFXRKZAGI-UHFFFAOYSA-N 2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical class C1C(F)C(N)(C(O)=O)C2C(C(O)=O)C12 DIWVNJFXRKZAGI-UHFFFAOYSA-N 0.000 description 5
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- SQKZZFWTOOPCDQ-UHFFFAOYSA-N dichloromethane;ethyl acetate;hexane Chemical compound ClCCl.CCCCCC.CCOC(C)=O SQKZZFWTOOPCDQ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 150000001469 hydantoins Chemical class 0.000 description 4
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 4
- 229960001252 methamphetamine Drugs 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 208000020925 Bipolar disease Diseases 0.000 description 3
- 201000006474 Brain Ischemia Diseases 0.000 description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 108010027915 Glutamate Receptors Proteins 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 3
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000029033 Spinal Cord disease Diseases 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000003957 anion exchange resin Substances 0.000 description 3
- 239000003729 cation exchange resin Substances 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 208000021245 head disease Diseases 0.000 description 3
- 229910017053 inorganic salt Inorganic materials 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- DSSYKIVIOFKYAU-OIBJUYFYSA-N (S)-camphor Chemical compound C1C[C@]2(C)C(=O)C[C@H]1C2(C)C DSSYKIVIOFKYAU-OIBJUYFYSA-N 0.000 description 2
- JUIOQBDYJXJVSZ-UHFFFAOYSA-N 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid Chemical compound C1CC(=O)C2C(C(=O)O)C21 JUIOQBDYJXJVSZ-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102000018899 Glutamate Receptors Human genes 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
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- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
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- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 2
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- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
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- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
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- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
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- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical compound F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、医薬として有用な
含フッ素アミノ酸誘導体に関し、例えば、精神分裂病、
不安及びその関連疾患、うつ病、二極性障害、てんかん
等の精神医学的障害、さらに、薬物依存症、認知障害、
アルツハイマー病、ハンチントン舞踏病、パーキンソン
病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障
害、頭部障害等の神経学的疾患の治療及び予防に有用で
ある新規な含フッ素アミノ酸誘導体に関する。TECHNICAL FIELD The present invention relates to a fluorine-containing amino acid derivative useful as a medicine, for example, schizophrenia,
Anxiety and its related diseases, depression, bipolar disorder, psychiatric disorders such as epilepsy, as well as drug dependence, cognitive disorders,
Novel fluorinated amino acid derivatives useful for the treatment and prevention of neurological diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, dyskinesias associated with muscle stiffness, cerebral ischemia, cerebral insufficiency, spinal cord disorders and head disorders About.
【０００２】[0002]
【従来の技術】近年、グルタミン酸受容体遺伝子のクロ
−ニングが相次ぎ、グルタミン酸受容体には驚異的な数
のサブタイプが存在することが明らかとなった。現在、
グルタミン酸受容体は、受容体がイオンチャネル型構造
を持つ「イオノトロピック型」及び、受容体がＧ−タン
パク質と共役している「メタボトロピック型」の２つに
大きく分類されている（Science, 258, 597-603, 199
2）。更に、イオノトロピック受容体は薬理学的にＮ−
メチル−Ｄ−アスパラギン酸（ＮＭＤＡ）、α−アミノ
−３−ヒドロキシ−５−メチルイソキサゾ−ル−４−プ
ロピオネ−ト（ＡＭＰＡ）及びカイネ−トの３種類に分
類され（Science, 258, 597-603, 1992）、メタボトロ
ピック受容体はタイプ１〜タイプ８の８種類に分類され
る（J.Neurosci., 13, 1372-1378, 1993; Neuropharmac
ol., 34, 1-26, 1995）。2. Description of the Related Art In recent years, the cloning of the glutamate receptor gene has been frequent, and it has been revealed that a surprising number of subtypes exist in the glutamate receptor. Current,
Glutamate receptors are broadly classified into two groups: "ionotropic", which has an ion channel type receptor, and "metatropic", which receptor is coupled to a G-protein (Science, 258). , 597-603, 199
2). In addition, ionotropic receptors are pharmacologically N-
Methyl-D-aspartic acid (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kinete are classified into three types (Science, 258 , 597-603). , 1992), and the metabotropic receptors are classified into eight types, type 1 to type 8 (J. Neurosci., 13 , 1372-1378, 1993; Neuropharmac).
ol., 34, 1-26, 1995).
【０００３】メタボトロピックグルタミン酸受容体は薬
理学的には３つのグループに分類される。この中で、グ
ループ２（ｍＧｌｕＲ２／ｍＧｌｕＲ３）は、アデニル
サイクラーゼと結合し、サイクリックアデノシン１リン
酸（ｃＡＭＰ）のホルスコリン刺激性の蓄積を抑制する
（Trends Pharmacol. Sci., 14, 13(1993)）ことから、
グループ２メタボトロピックグルタミン酸受容体に作用
する化合物は急性及び慢性の精神医学的疾患及び神経学
的疾患の治療又は予防に有効なはずである。そして、グ
ループ２メタボトロピックグルタミン酸受容体に作用す
る物質としては、特開平８−１８８５６１号公報に(+)-
(1S,2S,5R,6S)−２−アミノビシクロ[3.1.0]ヘキサン−
２，６−ジカルボン酸が開示されている。[0003] Metabotropic glutamate receptors are pharmacologically divided into three groups. Among them, group 2 (mGluR2 / mGluR3) binds to adenyl cyclase and suppresses forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) (Trends Pharmacol. Sci., 14 , 13 (1993). ))
Compounds that act on Group 2 metabotropic glutamate receptors should be effective in treating or preventing acute and chronic psychiatric and neurological disorders. As substances acting on group 2 metabotropic glutamate receptors, JP-A-8-188561 discloses (+)-
(1S, 2S, 5R, 6S) -2-aminobicyclo [3.1.0] hexane-
2,6-dicarboxylic acids are disclosed.
【０００４】ところで、フッ素原子は強い電子吸引性と
高い脂溶性を付与する傾向を有しており、フッ素原子の
導入された化合物は物性を大きく変える。このため、フ
ッ素原子の導入は化合物の吸収性、代謝的安定性及び薬
理作用に大きく影響を及ぼす可能性がある。しかし、フ
ッ素原子の導入は決して容易なことではない。実際に、
特開平８−１８８５６１号公報において、(+)-(1S,2S,5
R,6S)−２−アミノビシクロ[3.1.0]ヘキサン−２，６−
ジカルボン酸へのフッ素原子の導入は全く検討されてい
ない。[0004] Fluorine atoms tend to impart strong electron-withdrawing properties and high lipophilicity, and compounds into which fluorine atoms have been introduced significantly change physical properties. For this reason, the introduction of a fluorine atom may significantly affect the absorption, metabolic stability and pharmacological action of the compound. However, the introduction of fluorine atoms is not easy. actually,
In JP-A-8-188561, (+)-(1S, 2S, 5
(R, 6S) -2-aminobicyclo [3.1.0] hexane-2,6-
The introduction of fluorine atoms into dicarboxylic acids has not been studied at all.
【０００５】[0005]
【発明が解決しようとする課題】本発明の目的は、上記
した従来技術の現状に鑑み、例えば、精神分裂病、不安
及びその関連疾患、うつ病、二極性障害、てんかん等の
精神医学的障害、並びに、薬物依存症、認知障害、アル
ツハイマー病、ハンチントン舞踏病、パーキンソン病、
筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭
部障害等の神経学的疾患に治療効果及び予防効果を有す
る薬物であって、特に経口投与でグループ２メタボトロ
ピックグルタミン酸受容体に作用することのできる薬物
を提供することにある。SUMMARY OF THE INVENTION In view of the above-mentioned state of the art, it is an object of the present invention to provide, for example, psychiatric disorders such as schizophrenia, anxiety and related diseases, depression, bipolar disorder, and epilepsy. , And drug addiction, cognitive impairment, Alzheimer's disease, Huntington's disease, Parkinson's disease,
A drug having therapeutic and preventive effects on neurological diseases such as dyskinesias associated with muscle stiffness, cerebral ischemia, cerebral insufficiency, spinal cord disorders, and head disorders, and particularly, orally administered group 2 metabotropic glutamate receptors To provide a drug capable of acting on
【０００６】[0006]
【課題を解決するための手段】本発明者らは、(+)-(1S,
2S,5R,6S)−２−アミノビシクロ[3.1.0]ヘキサン−２,
６−ジカルボン酸にフッ素原子を導入した含フッ素アミ
ノ酸誘導体について鋭意検討した結果、グループ２メタ
ボトロピックグルタミン酸受容体に経口投与で影響を及
ぼすことのできる新規含フッ素アミノ酸誘導体を見出
し、本発明を完成した。Means for Solving the Problems The present inventors have proposed (+)-(1S,
2S, 5R, 6S) -2-Aminobicyclo [3.1.0] hexane-2,
As a result of intensive studies on a fluorine-containing amino acid derivative in which a fluorine atom has been introduced into 6-dicarboxylic acid, a novel fluorine-containing amino acid derivative capable of influencing group 2 metabotropic glutamate receptor by oral administration was found, and the present invention was completed. .
【０００７】すなわち、本発明は、式［Ｉ］That is, the present invention provides a compound of the formula [I]
【化３】 ［式中、Ｘ1は水素原子又はフッ素原子を示し、Ｒ1及び
Ｒ2は同一又は異なって水素原子又は炭素数１−１０の
アルキル基を示す。］で表される２−アミノ−３−フル
オロビシクロ[3.1.0]ヘキサン−２，６−ジカルボン酸
誘導体、その医薬上許容される塩又はその水和物であ
る。Embedded image [In the formula, X 1 represents a hydrogen atom or a fluorine atom, and R 1 and R 2 are the same or different and represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. 2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof.
【０００８】本発明において、炭素数１−１０のアルキ
ル基とは、直鎖状、分岐鎖状又は環状のアルキル基であ
り、直鎖状、分岐鎖状アルキル基としては、例えば、メ
チル基、エチル基、プロピル基、イソプロピル基、ブチ
ル基、イソブチル基、ペンチル基、イソペンチル基、１
−エチルプロピル基、へキシル基、イソへキシル基、１
−エチルブチル基、ヘプチル基、イソヘプチル基、オク
チル基、ノニル基、デシル基などを挙げることができ、
また、環状のアルキル基としては、炭素数３−１０の環
を含むアルキル基、例えば、シクロプロピル基、シクロ
ブチル基、シクロプロピルメチル基、シクロペンチル
基、シクロブチルメチル基、シクロヘキシル基、シクロ
ペンチルメチル基、シクロヘキシルメチル基、シクロヘ
プチル基などを挙げることができる。In the present invention, the alkyl group having 1 to 10 carbon atoms is a linear, branched or cyclic alkyl group. Examples of the linear or branched alkyl group include a methyl group, Ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 1
-Ethylpropyl group, hexyl group, isohexyl group, 1
-Ethylbutyl group, heptyl group, isoheptyl group, octyl group, nonyl group, decyl group, and the like,
Further, as the cyclic alkyl group, an alkyl group having a ring having 3 to 10 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopropylmethyl group, a cyclopentyl group, a cyclobutylmethyl group, a cyclohexyl group, a cyclopentylmethyl group, Examples thereof include a cyclohexylmethyl group and a cycloheptyl group.
【０００９】また、本発明における医薬上許容される塩
としては、例えば、硫酸、塩酸、燐酸などの鉱酸との
塩、酢酸、シュウ酸、乳酸、酒石酸、フマール酸、マレ
イン酸、メタンスルホン酸、ベンゼンスルホン酸などの
有機酸との塩、トリメチルアミン、メチルアミンなどの
アミンとの塩、又はナトリウムイオン、カリウムイオ
ン、カルシウムイオンなどの金属イオンとの塩などを挙
げることができる。なお、本発明化合物は、各種の溶媒
和物として存在し得るが、医薬としての適用性の面から
は水和物が好ましい。The pharmaceutically acceptable salts of the present invention include, for example, salts with mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid and methanesulfonic acid. And salts with organic acids such as benzenesulfonic acid, salts with amines such as trimethylamine and methylamine, and salts with metal ions such as sodium ion, potassium ion and calcium ion. The compound of the present invention may exist as various solvates, but hydrates are preferable from the viewpoint of applicability as a medicine.
