MXPA97006280A - Compounds 4-aminotetrahidrobenzisoxasol oisotia - Google Patents
Compounds 4-aminotetrahidrobenzisoxasol oisotiaInfo
- Publication number
- MXPA97006280A MXPA97006280A MXPA/A/1997/006280A MX9706280A MXPA97006280A MX PA97006280 A MXPA97006280 A MX PA97006280A MX 9706280 A MX9706280 A MX 9706280A MX PA97006280 A MXPA97006280 A MX PA97006280A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- hydrogen
- lower alkyl
- compound according
- phenyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 149
- BTCSSZJGUNDROE-UHFFFAOYSA-N GABA Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229960003692 aminobutyric acid Drugs 0.000 claims abstract description 28
- PJHRLVTXAHMOOF-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1,2-benzoxazol-4-amine Chemical compound NC1C=CC=C2ONCC12 PJHRLVTXAHMOOF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 206010010904 Convulsion Diseases 0.000 claims abstract description 11
- 150000003854 isothiazoles Chemical class 0.000 claims abstract description 7
- 201000009457 movement disease Diseases 0.000 claims abstract description 6
- 230000003387 muscular Effects 0.000 claims abstract description 5
- 206010002855 Anxiety Diseases 0.000 claims abstract description 4
- 206010057666 Anxiety disease Diseases 0.000 claims abstract description 4
- 230000036506 anxiety Effects 0.000 claims abstract description 4
- 206010061920 Psychotic disease Diseases 0.000 claims abstract description 3
- 230000036592 analgesia Effects 0.000 claims abstract description 3
- 201000008125 pain agnosia Diseases 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 84
- 229910052739 hydrogen Inorganic materials 0.000 claims description 79
- 125000000217 alkyl group Chemical group 0.000 claims description 78
- 239000001257 hydrogen Substances 0.000 claims description 77
- -1 trifluoromethylsulfonyloxy Chemical group 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 239000011780 sodium chloride Substances 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 206010039911 Seizure Diseases 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 230000005062 synaptic transmission Effects 0.000 claims description 6
- ZLTPDFXIESTBQG-UHFFFAOYSA-N Isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 239000011593 sulfur Chemical group 0.000 claims description 5
- 206010015037 Epilepsy Diseases 0.000 claims description 4
- 201000001971 Huntington's disease Diseases 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 101710004852 CHR11 Proteins 0.000 claims description 2
- 206010061536 Parkinson's disease Diseases 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 2
- 125000004434 sulfur atoms Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 6
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 5
- 230000036461 convulsion Effects 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 91
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 86
- 239000000243 solution Substances 0.000 description 73
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 63
- 239000003921 oil Substances 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 46
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 229960004132 diethyl ether Drugs 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 229960000583 Acetic Acid Drugs 0.000 description 24
- 238000001704 evaporation Methods 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- 239000012362 glacial acetic acid Substances 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 101700067048 CDC13 Proteins 0.000 description 15
- 230000000875 corresponding Effects 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- 238000007792 addition Methods 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drugs Drugs 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 230000002518 glial Effects 0.000 description 8
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 8
- 239000001184 potassium carbonate Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- QRXWMOHMRWLFEY-UHFFFAOYSA-N Isoniazid Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 7
- 239000001961 anticonvulsive agent Substances 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 238000009835 boiling Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229960003350 isoniazid Drugs 0.000 description 7
- 230000001537 neural Effects 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M Potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M Sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N cdcl3 Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- BEOOHQFXGBMRKU-UHFFFAOYSA-N Sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- MVFGXYPEQHIKIX-UHFFFAOYSA-M heptane;acetate Chemical compound CC([O-])=O.CCCCCCC MVFGXYPEQHIKIX-UHFFFAOYSA-M 0.000 description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- 150000002923 oximes Chemical class 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000012047 saturated solution Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- JFSGRRMNDJRVJU-UHFFFAOYSA-N 3-ethoxy-6,7-dihydro-5H-1,2-benzoxazol-4-one Chemical compound C1CCC(=O)C2=C1ON=C2OCC JFSGRRMNDJRVJU-UHFFFAOYSA-N 0.000 description 4
- QTDZOWFRBNTPQR-UHFFFAOYSA-N Guvacine Chemical compound OC(=O)C1=CCCNC1 QTDZOWFRBNTPQR-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- GANYMSDHMBJFIL-UHFFFAOYSA-N acetonitrile;ethoxyethane Chemical compound CC#N.CCOCC GANYMSDHMBJFIL-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000003042 antagnostic Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- 230000003287 optical Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Chemical compound [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- TZBLRBGHRYONMS-UHFFFAOYSA-N 2,2-bis(2-methylphenyl)oxolane Chemical compound CC1=CC=CC=C1C1(C=2C(=CC=CC=2)C)OCCC1 TZBLRBGHRYONMS-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000000240 adjuvant Effects 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 230000001773 anti-convulsant Effects 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 125000004561 phenothiazin-10-yl group Chemical group C1=CC=CC=2SC3=CC=CC=C3N(C12)* 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrugs Drugs 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- QAHACWQRIKXIJN-UHFFFAOYSA-N (4-iodo-1-phenylbutyl)benzene Chemical compound C=1C=CC=CC=1C(CCCI)C1=CC=CC=C1 QAHACWQRIKXIJN-UHFFFAOYSA-N 0.000 description 2
- LMMIUFWBTKEQRR-UHFFFAOYSA-N 1-[4-iodo-1-(2-methylphenyl)but-1-enyl]-2-methylbenzene Chemical compound CC1=CC=CC=C1C(=CCCI)C1=CC=CC=C1C LMMIUFWBTKEQRR-UHFFFAOYSA-N 0.000 description 2
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OVUSYWFWHDZIPD-UHFFFAOYSA-N 2-(benzylamino)cyclohexene-1-carboxamide Chemical compound C1CCCC(C(=O)N)=C1NCC1=CC=CC=C1 OVUSYWFWHDZIPD-UHFFFAOYSA-N 0.000 description 2
- CUYUPLKTWHWPQY-UHFFFAOYSA-N 2-benzyl-1,3-oxazole Chemical compound C=1C=CC=CC=1CC1=NC=CO1 CUYUPLKTWHWPQY-UHFFFAOYSA-N 0.000 description 2
- VEJFDOHDNHTOHW-UHFFFAOYSA-N 2-oxocyclohexane-1-carboxamide Chemical compound NC(=O)C1CCCCC1=O VEJFDOHDNHTOHW-UHFFFAOYSA-N 0.000 description 2
- XXKGGHBAJABZTC-UHFFFAOYSA-N 3-methoxy-6,7-dihydro-5H-1,2-benzothiazol-4-one Chemical compound C1CCC(=O)C2=C1SN=C2OC XXKGGHBAJABZTC-UHFFFAOYSA-N 0.000 description 2
- MYNZKGAXSSVGTG-UHFFFAOYSA-N 4,4-bis(2-methylphenyl)but-3-en-1-amine Chemical compound CC1=CC=CC=C1C(=CCCN)C1=CC=CC=C1C MYNZKGAXSSVGTG-UHFFFAOYSA-N 0.000 description 2
- BTQORKQFMDTRNZ-UHFFFAOYSA-N 4,4-bis(2-methylphenyl)butan-1-ol Chemical compound CC1=CC=CC=C1C(CCCO)C1=CC=CC=C1C BTQORKQFMDTRNZ-UHFFFAOYSA-N 0.000 description 2
- JQINUNPUGXFBDU-UHFFFAOYSA-N 4,4-bis(2-methylphenyl)butyl acetate Chemical compound C=1C=CC=C(C)C=1C(CCCOC(=O)C)C1=CC=CC=C1C JQINUNPUGXFBDU-UHFFFAOYSA-N 0.000 description 2
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- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
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- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
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- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to 4-aminotetrahydrobenzisoxazole or isothiazole compounds having the general formula (Ia) and (Ib), wherein R1-R6, X and P are further defined in the description. The described compounds have a GABA (4-aminobutanoic acid) inhibition activity and are useful in the treatments of analgesia, psychosis, convulsions, anxiety or muscular and movement disorders, especially epileps.
Description
COMPOUNDS 4-AMINOTETRAHIDROBENZISOXAZOL O -ISOTIAZOL
DESCRIPTION OF THE INVENTION
The present invention relates to novel 4-aminotetrahydrobenzisoxazoles or isothiazoles having GABA uptake inhibition activity and thus are useful in the treatment of analgesia, psychosis, seizures, anxiety or muscular and movement disorders, such as spastic disorders or symptoms in Huntington's disease or Parkinson's. The anticonvulsant activity especially provides utility as broad spectrum antiepileptic agents.
BACKGROUND OF THE INVENTION
The neutral amino acid, 4-aminobutanoic acid (GABA), is an inhibitory transmitter in the central nervous system. There is considerable direct and indirect evidence of the odd operation of the inhibitory synapse mediated by GABA that may be an important causative factor in the attack disorders (P. Krogsgaard-Larsen et al., Epilepsy Res. 1987, 1, 77-93 ) that elicits the therapeutic antiepileptic agents of GABA-ergic drug potential.
In addition, the increase in GABA-ergic activity may be useful in the treatment of anxiety, pain, muscular and movement disorders and mental and emotional disorders (W. Lóscher, Eur. J. Pharmacol., 1985, 110, 103-108 ). While direct stimulation of GABA receptors by agonist does not seem to represent the most therapeutically suitable method for epileptic diseases
(RG Fariello et al., Eds., Neu transmitters, Seizures, and Epilepsy II, 1984, New York, Raven Press, B. Meldrum and R. Horton, Eur. J. Pharmacol., 1980, 61, 231-237; Krogsgaard-Larsen et al., J. Med. Chem. 1994, 37, 2489-2505.), The neurotransmission of GABA can be facilitated by manipulation of GABA uptake mechanisms. The pharmacological inhibition of neuronal and / or glial GABA transport, assumed to be responsible for the termination of GABA neurotransmission processes, provides a mechanism to sustain the levels of GABA released synaptically in the synapse and thereby increasing the mediated transmission by GABA (P. Krogsgaard-Larsen et al., J. Med. Chem. 1994, 37, 2489-2505). Strategies for such pharmacological interventions may be: 1) effective blockade of both neuronal and glial GABA uptake, or 2) selective blockade of GABA uptake in glial cells in order to increase the amount of GABA uptake by the carrier neuronal with subsequent elevation of GABA concentration in the nerve terminals. There is a clear suggestion that selective glia GABA uptake inhibitors may be of particular interest as antiepileptic agents (Falch et al., Drug Design and Delivery, 1987, 2, 9-21; Falch et al., Drug Dev. Res. ., 1990, 21, 169-188). The classic GABA uptake inhibitors are nipecotic acids guvacine and THPO. Oral N-substituted active derivatives of nipecotic acid and guvacine are described in F.E. Ali et al., J. Med. Chem. 1985, 28, 553-560; U.S. Patent 4,383,999 and U.S. Patent 4,514,414 to SmithKline Beckman Corporation; EP 236342 and EP 231996 for Novo Industri A / S and H.S. White et al., Eur. J. Pharmacol. 1993, 236 147-149. With respect to seizure, especially epilepsy, despite the fact that antiepileptic drugs are available, many patients fail to experience seizure control. Accordingly, it is an object of the present invention to provide new effective GABA-energetic drugs in the treatment of diseases associated with GABA neurotransmission, in particular attack control.
BRIEF DESCRIPTION OF THE INVENTION
It has not been found that a class of novel 4-aminotetrahydrobenzisoxazoles or isothiazoles inhibit the uptake of neuronal and / or glial GABA. Accordingly, the present invention relates to the compounds 4-aminotetrahydrobenzisoxazole or isothiazole having the general formula Ia or Ib:
where R R < are independently selected from the group consisting of: A) hydrogen, cycloalkyl, phenyl or a group R7 wherein R7, R8 and R9 are selected R8-C-9 independently of the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, phenoxy-lower alkyl and heteroaryl selected from 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, imidazolyl, oxazolyl , pyrazolyl, pyrimidinyl, pyrrolyl, thiazolyl, 1,2-triazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, any phenyl or heteroaryl group optionally present which is substituted with one or more substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulfonyl, lower alkyl, or lower dialkylamino, cyano, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfonyloxy and phenyl which again can be used er substituted with halogen, methyl, methoxy or trifluoromethyl; and any alkyl group present which is optionally substituted with one to three hydroxy groups which are again optionally esterified with a C2 carboxylic acid) a group of the general formula Y-tCH ^) - * - (CHR11 ) s- (CH2) t - where Y is selected from the following groups (1) - (5):
R7b R7b 10b R7b R 10b I \ i \ I R? B-C-U- C = C- N-CH- I R9b (1). pßb (2) R »(3);
wherein U is CHR10b, NR10b, 0 or S, U1 is NR10b, 0 or S; p is 0 or 1; q is 0 or 1; V is C or N and the dotted line represents a bond when V is C and no bond when V is N; A is 0, S, CH2, (CH2) 2, CH = CH-CH2, (CH2) 3, CH = CH or
0-CH2; Ra and Rb each represent one or more substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulfonyl, lower alkyl or lower dialkylamino, cyano, trifluoromethyl, trifluoromethylsulfonyloxy and trifluoromethylthio. r and t are independently 0, 1, 2 or 3, s is O or
1, with the proviso that when Y is a group (1) where U is NR10b, 0 or S or a group (4), then r + s + t is at least 2; and when Y is a group (3) or a group (5) where V is
N, then r + s + t is at least 1; R7b, R8b and R9b are as defined for R7, R8 and R9 in A) with the proviso that they are not at the same time selected from hydrogen, lower alkyl, lower alkenyl and lower alkynyl;
RlOb and R11 are independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl; Y
C) a group of the general formula YC- (CH2) -W- (CH2) m- wherein n is 1, 2 or 3, m is 2 or 3; W is O or S; and Yc is a group (1) - (5) as defined in B) with the proviso that n may not be 1, when Y is a group (1) or (4) where U or U1, respectively, is NR10b , S or O; D) a group of the general formula R ^^ Yd- (CH2) k-CH-. { CE2) 1 - where k is 0, 1, 2 • or 3; 1 is 0, 1, 2 or 3; Rlld is defined by R1-1- in B) above; and Y is selected from groups (2) and (5) as defined in B) above and the following groups (6) - (10):
7d R10 R7d R7d I I I RM-C- CH- C = N-p? D-C-CH = N- I / t R9d (6) p? D (7) R9d. { 8).
where p, q, Ra, Rb and A are as defined in B) and R7b-Rlld are as defined for R7b-R10b and R11, respectively under B) or R! and R2 together designate the alkylene therefore forming a ring containing nitrogen of 4-8 members; or one of R1 and R2 is a group R2 'OCO where R2' is phenyl, or heteroaryl as defined in A) above or phenyl or such heteroaryl substituted with one or more substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulfonyl, lower alkyl or lower dialkylamino, cyano, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfonyloxy, phenyl and phenyl substituted by halogen, methyl, methoxy or trifluoromethyl; R3 - R ^ are independently selected from hydrogen, hydroxy and lower alkyl, any alkyl group which is optionally substituted with one or more hydroxy groups; X is oxygen or sulfur; P is hydrogen or a group ZR where Z is CO, CS, S02 or CRfcRu, Rfc and Ru being hydrogen, hydroxy or lower alkyl and if Z is CO or CS, then R is selected from the groups consisting of: i) hydrogen, C 1 -C 18 alkyl, C 1 -C 18 alkenyl C 3 C 8 cycloalkenyl C 1 -C 8 cycloalkyl (en) yl alkoxy (C 4 -C 8) cycloalkenyl optionally substituted with one or more hydroxy groups, or phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, C1-C4 alkyl, C-] - C4 alkoxy, C1-C4 alkylthio, C-j_ acyloxy C5, or cyano; or ii) QRV wherein Q is 0 or S and Rv is selected from the substituents defined for R under i) above; and iii) NRXRY, wherein R and RY independently are selected from the substituents defined by R under i) above or Rx and RY are combined to form a four to eight member heterocyclic ring containing from one to three nitrogen atoms and zero to three oxygen or sulfur atoms, or if Z is CRtRu, R is selected from the groups consisting of: iv) a QRV group as defined in ii); v) an NRXRY group as defined in iii); or vi) a group OC (0) Rz, SC (0) Rz, OC (S) Rz or SC (S) RZ where Rz is selected from the substituents defined for R under i) above; if Z is S02, R is selected from the group of i) defined in the above;
with the proviso that P can not be hydrogen, when R1 to R6 are all hydrogen, X is oxygen and the compound exists as a racemic mixture; or pharmaceutically acceptable salts thereof. The compounds of the invention were found to inhibit the uptake of neuronal and / or glial GABA, some of the compounds predominantly inhibiting glial uptake. In this way, the compounds are useful in the treatment of diseases associated with GABA neurotransmission, for example analgesics, antipsychotics, anticonvulsants, or anxiolytic drugs or as drugs for the treatment of muscular and movement disorders, such as spastic disorders, or symptoms in Huntington's or Parkinson's disease. In another aspect of the invention there is provided a pharmaceutical composition comprising at least one of the novel 4-aminotetrahydrobenzisoxazoles or isothiazoles of the Formula I in a therapeutically effective amount together with a pharmaceutically acceptable carrier and / or diluent. In a further aspect of the present invention there is provided the use of 4-aminotetrahydrobenzisoxazoles or isothiazoles of the Formula I for the manufacture of a pharmaceutical preparation for the treatment of the disorders and diseases mentioned above.