【００１０】式［Ｉ］で示される化合物の中でＸ1が水
素原子の場合は、１、２、３、５及び６位に５つの不斉
炭素原子が存在する。従って、Ｘ1が水素原子である本
発明化合物は、光学活性体、ラセミ体等の２種のエナン
チオマー混合物及びジアステレオマーの混合物として存
在できる。更に、Ｘ1がフッ素原子の場合、１、２、５
及び６位に４つの不斉炭素原子が存在する。従って、Ｘ
1がフッ素原子である本発明化合物は、光学活性体、ラ
セミ体等の２種のエナンチオマー混合物及びジアステレ
オマーの混合物として存在できる。When X 1 is a hydrogen atom in the compound represented by the formula [I], five asymmetric carbon atoms are present at the 1 , 2, 3, 5, and 6 positions. Therefore, the compound of the present invention in which X 1 is a hydrogen atom can exist as a mixture of two kinds of enantiomers such as an optically active substance and a racemate and a mixture of diastereomers. Further, when X 1 is a fluorine atom, 1, 2, 5
And four asymmetric carbon atoms at position 6. Therefore, X
The compound of the present invention wherein 1 is a fluorine atom can exist as a mixture of two kinds of enantiomers such as an optically active substance and a racemate, and a mixture of diastereomers.
【００１１】式［Ｉ］に示す化合物において好ましいＸ
1は水素原子である。さらに、Ｘ1が水素原子である場合
には、式［Ｉ］に示す化合物は下記の立体化学配置を有
することがより好ましい。Preferred X in the compound of the formula [I]
1 is a hydrogen atom. Further, when X 1 is a hydrogen atom, the compound represented by the formula [I] more preferably has the following stereochemical configuration.
【化４】 Embedded image
【００１２】また、Ｘ1、Ｒ1及びＲ2が水素原子の場
合、本化合物の光学異性体の中で最も好ましい光学活性
体は正の旋光性を有しており、この絶対立体化学配置
は、本化合物の合成前駆体である２−スピロ−５´−ヒ
ダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−
６−カルボン酸 (Ｒ)−(＋)−1−フェニルエチルアミン
塩のＸ線単結晶構造解析により、１Ｓ，２Ｓ，３Ｓ，５
Ｒ，６Ｓと決定された。When X 1 , R 1 and R 2 are hydrogen atoms, the most preferred optically active isomer of the present compound has a positive optical activity, and its absolute stereochemical configuration is 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane which is a synthetic precursor of the present compound
According to X-ray single crystal structure analysis of 6-carboxylic acid (R)-(+)-1-phenylethylamine salt, 1S, 2S, 3S, 5
R, 6S.
【００１３】一方、式［Ｉ］においてＲ1とＲ2の片方又
は両方が水素以外を示す場合、すなわちエステル体はグ
ループ２メタボトロピックグルタミン酸受容体に影響を
及ぼさない。しかし、このエステル体は生体内でカルボ
ン酸に加水分解され、グループ２メタボトロピックグル
タミン酸受容体に影響を及ぼすカルボン酸に変化する。
このように、本発明化合物のエステル体はプロドラッグ
として機能するため、極めて有用である。On the other hand, in formula [I], when one or both of R 1 and R 2 represent other than hydrogen, that is, the ester form does not affect the group 2 metabotropic glutamate receptor. However, this ester is hydrolyzed in the living body to a carboxylic acid, and is converted to a carboxylic acid that affects the group 2 metabotropic glutamate receptor.
Thus, the ester form of the compound of the present invention is extremely useful because it functions as a prodrug.
【００１４】[0014]
【発明の実施の形態】式［Ｉ］の化合物は、以下に示す
各反応式に従って製造することができる。下記の反応式
中、Ｒ1、Ｒ2、Ｘ1は前記と同様であり、Ｒ3とＲ4は同
一又は異なって炭素数１−１０の低級アルキル基を示
し、Ｙは一般的なアミノ基の保護基（PROTECTIVE GROUP
S IN ORGANIC SYNTHESIS,THEODORA W. GREENE and PETE
R G. M.WUTS著 参照）を示す。BEST MODE FOR CARRYING OUT THE INVENTION The compound of the formula [I] can be produced according to the following reaction formulas. In the following reaction formulas, R 1 , R 2 and X 1 are the same as described above, R 3 and R 4 are the same or different and represent a lower alkyl group having 1 to 10 carbon atoms, and Y represents a general amino group PROTECTIVE GROUP
S IN ORGANIC SYNTHESIS, THEODORA W. GREENE and PETE
R GMWUTS).
【００１５】まず、下記式［化５］に示されるように、
出発物質であるケトン体（１）の所定の位置に１又は２
のフッ素原子が導入される。First, as shown in the following formula [Formula 5],
1 or 2 at a predetermined position of the ketone body (1) as a starting material
Is introduced.
【化５】 Embedded image
【００１６】光学活性体、ラセミ体等の２種のエナンチ
オマー混合物又はジアステレオマーの混合物であるモノ
フッ化化合物(２)は、対応する光学活性体、ラセミ体等
の２種のエナンチオマー混合物又はジアステレオマーの
混合物であるケトン体(１)を一旦エノールシリルエーテ
ル体又はエノールエステル体とした後、フッ素化試薬と
反応させるか、或いはケトン体(１)に直接、フッ素化試
薬を反応させることによって得ることができる。また、
光学活性体、ラセミ体等の２種のエナンチオマー混合物
又はジアステレオマーの混合物であるジフッ化化合物
(３)は、モノフッ化化合物(２)を一旦エノールシリルエ
ーテル体とした後フッ化試薬と反応させるか、モノフッ
化化合物(２)に直接フッ化試薬と反応させるか、或いは
ケトン体(１)に２当量以上のフッ素化試薬を反応させる
ことによって得ることができる。The monofluorinated compound (2), which is a mixture of two kinds of enantiomers such as an optically active substance and a racemate, or a mixture of diastereomers, is a mixture of two kinds of enantiomers such as an optically active substance and a racemate, or a diastereomer. The ketone compound (1), which is a mixture of the mer, is once obtained as an enolsilyl ether compound or an enol ester compound and then reacted with a fluorinating reagent, or obtained by directly reacting the ketone compound (1) with the fluorinating reagent. be able to. Also,
A difluorinated compound which is a mixture of two kinds of enantiomers or a mixture of diastereomers such as an optically active substance and a racemic form
(3) The monofluorinated compound (2) is converted into an enolsilyl ether form and then reacted with a fluorinating reagent, the monofluorinated compound (2) is directly reacted with a fluorinating reagent, or the ketone body (1) By reacting at least two equivalents of a fluorinating reagent.
【００１７】ここで、エノールシリルエーテル体の製造
は、ケトン体(１)に、例えばテトラヒドロフラン、ジエ
チルエーテルなどのエーテル類、トルエン、ベンゼンな
どの炭化水素類、メタノール、ｔ−ブタノールなどのア
ルコール類、Ｎ,Ｎ−ジメチルホルムアミド等の不活性
溶媒中、例えばｎ−ブチルリチウム、ｓ−ブチルリチウ
ムなどのアルキルリチウム類、例えばリチウムビストリ
メチルシリルアミド、カリウムビストリメチルシリルア
ミド、ナトリウムアミドなどの金属アミド類、例えば水
素化ナトリウムなどの水素化金属類、又は、例えばトリ
エチルアミン等のアミン類等の塩基の存在下、例えばク
ロロトリメチルシラン、クロロｔ−ブチルジメチルシラ
ン等のシリル化剤を反応させることによって行うことが
できる。ここでの反応温度は１００℃以下が好ましく、
更に−７８℃から室温がより好ましい。Here, the enol silyl ether compound is produced by adding a ketone compound (1) to ethers such as tetrahydrofuran and diethyl ether, hydrocarbons such as toluene and benzene, alcohols such as methanol and t-butanol, and the like. In an inert solvent such as N, N-dimethylformamide, alkyl lithiums such as n-butyllithium and s-butyllithium, and metal amides such as lithium bistrimethylsilylamide, potassium bistrimethylsilylamide and sodium amide, for example, hydrogen The reaction can be carried out by reacting a silylating agent such as chlorotrimethylsilane or chloro t-butyldimethylsilane in the presence of a metal hydride such as sodium chloride or a base such as an amine such as triethylamine. The reaction temperature here is preferably 100 ° C. or less,
Further, the temperature is more preferably from -78 ° C to room temperature.
【００１８】また、エノールエステル体の製造は、上記
シリル化剤を、例えば無水酢酸等の酸無水物、例えばプ
ロピオニルクロライド等の酸ハライド、又は、例えば酢
酸等のカルボン酸とエトキシカルボニルクロライド等の
アルコキシカルボニルハライドから調製される混合酸無
水物等に代えることにより、エノールシリルエーテル体
の製造と同様に行うことができる。In the production of the enol ester compound, the silylating agent may be prepared by reacting the above silylating agent with an acid anhydride such as acetic anhydride, for example, an acid halide such as propionyl chloride, or a carboxylic acid such as acetic acid and an alkoxy compound such as ethoxycarbonyl chloride. The production can be carried out in the same manner as in the production of the enolsilyl ether compound by replacing with a mixed acid anhydride prepared from carbonyl halide.
【００１９】フッ素化試薬としては、例えば、Ｎ−フル
オロピリジニウムトリフラート、Ｎ−フルオロ−Ｎ−ｔ
−ブチルベンゼンスルホンアミド、Ｎ−フルオロサッカ
リンスルタム、Ｎ−フルオロビス（ベンゼンスルホン）
イミド、Ｎ−フルオロ−ｏ−ベンゼンスルホンイミドな
どのＮ−フルオロ型フッ素化剤、フッ素、フッ化水素、
酸性フッ化カリウム（ＨＫＦ2）等の無機フッ化化合
物、ＣｌＯ3Ｆ、又はＣＦ 3ＣＯＯＦ等を使用することが
できる。As the fluorinating reagent, for example, N-fur
Olopyridinium triflate, N-fluoro-Nt
-Butylbenzenesulfonamide, N-fluorosacchar
Linsultam, N-fluorobis (benzenesulfone)
Imide, N-fluoro-o-benzenesulfonimide
Which N-fluoro type fluorinating agent, fluorine, hydrogen fluoride,
Potassium acid fluoride (HKFTwo) And other inorganic fluorinated compounds
Object, CLOThreeF or CF ThreeCOOF etc. can be used
it can.
【００２０】ここで、直接フッ素化試薬を反応させる態
様としては、ケトン体(１)に、例えばテトラヒドロフラ
ン、ジエチルエーテルなどのエーテル類、トルエン、ベ
ンゼンなどの炭化水素類、メタノール、ｔ−ブタノール
などのアルコール類、Ｎ,Ｎ−ジメチルホルムアミド等
の不活性溶媒中、例えばｎ−ブチルリチウム、ｓ−ブチ
ルリチウムなどのアルキルリチウム類、例えばリチウム
ビストリメチルシリルアミド、ナトリウムアミドなどの
金属アミド類、例えば水素化ナトリウムなどの水素化金
属類、又は、例えばトリエチルアミン等のアミン類等の
塩基の存在下、反応温度を好ましくは１００℃以下で、
より好ましくは−７８℃から室温で、上記したようなフ
ッ素化試薬を反応させる態様が好ましい。Here, as an embodiment in which the fluorinating reagent is reacted directly, the ketone compound (1) is reacted with ethers such as tetrahydrofuran and diethyl ether, hydrocarbons such as toluene and benzene, methanol and t-butanol. In an inert solvent such as alcohols and N, N-dimethylformamide, alkyl lithiums such as n-butyllithium and s-butyllithium, and metal amides such as lithium bistrimethylsilylamide and sodium amide such as sodium hydride In the presence of a base such as a metal hydride such as or an amine such as triethylamine, the reaction temperature is preferably 100 ° C. or lower,
More preferably, an embodiment in which the above-described fluorinating reagent is reacted at -78 ° C to room temperature is preferable.
【００２１】このようにして得られた、光学活性体、ラ
セミ体等の２種のエナンチオマー混合物又はジアステレ
オマーの混合物であるモノ又はジフッ素化化合物(４)
は、下記式［化６］に示すように、例えば、ストレッカ
ーアミノ酸合成（Strecker Amino Acid Synthesis）（A
nn.,75,27(1850);91,349(1850)）、ブッヘラー−ベルグ
ス反応（Bucherer-Bergs Reaction）（J.Prakt.Chem.,1
40,69(1934)）又はこれらの変法によって得られたアミ
ノシアニド誘導体又はヒダントイン誘導体等を加水分解
することによって、本発明化合物である対応する光学活
性体、ラセミ体等の２種のエナンチオマー混合物又はジ
アステレオマーの混合物である含フッ素アミノ酸誘導体
(５)とすることができる。The mono- or difluorinated compound (4) thus obtained, which is a mixture of two kinds of enantiomers or a mixture of diastereomers such as an optically active compound and a racemic compound (4)
Is represented by, for example, Strecker Amino Acid Synthesis (A
nn., 75 , 27 (1850); 91 , 349 (1850)), Bucherer-Bergs Reaction (J. Prakt. Chem., 1 ).
40 , 69 (1934)) or an aminocyanide derivative or a hydantoin derivative obtained by a modification thereof to obtain a mixture of two enantiomers such as the corresponding optically active compound and racemic compound of the present invention or Fluorinated amino acid derivatives that are mixtures of diastereomers
(5).
【化６】 Embedded image
【００２２】具体的には、モノ又はジフッ化合物(４)
は、例えば、シアン化ナトリウム又はシアン化カリウム
及び炭酸アンモニウムと、例えばエタノールなどのアル
コール類又はアルコール類と水の混合溶媒中、好ましく
は３０℃〜５０℃で１日〜２日反応することにより、合
成中間体であるヒダントイン誘導体とすることができ
る。前記ヒダントイン誘導体は、続いて、例えば水酸化
ナトリウムなどの塩基、或いは塩酸、硫酸等の酸によっ
て、例えばエタノールなどのアルコール類、ジオキサン
などのエーテル類、アセトンなどのケトン類、又は水な
どの不活性溶媒中加水分解することによって、本発明化
合物である含フッ素アミノ酸誘導体(５)とすることが可
能である。Specifically, the mono- or difluorinated compound (4)
Is reacted with sodium cyanide or potassium cyanide and ammonium carbonate, for example, in an alcohol such as ethanol or a mixed solvent of alcohols and water, preferably at 30 ° C. to 50 ° C. for 1 day to 2 days to form a synthetic intermediate. It can be a hydantoin derivative that is a body. The hydantoin derivative is subsequently inerted with a base such as sodium hydroxide or an acid such as hydrochloric acid or sulfuric acid, for example, an alcohol such as ethanol, an ether such as dioxane, a ketone such as acetone, or water or the like. By hydrolyzing in a solvent, it is possible to obtain the fluorine-containing amino acid derivative (5) of the present invention.
【００２３】下記式［化７］に示すように、(１ＳＲ,５
ＲＳ,６ＳＲ)−(１)で示されるケトン体に１つのフッ素
原子が導入されたモノフッ化化合物（前出の（２）参
照）のブッヘラー−ベルグス反応によって得られる、
(１ＳＲ,５ＲＳ,６ＳＲ)−(６)で示されるヒダントイン
誘導体は、例えばシリカゲル等を用いたカラムクロマト
グラフィーや再結晶などの一般的な手法によって、（１
ＳＲ，２ＳＲ，３ＳＲ，５ＲＳ，６ＳＲ）、（１ＳＲ，
２ＳＲ，３ＲＳ，５ＲＳ，６ＳＲ）、（１ＳＲ，２Ｒ
Ｓ，３ＳＲ，５ＲＳ，６ＳＲ）、（１ＳＲ，２ＲＳ，３
ＲＳ，５ＲＳ，６ＳＲ）の４つのジアステレオマーに分
離することが出来る。As shown in the following formula [7], (1SR, 5
RS, 6SR) -obtained by a Bucherer-Bergs reaction of a monofluorinated compound having one fluorine atom introduced into a ketone represented by (1) (see (2) above).
The hydantoin derivative represented by (1SR, 5RS, 6SR)-(6) can be obtained by a general method such as column chromatography using silica gel or the like or recrystallization.
SR, 2SR, 3SR, 5RS, 6SR), (1SR,
2SR, 3RS, 5RS, 6SR), (1SR, 2R
S, 3SR, 5RS, 6SR), (1SR, 2RS, 3
RS, 5RS, 6SR).
【００２４】更に、この４つのジアステレオマーは、そ
れぞれ、そのエステル部位を加水分解して（７）で示さ
れるカルボン酸誘導体とした後、例えば塩基性キラル分
割剤を用いた分割等の一般的な分割を行うことによっ
て、（１Ｓ，２Ｓ，３Ｓ，５Ｒ，６Ｓ）、（１Ｒ，２
Ｒ，３Ｒ，５Ｓ，６Ｒ）、（１Ｓ，２Ｓ，３Ｒ，５Ｒ，
６Ｓ）、（１Ｒ，２Ｒ，３Ｓ，５Ｓ，６Ｒ）、（１Ｓ，
２Ｒ，３Ｓ，５Ｒ，６Ｓ）、（１Ｒ，２Ｓ，３Ｒ，５
Ｓ，６Ｒ）、（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）、（１
Ｒ，２Ｓ，３Ｓ，５Ｓ，６Ｒ）の８つのエナンチオマー
（８）に分割できる。そして、これらのエナンチオマー
（８）は、そのヒダントイン部位を加水分解によって、
本発明化合物である８つの光学活性な含フッ素アミノ酸
誘導体（９）とすることができる。Further, each of the four diastereomers is converted into a carboxylic acid derivative represented by the formula (7) by hydrolyzing the ester site thereof, and then subjected to a general method such as resolution using a basic chiral resolving agent. (1S, 2S, 3S, 5R, 6S), (1R, 2
R, 3R, 5S, 6R), (1S, 2S, 3R, 5R,
6S), (1R, 2R, 3S, 5S, 6R), (1S,
2R, 3S, 5R, 6S), (1R, 2S, 3R, 5)
S, 6R), (1S, 2R, 3R, 5R, 6S), (1
R, 2S, 3S, 5S, 6R) can be separated into eight enantiomers (8). Then, these enantiomers (8) convert their hydantoin sites by hydrolysis.
Eight optically active fluorine-containing amino acid derivatives (9) of the present invention can be obtained.
【化７】 Embedded image
【００２５】ここで、塩基性キラル分割剤としては、例
えば(＋)又は(−)−１−フェニルエチルアミン、(＋)又
は(−)−２−アミノ−１−ブタノール、(＋)又は(−)−
アラニノール、ブルシン、シンコニジン、シンコニン、
キニン、キニジン、デヒドロアビエチルアミン等の光学
活性なアミン類を使用することができる。Here, as the basic chiral resolving agent, for example, (+) or (−)-1-phenylethylamine, (+) or (−)-2-amino-1-butanol, (+) or (−) ) −
Alaninol, brucine, cinchonidine, cinchonine,
Optically active amines such as quinine, quinidine and dehydroabiethylamine can be used.
【００２６】一方、本発明化合物の１つである、２つの
フッ素原子を含有する４つの光学活性な（１Ｓ，２Ｓ，
５Ｒ，６Ｓ）、（１Ｒ，２Ｒ，５Ｓ，６Ｒ）、（１Ｓ，
２Ｒ，５Ｒ，６Ｓ）、（１Ｒ，２Ｓ，５Ｓ，６Ｒ）−含
フッ素アミノ酸誘導体（１２）は、下記式［化８］に示
すように、(１ＳＲ,５ＲＳ,６ＳＲ)−(１)を出発原料に
して上記の場合と同様にフッ素化、ヒダントイン化、ジ
アステレオマー（１０）の分離、エステル部位の加水分
解による誘導体（１１）の生成、分割及びヒダントイン
部位の加水分解を行うことによって合成することができ
る。On the other hand, one of the compounds of the present invention, four optically active (1S, 2S,
5R, 6S), (1R, 2R, 5S, 6R), (1S,
2R, 5R, 6S), (1R, 2S, 5S, 6R) -fluorinated amino acid derivative (12) starts from (1SR, 5RS, 6SR)-(1) as shown in the following formula [Formula 8]. In the same manner as described above, the raw material is synthesized by fluorination, hydantoinization, separation of diastereomer (10), formation of derivative (11) by hydrolysis of ester moiety, resolution, and hydrolysis of hydantoin moiety. be able to.
【化８】 Embedded image
【００２７】なお、１つのフッ素原子を有する、(１Ｓ
Ｒ,５ＲＳ,６ＳＲ)−(２)で示されるモノフッ化化合物
は、下記式［化９］に示すように、［化７］と同様の一
般的な手法によるジアステレオマーの分離、エステル部
位の加水分解及び分割を行うことにより、（１Ｓ，３
Ｓ，５Ｒ，６Ｓ）、（１Ｒ，３Ｒ，５Ｓ，６Ｒ）、（１
Ｓ，３Ｒ，５Ｒ，６Ｓ）、（１Ｒ，３Ｓ，５Ｓ，６Ｒ）
の４つの光学活性なケトカルボン酸（１３）とすること
ができる。In addition, (1S) having one fluorine atom
The monofluorinated compound represented by (R, 5RS, 6SR)-(2) can be separated into diastereomers by the same general method as in [Chemical formula 7], By performing hydrolysis and resolution, (1S, 3
S, 5R, 6S), (1R, 3R, 5S, 6R), (1
S, 3R, 5R, 6S), (1R, 3S, 5S, 6R)
And four optically active ketocarboxylic acids (13).
【化９】 Embedded image
【００２８】したがって、４つの光学活性なケトカルボ
ン酸(１３)について直接、或いはそのエステル化後に、
式（５）により示した化合物の合成の場合と同様の操作
を行い、また、更にジアステレオマーの分離を行うこと
によっても、光学活性な本発明化合物である含フッ素ア
ミノ酸誘導体を製造することができる。Thus, directly or after esterification of the four optically active ketocarboxylic acids (13),
By performing the same operation as in the synthesis of the compound represented by the formula (5), and further separating the diastereomer, the optically active fluorine-containing amino acid derivative of the present invention can be produced. it can.
【００２９】また、下記式［化１０］に示されるよう
に、２つのフッ素原子を有する（１Ｓ，５Ｒ，６Ｓ）、
（１Ｒ，５Ｓ，６Ｒ）の２つの光学活性なケトカルボン
酸（１４）は、２つのフッ素原子を有する(１ＳＲ,５Ｒ
Ｓ,６ＳＲ)−(３)で示されるケトン体から、［化９］に
おいて式（１３）により示した化合物の合成の場合と同
様の操作、すなわち、エステルの加水分解及び分割によ
って得ることができる。Further, as shown in the following formula [Chemical Formula 10], it has two fluorine atoms (1S, 5R, 6S);
The two optically active ketocarboxylic acids (14) of (1R, 5S, 6R) have two fluorine atoms (1SR, 5R
From the ketone body represented by (S, 6SR)-(3), it can be obtained by the same operation as in the synthesis of the compound represented by the formula (13) in [Chemical Formula 9], that is, hydrolysis and resolution of an ester. .
【化１０】 Embedded image
【００３０】したがって、２つの光学活性なケトカルボ
ン酸(１４)について直接、或いはエステル化後に、［化
６］において式（５）により示した化合物の合成の場合
と同様の操作を行い、更にジアステレオマーの分離を行
うことによっても光学活性な本発明化合物である含フッ
素アミノ酸誘導体を製造することができる。Therefore, directly or after esterification of the two optically active ketocarboxylic acids (14), the same operation as in the synthesis of the compound represented by the formula (5) in [Chem. The optically active fluorine-containing amino acid derivative of the present invention can also be produced by separating the mer.
【００３１】ところで、下記式［化１１］に示されるよ
うに、式(６)で示される光学活性体、ラセミ体等の２種
のエナンチオマー混合物又はジアステレオマーの混合物
として存在する本発明化合物である含フッ素アミノ酸
は、アミノ基をＹで示される保護基で保護した後、Ｒ3
−Ｘ2又はＲ4−Ｘ2で示されるアルキルハライド、もし
くはＲ3−ＯＨ又はＲ4−ＯＨで示されるアルコールを用
いて一般的な方法にてエステル化し、アミノ基の保護基
を除去することによって、式(１５)で示される本発明化
合物である含フッ素アミノ酸エステルに誘導することが
できる。By the way, as shown in the following formula [Chemical formula 11], the compound of the present invention which is present as a mixture of two kinds of enantiomers such as an optically active compound and a racemic compound represented by the formula (6) or a mixture of diastereomers is used. there fluorinated amino acids was protected by a protecting group represented the amino group in Y, R 3
-X 2 or an alkyl halide represented by R 4 -X 2, or esterified by a general method using an alcohol represented by R 3 -OH or R 4 -OH, removing the protecting group of the amino group Thus, a fluorine-containing amino acid ester of the present invention represented by the formula (15) can be derived.