Also, the present invention provides a method for the preparation of 4-amino-tetrahydrobenzisoxazoles or isothiazoles of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the general Formula I exist as optical isomers thereof and such optical isomers as well as any mixture thereof, including the racemic mixtures, are also encompassed by the invention. In the present context, the term "lower alkyl" designates the linear or branched alkyl of C-, 4, such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. Similarly, lower alkenyl and lower alkynyl designate such groups having above 4 carbon atoms and having at least one double or triple bond, respectively. Lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylamino, lower dialkylamino, etc., similarly designate such groups wherein the alkyl group is a lower alkyl group as defined above. The term cycloalkyl designates a saturated carbocyclic ring having from 3 to 7 carbon atoms, inclusive, and the term halogen defines F, Cl, Br or I.
The alk (ene) ino) yl means that the group can be an alkyl, alkenyl or alkynyl. Heteroaryl means 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, imidazolyl, oxazolyl, pyrazolyl, pyrimidinyl, pyrrolyl, thiazolyl, 1,2,4-triazolyl, 2-pyridyl, 3-pyridyl or 4- pyridyl. The compounds wherein P is a group ZR are prodrugs for the compounds wherein P is H. When P is H the compound exists in tautomeric form as follows:
Therefore, when they react with the appropriate reagent in order to introduce ZR, the group is introduced into the oxygen atom outside the isoxazole / isothiazole ring or at the ring nitrogen atom depending on the reaction conditions. Next, the compounds where P is H, are for the same convenience named as having the first mentioned form, that is, as having the formula la. Similarly, compounds where R1 or R2 is a group R2 '? CO are prodrugs for the corresponding compounds wherein R1 or R2 is hydrogen. The pharmaceutically acceptable acid addition salts of the compounds used in the invention are salts formed with non-toxic organic or inorganic acids. Examples of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulphonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic. , cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzenesulfonic and theophylline acetic, as well as the 8-haloteofilines, for example, 8-bromo-theophylline. Examples of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acid. It is preferred that R1 is a group as defined in A) above, namely, the (ene / ino) ilo lower optionally substituted with hydroxy which can be esterified with C2_22 carboxylic acid, preferably with a C2_4 carboxylic acid, or phenyl or phenyl-lower alkyl, optionally substituted by halogen, lower alkyl, lower alkoxy or trifluoromethyl; R1 which is most preferably methyl, ethyl or phenylbutyl;
B) above where Y is a group of the formula (1), (2) or (3), wherein R71D and R8b are phenyl, heteroaryl or phenyl or substituted heteroaryl, more preferably phenyl, phenyl substituted with halogen, lower alkyl , lower alkoxy or trifluoromethyl, 2-thienyl, 2-thienyl substituted with methyl, pyrrolyl or pyrrolyl substituted with methyl or ethyl. In particular Y is a group of the formula (1), where U is CH2 or 0 or a group of the formula (2), or Y is a group of the formula (4) or (5), where p and q are 0 it is either sulfur or -CH2CH2- and Ra and Rb are hydrogen. In the formula (1), (2) or (3) R9b is hydrogen, it is preferably hydrogen or lower alkyl, especially hydrogen and R10b is hydrogen, and in the formula (1), (2), (3),
(4) and (5) s is preferably 0 and r + t is 0-5, more preferably 1-3, more preferably 2. C) above, where Yc is a group of the formula (1) where U is CH2, a group of the formula (2), (3) or (5) in which R7b and R8b are phenyl, heteroaryl or substituted phenyl or heteroaryl, more preferably phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy or trifluoromethyl, 2-thienyl, 2-thienyl substituted with methyl, pyrrolyl or pyrrolyl substituted with methyl or ethyl. R9b is preferably halogen or lower alkyl, especially hydrogen, R1 (- | t) is hydrogen, and n + m is preferably 0-5, more preferably 1-3, most preferably 2, or D) above, where Y is a group of the formula (6), (7) u (8), wherein R7d and R8d are independently phenyl, phenyl substituted by halogen, lower alkyl, difluoromethyl or lower alkoxy, in particular, chloro, fluoro, methyl, trifluoromethyl, or methoxy, 2-thienyl, 2-thienyl substituted with lower alkyl; more preferably methyl, pyrrolyl or pyrrolyl substituted with methyl or ethyl. R9d-Rlld are preferably hydrogen and k + 1 is 0-4, most preferably 0-2, most preferably 1. R2 is preferably hydrogen, lower (ene / ino) ilo or a group R2 '? CO. More preferably R2 is hydrogen or lower alkyl, in particular hydrogen or methyl. Preferably R3 is hydrogen or lower alkyl, R4-R6 are hydrogen and X is oxygen. P is preferably hydrogen or a group ZR wherein Z is CRtRU, Rfc and Ru which are hydrogen, hydroxy or lower alkyl, more preferably hydrogen or methyl, and R is a group 0C (0) Rz, SC (0) Rz , OC (S) Rz or SC (S) RZ wherein Rz is a lower alko (ene) yl, in particular t-butyl, or optionally substituted phenyl; or where Z is CO or CS and R is NRXRY, wherein Rx and RY are hydrogen or lower alkyl or Rx and RY form a heterocyclic ring having one to two nitrogen atoms and which is optionally mono or disubstituted with oxo.
Preferably the compound has the structure of formula la. In particular, it is preferred that the group P is different from hydrogen when R1 is a preferred group selected from A) as defined above, especially a lower alko (ene / ino) yl and R2 is hydrogen or lower alko (ene / ino) yl . When R1 and / or R2 is a group that as defined under B), C) or D), it is preferred that P is hydrogen. In a preferred subclass of the compounds of the invention, R1 is a group as defined in A) namely, lower (ene / ino) yl optionally substituted with hydroxy which can be esterified with a c2-22 'carboxylic acid. Phenyl or phenyl-lower alkyl, optionally substituted with halogen, lower alkyl, lower alkoxy or trifluoromethyl, R 1 which is more preferably methyl, ethyl or phenylbutyl; R2 is hydrogen or lower alko (ene / ino) yl, in particular hydrogen or methyl; R3 is hydrogen or lower alkyl, in particular hydrogen or methyl, R4 - R ^ are hydrogen and X is oxygen; P is a group ZR wherein Z is CH2 or CH (CH3), and R is a group OC (0) Rz, wherein Rz is lower alkyl, or phenyl or heteroaryl optionally substituted; or where Z is CO and R is NRxRY, wherein Rx and RY are hydrogen or lower alkyl or Rx and RY form a heterocycle. In a further preferred subclass of the compounds of the invention R1 is a group as defined in B) above where s is 0 and r + t is 0-4, in particular 1-3, and Yb is a group of the formula (1) or (2), wherein R7b and R b are independently phenyl, phenyl substituted with halogen, lower alkyl, trifluoromethyl or lower alkoxy, in particular chlorine, fluorine, methyl, trifluoromethyl, or methoxy, 2-thienyl, 2-thienyl substituted with lower alkyl, more preferably methyl, pyrrolyl or pyrrolyl substituted with methyl or ethyl, R9b-R10b are hydrogens and U is CH2 or O or Yb is a group of the formula (5), where p and q are 0 and A is sulfur or -CH2CH2- and Ra and Rb are hydrogen; and R2, R3, R4-R6 and X are as defined in the above preferred subclass and P is hydrogen. According to another preferred subclass of the compounds of the invention R1 is a group as defined in C) above, wherein Y is a group of the formula (1), wherein U is CH2, or a group of the formula (3) or (5), in which formulas R7b and R8b are independently phenyl, phenyl substituted with halogen, lower alkyl, trifluoromethyl or lower alkoxy, in particular, chloro, fluoro, methyl, trifluoromethyl or methoxy, 2-thienyl, 2-thienyl substituted with lower alkyl, more preferably methyl, pyrrolyl or substituted pyrrolyl with methyl or ethyl, R9b and RlOb are hydrogen, W is 0, n is 1-3, most preferably 1, and m is 2-4, most preferably 2 or 3; and R2, R3, R4-R6 and X are as defined in the above preferred subclass and P is hydrogen. According to another preferred subclass of the compounds of the invention R1 is a group as defined in D) above, wherein Y is a group of the formula (6), (7) or (8), in which formulas R7d and R8d are independently phenyl, phenyl substituted with halogen, lower alkyl, trifluoromethyl, or lower alkoxy, in particular, chloro, fluoro, methyl, trifluoromethyl or methoxy, 2-thienyl, 2-thienyl substituted with lower alkyl, more preferably methyl, pyrrolyl, or pyrrolyl substituted with methyl or ethyl, R91, RlOd and R11 are hydrogen, W is O, k + 1 is 0-3, most preferably 1-2; and R2, R3, R4-6 and X are as defined in the above preferred subclass and P is hydrogen. The pharmaceutical compositions of this invention or those which are manufactured according to this invention can be administered by any suitable route, for example, orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. To prepare such compositions, methods well known in the art can be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives, usually accepted in the art, can be used. Conveniently, the compounds of the invention are administered in the dosage unit form containing the compounds in an amount of 0.1 to 1000 mg. The total daily dose is usually in the range of about 0.5-5000 mg, and more preferably from about 1.0 to 500 mg of the active compound of the invention. The method of the invention for preparing the novel compounds of the formula I comprises: a) In order to obtain a compound of the formula I wherein R2 is hydrogen, remove the acyl protecting group of a compound of the formula II or III :
"III
where R1, R3-R6, X and ZR are as defined above, and Ac is an acyl protecting group;
b) Alkylating an amine of the formula HNR1R2 where R1 and R2 both are as defined above, with an acetone of the formula IV or V:
IV
wherein R4-R6, X and ZR are as defined above, in the presence of a reducing agent; c) In order to obtain a compound of the formula I wherein P is H, eliminating the group B of the compound of the formula VI or VII:
where R1 - R ^ and X are as defined above, and B is lower alkyl, phenyl lower alkyl or a group ZR as defined above;
d) Reducing the double bond of a base Shiff, oxime, or oxime ether of the following formula VIII or IX:
where R1, R4-R6, X and ZR are as defined above. e) Arilating a compound of the formula X
where R1, R3-R6 and X are as defined above with an acylating agent of the formula R2 '-0-CO-hal, where hal is Cl or Br and R2' is as defined above. The starting material for the preparation of isoxazole intermediates of formulas II to X is 4,5,6,7-tetrahydro-1,2-benzisoxazol-3-ol, which is conveniently prepared to the method described by R. Jaquier et al. al., Bull. Soc. Chim. Fr. 1970, 5, 1978-1985. The starting material for the corresponding thioisoxazoles is cyclohexanone-2-carboxamide. Details for the conversion of these intermediates to compounds of the formula I are given in the Experimental Section. The acyl protection group in method a) is conveniently removed by aqueous hydrolysis catalyzed by bases (sodium or potassium hydroxide or potassium carbonate) or acids (hydrochloric or hydrobromic), hydrogenation of benzyloxycarbonyl or groups 1,1,1 -trichloroethyloxycarbonyl, or deprotection catalyzed by acid anhydride of for example, the t-Boc protection group. Hydrogenation also involves catalytic hydrogenation in a Parr apparatus, using Pd as a catalyst, or hydrogenation in the presence of metals such as zinc in aqueous acid solution such as dilute acetic acid. The amines used in the reductive alkylation in method b) are commercially available or prepared according to well established literature methods for example, as described in F.E. Ali et al., J. Med. Chem. 1985, 28, 553-560; U.S. Patent 4,383,999 and U.S. Patent 4,514,414 to SmithKline Beckmann Corporation; EP 236342 and EP 231996 to Novo Industri A / S and H.S. White et al., Eur. J. Pharmacol. 1993, 236, 147-149. NaBH4 or NaCNBH3 may be used, preferably in the presence of a dehydrating agent such as a molecular sieve, as a reducing agent in a protic solvent such as methanol, ethanol, water or mixtures thereof. The appropriate salts of the amines are used to obtain optimum pH conditions. The protective groups B in method c) are effectively removed by hydrolysis catalyzed by acid or base. If B is an O-alkyl group such as methoxy or ethoxy it can be conveniently removed by treatment with a strong acid (for example, 48% hydrobromic acid in glacial acetic acid) at elevated temperatures. The Schiff bases, oximes or oxime ethers in method d) are conveniently reduced to their corresponding amine derivatives by catalytic hydrogenation, using Pd or Pt as catalysts, or by reduction with amalgamated aluminum or LiAlH4 or AlH3.