【化１１】 Embedded image
【００３２】ここで、アミノ基の保護、エステル化及び
アミノ基の脱保護は、PROTECTIVE GROUPS IN ORGANIC S
YNTHESIS,THEODORA W. GREENE and PETER G. M.WUTS著
に示されるような一般的な方法で実施可能である。Here, the protection of the amino group, the esterification and the deprotection of the amino group are carried out by PROTECTIVE GROUPS IN ORGANIC S
It can be performed by a general method as shown by YNTHESIS, THEODORA W. GREENE and PETER GMWUTS.
【００３３】更に、式(１５)で示される含フッ素アミノ
酸エステル、又は、式(１７)で示されるＮ−保護含フッ
素アミノ酸エステルの各ジアステレオマーは、例えばシ
リカゲル等を用いたカラムクロマトグラフィーや再結晶
などの一般的な手法によって分離することが出来る。ま
た、式(１５)の各ジアステレオマーは、例えば酸性キラ
ル分割剤を用いた分割等の一般的な分割方法によって各
エナンチオマーに分割できる。Further, each diastereomer of the fluorinated amino acid ester represented by the formula (15) or the N-protected fluorinated amino acid ester represented by the formula (17) can be obtained by, for example, column chromatography using silica gel or the like. It can be separated by a general method such as recrystallization. In addition, each diastereomer of the formula (15) can be resolved into each enantiomer by a general resolution method such as resolution using an acidic chiral resolving agent.
【００３４】ここで、酸性キラル分割剤としては、(＋)
又は(−)−ジ−ｐ−トルオルイル酒石酸、(＋)又は(−)
−ジベンゾイル酒石酸、(＋)又は(−)−酒石酸、(＋)又
は(−)−マンデル酸、(＋)又は(−)−しょうのう酸、又
は(＋)又は(−)−しょうのうスルホン酸等の光学活性な
有機酸類を使用することが可能である。Here, as the acidic chiral resolving agent, (+)
Or (-)-di-p-toluoyl tartaric acid, (+) or (-)
-Dibenzoyltartaric acid, (+) or (-)-tartaric acid, (+) or (-)-mandelic acid, (+) or (-)-camphoric acid, or (+) or (-)-camphor. Optically active organic acids such as sulfonic acid can be used.
【００３５】本発明化合物は１つまたはそれ以上の医薬
的に許容される担体、賦形剤又は希釈剤と組み合わされ
て医薬的製剤とされることができる。前記担体、賦形剤
及び希釈剤の例には、水、乳糖、デキストロース、フラ
クトース、ショ糖、ソルビトール、マンニトール、ポリ
エチレングリコール、プロピレングリコール、でんぷ
ん、ガム、ゼラチン、アルギネート、ケイ酸カルシウ
ム、リン酸カルシウム、セルロース、水シロップ、メチ
ルセルロース、ポリビニルピロリドン、アルキルパラヒ
ドロキシベンゾエート、タルク、ステアリン酸マグネシ
ウム、ステアリン酸、グリセリン、ゴマ油、オリーブ
油、大豆油などの各種油が含まれる。The compounds of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical preparation. Examples of the carrier, excipients and diluents include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose. , Water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, and various oils such as soybean oil.
【００３６】本発明化合物は、これらの担体、賦形剤又
は希釈剤、そして、必要に応じて一般に使用される増量
剤、結合剤、崩壊剤、ｐＨ調整剤、溶解剤などの添加剤
が混合された上で、常用の製剤技術によって錠剤、丸
剤、カプセル剤、顆粒剤、粉剤、液剤、乳剤、懸濁剤、
軟膏剤、注射剤、皮膚貼付剤などの経口又は非経口用医
薬、特にグループ２メタボトロピックグルタミン酸受容
体作用薬として調製されることができる。本発明の化合
物は成人患者に対して０．０１〜５００ｍｇを１日１回
又は数回に分けて経口又は非経口で投与することが可能
であるが、使用の容易性及び薬効の点からみて経口投与
することが好ましい。なお、この投与量は治療対象とな
る疾病の種類、患者の年齢、体重、症状などにより適宜
増減することが可能である。The compound of the present invention comprises a mixture of these carriers, excipients or diluents and, if necessary, additives generally used such as extenders, binders, disintegrants, pH adjusters and solubilizers. Tablet, pill, capsule, granule, powder, liquid, emulsion, suspension,
It can be prepared as an oral or parenteral drug such as an ointment, an injection or a skin patch, particularly a Group 2 metabotropic glutamate receptor agonist. The compound of the present invention can be administered orally or parenterally to an adult patient in an amount of 0.01 to 500 mg once or several times a day, but from the viewpoint of ease of use and efficacy. Oral administration is preferred. The dose can be appropriately increased or decreased depending on the type of the disease to be treated, the age, weight, and symptoms of the patient.
【００３７】[0037]
【実施例】以下、実施例及び試験例を示し本発明を具体
的に説明する。ただし、それによって本発明をこれらの
例のみに限定するものでないことは云うまでもない。The present invention will be described below in detail with reference to examples and test examples. However, it goes without saying that the invention is not limited to these examples only.
【００３８】実施例１ (1SR,3RS,5RS,6SR)エチル ３−フルオロ−２−オキソビ
シクロ[3.1.0]ヘキサン−６−カルボキシレート、及び
(1SR,3SR,5RS,6SR)エチル ３−フルオロ−２−オキソビ
シクロ[3.1.0]ヘキサン−６−カルボキシレートの合成Example 1 (1SR, 3RS, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate, and
Synthesis of (1SR, 3SR, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate
【００３９】窒素雰囲気下、ｎ−ブチルリチウム３０.
９ｍｌ（１.５４Ｍヘキサン溶液）と1,1,1,3,3,3−ヘキ
サメチルジシラザン７.５０ｇから調製したリチウムビ
ストリメチルシリルアミドのテトラヒドロフラン１５０
ｍｌ中に、−７５℃でテトラヒドロフラン１５０ｍｌに
溶解した(1SR,5RS,6SR)エチル ２−オキソビシクロ[3.
1.0]ヘキサン−６−カルボキシレート６.６０ｇを滴下
した。この温度で１時間撹拌した後、クロロトリメチル
シラン７.５ｍｌを加え、室温で１時間撹拌した。反応
溶液を減圧下濃縮後、残渣に無水ヘキサンを加え、生じ
た無機塩を濾別し、濃縮した。In a nitrogen atmosphere, n-butyl lithium 30.
Lithium bistrimethylsilylamide tetrahydrofuran 150 prepared from 9 ml (1.54 M hexane solution) and 7.50 g of 1,1,1,3,3,3-hexamethyldisilazane
(1SR, 5RS, 6SR) ethyl 2-oxobicyclo [3.
1.0] Hexane-6-carboxylate (6.60 g) was added dropwise. After stirring at this temperature for 1 hour, 7.5 ml of chlorotrimethylsilane was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, anhydrous hexane was added to the residue, and the resulting inorganic salt was filtered off and concentrated.
【００４０】残渣を塩化メチレン６６ｍｌに溶解し、Ｎ
−フルオロベンゼンスルホンイミド１５.００ｇを加
え、室温で１６.５時間撹拌した。反応溶液を水で２回
洗浄後、無水硫酸ナトリウムで乾燥し、乾燥剤を濾別
後、減圧下、濃縮した。残渣をクロマトグラフィー（シ
リカゲル：ワコウゲル(和光純薬製)、展開溶媒：ヘキサ
ン−塩化メチレン−酢酸エチル＝６０：４：１）で精製
し、(1SR,3RS,5RS,6SR)エチル ３−フルオロ−２−オ
キソビシクロ[3.1.0]ヘキサン−６−カルボキシレート
と(1SR,3SR,5RS,6SR)エチル ３−フルオロ−２−オキ
ソビシクロ[3.1.0]ヘキサン−６−カルボキシレートの
混合物を４.３０ｇ得た。The residue was dissolved in 66 ml of methylene chloride,
-Fluorobenzenesulfonimide (15.00 g) was added, and the mixture was stirred at room temperature for 16.5 hours. The reaction solution was washed twice with water, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel: Wako gel (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: hexane-methylene chloride-ethyl acetate = 60: 4: 1), and (1SR, 3RS, 5RS, 6SR) ethyl 3-fluoro- A mixture of 2-oxobicyclo [3.1.0] hexane-6-carboxylate and (1SR, 3SR, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate was added to 4. 30 g were obtained.
【００４１】得られた化合物のプロトンＮＭＲとマスス
ペクトルデータを示す。1 Ｈ−ＮＭＲ(CDCl3)δ(ppm)；1.28(3Hx3/4,t,J=7.2Hz),
1.29(3Hx1/4,t,J=7.2Hz),2.11-2.79(5H,m),4.18(2H,q,J
=7.2Hz),4.51(1Hx1/4,dd,J=51Hz,8.1Hz),4.58(1Hx3/4,d
t,J=51Hz,8.1Hz) ＭＳ(FAB)(Pos)ｍ／ｅ；１８７(Ｍ+＋１)The proton NMR and mass spectrum data of the obtained compound are shown. 1 H-NMR (CDCl 3) δ (ppm); 1.28 (3Hx3 / 4, t, J = 7.2Hz),
1.29 (3Hx1 / 4, t, J = 7.2Hz), 2.11-2.79 (5H, m), 4.18 (2H, q, J
= 7.2Hz), 4.51 (1Hx1 / 4, dd, J = 51Hz, 8.1Hz), 4.58 (1Hx3 / 4, d
t, J = 51Hz, 8.1Hz) MS (FAB) (Pos) m / e; 187 (M ++ 1)
【００４２】実施例２ (1SR,3RS,5RS,6SR)エチル ３−フルオロ−２−オキソビ
シクロ[3.1.0]ヘキサン−６−カルボキシレート、及び
(1SR,3SR,5RS,6SR)エチル ３−フルオロ−２−オキソビ
シクロ[3.1.0]ヘキサン−６−カルボキシレートの合成Example 2 (1SR, 3RS, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate, and
Synthesis of (1SR, 3SR, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate
【００４３】窒素雰囲気下、ｎ−ブチルリチウム１.５
ｍｌ（１.５４Ｍヘキサン溶液）と1,1,1,3,3,3−ヘキサ
メチルジシラザン０.３８ｇから調製したリチウムビス
トリメチルシリルアミドのテトラヒドロフラン６ｍｌ中
に、−７５℃でテトラヒドロフラン６ｍｌに溶解した(1
SR,5RS,6SR)エチル ２−オキソビシクロ[3.1.0]ヘキサ
ン−６−カルボキシレート０.２０ｇを滴下した。この
温度で４５分間撹拌した後、Ｎ−フルオロベンゼンスル
ホンイミド０.７５ｇを加え、室温で２時間撹拌した。
反応溶液を水で２回洗浄後、無水硫酸ナトリウムで乾燥
し、乾燥剤を濾別後、減圧下、濃縮した。残渣をクロマ
トグラフィー（シリカゲル：ワコウゲル(和光純薬製)、
展開溶媒：ヘキサン−塩化メチレン−酢酸エチル＝６
０：４：１）で精製し、(1SR,3RS,5RS,6SR)エチル ３
−フルオロ−２−オキソビシクロ[3.1.0]ヘキサン−６
−カルボキシレートと(1SR,3SR,5RS,6SR)エチル ３−フ
ルオロ−２−オキソビシクロ[3.1.0]ヘキサン−６−カ
ルボキシレートの混合物を０.０８ｇ得た。Under a nitrogen atmosphere, n-butyllithium 1.5
in 1.5 ml of a 1.54 M hexane solution and 0.38 g of 1,1,1,3,3,3-hexamethyldisilazane were dissolved in 6 ml of tetrahydrofuran at −75 ° C. in 6 ml of tetrahydrofuran. (1
SR, 5RS, 6SR) Ethyl 0.20 g of 2-oxobicyclo [3.1.0] hexane-6-carboxylate was added dropwise. After stirring at this temperature for 45 minutes, 0.75 g of N-fluorobenzenesulfonimide was added, and the mixture was stirred at room temperature for 2 hours.