Experimental Section The melting points are determined in an apparatus of
Büchi SMP-20 and they are not corrected. The mass spectra are obtained in a Quattro MS-MS system from VG Biotech, Fisons
Instruments The MS-MS system is connected to a modulated HP CLAP 1050 system. A volume of 20-50 μl of the sample (10 μg / ml) dissolved in a mixture of 1% acetic acid in acetonitrile / water 1: 1 is introduced, via self-sampling at a flow of 30 μl / min in the Electrospray Source. The spectrum is obtained in two standard sets of operating conditions. One set to obtain the molecular weight information (MH +) (21 eV) and the other set to induce the fragmentation patterns (70 eV). The background is subtracted. The relative intensities of the ions are obtained, of the fragmentation pattern. When intensity is not indicated by the molecular ion (MH +), this ion is only present under the first set of operating conditions. The 1 H NMR spectrum of the novel compounds is recorded at 250 MHz in a Bruker AC 250 spectrometer, at 200 MHz in a Bruker AC 200 F spectrometer, or in any other way established in the experiments. Deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) are used as solvents. The TMS is used as an internal reference standard. The chemical displacement values are expressed in ppm values. The following abbreviations are used for multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, c = quartet, qui = quintet, h = heptet, dd = double doublet, dt = double triplet dq = double quartet, tt = triple triplet, m = multiplet. The NMR signals that correspond to the acidic protons are generally omitted. The water content in the crystalline compounds is determined by Karl Fischer titration. The standard working procedures refer to the extraction with the indicated organic solvent of the appropriate aqueous solutions, drying of the combined organic extracts (anhydrous MgSO4 or Na2SO4), filtering and evaporating the solvent in vacuo. Column chromatography on silica gel of type Kieselgel 60, with ASTM 230-400 mesh is used.
Example 1 3-Ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazole The starting material 4,5,6,7-tetrahydro-1,2-benzisoxazole-3-ol is prepared according to to the procedure of the literature (R. Jaquier et al., Bull. Soc. Chim. Fr. 1970, 5, 1978-1985). To a solution of this isoxazole derivative (100 g) in acetone (3 1), potassium carbonate (200 g) is added. After heating at 50 ° C for
45 minutes, a solution of bromoethane is added by dripping
(170 ml) in acetone (300 ml), for 1.5 hours. The mixture is stirred overnight at 50 ° C. After cooling, the inorganic salts are filtered and removed and the acetone is evaporated in vacuo. The remaining mixture of the O- and N-alkylated product is separated by column chromatography on silica gel
(eluted with ethyl acetate / heptane 40:60). Evaporation of the solvents gives 65 g of the product of the compound as a viscous oil. X H NMR (CDCl 3): d 1.40 (t, 3 H), 1.70-1.85 (m, 4 H), 2.25-2.30 (m, 2 H), 2.50-2.60 (m, 2 H), 4.30 (c, 2 H).
Example 2 3-Ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-one, 2a (Method d)) It is added to a solution of 3-ethoxy-4,5,6-7. tetrahydro-1,2-benzisoxazole (35 g) in glacial acetic acid (500 ml) at 10 ° C, concentrated H2SO4 (29 ml). A solution of sodium dichromate (71 g) in glacial acetic acid (300 ml), kept at 40-45 ° C, is added dropwise for one hour at 20-25 ° C. The mixture is stirred for another 3 hours at
-30 ° C. The reaction mixture is poured into ice and diethylether
(3 1) The pH is adjusted to > 10 by the addition of concentrated aqueous NaOH. The organic phase is separated and worked. The remaining, non-purified title compound is purified by column chromatography on silica gel (eluted with ethyl acetate / heptane 1: 1). Wash in pure 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazole-l, 4-one with diisopropyl ether and dry. The yield is 27 g, P.f. 98-99 ° C.
Example 3 (R, S) -4-amino-3-ethoxy -4,5,6,7-tetrahydro-l, 2-benzisoxazole, 3a
It is added to a solution of 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-one 2a (8 g) in ethanol (400 ml), hydroxylammonium hydrochloride (20 g), Na 2 CO 3 (16 g), and water (600 ml). The mixture is heated at reflux temperature for 3 hours. The solvents are partially evaporated (2/3). The remaining mixture is left at room temperature for 0.5 hours and the precipitated crystalline product is finally removed by filtration, washed with water and dried. The yield of the oxime derivative is 7 g, P.f. 216-218 ° C. A sheet of aluminum (125 g) cut into small pieces (0.5 x 0.5 cm) is added to a solution of HgCl2 (200 g) in water (4 1). These pieces are left for about 1 minute and subsequently removed by filtration and washed with ethanol. The oxime derivative (25 g) is suspended in methanol (2 1) and water (500 ml) and the aluminum foil is added. The resulting mixture is stirred for 5 days. The precipitates are filtered off and washed with methanol. The combined methanol solutions are evaporated in vacuo. The remaining unpurified product is stirred with diethyl ether. The undissolved starting material (oxime) is removed by filtration and the diethyl ether is evaporated in vacuo to obtain the title compound as a visceral oil. Yield 23 g. ^ E NMR (CDC13) d 1.40 (t, 3H), 1.40-1.1.75 (m, 4H), 1.90-2.05 (m, 2H), 2.50-2.60 (m, 2H), 3.90 (broad t, ÍH) 4.30 (c, 2H).
Example 4 4-amino-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole bromohydrate 4a enantiomer A The (R, S) -4-amino-3-ethoxy-4 is dissolved , 5, 6, 7-tetrahydro-1,2-benzisoxazole 3a (17.5 g) in dichloromethane
(500 ml), and triethylamine (30 ml) is added at 5 ° C. A solution of (R) - (-) - α-methoxyphenylacetyl chloride (22 g) in dichloromethane (80 ml) is added dropwise at 5-10 ° C. The resulting mixture is stirred for 2 hours at room temperature. Water (2 1) is added and the organic phase is separated, washed with diluted hydrochloric acid and worked as above. The yield is 34 g. The diastereomers of this mixture are separated by preparative CLAP on silica gel (eluted with heptane / ethyl acetate 3: 2). The yield of the least polar diastereomer B is 13 g as an oil. The yield of the most polar diastereomer A is 11.5 g. P.f. 96-97 ° C. XH NMR. { CDCI3) d 1.30 (t, 3H), 1.80-2.05 (m, 4H), 2.45-2.75 (m, 2H), 3.30 (s, 3H), 4.25 (c, 2H), 4.60 (s, ÍH), 4.95 (dt, ÍH), 6.85 (broad d, HI), 7.30-7.45 (m, 5H). The diastereomer A (3.7 g) is dissolved in 48% aqueous hydrobromic acid (175 ml) and water (175 ml). The solution is refluxed for 1.25 hours. The solvent is evaporated in vacuo. Dichloromethane and water are added. The Organic phase is separated, washed with water and finally discharged. The aqueous phases are evaporated combined in vacuo. Ethanol / ether 1: 1 is added, the precipitates are filtered off, and upon evaporation of the solvents an impure crude hydrobromide salt 4a (enantiomer A) is obtained as an oil. The yield is 4.0 g. The purification is shown below in Examples 5 and 6. The unpurified bromohydrate salt of enantiomer B, 4b is correspondingly isolated from diastereomer B.
Example 5 4- (tert-butyloxycarbonylamino) -3-hydroxy-4,5,6,6-7-tetrahydro-1,2-benzisoxazole 5a enantiomer A. A mixture is dissolved in the bromohydrate 4-amino-3-hydroxy-4,5. , 6,7-tetrahydro-l, 2-benzisoxazole, 4a, enantiomer A of Example 4 (4.0 g) in a 1: 1 mixture of water / dioxane. After cooling to 10 ° C, a solution of NaOH (1.2 g in 12 ml of water) is added. The diterbutyl dicarbonate (3.5 g) dissolved in dioxane (12 ml) is added at 15-20 ° C. The mixture is stirred at room temperature for 1.5 hours. Water (120 ml) is added and the pH is adjusted to > 10 adding a small amount of NaOH. After stirring for an additional 30 minutes, diethyl ether (200 ml) is added. The organic phase is separated and discharged. The pH is adjusted to 3-4 by the addition of KHS04 and the aqueous phase is extracted with diethylether (2 x 100 ml). Work the combined organic phases as above, obtaining the title compound protected with Boc without purification. The pure title compound 5a is obtained by chromatography on silica gel (eluted with heptane / ethyl acetate / ethanol 7: 3: 1) Yield 0.9 g, Mp 135 ° C. XH NMR (CDC13) d 1.45 (s, 9H ), 1.75-2.10 (m, 4H), 2.45-2.70 (m, 2H), 4.50 (dt, ÍH), 5.05 (broad d, ÍH) The corresponding B enantiomer is prepared in a similar way: 4- (ter butyloxycarbonylamino) -3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole, 5b enantiomer BPf 134 ° C. The NMR spectrum is identical to the previous spectrum for compound 5a.
Example 6 (+) - 4-amino-3-hydroxy-4,5,6,7-tetrahydro-2-benzisoxazole hydrochloride, 6a (= (s) -isomer) The boc protected enantiomer 5a obtained in Example 5, the product (0.9 g) is dissolved in a saturated solution of HCl in ether (200 ml) and stirred at room temperature for 1.25 hours.The solvent is evaporated and the remaining oil is dissolved in a mixture. Ethanol in ether The precipitated crystalline title compound is filtered off Yield: 0.5 g Pf 209-210 ° C [o;] D = + 19.4 ° (c = 1.0 M, methanol) 1 H NMR (DMSO-dg) d 1.75-2.05 (m, 4H), 2.55-2.65 (m, 2H), 4.25 (broad t, ÍH), 8.40 (broad s, 4H), MS m / z (%): 155 ( MH + 49%, 138 (100%), 113 (16%), 65 (58%). The (-) isomer (or (R-) -isomer) is prepared in a corresponding form: (-) - hydrochloride (R) -4-amino-3-hydroxy-4,5,6,7-tetrahydro-l, 2-benzisoxazole, 6b, Pf 209-210 ° C. [] D = -20.0 ° (c = 1.0 M, The 1H NMR spectrum and EM are similar as pa to the above (+) -enantiomer. Compound 8a is resolved in a corresponding manner via the CLAP separation of the diastereomeric (R) - (-) -a-methoxyphenylacyl carboxamide derivatives of compound 7a. A modification of the method in Example 4 is used to separate the protection groups. (+) - 3-hydroxy-4-methylamino-4,5,6,7-tetrahydro-l, 2-benzisoxazole hydrobromide, 6c The more polar diastereomer (9 g) is dissolved, separated by means of CLAP chromatography in Dry THF, a solution of 1M lithium-triethylborohydride in dry THF (80 ml) is added dropwise over 20 minutes at 0-5 ° C. The mixture is further stirred overnight at room temperature. The mixture is placed on ice (500 g) and the pH is adjusted to 2 by the addition of concentrated hydrochloric acid. Evaporate to remove THF in the mixture by vacuum. The remaining aqueous solution is extracted twice with ethyl acetate (50 ml). The remaining aqueous solution is brought to an alkaline pH by addition of the concentrated NaOH solution (pH = 11). I Ethyl acetate (100 ml) is added and the organic phase is subsequently separated and worked as above. All the enantiomers of 3-ethoxy-4-methylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole (4.6 g) isolated in this way are dissolved in a mixture of Hbr in glacial acetic acid (150 ml) to 33%. The mixture is heated to 90 ° C and stirred for one hour. The solution is evaporated in vacuo. The remaining viscous oil is stirred with a 1: 1 ethanol / diethylether mixture. The precipitated hydrobromic acid salt is filtered off and dried overnight in vacuo. The yield is 4.2 g. P.f. 207-209 ° C. [o?] D = + 5.6 ° (C = 1.0 M, methanol). The NMR spectrum and EM are identical to the spectra of the racemic mixture, the enantiomeric compound 8a is purified by the CLAP: ee >determination; 99. The (-) - 3-hydroxy-4-methylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole, 6d hydrobromide is prepared analogously to the diastereomeric carboxamide derivative. P.f. 208-209 ° C. [a] D = 5.9 ° (c = 1.0 M, methanol). Enantiomeric purity by the determination CLAP: ee > 99
Example 7 (R, S) -3-ethoxy-4-methylamino-4,5,6,7-tetrahydro-l, 2-benzisoxa-zol 7a It is added to a solution of 3-ethoxy-4,5,6. , 7-tetrahydro-1,2-benzisoxazol-4-one 2a (4.5 g) in methanol (100 ml) methylamine hydrochloride (15 g), a 33% solution of methylamine (5 ml) in ethanol, and molecular sieve (3 Á). Finally, sodium cyanoborohydride (7 g) is added. The mixture is stirred overnight. The inorganic salts are filtered off and the solvents are evaporated in vacuo. Ethyl acetate and water are added and the pH is adjusted to > of 10 by the addition of a concentrated NaOH solution. The organic phase is subsequently worked as above. The crude title compound is used without further purification. The yield 4.8 g. ^ -H NMR (CDC13) d 1.40 (t, 3H), 1.65-1.80 (m, 3H), 1.85-2.00 (m, ÍH), 2.05 (s, ÍH), 2.45 (s, 3H), 2.50-2.60 (m, 2H); 3.60 (t, ÍH), 4.30 (c, 2H). The following 3-ethoxyisoxazoles are synthesized in a similar manner: (R, S) -4- [4, 4-bis (4-fluorophenyl) butan-1-ylamino] -3-ethoxy-4, 5, 6, 7- tetrahydro-l, 2-benzisoxazole 7b. 1 H NMR (CDCl 3) d 1.35 (t, 3 H), 1.40-1.55 (m, 3 H), 1.60-1.85 (m, 3 H), 1.90-2.10 (m, 3 H), 2.45-2.60 (m, 2 H), 2.65 (t, 2H), 3.70 (t, ÍH), 3.85 (t, ÍH), 4.30 (c, 2H); 6.95 (t, 4H), 7.15 (dd, 4H). (R, S) -3-ethoxy -4- (2-hydroxyethylamino) -4,5,6,7-tetrahydro-1,2-benzisoxazole 7c P.f. 72-74 ° C. H NMR (CDCl 3) d 1.40 (t, 3H), 1.65-2.00 (m, 4H), 2.45 (s, 2H), 2.45-2.70 (m, 2H), 2.85 (t, 2H), 3.60-3.70 (m , 2H), 3.75 (t, ÍH), 4.30 (c, 2H). (R, S) -3-ethoxy-4- (1-pyrrolidinyl) -4,5,6,7-tetrahydro-l, 2-benzisoxazole 7d XH NMR (CDCl 3) d 1.40 (t, 3H), 1.40-1.55 (m, 2H), 1.70-1.90 (, 6H), 2.00-2.25 (m, 2H), 2.50-2.80 (m, 4H), 3.25 (t, ÍH), 4.30 (of, 2H). (R, S) -4- (4,4-diphenylbutan-1-ylamino] -3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 7e Prepared via butylamine 30a and isolated as a oil. 1H NMR (CDCl3) d 1.35 (t, 3H), 1.40-1.50 (m, 2H), 1.60 (s, ÍH), 1.60-2.00 (m,
6H), 2.00-2.20 (m, 2H), 2.45-2.60 (m, 2H), 2.65 (t, 2H), 3.65
(t, ÍH), 3.85 (t, ÍH), 4.30 (c, 2H), 7.10-7.30 (m, 10H). (R, S) -4- (4-phenylbutan-1-ylamino] -3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazole-7f., Isolated as an oil XH NMR (CDCl 3) d 1.40 (t, 3H), 1.60 (s, ÍH), 1.50-2.00 (m, 8H), 2.50-2.70 (m, 6H), 3.70 (t, ÍH), 4.30 (c, 2H), 7.15-7.35 (m, 5H). (R, S) -4- (3,3-diphenylphenylpropan-1-ylamino] -3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 7g. oil. ^ -H NMR (CDCl 3) d 1.40 (t, 3H), 1.60 (s, ÍH), 1.60-1.80 (m, 4H), 1.85-2.00 (m, ÍH), 2.25 (c, 2H), 2.50 -2.65 (m, 3H), 3.65 (t, ÍH), 4.10 (t, ÍH), 4.25 (c, 2H), 7.15-7.35 (m, 10H). (R, S) -4- [N- [ 3- (10,11-dihydrodibenzo [a, d] cyclohept-5-ylidene) propane-1-yl] amino] -3-ethoxy -4,5,6,7-tetrahydro-1,2-benzisoxazole, 7h. Prepared via 3- (10,11-dihydrodibenzo [a, d] cyclohepty-5-ylidene) propylamine, hydrochloride (prepared as described in J. Org. Chem.