The reaction solution was washed twice with water, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The residue was chromatographed (silica gel: Wako gel (manufactured by Wako Pure Chemical Industries),
Developing solvent: hexane-methylene chloride-ethyl acetate = 6
0: 4: 1) to give (1SR, 3RS, 5RS, 6SR) ethyl 3
-Fluoro-2-oxobicyclo [3.1.0] hexane-6
0.08 g of a mixture of -carboxylate and (1SR, 3SR, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate was obtained.
【００４４】得られた化合物のプロトンＮＭＲとマスス
ペクトルデータを示す。1 Ｈ−ＮＭＲ(CDCl3)δ(ppm)；1.28(3Hx3/4,t,J=7.2Hz),
1.29(3Hx1/4,t,J=7.2Hz),2.11-2.79(5H,m),4.18(2H,q,J
=7.2Hz),4.51(1Hx1/4,dd,J=51Hz,8.1Hz),4.58(1Hx3/4,d
t,J=51Hz,8.1Hz) ＭＳ(FAB)(Pos)ｍ／ｅ；１８７(Ｍ+＋１)The proton NMR and mass spectrum data of the obtained compound are shown. 1 H-NMR (CDCl 3) δ (ppm); 1.28 (3Hx3 / 4, t, J = 7.2Hz),
1.29 (3Hx1 / 4, t, J = 7.2Hz), 2.11-2.79 (5H, m), 4.18 (2H, q, J
= 7.2Hz), 4.51 (1Hx1 / 4, dd, J = 51Hz, 8.1Hz), 4.58 (1Hx3 / 4, d
t, J = 51Hz, 8.1Hz) MS (FAB) (Pos) m / e; 187 (M ++ 1)
【００４５】実施例３ (1SR,5RS,6SR)エチル 3,3−ジフルオロビシクロ[3.1.0]
ヘキサン−６−カルボキシレートの合成Example 3 (1SR, 5RS, 6SR) ethyl 3,3-difluorobicyclo [3.1.0]
Synthesis of hexane-6-carboxylate
【００４６】窒素雰囲気下、ｎ−ブチルリチウム３０.
９ｍｌ（１.５４Ｍヘキサン溶液）と1,1,1,3,3,3−ヘキ
サメチルジシラザン７.５０ｇから調製したリチウムビ
ストリメチルシリルアミドのテトラヒドロフラン１５０
ｍｌ中に、−７５°Ｃでテトラヒドロフラン１５０ｍｌ
に溶解した(1SR,5RS,6SR)エチル ２−オキソビシクロ
[3.1.0]ヘキサン−６−カルボキシレート６.６０ｇを滴
下した。この温度で１時間撹拌した後、クロロトリメチ
ルシラン７.５ｍｌを加え、室温で１時間撹拌した。反
応溶液を減圧下濃縮後、残渣に無水ヘキサンを加え、生
じた無機塩を濾別し、濃縮した。残渣を塩化メチレン６
６ｍｌに溶解し、Ｎ−フルオロベンゼンスルホンイミド
１５.００ｇを加え、室温で１６.５時間撹拌した。反応
溶液を水で２回洗浄後、無水硫酸ナトリウムで乾燥し、
乾燥剤を濾別後、減圧下、濃縮した。残渣をクロマトグ
ラフィー（シリカゲル：ワコウゲル(和光純薬製)、展開
溶媒：ヘキサン−塩化メチレン−酢酸エチル＝６０：
４：１）で精製し、(1SR,5RS,6SR)エチル 3,3−ジフル
オロビシクロ[3.1.0]ヘキサン−６−カルボキシレート
を０.０２ｇ得た。Under a nitrogen atmosphere, n-butyl lithium 30.
Lithium bistrimethylsilylamide tetrahydrofuran 150 prepared from 9 ml (1.54 M hexane solution) and 7.50 g of 1,1,1,3,3,3-hexamethyldisilazane
150 ml of tetrahydrofuran at -75 ° C
(1SR, 5RS, 6SR) ethyl 2-oxobicyclo dissolved in
6.60 g of [3.1.0] hexane-6-carboxylate was added dropwise. After stirring at this temperature for 1 hour, 7.5 ml of chlorotrimethylsilane was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, anhydrous hexane was added to the residue, and the resulting inorganic salt was filtered off and concentrated. The residue was methylene chloride 6
The mixture was dissolved in 6 ml, and 15.00 g of N-fluorobenzenesulfonimide was added, followed by stirring at room temperature for 16.5 hours. After washing the reaction solution twice with water, drying over anhydrous sodium sulfate,
After filtering off the desiccant, it was concentrated under reduced pressure. The residue was chromatographed (silica gel: Wako gel (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: hexane-methylene chloride-ethyl acetate = 60:
4: 1) to give 0.02 g of (1SR, 5RS, 6SR) ethyl 3,3-difluorobicyclo [3.1.0] hexane-6-carboxylate.
【００４７】得られた化合物のプロトンＮＭＲとマスス
ペクトルデータを示す。1 Ｈ−ＮＭＲ(CDCl3)δ(ppm)；1.30(3H,t,J=7.1Hz),2.42
-2.80(5H,m),4.20(2H,q,J=7.1Hz) ＭＳ(Ion Spray)(Nega)ｍ／ｅ；２０３(Ｍ+−１)The proton NMR and mass spectrum data of the obtained compound are shown. 1 H-NMR (CDCl 3 ) δ (ppm); 1.30 (3H, t, J = 7.1 Hz), 2.42
-2.80 (5H, m), 4.20 (2H, q, J = 7.1Hz) MS (Ion Spray) (Nega) m / e; 203 (M + -1)
【００４８】実施例４ (1SR,5RS,6SR)エチル 3,3−ジフルオロビシクロ[3.1.0]
ヘキサン−６−カルボキシレートの合成Example 4 (1SR, 5RS, 6SR) ethyl 3,3-difluorobicyclo [3.1.0]
Synthesis of hexane-6-carboxylate
【００４９】窒素雰囲気下、ｎ−ブチルリチウム５.０
ｍｌ（１.５４Ｍヘキサン溶液）と1,1,1,3,3,3−ヘキサ
メチルジシラザン１.４０ｇから調製したリチウムビス
トリメチルシリルアミドのテトラヒドロフラン２６ｍｌ
中に、−７５℃でテトラヒドロフラン６.５ｍｌに溶解
した実施例１で合成した化合物１.３ｇを滴下した。こ
の温度で１時間撹拌した後、クロロトリメチルシラン
１.３ｍｌを加え、室温で１時間撹拌した。反応溶液を
減圧下濃縮後、残渣に無水ヘキサンを加え、生じた無機
塩を濾別し、濃縮した。In a nitrogen atmosphere, n-butyllithium 5.0
(1.54 M hexane solution) and 1.40 g of 1,1,1,3,3,3-hexamethyldisilazane in 26 ml of tetrahydrofuran of lithium bistrimethylsilylamide
Into this, 1.3 g of the compound synthesized in Example 1 dissolved in 6.5 ml of tetrahydrofuran at -75 ° C was added dropwise. After stirring at this temperature for 1 hour, 1.3 ml of chlorotrimethylsilane was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, anhydrous hexane was added to the residue, and the resulting inorganic salt was filtered off and concentrated.
【００５０】残渣を塩化メチレン１３ｍｌに溶解し、Ｎ
−フルオロベンゼンスルホンイミド３.３０ｇを加え、
室温で５時間撹拌した。反応溶液を水で２回洗浄後、無
水硫酸ナトリウムで乾燥し、乾燥剤を濾別後、減圧下、
濃縮した。残渣をクロマトグラフィー（シリカゲル：ワ
コウゲル(和光純薬製)、展開溶媒：ヘキサン−塩化メチ
レン−酢酸エチル＝６０：４：１）で精製し、(1SR,5R
S,6SR)エチル 3,3−ジフルオロビシクロ[3.1.0]ヘキサ
ン−６−カルボキシレートを０.３４ｇ得た。The residue was dissolved in 13 ml of methylene chloride,
-3.30 g of fluorobenzenesulfonimide are added,
Stir at room temperature for 5 hours. The reaction solution was washed twice with water, dried over anhydrous sodium sulfate, and the desiccant was filtered off.
Concentrated. The residue was purified by chromatography (silica gel: Wako gel (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: hexane-methylene chloride-ethyl acetate = 60: 4: 1), and (1SR, 5R)
(S, 6SR) ethyl 0.34 g of 3,3-difluorobicyclo [3.1.0] hexane-6-carboxylate was obtained.
【００５１】得られた化合物のプロトンＮＭＲとマスス
ペクトルデータを示す。1 Ｈ−ＮＭＲ(CDCl3)δ(ppm)；1.30(3H,t,J=7.1Hz),2.42
-2.80(5H,m),4.20(2H,q,J=7.1Hz) ＭＳ(Ion Spray)(Nega)ｍ／ｅ；２０３(Ｍ+−１)The proton NMR and mass spectrum data of the obtained compound are shown. 1 H-NMR (CDCl 3 ) δ (ppm); 1.30 (3H, t, J = 7.1 Hz), 2.42
-2.80 (5H, m), 4.20 (2H, q, J = 7.1Hz) MS (Ion Spray) (Nega) m / e; 203 (M + -1)
【００５２】実施例５ (1SR,2SR,3SR,5RS,6SR)エチル ２−スピロ−５´−ヒダ
ントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６
−カルボキシレート、(1SR,2SR,3RS,5RS,6SR)エチル
２−スピロ−５´−ヒダントイン−３−フルオロビシク
ロ[3.1.0]ヘキサン−６−カルボキシレート、及び(1SR,
2RS,3RS,5RS,6SR)エチル ２−スピロ−５´−ヒダント
イン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カ
ルボキシレートの合成Example 5 (1SR, 2SR, 3SR, 5RS, 6SR) ethyl 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6
-Carboxylate, (1SR, 2SR, 3RS, 5RS, 6SR) ethyl
2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylate, and (1SR,
Synthesis of 2RS, 3RS, 5RS, 6SR) ethyl 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylate
【００５３】(1SR,3RS,5RS,6SR)エチル ３−フルオロ−
２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシ
レートと(1SR,3SR,5RS,6SR)エチル ３−フルオロ−２−
オキソビロビシクロ[3.1.0]ヘキサン−６−カルボキシ
レートの混合物４.８４ｇを、水２６ｍｌとエタノール
３８ｍｌの混合溶液に溶解し、炭酸アンモニウム６.２
５ｇとシアン化カリウム１.８６ｇを加え３５°Ｃで３
７時間撹拌した。反応混合物を室温まで冷却後水３１ｍ
ｌを加え、更に氷冷下２.５時間撹拌し生じた結晶を濾
取し、２.１０ｇの第１結晶を得た。濾液に氷冷下濃塩
酸を加えｐＨを１.０に調整し、生成した結晶を濾取
し、２.００ｇの第２結晶を得た。(1SR, 3RS, 5RS, 6SR) ethyl 3-fluoro-
2-oxobicyclo [3.1.0] hexane-6-carboxylate and (1SR, 3SR, 5RS, 6SR) ethyl 3-fluoro-2-
4.84 g of a mixture of oxovirobicyclo [3.1.0] hexane-6-carboxylate was dissolved in a mixed solution of 26 ml of water and 38 ml of ethanol, and 6.2 ml of ammonium carbonate was added.
Add 5 g and 1.86 g of potassium cyanide, and add 3 g at 35 ° C.
Stir for 7 hours. After cooling the reaction mixture to room temperature,
After stirring for 2.5 hours under ice-cooling, the resulting crystals were collected by filtration to obtain 2.10 g of first crystals. Concentrated hydrochloric acid was added to the filtrate under ice cooling to adjust the pH to 1.0, and the generated crystals were collected by filtration to obtain 2.00 g of second crystals.
【００５４】第１結晶をクロマトグラフィー（シリカゲ
ル：ワコウゲル(和光純薬製)、展開溶媒：クロロホルム
−メタノール＝１００：１）に付し、低極性ジアステレ
オマーを０.６１ｇと極性ジアステレオマーＡ（極性ジ
アステレオマーＢを約２５％を含む、極性ジアステレオ
マーＡと極性ジアステレオマーＢのＲｆ値は同じ）０.
５５ｇに分離した。The first crystal was subjected to chromatography (silica gel: Wako gel (manufactured by Wako Pure Chemical Industries, Ltd., developing solvent: chloroform-methanol = 100: 1)), and 0.61 g of the low-polar diastereomer and polar diastereomer A were obtained. (Containing about 25% polar diastereomer B, polar diastereomer A and polar diastereomer B have the same Rf value)
Separated to 55 g.