(1962). Vol. 27, 4134-37) and isolated as an oil. XH NMR (CDC13) d 1.40 (t, 3H), 1.50-2.05 (m, 6H), 2.35 (c, 2H),
2. 40-2.65 (m, 2H), 2.65-2.85 (m, 2H), 2.85-3.50 (m, 3H), 3.65
(t, ÍH), 4.25 (c, 2H), 5.90 (t, ÍH), 7.00-7.07 (m, ÍH), 7.07- 7.21 (m, 6H), 7.21-7.33 (m, ÍH).
EXAMPLE 8 Hydrochloride of (R, S) -3-hydroxy-4-methylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole, 8a (Method c). A solution of (R, S) -3-ethoxy-4-methylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole 7a (3.8 g) in a solution of 33% HBr in glacial acid is heated acetic acid (150 ml) at 60-75 ° C for one hour. The solvents are evaporated in vacuo and a mixture of ethanol / ether 1: 1 is added. The crystalline hydrobromic salt 8a is filtered. Yield: 3.6 g.
P.f .: 184-186 ° C. Ifí NMR (DMSO-dg) d 1.75-2.15 (m, 4H), 2.65 (s, 3H), 2.60-2.70 (m, 2H), 4.20 (broad signal, ÍH), 8.60 (s broad, ÍH). The following compounds are synthesized correspondingly: (R, S) -4- [4, 4-bis (4-fluorophenyl) butan-1-ylamino] -3-hydroxy-4,5,6,7-tetrahydrohydrobromide. 1,2-benzisoxazole, 8b Pf 205-206 ° C. XH NMR (DMSO-dg) d 1.45 (1.60 (m, 2H); 1.70-2.10 (m, 6H), 2.55-2.70 (m, 2H), 3.05 (t, 2H), 4.00 (t, ÍH), 4.20 (s broad, ÍH), 7.15 (t, 4H), 7.35 (dd) , 4H), MS m / z (%): 399 (MH + 4%), 138 (100%) 67 (84%). hydrobromide of (R, S) -4- (2-acetyloxyethylamino) -3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole, 8c. P.f. 164-165 ° C. iH NMR (DMSO-dg) d 1.75-1.95 (m, 2H), 2.00-2.20 (m, 2H), 2.10 (s, 3H), 2.55-2.70 (m, 2H), 3.30 (t, 2H), 4.20 -4.40 (m, 3H), MS m / z (%): 241 (MH + 17%), 138 (59%), 67 (100%), 41 (84%). hydrobromide of (R, S) -3-hydroxy-4- (1-pyrrolidinyl) -4,5,6,7,7-tetrahydro-1,2-benzisoxazole, 8d P.f. 209-210 ° C H NMR (DMSO-dg) d 1.70-2.30 (m, 8H), 2.60-2.75 (m, 2H), 3.10-3.70 (m, 4H), 4.35 (s broad, ÍH) MS m / z (%): 209 (MH +, 5%), 138 (35%), 72 (56%), 67 (100%), 41 (79%). oxalate of the (R, S) -4- (2-propenyl-ylamino) -3-hydroxy-4,5,6,7-tetrahydro-l, 2-benzisoxazole, (acetone) 8f. This compound is purified via the 4-tert-butyloxy-carbonyl-amino derivative, which is deprotected as described in Example 8b. P.f. 182-183 ° C. ^ NMR (DMSO-dg) d 1.75-2.20 (m, 4H), 2.60-2.75 (m, 2H), 3.65 (d, 2H), 4.15 (broad s, ÍH), 5.40 (d, ÍH), 5.45 ( d, ÍH), 5.85-6.00 (m, ÍH), 7.70 (broad signal, 3H), MS m / z (%): 195 (MH +, 9%), 138 (57%), 67 (100%), 41 (92%).
(R, S) -4- (4,4-diphenylbutan-1-ylamino] -3-hydroxy-4,5,6,7-tetrahydro-l, 2-benzisoxazole hydrobromide, 8g, Pf 221-222 ° C (ethanol, XH NMR (DMSO-dg) d 1.45-1.65 (m, 2H), 1.70-2.10 (ra, 6H), 2.55-2.75 (m, 2H), 3.05 (t, 2H), 3.95 (t, ÍH), 4.20 (s broad, ÍH), 7.15-7.40 (m, 10H), MS m / z (%): 363 (MH +, 100%), 138 (89%), hydrobromide of (R, S) -4- (4-Phenylbut-1-ylamino] -3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole, 8h Pf 202-204 ° C (ethanol) .MRN (DMSO-) dg) d 1.55-1.65 (m, 4H), 1.70-2.15 (m, 4H), 2.50-2.70 (m, 4H), 3.00 (broad t, 2H), 4.25 (broad s, ÍH), 7.15-7.35 ( m, 5H), MS m / z (%): 287 (MH +, 6%), 138 (100%), 91 (42%), 67 (63%), hydrobromide of (R, S) -4- (3, 3-diphenylpropan-1-ylamino] -3-hydroxy-4,5,6,6,7-tetrahydro-1,2-benzisoxazole, 8i, Pf 218-220 ° C (ethanol).? E NMR (DMSO- dg) d 1.70-2.10 (m, 4H), 2.40 (t, 2H), 2.55-2.70 (m, 2H), 2.95 (t, 2H), 4.05 (t, ÍH), 4.25 (s broad, ÍH), 7.15-7.40 (m, 10H) MS m / z (%): 349 (MH +, 5%), 138 (100%), 67 (30%). The following compounds are prepared in a similar manner, except that the title compounds are crystallized from acetone (8j, 8k, 81, 8m, 8n, 8p) or diethyl ether (8o). hydrobromide of the (R, S) -4- [N- [3- (10,11-dihydrodibenzo [a, d] cyclohepty-5-ylden) propan-1-yl] amino] -3-hydroxy-4, 5 6,7-tetrahydro-l, 2-benzisoxazole, 8j. P.f. 228-230 ° C (decomposition). H NMR (DMSO-dg) d 1.55-2.00 (m, 4H), 2.15-2.65 (m, 4H), 2.65-3.00 (, 4H), 3.10-3.40 (m, 2H), 3.77-3.87 (m, ÍH ), 5.80 (t, ÍH), 7.00-7.28 (m, 8H), MS m / z (%): 387 (MH +, 5%), 233 (7%), 138 (41%), 43 (100% ) hydrobromide of (R, S) -4- [N- [3- (10,11-dihydrobenzo [a, d] cyclohepty-5-ylidene) propan-1-yl] methylamino] -3-hydroxy-4, 5, 6, 7-tetrahydro-l, 2-benzisoxazole, 8k. P.f. 215-217 ° C (decomposing) H NMR (DMSO-dg) d 1.70-2.10 (m, 4H), 2.40-2.95 (m, 6H), 3.05-3.44 (m, 7H), 4.34-4.43 (m, 1H) ), 5.80 (t, ÍH), 7.05-7.30 (m, 8H), MS m / z (%): 401 (MH +, 26%), 265 (66%), 233 (30%), 138 (84% ), 43 (100%) hydrobromide of (RS) -4- [N-3- (phenothiazin-10-yl) propan-1-yl] amino] -3-hydroxy-4,5,6,6-tetrahydro -l, 2-benzisoxazole, 81. Pf 187-189 ° C. H NMR (DMSO-dg) d 1.65-2.12 (m, 6H), 2.50-2.71 (m, 2H), 3.00-3.16 (m, 2H), 3.95 (t, 2H), 4.09-4.20 (m, ÍH) , 6.97 (dd, 2H), 7.07 (d, 2H), 7.10-7.26 (m, 4H), MS m / z (%): 394 (MH +, 3%), 256 (7%), 138 (18% ), 43 (100%) hydrobromide of (R, S) -4- [N- [4, 4-di (2-tolyl) butan-1-yl] methylamino] -3-hydroxy-4, 5,6 , 7-tetrahydro-l, 2-benzisoxazole, 8m. P.f. 193-195 ° C (decomposition). H NMR (DMSO-dg) d 1.65-2.20 (m, 8H), 2.26 (s, 6H), 2.55-2.80 (m, 5H), 3.15-3.35 (m, 2H), 4.25 (t, ÍH), 4.36 -4.47 (m, ÍH), 7.03-7.21 (m, 8H), MS m / z (%): 405 (MH +, 4%), 268 (27%), 138 (30%), 43 (100%) hydrobromide of (R, S) -4 - [N- [4, 4-di- (2-tolyl) butan-1-yl] amino] -3-hydroxy-4,5,6,6-tetrahydrole , 2-benzisoxazole, 8n. P.f. 217-219 ° C (decomposition). XH NMR
(DMSO-dg) d 1.55-2.18 (m, 8H), 2.25 (d, 6H), 2.52-2.75 (m, 2H), 3.06 (t, 2H), 4.13-4.27 (m, 2H), 7.03-7.20 (m, 8H), MS m / z (%): 391 (MH +, 7%), 195 (15%), 145 (80%), 138 (92%), 105
(100%) (R, S) -4- [N- [1,1-dim- (2-tolyl) but-l-en-4-yl] -methylamino] -3-hydroxy-4,5,6,7-tetrahydro -l, 2-benzisoxazole 8o. P.f. 177-179 ° C. H NMR (DMSO-dg) d 1.70-2.14 (m, 8H), 2.21 (s, 3H), 2.36-2.80 (m, 6H), 3.15-3.40 (m, 2H), 4.35-4.47 (m, ÍH) , 5.74 (t, ÍH), 6.98-7.30 (m, 8H) MS m / z (%): 403 (MH +, 19%), 266 (40%), 143 (77%), 138 (100%), 105 (49%), 67 (20%). hydrobromide of (R, S) -4- [Nl, 1-di- (2-tolyl) but-1-en-4-yl] amino] -3-hydroxy-4,5,6,6-tetrahydro- 1, 2-benzisoxazole, 8p. P.f. 209-211 ° C (decomposition). H NMR (DMSO-dg) d 1.70-2.15 (m, 7H), 2.22 (s, 3H), 2.27-2.45 (m, 2H), 2.54-2.73 (m, 2H), 3.11 (t, 2H), 4.16 -4.24 (m, ÍH), 5.73 (t, ÍH), 6.96-7.26 (m, 8H), MS m / z (%): 389 (MH +, 5%), 143 (33%), 138 (100% ); 105 (29%), 67 (44%).
Example 8B (R, S) -3-Hydroxy-4-methylamino-4,5,6,7-tetrahydro-1 hydrobromide, 2-benzisoxazole, 8a (Method)) This method is an alternative form to the method in Example 8A to prepare compound 8a and similar derivatives. A solution of diterbutyl dicarbonate (3.56 g) in THF (50 ml) is added to a solution of (R, S) -3-ethoxy-4-amino-4,5,6,7-tetrahydro-1 hydrobromide. , 2-benzisoxazole, 3a (2.60 g) and potassium carbonate (2.07 g) in water (25 ml). The mixture is stirred at room temperature for 20 hours and evaporated. Water (30 ml) is added to the residue and the mixture is extracted with ether (3 x 50 ml). Dry the combined organic extracts and evaporate, and recrystallize the ether / light petroleum residue to give (R, S) -3-ethoxy-4- (tert-butyloxycarbonylamino) -4,5,6,7-tetrahydro- 1,2-benzisoxa-zol (2.69 g). P.f. 111-113 ° C. Sodium hydride in 60% mineral oil (425 mg) is added portionwise to a solution of the compound (1.00 g) and methyl iodide (2.18 ml) in THF (45 ml). The mixture is stirred overnight at room temperature and methanol is added to destroy excess sodium hydride. After evaporation water (25 ml) is added to the residue. Extracting with ethyl acetate (3 x 50 ml), drying and evaporating yields (R, S-3-ethoxy-4- (N-methyl-tert.-butyloxycarbonylamino) -4,5,6,7-tetrahydro- 1, 2-benzisoxazole (1.05 g) as a yellow oil.H NMR (60 MHz, CDC13) d 1.40 (t, 3H), 1.55 (s, 9H), 1.65-2.2 (m, 4H), 2.55 (m, 2H), 2.60 (s, 3H), 4.35 (c, 2H), 5.20 (m, 1H) A 33% solution of hydrobromic acid in glacial acetic acid (15 ml) is added to (R, S) -3 -ethoxy-4- (N-methyl-tert-butyloxycarbonylamino) -4,5,6,7-tetrahydro-1,2-benzisoxazole (1.05 g) and the mixture is stirred at 80 ° C for 25 minutes. After evaporation, 33% hydrobromic acid in glacial acetic acid (15 ml) is added to the residue and the mixture is stirred at 80 ° C. for 25 minutes.The evaporation and recrystallization of the residue (acetonitrile-ethanol-ether) gives the compound of the title (807 mg): mp 188-190 ° C. XH NMR (60 MHz, D20) d 2.05 (m, 4H), 2.75 (m, 2H), 2.85 (s, 3H), 4.35 (m, ÍH) The next compound is prepared e in a similar manner using ethyl iodide in place of methyl iodide: hydrobromide of (R, S) -4-ethylamino-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 8e. P.f. 188-191 ° C (from acetonitrile-ethanol-ether). X H NMR (60 MHz, D 20) d 1.30 (t, 3 H), 2.05 (m, 4 H), 2.70 (m, 2 H); 3.25 (c, 2H), 4.35 (m, ÍH).
Example 9 Hydrochloride of (R, S) -4- (2-hydroxyethylamino) -3-hydroxy-4,5,6,7-tetrahydro-l, 2-benzisoxazole, 9a. To a solution of (R, S) -4- (2-acetyloxyethylamino) -3-hydroxy-4,5,6,6-tetrahydro-1,2-benzisoxazole hydrochloride, 8c. Add (1.3 g) in water (50 ml), a 48% aqueous solution of HBr (7 ml). The mixture is heated at 100 ° C for one hour. The solvent is evaporated in vacuo and the remaining oil is dissolved in ethanol. Upon evaporation of a larger fraction of the ethanol, the hydrobromide salt of compound 9a crystallizes and is subsequently removed by filtration, and dried. Yield: 0.9 g. P.f. 172-173 ° C. H NMR (DMSO-dg) d 1.70-1.95 (m, 2H), 1.95-2.30 (m, 2H), 2.55-2.75 (m, 2H), 3.10 (t, 2H), 3.70 (c, 2H), 4.25 (s broad, ÍH), 5.20 (s broad, ÍH), 8.65 (s broad, 2H), 11.95
(s broad, ÍH). MS m / z (%): 199 (MH +, 16%), 138 (33%), 67
(91%), 41 (100%).
Example 10 (R, S) -4- [4,4-bis (4-fluorophenyl) butan-1-yl] -N-methylamino] -3-ethoxy-4,5,6,7-tetrahydro-2 -benzisoxazole 10a. Al (R, S) -3-ethoxy-4-methylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole 7a (1.0 g) in methyl isobutyl ketone (MIBK) (10 ml), bis-4 is added , 4- (4-fluorophenyl) -1-butylchloride (2.0 g), potassium carbonate (1.0 g) and potassium iodide
(0.5 g). The mixture is refluxed overnight. The inorganic salts are removed by filtration and evaporated in
MIBK. The remaining oil is purified by column chromatography with silica gel (eluted with heptane / ethyl acetate 2: 3). Yield of the title compound is 1.6 g of oil. H NMR (CDCl 3) d 1.35 (t, 3H), 1.35-1.50 (m, 2H), 1.60-1.75 (m, 3H), 1.90-2.05 (m, 3H), 2.20 (s, 3H), 2.35-2.60 (m, 4H), 3.60 (t, ÍH), 3.85 (t, ÍH), 4.25 (c, 2H), 6.95 (t, 4H), 7.15 (dd, 4H). The following 3-ethoxy derivatives are prepared in a corresponding manner: (R, S) -4- [N- (4,4-diphenylbut-l-yl) -N-methylamino] -3-ethoxy-4,5,6 , 7-tetrahydro-l, 2-benzisoxazole 10b. Prepared via alkylation with 4,4-diphenyl-1-butyl iodide, 29a and isolated as an oil. ? E NMR (CDCI3) d 1.30 (t, 3H), 1.35-1.50 (m, 2H), 1.60-1.70 (m, 4H), 1.90-2.10 (m, 2H), 2.15 (s, 3H), 2.30- 2.50 (m, 4H), 3.55 (t, ÍH), 3.85 (t, ÍH), 4.25 (c, 2H), 7.10-7.30 (m, 10H). The following compounds are prepared in a similar manner, except that the alkylations are carried out in acetone without the addition of potassium iodide. (R, S) -4- [N- [3- (10,11-dihydrodibenzo [a, d] cyclohepty-5-ylidene) propan-1-yl] methylamino] -3-eto, xi-4, 5, 6,7-tetrahydro-1,2-benzisoxazole, 10c. Prepared via alkylation with 3- (10,11-dihydrodibenzo [a, d] cyclohepty-5-ylidene) -1-propylbromide (prepared as described in J. Org. Chem. (1962), Vol. 27, 4134-37 ) and isolated as an oil. X H NMR (CDCl 3) d 1.30 (t, 3 H), 1.60-1.74 (m, 3 H), 1.87-2.06 (m, H H), 2.20 (s, 3 H), 2.20-2.35 (m, 2 H), 2.45-2.70 (m, 4H), 2.70-3.50 (m, 4H), 3.50-3.63 (m, HH), 4.24 (c, 2H), 5.88 (t, HH), 6.98-7.30 (m, 8H). (R, S) -4- [N- [4,4-di (2-tolyl) utan-1-yl] methylamino] -3-ethoxy-4,5,6,7-tetrahydro-l, 2-benzisoxazole , lOd. Prepared via alkylation with 4-di- (2-tolyl) -1-butyl iodide 34a and isolated as an oil. H NMR (CDC13) d 1.28 (t, 3H), 1.42-1.56 (m, 2H), 1.60-1.80 (m, 4H), 1.87-2.05 (m, 3H), 2.20 (s, 3H), 2.26 (dd) , 6H), 2.35-2.60 (m, 4H), 3.60 (t, ÍH), 4.23 (c, 2H), 7.00-7.17 (m, 8H). (R, S) -4- [N- [1, I-Di- (2-tolyl) but-1-en-4-yl] methylamino] -3-ethoxy-4,6,6,7-tetrahydro- 1, 2-benzisoxazole lOe. Prepared via alkylation with 4,4-di- (2-tolyl) -3-butenyloduro, 36a and isolated as an oil. H NMR (CDCl 3) d 1.33 (t, 3H), 1.55-1.80 (m, 4H); 1.90-2.07 (m, 2H), 2.17 (dd, 6H), 2.26 (s, 3H), 2.45-2.67 (m, 4H), 3.57 (t, ÍH), 4.26 (c, 2H), 5.81 (t, ÍH), 7.00-7.17 (m, 8H).
Example 11 (Method c)) Hydrobromide of (R, S) -4- [N- [4, 4-bis (4-fluorophenyl) butan-1-yl] -N-methylamino] -3-hydroxy-4, 5,6,7-tetrahydro-1,2-benzisoxazole, All of the product 10a (1.6 g) of Example 10 is heated at 80 ° C in a 33% solution of hydrogen bromide in glacial acetic acid (60 ml) for an hour. The solvent is evaporated in vacuo. The unpurified product is repeatedly dissolved in ethanol and evaporated in vacuo. The remaining viscous oil is dissolved in glacial acetic acid (15 ml) and water (150 ml) is added. After drying with ice all night, an amorphous powder of the title compound lia is obtained. This powder is stirred with diethyl ether and removed by filtration. After drying in vacuo at 50 ° C for 24 hours, the pure amorphous bromohydrate is collected. Performance 1.2. P.f. 68-70 ° C. ? E NMR (DMSO-dg) recorded at 60 ° C) d 1.60-2.15 (m, 8H), 2.55-2.70 (m, 2H), 2.70 (broad s, 3H), 3.20 (broad t, 2H), 4.05 (t, ÍH), 4.45 (t, ÍH), 7.10 (t, 4H), 7.35 (dd, 4H). MS m / z (%): 413 (MH +, 10%), 203 (13%), 138 (100%) 109 (12%), 67 (58%). The following 3-hydroxy derivatives are prepared in a corresponding manner: (R, S) -N- [4,4-diphenylbut-1-yl) -N-methylamino] -3-hydroxy-4,6 hydrobromide. , 7-tetrahydro-l, 2-benzisoxazole, llb. P.f. 174-176 ° C (ethanol / diethyl ether 1: 1). XH NMR (DMSO-dg) d 150-2.10 (m, 6H), 2.60-2.80 (m, 4H), 3.15-3.40 (m, 2H), 3.30 (s, 3H), 3.95 (t, ÍH), 4.40 (broad s, HI), 7.15-7.45 (m, 10H), MS m / z (%): 3.77 (MH +, 100%), 240 (56%), 138 (49%).
Example 12 (R, S) -4- (N-tert-butyloxycarbonyl-N-methylamino) -3-hydroxy-4,5,6,7-tetrahydro-l, 2-benzisoxazole 12a To a solution of hydrobromide of ( R, S) -3-hydroxy-4-methylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole, 8a (7.0 g) in a mixture of dioxane (50 ml) and water (80 ml) was add at 10 ° C NaOH (1.1 g) and a solution of di-tert-butyldicarbonate (6.0 g) in dioxane (20 ml). The mixture is stirred at room temperature for 1.5 hours. Water (150 ml) is added. After stirring for an additional 20 minutes, diethyl ether (100 ml) is added. The organic phase is separated and discharged. The pH of the aqueous phase is adjusted to 4 by the addition of KHS04. The aqueous phase is extracted repeatedly with diethyl ether (3 x 100 ml). The combined organic phases are worked as in the previous. Yield 5.3 g. P.f. 151-152 ° C. E NMR (CDCl3) d 1.50 (s, 9H), 1.65-2.10 (m, 4H), 2.55-2.65 (m, 2H), 2.75 (s, 3H), 5.15 (s broad, ÍH). By the same method, it is synthesized: (R, S) -4- (tert-butyloxycarbonylamino) -3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 12b. P.f. 175-177 ° C (from light ethyl acetate-oil).
Example 13 (R, S) -4- (N-tert-Butyloxycarbonyl-N-methylamino) -3-pivaloyloxymethyloxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 13a To a suspension of (R , S) -4- (N-tert-Butyloxycarbonyl-1-N-methylamino) -3-hydroxy-4,5,6,6-tetrahydro-1,2-benzisoxazole 12a, (5 g) in acetone (50 ml) carefully add potassium terbutoxide (at a temperature below 30 ° C) (2.5 g). A solution of pivaloxymethylioduro (7.5 g) in acetone (10 ml) is added and the mixture is stirred overnight. The organic salts are filtered off and the acetone is evaporated. The yield by column chromatography on silica gel (eluted with heptane / ethyl acetate 3: 2) is 3.9 g of the title compound 13a as an oil. XH NMR (CDC13) d 1.30 (s, 9H), 1.50 (s, 9H), 1.50-2.10 (m, 6H), 2.50-2.60 (m, 5H), 5.00-5.30 (broad signal, ÍH), 5.85 ( dd, 2H). A more polar fraction of the column chromatography contains 2.1 g of (R, S) -4- (N-tert-butyloxycarbonyl-N-methylamino) -2-pivaloyloxymethyl-4,5,6,7-tetrahydro-2. -benzisoxazole -3 -one 13b. H NMR (CDCI3) d 1.20 (s, 9H), 1.50 (s, 9H), 1.60-2.10 (m, 4H), 2.40-2.50 (m, 2H), 2.65 (s, 3H), 5.00-5.10 (signal broad, ÍH), 5.75 (s, 2H). The following compounds are correspondingly synthesized: (R, S) -4- (tert-butyloxycarbonylamino) -3-pivaloyloxy-methyloxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 13c (oil). H NMR (CDCI3) d 1.25 (s, 9H), 1.45 (s, 9H), 1.80-1.95 (m, 4H), 2.50-2.75 (m, 2H), 4.75 (s broad, 2H), 5.90 (s, 2H). (R, S) -4- (tert-butyloxycarbonylamino) -2-pivaloyloxy-methyl-4,5,6,7-tetrahydro-1,2-benzisoxazole 13d (oil). 1H-NMR (CDCl 3) d 1.20 (s, 9H), 1.45 (s, 9H), 1.80-200 (m, 4H), 2.30-2.55 (m, 2H), 4.50-4.90 (m, 2H), 5.75 ( s, 2H).
EXAMPLE 14 Hemioxalate of (R, S,) -4-methylamino-3-pivaloyloxymethyloxy-4,5,6,7-tetrahydro-1,2-benzisoxazole, 14a (Method a)) To a solution of (R, S ) -4 - (N-tert-butyloxycarbonyl-N-methylamino) -3-pivaloyloxymethyloxy-4,5,6,6-tetrahydro-1,2-benzisoxazole 13a. Add (3.7 g) in dichloromethane maintained at 20 ° C, trifluoroacetic acid (19 ml). The mixture is stirred at 20 ° C for another hour. The solvents are evaporated at room temperature in vacuo. The remaining oil is dissolved in diethyl ether (100 ml) and water (100 ml). The potassium carbonate is added to obtain a pH > 9. The organic phase is separated and worked as in the above. The yield of the unpurified title compound as a free base is 2.4 g. A solution of the entire base of 14a in ethanol (10 ml) is added to oxalic acid (0.7 g). The salt of the precipitated hemioxalate is removed by filtration. Yield 1.2 g. P.f. 201-202 ° C. ^ NMR (DMSOdg) d 1.15 (s, 9H), 1.65-2.05 (m, 4H), 2.40 (s, 3H), 2.55-2.80 (m, 2H), 3.85 (t, ÍH), 5.90 (dd, 2H ). MS m / z (%): 283 (MH +), 138 (30%), 57 (100%). In a corresponding form of (R, S) -4- (N-tert-butyloxycarbonyl-N-methylamino) -2-pivaloyloxymethyl-4,5,6,7-tetrahydro-1,2-benzisoxazol-3-one (13b) ) the hemioxalate is isolated from (R, S) -4-methylamino-2-pivaloyloxymethyl-4,5,6,7-tetrahydro-1,2-benzisoxazole-3 -one, 14b. P.f. 177-178 ° C (acetone). H NMR (DMSO-dg) d 1.15 (s, 9H), 1.60-205
(m, 4H), 2.50 (s, 3H), 2.45-2.60 (m, 2H), 3.80 (t, ÍH), 5.80 (dd, 2H). MS m / z (%): 283 (MH +), 123 (52%), 57 (52%), 55
(100%) Similarly, the treatment of (R, S) -4- (tert-butyloxycarbonylamino) -3-pivaloyloxy-methyl-oxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 13c with a solution of 2.5 M of HCl in ethyl acetate gives hydrochloride of (R, S) -4-amino-3-pivoaloyloxymethyloxy-, 5,6,7-tetrahydro-1,2-benzisoxazole 14c. P.f. 157-168 ° C (from acetonitrile-ether). H NMR (CDC13) d 1.20 (s, 9H), 2.0-2.35 (m, 4H), 2.50-2.85 (m, 2H), 4.25-4.50 (, ÍH), 5.90 (s, 2H). The enantiomers of compound 14a are prepared as follows: From the hydrobromide of (+) - 3-hydroxy-4-methylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole, 6c, the corresponding enantiomer of 4- (N-tert-Butyloxycarbonyl-N-methylamino) -3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole by reaction with diterbutyldicarbonate according to the procedure in Example 12. The additional reaction with pivaloixomethyl iodide as in Example 13 gives the pure isomer of 4- (N-tert-butyloxycarbonyl-N-methylamino) -3-pivaloyloxy-methyloxy-4,5,6,7-tetrahydro-1,2-benzisoxazole. As previously described (in Example 14) the BOC protection group is separated by treatment with trifluoroacetic acid. The pure enantiomer A of compound 14a is crystallized as a hemioxalate salt. P.f. 211-213 ° C. The optical rotation was [a] D = -5.4 ° (C = l, MeOH). In a corresponding form of compound 6d the other isomer is prepared: hemioxalate of 4-methylamino-3-pivaloyloxymethyloxy-4,5,6,6-7-tetrahydro-1,2-benzisoxazole, enantiomer B, P.f. 210-213 ° C. The optical rotation is [a] D = + 5.6 ° (C = l, MeOH). To analyze the enantiomeric purity of both compounds, they are analyzed by H NMR in the presence of R (-) - l- (9-anthryl) -2,2,2-trifluoroethanol. There is a division of the singlets of the terbutyl group and the methyl group, both in two singlet signals for the racemic mixture. The enantiomer
A gives the singlets at d (ppm) 1.15 (s, 9H), and 2.15 (s, 3H). The B-enantiomer gives the singlets at d (ppm) 1.20 (s, 9H) and 2.25
(s, 3H). No impurities of the other isomers were detected in the two compounds. The limit detection is estimated to be 2%.