【００５５】低極性ジアステレオマー０.６１ｇを水−
エタノール＝１：１の混合溶液より再結晶し、(1SR,2S
R,3SR,5RS,6SR)エチル ２−スピロ−５´−ヒダントイ
ン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カル
ボキシレートを０.５２ｇを得た。0.61 g of the low-polar diastereomer was dissolved in water-
Recrystallized from a mixed solution of ethanol = 1: 1, (1SR, 2S
0.52 g of (R, 3SR, 5RS, 6SR) ethyl 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylate was obtained.
【００５６】得られた化合物のプロトンＮＭＲとマスス
ペクトルデータを示す。1 Ｈ−ＮＭＲ(DMSO-d6)δ(ppm)；1.19(3H,t,J=7.0Hz),1.
95-2.46(5H,m),4.06(2H,q,J=7.0Hz),4.81(1H,dd,J=52H
z,5.1Hz),8.44(1H,s),10.91(1H,s) ＭＳ(ＥＩ)ｍ／ｅ；２５６(Ｍ+)The proton NMR and mass spectrum data of the obtained compound are shown. 1 H-NMR (DMSO-d 6 ) δ (ppm); 1.19 (3H, t, J = 7.0 Hz), 1.
95-2.46 (5H, m), 4.06 (2H, q, J = 7.0Hz), 4.81 (1H, dd, J = 52H
z, 5.1Hz), 8.44 (1H, s), 10.91 (1H, s) MS (EI) m / e; 256 (M + )
【００５７】また、極性ジアステレオマーＡ ０.５５
ｇを水−エタノール＝１：１の混合溶液より再結晶し、
(1SR,2SR,3RS,5RS,6SR)エチル ２−スピロ−５´−ヒダ
ントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６
−カルボキシレート０.３７ｇを得た。In addition, the polar diastereomer A 0.55
g was recrystallized from a mixed solution of water-ethanol = 1: 1,
(1SR, 2SR, 3RS, 5RS, 6SR) ethyl 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6
0.37 g of carboxylate were obtained.
【００５８】得られた化合物のプロトンＮＭＲとマスス
ペクトルデータを示す。1 Ｈ−ＮＭＲ(DMSO-d6)δ(ppm)；1.18(3H,t,J=7.1Hz),1.
85-2.43(5H,m),4.05(2H,q,J=7.1Hz),4.70(1H,dt,J=52H
z,8.0Hz),8.21(1H,s),10.83(1H,s) ＭＳ(ＥＩ)ｍ／ｅ；２５６(Ｍ+)The proton NMR and mass spectrum data of the obtained compound are shown. 1 H-NMR (DMSO-d 6 ) δ (ppm); 1.18 (3H, t, J = 7.1 Hz), 1.
85-2.43 (5H, m), 4.05 (2H, q, J = 7.1Hz), 4.70 (1H, dt, J = 52H
z, 8.0 Hz), 8.21 (1H, s), 10.83 (1H, s) MS (EI) m / e; 256 (M + )
【００５９】一方、第２結晶を酢酸エチルで洗浄し不溶
物を濾別後濾液を減圧下濃縮し、残渣を水−エタノール
＝１：１で２回再結晶した。この２回の再結晶濾液を減
圧下濃縮し、残渣をクロマトグラフィー（シリカゲル：
ワコウゲル(和光純薬製)、展開溶媒：クロロホルム−メ
タノール＝１００：１）に付し前記低極性ジアステレオ
マーを完全に除去した。得られた極性ジアステレオマー
Ｂ（極性ジアステレオマーＡを約１０％を含む）の結晶
０.２５ｇを水−エタノール＝１：１で再結晶を行
い、、(1SR,2RS,3RS,5RS,6SR)エチル ２−スピロ−５´
−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサ
ン−６−カルボキシレートを０.１８ｇ得た。On the other hand, the second crystals were washed with ethyl acetate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was recrystallized twice with water-ethanol = 1: 1. The two recrystallization filtrates are concentrated under reduced pressure and the residue is chromatographed (silica gel:
The product was subjected to Wako gel (manufactured by Wako Pure Chemical Industries, Ltd., developing solvent: chloroform-methanol = 100: 1) to completely remove the low-polar diastereomer. 0.25 g of the obtained crystals of polar diastereomer B (containing about 10% of polar diastereomer A) were recrystallized with water-ethanol = 1: 1 to give (1SR, 2RS, 3RS, 5RS, 6SR) ethyl 2-spiro-5 '
0.18 g of -hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylate was obtained.
【００６０】得られた化合物のプロトンＮＭＲとマスス
ペクトルデータを示す。1 Ｈ−ＮＭＲ(DMSO-d6)δ(ppm)；1.18(3H,t,J=7.1Hz),1.
81-2.17(4H,m),2.36(1H,dd,J=13Hz,7.2Hz),3.95-4.11(2
H,m),4.90(1H,ddd,J=51Hz,8.9Hz,7.2Hz),8.54(1H,s),1
0.87(1H,s) ＭＳ(ＥＩ)ｍ／ｅ；２５６(Ｍ+)The proton NMR and mass spectrum data of the obtained compound are shown. 1 H-NMR (DMSO-d 6 ) δ (ppm); 1.18 (3H, t, J = 7.1 Hz), 1.
81-2.17 (4H, m), 2.36 (1H, dd, J = 13Hz, 7.2Hz), 3.95-4.11 (2
H, m), 4.90 (1H, ddd, J = 51Hz, 8.9Hz, 7.2Hz), 8.54 (1H, s), 1
0.87 (1H, s) MS (EI) m / e; 256 (M + )
【００６１】なお、上記と同様にして下記の化合物を合
成した。(1SR,2SR,5RS,6SR)エチル ２−スピロ−５´−
ヒダントイン−3,3−ジフルオロビシクロ[3.1.0]ヘキサ
ン−６−カルボキシレートThe following compounds were synthesized in the same manner as described above. (1SR, 2SR, 5RS, 6SR) ethyl 2-spiro-5'-
Hydantoin-3,3-difluorobicyclo [3.1.0] hexane-6-carboxylate
【００６２】この化合物のプロトンＮＭＲとマススペク
トルデータを示す。1 Ｈ−ＮＭＲ(DMSO-d6)δ(ppm)；1.19(3H,t,J=7.0Hz),1.
85-1.89(1H,m),2.00-2.08(1H,m),2.15-2.27(1H,m),2.33
-2.50(1H,m),2.55-2.86(1H,m),4.07(2H,q,J=7.0Hz),8.4
9(1H,m) ＭＳ(ＥＩ)ｍ／ｅ；２７４(Ｍ+)The proton NMR and mass spectrum data of this compound are shown. 1 H-NMR (DMSO-d 6 ) δ (ppm); 1.19 (3H, t, J = 7.0 Hz), 1.
85-1.89 (1H, m), 2.00-2.08 (1H, m), 2.15-2.27 (1H, m), 2.33
-2.50 (1H, m), 2.55-2.86 (1H, m), 4.07 (2H, q, J = 7.0Hz), 8.4
9 (1H, m) MS (EI) m / e; 274 (M + )
【００６３】実施例６ (1SR,2SR,3RS,5RS,6SR)−２−アミノ−３−フルオロビ
シクロ[3.1.0]ヘキサン−2,6−ジカルボン酸の合成Example 6 Synthesis of (1SR, 2SR, 3RS, 5RS, 6SR) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
【００６４】(1SR,2SR,3RS,5RS,6SR)エチル ２−スピロ
−５´−ヒダントイン−３−フルオロビシクロ[3.1.0]
ヘキサン−６−カルボキシレート３００ｍｇを３Ｍ水酸
化ナトリウム水溶液２.５ｍｌに溶解し、１６時間加熱
還流した。反応溶液を室温まで冷却後、ガラスフィルタ
ーで濾過し、濾液を濃塩酸でｐＨ３にした後、イオン交
換クロマトグラフィー（ＡＧ１−Ｘ８ 陰イオン交換樹
脂(Ｂｉｏ−Ｒａｄ)、展開溶媒：０.１Ｍ酢酸〜３Ｍ酢
酸）で精製し、(1SR,2SR,3RS,5RS,6SR)−２−アミノ−
３−フルオロビシクロ[3.1.0]ヘキサン−２,６−ジカル
ボン酸を５１ｍｇ得た。(1SR, 2SR, 3RS, 5RS, 6SR) ethyl 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0]
Hexane-6-carboxylate (300 mg) was dissolved in a 3 M aqueous sodium hydroxide solution (2.5 ml), and the mixture was refluxed for 16 hours. The reaction solution was cooled to room temperature, filtered through a glass filter, the filtrate was adjusted to pH 3 with concentrated hydrochloric acid, and then subjected to ion exchange chromatography (AG1-X8 anion exchange resin (Bio-Rad), developing solvent: 0.1 M acetic acid). 3M acetic acid) to give (1SR, 2SR, 3RS, 5RS, 6SR) -2-amino-
51 mg of 3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained.
【００６５】得られた化合物のプロトンＮＭＲとマスス
ペクトルデータを示す。1 Ｈ−ＮＭＲ(TFA-d)δ(ppm)；2.23-2.24(1H,m),2.56-2.
96(4H,m),5.15(1H,dt,J=52Hz,7.5Hz) ＭＳ(ＣＩ)ｍ／ｅ；２０４(Ｍ+＋１)The proton NMR and mass spectrum data of the obtained compound are shown. 1 H-NMR (TFA-d ) δ (ppm); 2.23-2.24 (1H, m), 2.56-2.
96 (4H, m), 5.15 (1H, dt, J = 52 Hz, 7.5 Hz) MS (CI) m / e; 204 (M ++ 1)
【００６６】なお、上記と同様にして下記の化合物を合
成した。(1SR,2SR,5RS,6SR)−２−アミノ−3,3−ジフル
オロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸The following compounds were synthesized in the same manner as described above. (1SR, 2SR, 5RS, 6SR) -2-amino-3,3-difluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
【００６７】この化合物のプロトンＮＭＲとマススペク
トルデータを示す。1 Ｈ−ＮＭＲ(TFA-d)δ(ppm)；2.46(1H,brs),2.63-2.90
(3H,m),3.01-3.12(1H,m) ＭＳ(ＣＩ)ｍ／ｅ；２２２(Ｍ+＋１)The proton NMR and mass spectrum data of this compound are shown. 1 H-NMR (TFA-d ) δ (ppm); 2.46 (1H, brs), 2.63-2.90
(3H, m), 3.01-3.12 (1H, m) MS (CI) m / e; 222 (M ++ 1)
【００６８】実施例７ (1SR,2SR,3SR,5RS,6SR)−２−アミノ−３−フルオロビ
シクロ[3.1.0]ヘキサン−２,６−ジカルボン酸の合成Example 7 Synthesis of (1SR, 2SR, 3SR, 5RS, 6SR) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
【００６９】(1SR,2SR,3SR,5RS,6SR)エチル ２−スピロ
−５´−ヒダントイン−３−フルオロビシクロ[3.1.0]
ヘキサン−６−カルボキシレート１００ｍｇを６０％硫
酸水溶液１.５ｍｌに溶解し、１４０℃で１２時間加熱
した。反応溶液を室温まで冷却後、５Ｍ水酸化ナトリウ
ム水溶液でｐＨ８にした後、イオン交換クロマトグラフ
ィー（ＡＧ１−Ｘ８ 陰イオン交換樹脂（Ｂｉｏ−Ｒａ
ｄ）、展開溶媒：０.１Ｍ酢酸〜２Ｍ酢酸）で精製し、
(1SR,2SR,3SR,5RS,6SR)−２−アミノ−３−フルオロビ
シクロ[3.1.0]ヘキサン−2,6−ジカルボン酸を２０ｍｇ
得た。(1SR, 2SR, 3SR, 5RS, 6SR) ethyl 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0]
100 mg of hexane-6-carboxylate was dissolved in 1.5 ml of a 60% aqueous sulfuric acid solution and heated at 140 ° C. for 12 hours. The reaction solution was cooled to room temperature, adjusted to pH 8 with a 5 M aqueous sodium hydroxide solution, and then subjected to ion exchange chromatography (AG1-X8 anion exchange resin (Bio-Ra).
d), developing solvent: 0.1 M acetic acid to 2 M acetic acid)
20 mg of (1SR, 2SR, 3SR, 5RS, 6SR) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
Obtained.
【００７０】得られた化合物のプロトンＮＭＲとマスス
ペクトルデータを示す。1 Ｈ−ＮＭＲ(TFA-d)δ(ppm)；2.49(1H,brs),2.59-3.06
(4H,m),5.40(1H,dd,J=52Hz,5.3Hz) ＭＳ(ＣＩ)ｍ／ｅ；２０４(Ｍ+＋１)The proton NMR and mass spectrum data of the obtained compound are shown. 1 H-NMR (TFA-d ) δ (ppm); 2.49 (1H, brs), 2.59-3.06
(4H, m), 5.40 (1H, dd, J = 52Hz, 5.3Hz) MS (CI) m / e; 204 (M ++ 1)
【００７１】なお、上記と同様にして下記の化合物を合
成した。(1SR,2RS,3RS,5RS,6SR)−２−アミノ−３−フ
ルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸The following compounds were synthesized in the same manner as described above. (1SR, 2RS, 3RS, 5RS, 6SR) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
【００７２】この化合物のプロトンＮＭＲとマススペク
トルデータを示す。1 Ｈ−ＮＭＲ(TFA-d)δ(ppm)；2.33(1H,brs),2.54-2.89
(4H,m),5.42-5,59(1H,m) ＭＳ(ＣＩ)ｍ／ｅ；２０４(Ｍ+＋１)The proton NMR and mass spectrum data of this compound are shown. 1 H-NMR (TFA-d ) δ (ppm); 2.33 (1H, brs), 2.54-2.89
(4H, m), 5.42-5,59 (1H, m) MS (CI) m / e; 204 (M ++ 1)
【００７３】実施例８ (1S,2S,3S,5R,6S)−２−アミノ−３−フルオロビシクロ
[3.1.0]ヘキサン−2,6−ジカルボン酸の合成Example 8 (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo
[3.1.0] Synthesis of hexane-2,6-dicarboxylic acid
【００７４】(１) (1SR,2SR,3SR,5RS,6SR)エチル ２−
スピロ−５´−ヒダントイン−３−フルオロビシクロ
[3.1.0]ヘキサン−６−カルボキシレート２.２０ｇと２
Ｍ水酸化ナトリウム１７ｍｌの混合物を室温で撹拌し
た。２時間後、濃塩酸を加えｐＨを１.０に調整した。
生成した結晶を濾過により単離し、乾燥して(1SR,2SR,3
SR,5RS,6SR)２−スピロ−５´−ヒダントイン−３−フ
ルオロビシクロ[3.1.0]ヘキサン−６−カルボン酸を１.
８１ｇ得た。(1) (1SR, 2SR, 3SR, 5RS, 6SR) ethyl 2-
Spiro-5'-hydantoin-3-fluorobicyclo
[3.1.0] 2.20 g of hexane-6-carboxylate and 2
A mixture of 17 ml of M sodium hydroxide was stirred at room temperature. Two hours later, concentrated hydrochloric acid was added to adjust the pH to 1.0.
The resulting crystals were isolated by filtration, dried and dried (1SR, 2SR, 3
SR, 5RS, 6SR) 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid in 1.
81 g were obtained.
【００７５】この化合物のプロトンＮＭＲとマススペク
トルデータを示す。1 Ｈ−ＮＭＲ(DMSO-d6)δ(ppm)；1.85-2.44(5H,m),4.80
(1H,dd,J=52Hz,5.3Hz),8.44(1H,s),10.88(1H,s),12.30
(1H,brs) ＭＳ(FAB)(Nega)ｍ／ｅ；２２７(Ｍ+−１)The proton NMR and mass spectrum data of this compound are shown. 1 H-NMR (DMSO-d 6 ) δ (ppm); 1.85-2.44 (5H, m), 4.80
(1H, dd, J = 52Hz, 5.3Hz), 8.44 (1H, s), 10.88 (1H, s), 12.30
(1H, brs) MS (FAB) (Nega) m / e; 227 (M + -1)
【００７６】(２) (1SR,2SR,3SR,5RS,6SR)２−スピロ
−５´−ヒダントイン−３−フルオロビシクロ[3.1.0]
ヘキサン−６−カルボン酸１.８０ｇをアセトン：水＝
８：５の混合溶液２６ｍｌ中５５℃で撹拌し、(Ｒ)−
(＋)−1−フェニルエチルアミン０.９６ｇを加えた後、
室温で１５時間 撹拌した。生成した結晶を濾過し、(Ｒ)
−(＋)1−フェニルエチルアミン塩１.３０ｇを得た。な
お、濾液は実施例９において使用した。(2) (1SR, 2SR, 3SR, 5RS, 6SR) 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0]
1.80 g of hexane-6-carboxylic acid is dissolved in acetone: water =
The mixture was stirred at 55 ° C in 26 ml of a 8: 5 mixed solution, and (R)-
After adding 0.96 g of (+)-1-phenylethylamine,
Stirred at room temperature for 15 hours. The crystals formed are filtered and (R)
1.30 g of-(+) 1-phenylethylamine salt was obtained. The filtrate was used in Example 9.
【００７７】次に、この塩１.２０ｇを水１５ｍｌに懸
濁し、１Ｍ塩酸を用いてｐＨを１.０に調整し、室温で
１４時間撹拌した。生成した結晶を濾過により単離し(1
S,2S,3S,5R,6S)２−スピロ−５´−ヒダントイン−３−
フルオロビシクロ[3.1.0]ヘキサン−６−カルボン酸０.
６５ｇを得た。更に濾液はイオン交換クロマトグラフィ
ー（ＡＧ５０Ｗ−Ｘ８ 陽イオン交換樹脂(Ｂｉｏ−Ｒ
ａｄ)、展開溶媒：１Ｍ酢酸）で精製し、(1S,2S,3S,5R,
6S)２−スピロ−５´−ヒダントイン−３−フルオロビ
シクロ[3.1.0]ヘキサン−６−カルボン酸を０.０６ｇ得
た。この化合物の比旋光度は以下のとおりであった。22 ［α］D＝＋３６.８４(ｃ＝０.２０,ＭｅＯＨ)Next, 1.20 g of this salt was suspended in 15 ml of water, the pH was adjusted to 1.0 with 1M hydrochloric acid, and the mixture was stirred at room temperature for 14 hours. The resulting crystals were isolated by filtration (1
(S, 2S, 3S, 5R, 6S) 2-spiro-5'-hydantoin-3-
Fluorobicyclo [3.1.0] hexane-6-carboxylic acid 0.1
65 g were obtained. Further, the filtrate was subjected to ion exchange chromatography (AG50W-X8 cation exchange resin (Bio-R).
ad), developing solvent: 1M acetic acid), and purified by (1S, 2S, 3S, 5R,
6S) 0.06 g of 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid was obtained. The specific rotation of this compound was as follows. 22 [α] D = + 36.84 (c = 0.20, MeOH)
【００７８】(３) (1S,2S,3S,5R,6S)２−スピロ−５´
−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサ
ン−６−カルボン酸０.６０ｇを６０％硫酸水溶液１０
ｍｌに溶解し、１４０℃で２日間撹拌した。反応溶液を
室温まで冷却後、５Ｍ水酸化ナトリウム水溶液でｐＨ８
にした後、イオン交換クロマトグラフィー(ＡＧ１−Ｘ
８ 陰イオン交換樹脂（Ｂｉｏ−Ｒａｄ）、展開溶媒：
０.１Ｍ酢酸〜２Ｍ酢酸）で精製し、(1S,2S,3S,5R,6S)
−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン
−2,6−ジカルボン酸を０.３４ｇ得た。この化合物の比
旋光度は以下のとおりであった。22 ［α］D＝＋５８.６１(ｃ＝０.２０,１Ｎ ＨＣｌ)(3) (1S, 2S, 3S, 5R, 6S) 2-spiro-5 '
-0.60 g of hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid in 60% aqueous sulfuric acid 10
and stirred at 140 ° C. for 2 days. After cooling the reaction solution to room temperature, pH 8 with 5M aqueous sodium hydroxide solution.
After that, ion exchange chromatography (AG1-X
8 Anion exchange resin (Bio-Rad), developing solvent:
0.1M acetic acid to 2M acetic acid), and (1S, 2S, 3S, 5R, 6S)
0.34 g of -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained. The specific rotation of this compound was as follows. 22 [α] D = + 58.61 (c = 0.20, 1N HCl)
【００７９】実施例９ (1R,2R,3R,5S,6R)−２−アミノ−３−フルオロビシクロ
[3.1.0]ヘキサン−2,6−ジカルボン酸の合成Example 9 (1R, 2R, 3R, 5S, 6R) -2-amino-3-fluorobicyclo
[3.1.0] Synthesis of hexane-2,6-dicarboxylic acid
【００８０】(１) 実施例８(２)の濾液を減圧下、濃縮
した。得られた結晶１.３ｇと水１７ｍｌの混合物を１
Ｍ塩酸を用いてｐＨを１.０に調整し、室温で撹拌し
た。４時間後、生成した結晶を濾取し０.８１ｇの結晶
を得た。濾液はイオン交換クロマトグラフィー（ＡＧ５
０Ｗ−Ｘ８ 陽イオン交換樹脂(Ｂｉｏ−Ｒａｄ)、展開
溶媒：１Ｍ酢酸）で精製し、０.０８ｇの結晶を得た。(1) The filtrate of Example 8 (2) was concentrated under reduced pressure. A mixture of 1.3 g of the obtained crystals and 17 ml of water was added to 1
The pH was adjusted to 1.0 with M hydrochloric acid and stirred at room temperature. After 4 hours, the generated crystals were collected by filtration to obtain 0.81 g of crystals. The filtrate was subjected to ion exchange chromatography (AG5
Purification was performed using 0W-X8 cation exchange resin (Bio-Rad), developing solvent: 1 M acetic acid) to obtain 0.08 g of crystals.
【００８１】(２) 前記２つの結晶を合わせ(０.８９
ｇ)、アセトン：水=８：５の混合溶液１３ｍｌを加え、
５５℃で撹拌した。この溶液に(Ｓ)−(−)−1−フェニ
ルエチルアミン０.４７ｇを加えた後、室温で１５時間
撹拌した。生成した結晶を濾過し、(Ｒ)−(−)−1−フ
ェニルエチルアミン塩を１.１０ｇ得た。(2) The two crystals are combined (0.89)
g), 13 ml of a mixed solution of acetone: water = 8: 5 was added,
Stirred at 55 ° C. After adding 0.47 g of (S)-(-)-1-phenylethylamine to the solution, the mixture was stirred at room temperature for 15 hours. The generated crystals were filtered to obtain 1.10 g of (R)-(-)-1-phenylethylamine salt.