Example 15 (Method a)) (R, S) -4-methylamino-2-phenylaminocarbonyl-4,5,6,7-tetrahydro-l, 2-benzisoxazol-3-one hydrochloride, 15a To a solution of ( R, S) -4- (N-tert-Butyloxycarbonyl-N-methylamino) -3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 12a (1.0 g) in dichloromethane (10 ml) ), phenylisocyanate (0.6 ml). The mixture is stirred overnight at room temperature. The dichloromethane is evaporated. The diethyl ester of (R, S) -4- (N-tert-butyloxycarbonyl-N-methylamino) -2-phenylaminocarbonyl-4,5,6,7-tetrahydro-1,2-benzisoxazol-3-one is crystallized. The crystallized compound (0.4 g) is suspended in a saturated solution of hydrogen chloride in diethyl ether. After stirring for a few minutes, almost all of the compound dissolves and the hydrochloride salt of the title compound begins to precipitate. After stirring for 2 hours the precipitated title compound is filtered and washed carefully with diethyl ether. Yield 0.3 g. P.f. 168-170 ° C, XH NMR (DMSOdg) d 1.65-2.05 (m, 2H), 2.15-2.30 (m, 2H), 2.65 (s, 3H), 2.60-2.8s (m, 2H), 4.20 ( s broad, ÍH), 7.20 (t, ÍH), 7.40 (t, 2H), 7.55 (d, 2H). The following compounds are prepared in a corresponding form: oxalate of (R, S-2-methylaminocarbonyl-4-methylamino-4, 5,6,7-tetrahydro-l, 2-benzisothiazol-3-one, 15b .Pf 153 ° C (acetone) 1 H NMR (DMSO-dg) d 1.75-2.15 (m, 4H), 2.60-2.70 (m, 2H), 2.65 (s, 3H), 2.85 (d, 3H), 4.15 ( s broad, ÍH), 7.80 (c, ÍH), 9.15 (s broad, 3H), MS m / z (%): 226 (MH +), 160 (9%), 138 (57%), 67 (100% ), 65 (50%). Hydrochloride of (R, S) -2-benzylaminocarbonyl-4-methylamino-4,5,6,7-tetrahydro-l, 2-benzisothiazol-3-one, 15c, Pf 85- 89 ° C (diethyl ether) XH NMR (DMSO-dg) d 1.80-2.05 (m, 2H), 2.10-2.30 (m, 2H), 2.60-2.80 (m, 2H), 2.65 (s, 3H), 4.15 (s broad, ÍH), 4.45 (d, 2H), 7.20-7.40 (m, 5H), 8.45 (t, ÍH), 9.30-9.60 (broad d, 2H) EM m / z (%): 302 ( MH +), 169 (8%), 138 (58%), 91 (97%), 65 (100%).
Example 16 Sodium salt of (R, S) -4- [N- [bis- (4-fluorophenyl) methyl-2-oxyethyl] -N-methylamino] -3-hydroxy-4,5,6-7 tetrahydro-l, 2-benzisoxazole, 16a (method c)) Add to a solution of (R, S) -4-methylamino-3-pivaloyloxymethyloxy-4,5,6,7-tetrahydro-l, 2-benzisoxazole 14a
(1.1 g) in MIB (18 ml), potassium carbonate (0.7 g) and the bis (4-fluorophenyl) methyl-2-oxyethanol methanesulfonate ester
(1.8 g). The mixture is refluxed overnight. The organic salts are filtered off and the MIBK is evaporated. Column chromatography gives (R, S) -4- [N- [bis- (4-fluorophenyl) methyl-2-oxyethyl] -N-methylamino] -3-pivaloyloxy-methyloxy-4, 5, 6, 7- pure tetrahydro-l, 2-benzisoxazole. The yield is 1.4 g. X H NMR (CDCl 3) d 1.20 (s, 9H), 1.60-1.80 (m, 3H), 1.95-2.05 (m, ÍH), 2.25 (s, 3H), 2.55 (broad t, 2H), 2.60-2.80 ( m, 2H), 3.50 (t, 2H), 3.65 (dt, ÍH), 5.35 (s, ÍH), 5.90 (dd, 2H), 7.00 (t, 4H), 7.30 (dd, 4H), 7.55 (d , 2H). It is added to the protected derivative of pivaloyloxymethyl (0.6 g) in ethanol (7 ml), water (1.4 ml) and NaOH powder (0.7 g). The mixture is stirred overnight. The ethanol is evaporated in vacuo and water (25 ml) is added. The precipitated crystalline product is filtered off and washed with water. It is then dried overnight at 70-80 ° C in vacuo, 350 mg of pure sodium salt of the remaining title compound. Mp: 178-81 E NMR (DMSO-dg) d 1.30-1.90 (m, 2H), 2.15-2.35 (m, 4H), 2.60-2.85 (m, 2H), 3.25 (t, ÍH), 3.40 (t , 2H), MS m / z (%): 415 (MH +, 4%), 203 (100%), 183 (63%), 138 (42%), 67 (30%). The following compounds are prepared in a corresponding manner: sodium salt of (R, S) -4- [N- [bis- (4-chlorophenyl) methyl-2-oxyethyl] -N-methylamino] -3-hydroxy- 4, 5,6,7-tetrahydro-l, 2-benzisoxazole, 16b. P.f .: 201-203 ° C (water / ethanol). HH NMR (DMSO-dg) d 1.40-1.60 (m, 2H), 1.60-1.70 (m, HH), 1.75-1.85 (m, HH), 2.20-2.35 (m, 2H), 2.20 (s, 3H) , 2.65-2.90 (m, 2H), 3.35 (t, ÍH), 3.35-3.50 (m, 2H), 5.55 (s, ÍH), 7.45 (s, 8H), MS m / z (%): 447 ( MH +), 235 (78%), 165 (57%), 138 (100%), 67 (56%). hydrochloride of (R, S) -4- [N- (diphenylmethyl-2-oxyethyl) -N-methylamino] -3-hydroxy-4,5,6,6-7-tetrahydro-l, 2-benzisoxazole, 16c. P.f. 108-113 ° C (amorphous) (diethyl ether). XH NMR (DMSO-dg) d 1.70-2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.60-2.75 (m, 2H), 2.80 (broad s, 3H), 3.40-3.60 (m, 2H) ), 2.80 (broad t, 2H), 4.55 (broad s, ÍH), 5.55 (s, ÍH), 7.20-7.45 (m, 10H), MS m / z (%): 379 (MH +, 4%), 167 (100%), 152 (74%), 138 (36%), 67 (32%). In a similar manner, the treatment of (R, S) -4- [N- (4,4-bis [3-methylthien-2-yl] -3-butenyl) -N-methylamino] -3-pivaloyloxymethyloxy-4 , 5,6,7-tetrahydro-1,2-benzisoxazole with NaOH in aqueous ethanol followed by acidification with 4M HCl and extraction with methylene chloride gives hydrochloride of (R, S) -4- [N- (4, 4- bis [3-methylthien-2-yl] -3-butenyl) -N-methylamino] -3-hydroxy-4,5,6,7-tetrahydro-l, 2-benzisoxazole 16d. P.f. 135-138 ° C (from acetonitrile-ether). X H NMR (DMSO-dg) d 195 (s, 3 H), 2.0 (s, 3 H), 1.95-2.20 (m, 4 H), 2.55-2.90 (m, 6 H), 3.35 (s, 3 H), 4.40-4.50 (m, ÍH), 6.0 (t, ÍH), 6.85 (d, ÍH), 6.95 (d, ÍH); 7.35 (d, ÍH), 7.55 (d, ÍH).
Example 17 (R, S) -3-ethoxy-4-dimethylamino-, 5, 6, 7-tetrahydro-1,2-benzisoxazole hydrobromide, 17a A mixture of hydrobromide (R, S) -3 is extracted -ethoxy-4-amino-4, 5,6,7-tetrahydro-l, 2-benzisoxazole, 3a
(526 mg) and 1M sodium hydroxide (8 ml) with methylene chloride (3x10 ml). The combined extracts are dried and evaporated. Formic acid (3 ml) of 30% formaldehyde (3 ml) and sodium formate (3 g) are added to the residue and the mixture is stirred at 60 ° C for 3 hours and at 100 ° C for 20 hours. After evaporation, water (20 ml) is added to the residue and the pH is adjusted to 10 with 2M sodium hydroxide. The mixture is extracted with methylene chloride (3x40 ml) and the combined extracts are dried and evaporated. The residues are dissolved in ether (25 ml) and an excess of 33% hydrobromic acid in glacial acetic acid is added dropwise to precipitate the title compound (422 mg). Recrystallization of the acetonitrile-ether gives a pure analytical compound: m.p. 158-160 ° C. ? E NMR (60 MHz, D20) d 1.60 (t, 3H), 2.20 (m, 4H), 2.85 (m, 2H), 3.05 (s, 6H); 4.50 (c, 2H), 4.55 (m, ÍH).
Example 18 (R, S) -4-dimethylamino-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole hydrobromide (Method c)) is stirred at 80 ° C for 25 minutes , a solution of hydrobromide of the (R, S) -3-ethoxy-4-dimethylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole 17a (250 mg) and 33% hydrobromic acid in acetic acid glacial (5 ml). The mixture is evaporated and 33% hydrobromic acid is added in glacial acetic acid.
(5 ml) to the residue. After stirring at 80 ° C for 25 minutes, the mixture is evaporated and the residue of acetonitrile-ethanol-ether is recrystallized to give the title compound (199 mg): m.p. 183-186 ° C. The compound crystallizes with 0.33 moles of water. E NMR (60 MHz. D20) d 2.35 (m, 4H), 3.00 (m, 2H), 3.25 (s, 6H), 4.70 (m, ÍH).
Example 19 (R, S) -3-benzyloxy-4-methylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole hydrochloride, 19a A mixture of (R) is stirred at 40 ° C for 45 minutes. , S) -3-hydroxy-4- (N-methyl-N-tert-butyloxycarbonylamino) -4,5,6,7-tetrahydro-1,2-benzisoxazole 12a (1.20 g) and potassium carbonate (1.23 g) in DMF (25 ml) at 40 ° C for 45 minutes. Benzyl bromide (1.59 ml) is added and stirred at 40 ° C for 20 hours. The reaction mixture is evaporated and water (25 ml) is added to the residue. Extract with methylene chloride (3x50 ml), dry and evaporate to give an oil. Flash chromatography on silica gel (eluent: toluene containing ethyl acetate (0-75%)) gives (R, S) -3-benzyloxy-4- (N-methyl-N-tert-butyloxycarbonylamino) -4 , 5,6,7-tetrahydro-l, 2-benzisoxazole (oil, 620 mg). A mixture of the compound (620 mg), 1M HCl (15 ml) and ethanol (20 ml) is stirred at 45 ° C for 80 minutes. Evaporation and recrystallization of the residue with acetonitrile-ether gives the title compound (460 mg). P.f. 156-159 ° C.
The following compound is synthesized correspondingly: (R, S) -3-benzyloxy-4-amino-4,5,6,7-tetrahydro-1,2-benzyloxazole 19b hydrochloride. P.f. 168-170 ° C.
Example 20 (R, S) -3-hydroxy-4- [N- (4,4-diphenyl-3-butenyl) methylamino] -4,5,6,7-tetrahydro-1,2-benzisoxazole hydrochloride 20a (Method c)) A mixture of compound 19a (442 mg), potassium carbonate (622 mg), sodium iodide (50 mg) and 4,4-diphenyl-3-bromide is stirred at 120 ° C for 24 hours. -butenyl (646 mg) in DMF (8 ml). A solution of 4,4-diphenyl-3-butenyl iodide (500 mg) in DMF (3 ml) is added and stirred at 120 ° C for 24 hours. The reaction mixture is evaporated and water (20 ml) is added to the residue. Extractions with ether (3 x 25 ml), drying and evaporation give an oil. Flash chromatography on silica gel (eluent: toluene-ethyl acetate (0-100%)) gives (R, S) -3-benzyloxy-4- [N- (4,4-diphenyl-3-butenyl) methylamino ] -4.5.6, 7-tetrahydro-1,2-benzisoxazole (590 mg) as a light yellow oil. A solution of the compound (590 mg) in ethanol (16 ml) and concentrated with hydrochloric acid (8 ml) is refluxed for 3 days. Evaporation and recrystallization of the residue with acetone-ethanol-ether gives the title compound (212 mg). P.f. 119-120 ° C. ÍH NMR (D20 and DMSO-dg) d 1.60-1.98 (m, 4H), 2.35-2.6
(m, 2H); 2.58 (s, 3H), 3.10 (m, 2H), 4.18 (m, ÍH), 5.91 (t,
ÍH), 7.0-7.4 (m, 10H). The H NMR spectrum shows the presence of 0.75 equivalents of ethanol. The following compounds are synthesized correspondingly: Hydrated hydrochloride of the (R, S) -3-hydroxy-4- [N- (4,4-diphenyl-3-butenyl) amino] -4,5,6, 7-tetrahydro- 1, 2-benzisoxazole 20b. P.f. 140-143 ° C (from acetonitrile). XH NMR (D20 and DMSO-dg) d 1.80-2.20 (m, 4H), 2.40-2.60 (m, 4H), 3.10-3.30 (m, 2H), 4.15-4.30 (m, ÍH), 6.10 (t, ÍH), 7.10-7.45 (m,
10H). Hydrochloride of (R, S) -3-hydroxy-4- [N- (4,4-bis [3-methylthien-2-yl] -3-butenyl) amino] -4,5,6,7-tetrahydro -l, 2-benzisoxazole 20s. P.f. 188-191 ° C (from ethanol-acetonitrile).
ÍH NMR (D20 and DMSO-d6) d 1.85-2.15 (m, 4H), 2.05 (s, 3H),
2. 08 (s, 3H), 2.45-2.90 (m, 4H), 3.15-3.30 (, 2H); 4.20-4.35
(m, ÍH), 6.10 (t, ÍH), 6.90 (m, ÍH), 7.0 (m, ÍH), 7.25 (t,
ÍH), 7.40 (t, ÍH).
Example 21 2-Benzylamino-3, 4,5,6-tetrahydrobenzamide 21a A mixture of cyclohexanone-2-carboxamide is brought to reflux (U.S. Patent 4169952 to du Pont de Nemours, (1979)) (10.0 g), benzylamine (8.4 g), toluene (35 ml) and molecular sieve (Union Carbide 3A, 2 g) during »2 hours in a Dean-Stark water separator. The reaction mixture is filtered, and the filtrate is evaporated. The residue is recrystallized with light petroleum to give the title compound (16 g). P.f. 73-74 ° C.
EXAMPLE 22 3-Hydroxy-4,5,6,7-tetrahydro-1,2-benzisothiazole 22a It is added to a solution of 2-benzylamino-3,4,5,6-tetrahydrobenzamide 21a (15 g) in glacial acetic acid (100 ml), an excess of hydrogen sulphide at 80 ° C for 4 hours. The reaction mixture is evaporated and ether is added to the residue to allow crystallization. The crystals are dissolved in ethyl acetate (30 ml) and a solution of bromide (8.3 ml) in ethyl acetate (30 ml) is added dropwise at room temperature. The mixture is stirred for 20 hours at room temperature and evaporated. Column chromatography on silica gel (eluent: ethyl acetate-ethanol 1: 1 containing 1% glacial acetic acid) gives the title compound (3.3 g): M.p. 157-158 ° C.
EXAMPLE 23 3-Chloro-4,5,6,7-tetrahydro-1,2-benzisothiazole 23a A mixture of 3-hydroxy-4,5,6,7-tetrahydro-l is stirred at 90 ° C for 5 hours. 2-benzisothiazole 22a (4.74 g), pyridinium hydrochloride (12.7 g), phosphoric acid (2.1 g) and phosphorus oxychloride (25 ml). The reaction mixture is evaporated and ethyl acetate (130 ml) is added to the residue. A saturated solution of sodium hydrogencarbonate (130 ml) is added and after 10 minutes of stirring the phases are separated. The aqueous phase is extracted with ethyl acetate (2 x 150 ml) and the combined organic phases are dried and evaporated to give an oil. Column chromatography on silica gel (eluent: toluene-ethyl acetate 1: 1) gives the title compound as a yellow oil (2.8 g).
EXAMPLE 24 3-Chloro-4, 5,6,7-tetrahydro-1,2-benzisothiazol-4-one 24a A solution of 3-chloro-4,5,6,7-tetrahydroxycarbonate is added dropwise over 1 hour. 1, 2-benzisothiazole 23a (2.7 g) sodium dichromate (4.4 g) in glacial acetic acid (30 ml) and concentrated sulfuric acid (1.8 ml) in glacial acetic acid (80 ml). The reaction mixture is stirred at room temperature for an additional 2 hours, and neutralized with a saturated solution of sodium hydrogencarbonate. Extraction with ether (3 x 150 ml), drying and evaporation give an oil. Column chromatography on silica gel (eluent: toluene-ethyl acetate 1: 1) gives first 3-chloro-4,5,6,7-tetrahydro-1,2-benzisothiazol-7-one (680 mg) .
The last fractions contain the title compound (780 mg). P.f. 84-85 ° C.
Example 25 3-methoxy-4,5,6,7-tetrahydro-1,2-benzisothiazol-4-one 25a A mixture of 3-chloro-4,5,6-7 is stirred at 90 ° C for 1 hour. tetrahydro-l, 2-benzisothiazol-4-one 24a (600 mg) and a solution of sodium (506 mg) in methanol (22 ml). The reaction mixture is evaporated and water (20 ml) is added to the residue. Extractions with methylene chloride (3 x 30 ml), drying and evaporation give an oil. Column chromatography on silica gel (eluent: toluene-ethyl acetate 4: 1) gives the title compound (251 mg). P.f. 45-46 ° C.
Example 26 (Method c) hydrobromide of (R, S) -4-amino-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisothiazole, 26a. Sodium borohydride (44 mg) is added in portions to a solution of 3-methoxy-4,5,6,7-tetrahydro-1,2-benzisothiazol-4-one 25a (185 mg) and ammonium acetate (780 mg). mg) in methanol (7 ml). The mixture is stirred at room temperature for 48 hours and acidified with concentrated hydrochloric acid. The mixture is evaporated and water (3 ml) is added to the residue. The aqueous solution is washed with ether (3 x 15 ml) and solid potassium hydroxide is added until a pH> 0. 10. Extraction with ether (3 x 15 ml), drying and evaporation give an oil. The oil is dissolved in ethanol and an excess of hydrochloric acid in ethyl acetate is added to precipitate the
(R, S) -3-methoxy-4-amino-4,5,6,7-tetrahydro-l, 2-benzisothiazole, hydrochloride (68 mg). A solution of 33% hydrobromic acid in glacial acetic acid (3 ml) is added to the hydrochloride (60 mg) and the mixture is stirred at room temperature for 48 hours. Evaporation and recrystallization of the residue (methanol-ether) gives the title compound (28 mg). P.f. 160-165 ° C. XH NMR (D20) d 1.78-2.04 (m, 3H),
2. 05-2.28 (m, ÍH), 2.72-2.87 (m, 2H), 4.23-4.39 (m, ÍH).
Example 27 (R, S) -3-hydroxy-4-methylamino-4,5,6,7-tetrahydro-1,2-benzisothiazole hydrobromide, 27a (R, S) -3-methoxy-4 is synthesized -methylamino-4, 5, 6, 7-tetrahydro-1,2-benzisothiazole as described for Compound 7a in Example 7 using Compound 25a (200 g) in methanol (5 ml), a 33% solution of methylamine (217 μl) in ethanol, molecular sieve powder (3 Á) and sodium cyanoborohydride (234 mg). The resulting oil is dissolved in ether and an excess of hydrochloric acid in ethyl acetate is added to precipitate (R, S) 3-methoxy-4-methylamino-4,5,6,7-tetrahydro-1,2-hydrochloride. -benzisothiazole (172 mg), mp 146-148. A solution of hydrobromic acid in glacial acetic acid (33%, 6 ml) is added to 100 mg thereof and the mixture is stirred at room temperature for 48 hours. Evaporation and recrystallization of the methanol-ether residue give the title compound (53 mg), m.p. 192 ° C (decomposition). H NMR (200 MHz, D20): d 1.82-2.24 (m, 4H), 2.72 (s, 3H), 2.68-2.92 (m, 2H), 4.16-4.30 (ÍH).
Example 28 (method e) (R, S) -3-Hydroxy-N-methyl-N- (4-phenyloxycarbonyl) amino-, 5,6,7-tetrahydro-1,2-benzisoxazole 28a Chloroformate is added dropwise. phenyl (0.7 g) in THF (10 ml) to a solution of (R, S) -3-hydroxy-N-methylamino-4,5,6,7-tetrahydro-l, 2-benzisoxazole hydrobromide (1.0 g) and triethylamine (1.8 ml) in dry dimethylformamide (10 ml) maintained at 0 ° C. Stir overnight at room temperature and add water (200 ml) and ethyl acetate (100 ml). The pH is adjusted to 1-2 by the addition of hydrochloric acid. The organic phase is separated and worked as before. The title compound is crystallized by stirring with diethyl ether. The yield is 1.0 g. P.f. 147-149 ° C. H NMR (CDCI3) d 1.70-1.95 (m, 2H), 2.05-2.20 (m, 2H), 2.6-2.7 (m, 2H), 2.85 (s, ÍH), 2.95 (s, 2H), 5.35 (s) broad, HI), 7.10-7.40 (m, 5H), 8.05 (s broad, ÍH), MS m / z (%): 289 (MH +, 10%), 138 (100%), 95 (24%), 67 (77%).
Example 29 4,4-diphenyl-1-butyl iodide, 29a To a suspension of magnesium (15 g) in dry THF (75 ml), little bromobenzene (0.5 g) is added. After a first exothermic reaction has started, the mixture is brought to reflux, and a solution of bromobenzene (90 g) in dry THF (200 ml) is added dropwise over 30 minutes. The mixture is heated additionally for 1.5 hours. The mixture is cooled to room temperature and excess Mg is removed by filtration in an inert atmosphere. It is added by drip
-25 ° C, a solution of 4-chlorobutyric acid methyl ester
(40 g) in dry THF (160 ml). After further stirring for 30 minutes, the mixture is placed in an aqueous solution of NH 4 Cl and ice. Diethyl ether (500 ml) is added. The organic phase is worked according to the standard work procedure. 65 g of 4-chloro-1, 1-diphenylbutan-1-ol are obtained without purification. Dissolve the unpurified alcohol (30 g) in a mixture of glacial acetic acid
(60 ml) and 57% aqueous yodic acid (60 ml). Red phosphorus (5 g) is added and the mixture is refluxed for 6 hours. After cooling slowly to room temperature, place the mixture in water and diethyl ether. The organic phase is worked up following the above standard procedure, giving a yield of 39 g of butyl iodide 29a as an oil, which is used without further purification. Example 30 4-diphenyl-l-butylamine hydrochloride, 30a To a solution of butyl iodide, 4,4-diphenyl-1,29a (20 g) in dry DMF (150 ml) is added., sodium azide (10 g). After refluxing for 1.5 hours, the mixture is cooled to room temperature and subsequently placed in diethyl ether and water. The organic phase is worked up following the previous standard procedure. 14 g of 4,4-diphenyl-1-butylazide are obtained. The unpurified azide (10 g) is dissolved in ethanol (150 ml), water (10 ml) and glacial acetic acid (10 ml). Palladium at 2% in black carbon is added and the mixture is hydrogenated in a Parr apparatus at 3 atm for 1.5 hours. The catalyst is removed by filtration and the solvents are evaporated in vacuo. The remaining viscous oil is dissolved in water and dichloromethane. The aqueous NaOH solution is added to adjust the pH to >;eleven. The organic phase is separated and worked according to the previous standard procedure. The hydrochloric salt is prepared by adding HCl to a solution of the amine-free compound in diethyl ether. The yield is 3.4 g. P.f. 172-175 ° C.
The following compounds are prepared in a similar manner, except that the amines do not precipitate as hydrochloride salts. 4, -di- (2-tolyl) -1-butylamine, 30b. Prepared via 4,4- di- (2-tolyl) -1-butyl iodide, 33a and isolated as an oil. ÍH NMR (CDCl3) d 1.20 (s broad, 2H), 1.42-1.58
(m, 2H), 1.87-2.03 (m, 2H), 2.27 (s, 6H), 2.70 (t, 2H), 4.23
(t, ÍH), 7.05-7.16 (m, 8H) 4, 4-di- (2-tolyl) -3-butenylamine, 30c. prepared via a 4, 4-di- (2-tolyl) -3-butenyl iodide 36a and isolated as an oil. XH NMR (CDC13) d 1.20 (broad s, 2H), 2.11 (s, 3H),
2. 18 (c, 2H), 2.26 (s, 3H), 2.77 (t, 2H), 5.75 (t, ÍH), 7.02- 7.18 (m, 8H).
EXAMPLE 31 (R, S) -3-Benzoyloxymethyloxy-4-methylamino-4,5,6,7-tetrahydro-l, 2-benzisoxazole hemioxalate 31a A mixture of the following is heated at 100-105 ° C for 2.5 hours. benzoyl chloride (22 g), paraformaldehyde (6 g), and a few crystals of ZnCl2. The benzoyloxymethyl chloride is isolated without purification by eluting the reaction mixture through silica gel (eluted with heptane / dichloromethane 1: 1). The yield is 12 g. Dissolve all the unpurified chloride in acetone (100 ml) and add sodium iodide. The acetone is evaporated after refluxing for 7 hours in vacuo and the unpurified benzoyloxymethyl iodide is isolated by extraction with diethyl ether of water containing sodium thiosulfate by the standard working procedure. The pure iodide derivative is isolated by column chromatography on silica gel
(eluted with heptane / dichloromethane 1: 1). Yield 5 g. Potassium terbutoxide (0.8 g) is added to a solution of
(R, S) -4- (n-tert-butyloxycarbonyl-N-methylamino) -3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 12a (1.5 g) in acetone (30 ml) in an atmosphere of inert nitrogen. The mixture is cooled to 10 ° C and a solution of benzoyloxymethyl iodide (2.5 g) is added. The mixture is stirred overnight at room temperature in the dark. The acetone is evaporated in vacuo and the remaining unpurified product is purified by column chromatography on silica gel (eluted with heptane / ethyl acetate 7: 3). Yield 1.3 g of oil. The ter-BOC protection group is removed as described above by treatment with trifluoroacetic acid in dichloromethane. After evaporation of the solvents, the unpurified product is dissolved in ice-cold water, the pH is adjusted to 9-10 by the addition of dilute aqueous potassium carbonate. Extraction with diethylether and work of the organic phase using the standard procedure above gives 1 g of the crude title product. The hemioxalate salt 31a crystallizes from the acetone. Yield 900 mg. P.f. 188-189 ° C. 2 H NMR (DMSO-dg) d 1.60-2.05 (m, 4H), 2.45 (s, 3H), 2.55-2.80 (m, 2H), 3.85 (t, ÍH), 6.15 (s, ÍH), 7.60 (t , 2H), 7.65-7.75 (m, ÍH), 8.00 (dd, 2H). MS m / z (%): 303 (MH +), 198 (17%), 105 (100%). In a corresponding manner, the following 3-substituted derivatives are prepared: (R, S) -4-methylamino-3- (2,4,6-trimethylbenzoyloxymethyloxy) -4,5,6,7-tetrahydro-1 hemioxalate, 2-benzisoxazole, 31b. P.f. 217 ° C (acetone). E NMR (DMSO-dg) d 1.60-2.05 (m, 4H), 2.20 (s, 6H), 2.25 (s, 3H), 2.45 (s, 3H), 2.55-2.80 (m, 2H-), 3.90 ( t, ÍH), 6.10 (s, ÍH), 6.95 (s, 2H), MS m / z (%): 345 (MH +), 240 (100%), 147 (94%). (R, S) -3-methylamino-3- (2,6-difluorobenzoyloxymethyloxy) -4,5,6,7-tetrahydro-l, 2-benzyl-oxazole hemioxalate 31c. P.f. 196-197 ° C (acetone). H NMR (DMSO-dg) d 1.60-2.05 (m, 4H), 2.45 (s, 3H), 2.55-2.80 (m, 2H), 3.85 (t, ÍH), 6.15 (s, 2H), 7.30 (t , 2H), 7.70-7.85 (m, 1H), MS m / z (%): 339 (MH +), 234 (17%), 141 (100%). hemioxalate of (R, S) -4-methylamino-3- (2-methylbenzoyloxymethyloxy) -4,5,6,7-tetrahydro-1,2-benzisoxazole, 31d. P.f. 195-196 ° C. H NMR (DMSO-dg) d 1.60-2.05 (m, 4H), 2.40 (s, 3H), 2.50 (s, 3H), 2.55-2.80 (m, 2H), 3.85 (t, ÍH), 6.10 (s) , ÍH), 7.35-7.45 (m, 2H), 7.55 (t, ÍH), 7.90 (d, ÍH), MS m / z (%): 317 (MH +, 2%), 212 (19%), 119 (100%), 91 (74%).
Example 32 (R, S) -4- [N-3- (phenothiazin-10-yl) propan-1-yl] amino] -3-ethoxy-4,5,5,6,7-tetrahydro-l, 2-benzisoxazole , 32a A solution of 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-one 2a (654 mg) and 3- (under heating) is heated under reflux (105 ° C) for 6 hours. phenothiazin-10-yl) -1-propylamine (prepared as described in EP-A-0-200-450), (1.02 g) in toluene (130 ml). The p-toluenesulfonic acid, monohydrate (10 mg) is added to the boiling solution, which is boiling for an additional 16 hours. This solution is cooled to 5 ° C and then a solution of NaCNBH4 (635 mg) in methanol (50 ml) is added at 10 ° C. The resulting reaction mixture is stirred for 20 minutes, before addition of additional NaCNBH4 (500 mg). The reaction mixture is stirred for an additional 10 minutes at 10 ° C. The reaction mixture is placed in water and the phases are separated. The aqueous phase is extracted with ethyl acetate (3 x 250 ml). The combined organic phases are washed with an aqueous solution of saturated, dry NaCl (Na 2 SO 4) and evaporated in vacuo. The residue is subjected to CC (n-heptane / ethyl acetate 1: 1) to give the title compound as an oil (640 mg). ÍH NMR (CDC13) d 1.33 (t, 3H), 1.50-200 (m, 7H), 2.40-2.60 (m, 2H), 2.70-2.84 (m, 2H), 3.65 (t, ÍH), 3.97 (t , 2H), 4.26 (c, 2H), 6.85-6.95 (m, 4H), 7.08-7.18 (m, 4H).