【００８２】この塩を実施例８の(２)と同様に１Ｍ塩酸
を用いてフリー体とし、(1R,2R,3R,5S,6R)２−スピロ−
５´−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘ
キサン−６−カルボン酸０.５８ｇを得た。濾液をイオ
ン交換クロマトグラフィー（ＡＧ５０Ｗ−Ｘ８ 陽イオ
ン交換樹脂(Ｂｉｏ−Ｒａｄ)、展開溶媒：１Ｍ酢酸）で
精製し、(1R,2R,3R,5S,6R)２−スピロ−５´−ヒダント
イン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カ
ルボン酸を０.０７ｇ得た。この化合物の比旋光度は以
下のとおりであった。22 ［α］D＝−３７.５２(ｃ＝０.２０,ＭｅＯＨ)This salt was converted into a free form with 1M hydrochloric acid in the same manner as in Example 8 (2), and (1R, 2R, 3R, 5S, 6R) 2-spiro-
0.58 g of 5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid was obtained. The filtrate was purified by ion exchange chromatography (AG50W-X8 cation exchange resin (Bio-Rad), developing solvent: 1 M acetic acid), and (1R, 2R, 3R, 5S, 6R) 2-spiro-5'-hydantoin- 0.07 g of 3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid was obtained. The specific rotation of this compound was as follows. 22 [α] D = −37.52 (c = 0.20, MeOH)
【００８３】(３)(1R,2R,3R,5S,6R)２−スピロ−５´−
ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン
−６−カルボン酸０.５８ｇを実施例８の(３)と同様に
反応し、(1R,2R,3R,5S,6R)−２−アミノ−３−フルオロ
ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸０.３７
ｇを得た。この化合物の比旋光度は以下のとおりであっ
た。22 ［α］D＝−５９.３６(ｃ＝０.２０,１Ｎ ＨＣｌ)(3) (1R, 2R, 3R, 5S, 6R) 2-spiro-5'-
0.58 g of hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid was reacted in the same manner as in Example 8, (3) to give (1R, 2R, 3R, 5S, 6R) -2-amino- 3-Fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid 0.37
g was obtained. The specific rotation of this compound was as follows. 22 [α] D = −59.36 (c = 0.20, 1N HCl)
【００８４】試験例１（被検薬のcＡＭＰ蓄積に及ぼす
効果） 代謝型グルタメ−ト受容体 ｍＧｌｕＲ２安定発現ＣＨ
Ｏ細胞を、１０％透析馬胎児血清含有ダルベッコ改変イ
−グル培地［１％Proline 50units/ml,Penicillin 50μ
g/ml,Streptomycin 2mM,L-glutamine（用時添加）］を
用いて１.２６×１０４cells/well/0.32cm2/150μlの割
合で９６穴プレ−トに播種し、３７℃、５％ＣＯ2下で
２日間培養を行った。その後、L-Glutamine free培地に
交換し、４時間後に上清を吸引除去し、１５０μｌのＰ
ＢＳ(＋)−ＩＢＭＸ(10mM PBS(-),1mM MgCl2,1mM CaC
l2,1mM IBMX)を添加して、２０分間、３７℃、５％ＣＯ
2存在下でインキュベ−ションを行った。再び上清を吸
引除去し、６０μｌの１０−５Ｍ Forskolin、１０−１
０〜１０−４Ｍの表１に示す被検体を含有したＰＢＳ
(＋)−ＩＢＭＸを添加して１５分間、３７℃で５％ＣＯ
2存在下インキュベ−ションを行い、Forskolin刺激ｃＡ
ＭＰ蓄積量に対するアゴニストの抑制効果の検討を行っ
た［コントロ−ルは、Forskolinと化合物無添加の条件
とした。（Tanabe et al,Neuron,8,169-179(199
2)）］。１００μｌの氷冷エタノールを添加して反応停
止し、上清を別のプレ−トに全量回収した後、エバポレ
ーターで常温乾固し、−２０℃で保存した。乾固したサ
ンプルは、ｃＡＭＰ EIA kit（アマシャム社）を用いて
ｃＡＭＰ量を定量した。各ｃＡＭＰ量からコントロ−ル
の値を差し引いた。１０−５ＭのForskolinで刺激を行
ったときのｃＡＭＰ蓄積を５０％抑制する被検薬の濃度
ＥＤ50値を求めた。結果を表１に示す。Test Example 1 (Effect of Test Drug on Accumulation of cAMP) Metabolic glutamate receptor mGluR2 stably expressed CH
O cells were cultured in Dulbecco's modified Eagle's medium containing 10% dialyzed fetal equine serum [1% Proline 50 units / ml, Penicillin 50 µl].
g / ml, Streptomycin 2mM, 96 well plate L-glutamine (before use additives) at a rate of 1.26 × 104cells / well / 0.32cm 2 / 150μl with - seeded on preparative, 37 ℃, 5% CO 2 days at 2 under and culture was performed. Thereafter, the medium was replaced with an L-Glutamine free medium, and after 4 hours, the supernatant was removed by suction, and 150 μl of P
BS (+)-IBMX (10 mM PBS (-), 1 mM MgCl 2 , 1 mM CaC
l 2 , 1 mM IBMX) and added at 37 ° C, 5% CO for 20 minutes.
Incubation was performed in the presence of 2 . The supernatant was again removed by suction, and 60 μl of 10-5M Forskolin, 10-1 was added.
0-10-4M PBS containing the analytes shown in Table 1
Add (+)-IBMX and add 5% CO at 37 ° C for 15 minutes
2 Perform incubation in the presence of Forskolin-stimulated cA
The inhibitory effect of the agonist on the amount of accumulated MP was examined [control was performed under the condition where Forskolin and the compound were not added. (Tanabe et al, Neuron, 8 , 169-179 (199
2))]. The reaction was stopped by the addition of 100 μl of ice-cold ethanol, and the supernatant was recovered in its entirety on another plate, then dried at room temperature with an evaporator and stored at −20 ° C. The cAMP amount of the dried sample was quantified using a cAMP EIA kit (Amersham). The control value was subtracted from each cAMP amount. CAMP accumulation when performing stimulation of Forskolin 10-5M concentrations were determined ED 50 values and 50% inhibition of the test drug. Table 1 shows the results.
【表１】 [Table 1]
【００８５】試験例２（マウスのメタンフェタミン運動
過多に及ぼす効果） 雄性ＩＣＲ系マウス（体重２３−３２ｇ、日本チャール
スリバー）を１群１１〜１２匹用いた。マウスは塩化ビ
ニール製円筒透明測定ケージ（直径３０ｃｍ、高さ３０
ｃｍ）に入れ９０分間環境順化させた。Test Example 2 (Effect on Excessive Exercise of Methamphetamine in Mice) 11-12 male ICR mice (body weight: 23-32 g, Charles River Japan) were used per group. The mouse is a vinyl chloride transparent measuring cage (diameter 30 cm, height 30)
cm) for 90 minutes.
【００８６】次に、マウスに表２に示す各化合物を経口
投与し、その３０分後にメタンフェタミンを１ｍｇ／ｋ
ｇ腹腔内投与した。その１５分後に自動活動量測定装置
（ＳＣＡＮＥＴ／ＳＶ−１０、東洋産業株式会社）を用
いてマウスの３０分間の運動量をカウント数により測定
した。前記各化合物は０.３％tween80−生理食塩水を溶
媒として、これに懸濁して使用した。Next, each compound shown in Table 2 was orally administered to a mouse, and 30 minutes later, 1 mg / k of methamphetamine was administered.
g was administered intraperitoneally. Fifteen minutes later, the amount of exercise of the mouse for 30 minutes was measured by a count using an automatic activity measuring device (SCANET / SV-10, Toyo Sangyo Co., Ltd.). Each of the above compounds was used as a suspension in 0.3% Tween 80-physiological saline as a solvent.
【００８７】そして、溶媒のみを投与したマウス群のカ
ウント数と、表２に示す各化合物を所定の用量づつ投与
したマウス群のカウント数より抑制率を求め、ＥＤ50値
を算出した。結果を表２に示す。なお、統計処理は分散
分析（ＡＮＯＶＡ）後、ダンネット検定によって行っ
た。Then, the inhibition rate was determined from the count number of the mouse group to which only the solvent was administered and the count number of the mouse group to which each compound shown in Table 2 was administered at a predetermined dose, and the ED 50 value was calculated. Table 2 shows the results. The statistical processing was performed by a Dunnett test after analysis of variance (ANOVA).
【００８８】表２に示されるように、比較例としてのＬ
Ｙ３５４７４０は０.０１ｍｇ／ｋｇ経口投与群を除
き、用量依存的にメタンフェタミン運動過多を抑制［Ｆ
(４,５４)＝３.２４２,Ｐ＜０.０５］するが、ＥＤ50値
は０.８７ｍｇ／ｋｇであった。一方、本発明化合物で
あるＣｏｍｐ．１についても同様な作用が認められ［Ｆ
(３,４３)＝３.３０６,Ｐ＜０.０５］たが、本発明化合
物のＥＤ50値は０.０５ｍｇ／ｋｇであり、ＬＹ３５４
７４０の１７.４倍のメタンフェタミン運動過多抑制効
果を有していた。As shown in Table 2, L as a comparative example
Y354740 suppressed methamphetamine hyperactivity in a dose-dependent manner except for the 0.01 mg / kg oral administration group [F
(4,54) = 3.242, P <0.05], but the ED 50 value was 0.87 mg / kg. On the other hand, the compound of the present invention, Comp. A similar effect was observed with respect to No. 1 [F
(3,43) = 3.306, P <0.05], however, the ED 50 value of the compound of the present invention is 0.05 mg / kg, and LY354
740 had a methamphetamine hyperactivity suppression effect of 17.4 times.
【表２】 [Table 2]
【００８９】[0089]
【発明の効果】本発明の含フッ素アミノ酸誘導体は医薬
として有用であり、特にメタボトロピックなグルタミン
酸受容体の作動薬として有用である。したがって、本発
明は、例えば精神分裂病、不安及びその関連疾患、うつ
病、二極性障害、てんかん等の精神医学的障害、例えば
薬物依存症、認知障害、アルツハイマー病、ハンチント
ン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳
虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患の
治療及び予防に使用することができる。Industrial Applicability The fluorine-containing amino acid derivative of the present invention is useful as a medicine, and particularly useful as a metabotropic glutamate receptor agonist. Accordingly, the present invention provides psychiatric disorders such as, for example, schizophrenia, anxiety and related disorders, depression, bipolar disorder, epilepsy, such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, It can be used for the treatment and prevention of neurological diseases such as movement disorders, cerebral ischemia, cerebral insufficiency, spinal cord disorders, and head disorders associated with muscle stiffness.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ａ６１Ｋ 31/195 ６０１ Ａ６１Ｋ 31/195 ６０１ 31/215 31/215 // Ｃ０７Ｍ 7:00 (72)発明者 冨沢 一雪 東京都豊島区高田３−24−１ 大正製薬株 式会社内──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 6 Identification code FI A61K 31/195 601 A61K 31/195 601 31/215 31/215 // C07M 7:00 (72) Inventor Kazuki Tomizawa Tokyo 3-24-1, Takada, Toshima-ku Taisho Pharmaceutical Co., Ltd.
Claims (6)
Ｒ2は同一又は異なって水素原子又は炭素原子数１−１
０のアルキル基を示す。］で表される含フッ素アミノ酸
誘導体、その医薬上許容される塩又はその水和物。(1) Formula (1) [In the formula, X 1 represents a hydrogen atom or a fluorine atom, and R 1 and R 2 are the same or different and represent a hydrogen atom or a carbon atom number of 1-1.
And represents an alkyl group of 0. And a pharmaceutically acceptable salt or hydrate thereof.
素原子数１−１０のアルキル基を示す。］で表される相
対的立体化学配置を有する含フッ素アミノ酸誘導体、そ
の医薬上許容される塩又はその水和物。2. The formula: [Wherein, R 1 and R 2 are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. And a pharmaceutically acceptable salt or hydrate thereof having the relative stereochemical configuration represented by the formula:
−アミノ−３−フルオロビシクロ［３．１．０］ヘキサ
ン−２，６−ジカルボン酸、その医薬上許容される塩又
はその水和物。3. (1S, 2S, 3S, 5R, 6S) -2
-Amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid, a pharmaceutically acceptable salt thereof or a hydrate thereof.
担体、賦形剤又は希釈剤と組み合わされた請求項１〜３
のいずれかに記載の化合物を含有してなる医薬的製剤。4. A composition according to claim 1, which is combined with one or more pharmaceutically acceptable carriers, excipients or diluents.
A pharmaceutical preparation comprising the compound according to any one of the above.
を有効成分とする医薬。A pharmaceutical comprising the compound according to any one of claims 1 to 3 as an active ingredient.
酸受容体作用薬である請求項５に記載の医薬。6. The medicament according to claim 5, which is a group 2 metabotropic glutamate receptor agonist.
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| JP01913799A JP4171549B2 (en) | 1998-01-28 | 1999-01-27 | Fluorine-containing amino acid derivatives |
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|---|---|---|---|
| JP1544498 | 1998-01-28 | ||
| JP10-15444 | 1998-01-28 | ||
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|---|---|
| JPH11279129A true JPH11279129A (en) | 1999-10-12 |
| JP4171549B2 JP4171549B2 (en) | 2008-10-22 |
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ID=26351584
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| WO2000012464A1 (en) * | 1998-08-31 | 2000-03-09 | Taisho Pharmaceutical Co., Ltd. | 6-fluorobicyclo[3. 1.0]hexane derivatives |
| WO2000037410A1 (en) * | 1998-12-18 | 2000-06-29 | Taisho Pharmaceutical Co., Ltd. | Intermediates and process for producing fluorine-containing amino acid compound by using the same |
| WO2013180271A1 (en) | 2012-06-01 | 2013-12-05 | 大正製薬株式会社 | Prodrug of fluorine-containing amino acid |
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| US6333428B1 (en) | 1998-08-31 | 2001-12-25 | Taisho Pharmaceutical Co., Ltd. | 6-fluorobicyclo[3.1.0]hexane derivatives |
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