Example 33 2, 2 -di- (2-tolyl) -tetrahydrofuran, 33a. 2-Bromotoluene (4 ml) is added to a suspension of magnesium birutas (33 g) in dry THF (150 ml). The reaction mixture is heated to reflux and the exothermic reaction begins. The heating blanket is removed and 2-bromotoluene (137 ml) is added in dry THF (500 ml), dripping under one hour at reflux temperature (exothermic reaction). The resulting reaction mixture is boiled under reflux for an additional 1.5 hours. The mixture is cooled to room temperature and the excess Mg is removed by filtration in an inert atmosphere. A solution of 4-chlorobutyric acid methyl ester (56.4 g) in dry THF
(200 ml) is added dropwise at 20 ° C. The mixture is stirred at room temperature for an additional hour and then placed in an aqueous solution of NH 4 Cl and ice. The organic phase is worked according to the standard work procedure. After evaporation of the organic solvent, the residue is suspended in a mixture of n-heptane / ethyl acetate, 4/1. Filtration of the resulting crystals gives 2,2-di- (2-tolyl) -tetrahydrofuran 33a (32.5 g). X H NMR (CDCl 3) d 1.96 (s, 6 H), 1.96-2.10 (m, 2 H), 2.57 (t, 2 H), 4.02 (t, 2 H), 7.00-7.07 (m, 2 H), 7.07-7.23 (m , 4H), 7.57-7.65 (m, 2H) Example 34 4, 4-di- (2-tolyl) -1-butyl, 34a iodide 2,2-di- (2-tolyl) -tetrahydrofuran is dissolved without purify 33a (28 g) in acetic acid (250 ml). Palladium at 5% in black carbon (3 g) is added and the mixture is hydrogenated in a Parr apparatus at 3 atm at 55 ° C for 5 hours. The catalyst is removed by filtration and the solvent is evaporated in vacuo. The remaining oil is subjected to CC (n-heptane / ethyl acetate 15: 1) to give 4,4-di- (2-tolyl) -1-butanol (17 g). A solution of 4, 4-di- (2-tolyl) -1-butanol
(19 g) in acetic acid (400 ml), boiling under reflux for 3 hours. The cooled solution was evaporated in vacuo to give 4,4- di- (2-tolyl) -1-butyl acetate (17 g) as an oil. A solution of 4,4-di- (2-tolyl) -1-butyl acetate (9.2 g) in 57% aqueous yodic acid (150 ml) is boiled under reflux for 3 hours. The cooled solution is poured into a mixture of ice and water and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with water and a saturated aqueous NaCl solution, dried (Na2SO4) and evaporated in vacuo to give the title compound 34a (11.7 g) as an oil, which is used without further purification. X H NMR (CDCl 3) d 1.80-2.10 (m, 4H), 2.28 (s, 6H), 3.17- (t, 2H), 4.26 (t, ÍH), 7.12 (s, 8H).
Example 35 (R, S) -4- [N- [4-4-di- (2-tolylbutan-l-yl] amino] -3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazole, 35a prepare the title compound according to the procedure described in Synlett (1995) 1079-1080 using 4,4-di- (2-tolyl) -1-butylamine 30b (1.7 g), 3-ethoxy-4, 5, 6, 7-tetrahydro-1,2-benzisoxazol-4-one 2a (1.0 g), titanium (IV) isopropylate (4.3 ml), NaCNBH3 (0.6 g) and ethanol (20 ml) The yield of the title compound is 1.0 g which is isolated as an oil. H NMR (CDC13) d 1.32 (t, 3H), 1.40-1.85 (m, 7H), 1.85-2.05 (m, 3H), 2.27 (s, 6H), 2.45- 2.75 (m, 4H), 3.68 (t, ÍH), 4.27 (c, 2H), 7.05-7.15 (m, 8H).
(R, S) -4- [Nl, 1-di- (2-tolyl) but-l-en-4-yl] amino] -3-ethoxy-4,5,6,7-tetrahydro-l, 2 -benzisoxazole, 35b The title compound is prepared according to the procedure described in Synlett (1995) 1079-1080 using 4,4-di- (2-tolyl) -3-butenylamine, 30c (3.3 g), 3-ethoxy- 4, 5, 6, 7-tetrahydro-l, 2-benzisoxazol-4-one 2a (2.0 g), titanium (IV) isopropylate (8.2 ml), NaCNBH3 (1.4 g) and ethanol (40 ml). The yield of the title compound was 1.9 g which was isolated in an oil. E NMR (CDCl3) d 1.33 (t, 3H), 1.40-2.05 (m, 5H), 2.10 (s, 3H), 2.17-2.30 (m, 5H), 2.40-2.70 (m, 2H), 2.76 (t , 2H), 3.67 (t, ÍH), 4.27 (c, 2H), 5.80 (t, ÍH), 7.03-7.17 (m, 8H).
Example 36 4,4- di- (2-tolyl) -3-butenyl iodide, 36a Boiling under reflux for
minutes a solution of 2,2-di- (2-tolyl) -tetrahydrofuran 33a (40 g) in 57% aqueous yodic acid (250 ml). The cooled solution is extracted with diethyl ether. The combined organic phases are washed with water and a saturated aqueous solution of dry NaCl (Na 2 SO 4) and evaporated in vacuo. The residue is subjected to CC (n-heptane / ethyl acetate 15: 1) to give the title compound 36a as an oil (44 g). ÍH RMN
(CDC13) d 2.10 (s, 3H), 2.30 (s, 3H), 2.65 (c, 2H), 3.19 (t,
2H), 5.73 (t, ÍH), 7.05-7.22 (m, 8H).
Example 37 (R, S) -3-benzenesulfonyloxy-4- (N-tert-butyloxycarbonyl-N-methylamino) -4,5,6,7-tetrahydro-1,2-benzisoxazole, 37a A 0 ° C is cooled to 0 ° C solution of (R, S) -4- (N-tert-butyloxycarbonyl-N-methylamino) -4,5,6,7-tetrahydro-l, 2-benzisoxazole, 12a (9 g), triethylamine (7.5 ml) and Dry THF (350 ml). Benzenesulfonyl chloride (5.2 ml) in dry THF (100 ml) is added dropwise at 0 ° C. The resulting reaction mixture is stirred for 3 hours at 0 ° C and for 60 hours at 22 ° C. the precipitate formed is removed by filtration and the organic solvent is evaporated in vacuo. The residue is subjected to CC (n-heptane / ethyl acetate 1: 1) to give the title compound 37a (5.5 g) as an oil. XH NMR (CDC13) d 1.40-1.94 (m, 11H), 1.94-2.14 (m, 2H), 2.60-2.72 (m, 5H), 4.95-5.36 (m, ÍH), 7.58 (t, 2H), 7.70 (t, ÍH), 8.02 (d, 2H).
Example 38 (R, S) -3-Benzenesulfonyloxy-4-methylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole hydrochloride, 38a It is added to a solution of (R, S) -3- benzenesulfonyloxy -4- (N-tert-butyloxycarbonyl-N-methylamino). -4, 5, 6, 7-tetrahydro-1,2-benzisoxazole, 37a (5.4 g) in dry diethyl ether (100 ml), a saturated solution of HCl (g) in dry diethyl ether (50 ml) and the resulting mixture is stirred by
48 hours at room temperature. The reaction mixture is evaporated in vacuo and the residue is suspended in dry diethyl ether (100 ml). The resulting crystals are collected by filtration and the title compound 38a (4.0 g) is dried.
P.f. 162-163 ° C (decomposition). ÍH NMR (CDCI3) d 1.75-2.15
(m, 2H), 2.46-3.04 (m, 7H), 4.25 (dd, ÍH), 7.60 (t, 2H), 7.76
(t, ÍH), 8.03 (d, 2H).
Example 39 (R, S) -3-Benzenesulfonyloxy-4- [N-methyl-N- (propynyl) amino] -4,5,6,7-tetrahydro-1,2-benzisoxazole, 39a Is heated to 50 ° C for 1 hour, a suspension of (R, S) -3-benzenesulfonyloxy-4-methylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole hydrochloride, 38a (3.5 g) and K2C03
(4.2 g) in methyl isobutyl ketone (200 ml). 3-Bromo-1-propyne (1.8 ml) in methyl isobutyl ketone (50 ml) is added dropwise at 50 ° C. The resulting reaction mixture is stirred for an additional 2 hours at 50 ° C and then during
72 hours at 117 ° C (reflux temperature) The cooled mixture is filtered and the solvent is evaporated in vacuo.The residue is subjected to CC (n-heptane / ethyl acetate / triethylamine 14: 5: 1) to give the compound of title 39a (0.92 g) .Pf 85-87 ° C .H NMR (CDC13) d 1.54-2.15 (m, 4H), 2.25 (t, ÍH), 2.33 (s,
3H), 2.52-2.77 (m, 2H), 3.40 (t, 2H), 3.79 (t, ÍH), 7.57 (t,
2H), 7.71 (t, ÍH), 8.05 (dd, 2H)
Example 40 (R, S) -4- (N-tert-Butyloxycarbonyl-N-methylamino) -3-ethoxymethyloxy-4,5,6,6-tetrahydro-1,2-benzisoxazole, 40a K2C03 (2.2 g) is added to a solution of (R, S) -4- (N-tert-butyloxycarbonyl-1-N-methylamino) -3-hydroxy-4,5,6,6-tetrahydro-1,2. -benzisoxazole 12a (3.5 g) in acetone (200 ml). The resulting suspension is heated to reflux temperature. Etoxymethyl chloride (1.5 g) in acetone (100 ml) is added dropwise at 65 ° C and the resulting reaction mixture is boiled under reflux for 2 hours. The cooled suspension is filtered and the organic solvent is evaporated in vacuo. The residue is subjected to CC (n-heptane / ethyl acetate / methanol 10: 10: 1) to give the title compound 40a (0.5 g) as an oil. H NMR (CDC13) d 1.24 (t, 3H), 1.48 (s, 9H), 1.50-2.10 (m, 4H), 2.50-2.70 (m, 5H), 3.75 (c, 2H), 4.90-5.13 (s) broad, IH), 5.20-5.44 (m, 2H).
Example 41 (R, S) -3-hydroxy-4-benzylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole hydrochloride 41a. Benzaldehyde (0.31 ml) is added to a solution of (R, S) -4-amino-3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 3a
(0.53 g and the hydrobromide) in ethanol (10 ml). The mixture is stirred at room temperature for 20 minutes and then cooled in an ice bath. Sodium borohydride is added
(0.15 g) and the mixture is stirred at 0 ° C for 30 minutes and at room temperature after evaporation, water (10 ml) is added and the mixture is acidified with 4 M HCl. The aqueous solution is washed with ether ( 2x10 ml) and made basic by the addition of 4M NaOH. Extraction with methylene chloride (3x15 ml), drying and evaporation gave (R, S) -3-ethoxy-benzylamino-4,5,6,7-tetrahydro-1,2-benzisoxazole (0.31 g). The hydrochloride is prepared by adding a solution of HCl in ethyl acetate and precipitating the hydrochloride by addition of ether. P.f. 192-194 ° C. Treatment of the compound with HBr as described in Example 8a gives 41a. P.f. 202-205 ° C. XH NMR (D20) d 1.95-2.25 (m, 4H), 2.60-2.90 (m, 2H), 4.45 (s, 2H), 4.35-4.60 (m, HH), 7.55 (s, 5H). The following compound is synthesized corresponding: (R, S) -3-hydroxy-4- (2, 2-diphenylethylamino) -4,5,6,7-tetrahydro-l, 2-benzisoxazole 41b-hydrobromide. P.f. 180-183 ° C, XH NMR (D20 and DMSO-dg.1: 1) d 1.80-2.15 (m, 4H), 2.45-2.75 (m, 2H), 3.70-4.00 (m, 2H), 4.30-4.65 (m, 2H), 7.50 (s, 10H).
Pharmacology The compounds of the invention are tested in the following well-known and recognized test models:
Synaptosomes of GABA Uptake The inhibition of GABA uptake is carried out by the method described by Falch et al., Drug Dev. Res. , 1990,
21, 169-188. By this method the inhibition of uptake of
Total GABA ie, neuronal and glial is determined. The results are shown in Table I below.
Antagonism of Isoniazide
The test is a test for antagonism of seizures induced by isoniazid in mice. The test substance is given s.c. to mice (male NMR / BOM, body weight 20-25 g) and 30 minutes later 300 mg of isoniazid is given s.c .. Five mice are used for doses and a group control is included only receiving isoniazid. This dose of isoniazid induces intermittent tonics. The animals are placed in cages of Macrolon type II and recorded at the time in which the first convulsions occur. The experiment is stopped after 90 minutes. Animals that have not had seizures within 60 minutes are recorded as + (protected). The results, that is, the number of mice protected by number of test mice is set in fractions as follows: 0/5, 1/5, 5/5. The DE50 values are calculated by analysis of logarithmic percentage units as shown in Table I below.
Table I: Inhibition of GABA uptake in synaptosomes and Isoniazid antagonisms
'= Preliminary Data
Additionally, some of the compounds of the invention have been tested for inhibition of neuronal and glial GABA uptake, respectively, by the method described by Falch et al, Drug Dev. Res., 1990, 21, 169-188. These tests show that some of the compounds predominantly inhibit glial uptake. Finally some of the compounds have shown effect in other convulsion models. From the above table it appears that some of the compounds of the invention, which do not inhibit GABA uptake in vitro show effect in the isoniazid antagonism test in vivo which indicate that these compounds are pro-drugs. Accordingly, the compounds of the invention are considered useful in the treatment of diseases associated with GABA neurotransmission, for example as analgesic, antipsychotic, anticonvulsant, or anxiolytic drugs or as drugs for the treatment of muscle or movement disorders, such as antispasmodics or antisymptomatic in Huntington's disease or Parkinsonism.
Formulation Examples The pharmaceutical formulations of the invention can be prepared by conventional methods in the art.
Tablets may, for example, be prepared by mixing the active ingredient with ordinary adjuvants and / or diluents and subsequently compressing the mixture in a conventional tableting machine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Other adjuvants or additives usually used for such purposes as dyes, flavors, preservatives, etc., may be used provided they are compatible with the active ingredients. The solutions for injections can be prepared by dissolving the active ingredient and the possible additives in one part for the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution, and filling in suitable vials or vias. Any suitable additive conventionally used in the art can be added, such as tonicity agents, preservatives, antioxidants, etc. Typical examples of recipes for the formulation of the invention are the following: Tablets containing 5.0 mg of compound 20a calculated as the free base Compound 20a 5.0 mg Lactose 60 mg Corn starch 30 mg Hydroxypropylcellulose 2.4 mg Microcrystalline cellulose 19.2 mg Croscarmellose disodium Type A 2.4 mg Magnesium stearate 0.84 mg
2) Tablets containing 50 mg of compound 8b calculated as the free base Compound 8b 0.5 mg Lactose 46.9 mg Corn starch 23.5 mg Povidone 1.8 mg Microcrystalline cellulose 14.4 mg Croscarmellose sodium A type 1.8 mg Magnesium stearate 0.63 mg
3) Syrup containing per milliliter: Compound lia 25 mg Sorbitol 500 mg Hydroxypropyl cellulose 15 mg Glycerol 50 mg Methylparaben 1 mg Propylparaben 0.1 mg Ethanol 0.005 ml Flavor 0.05 mg Natrium saccharine 0.5 mg Water add 1 ml
n for injection containing per millimeter:
Compound 14a 10 mg Sorbitol 5.1 mg Acetic acid 0.08 mg Water for injection add 1 ml
Claims (30)
1. A 4-aminotetrahydrobenzisoxazole or isothiazole compounds having the general formula I: characterized in that R1 and R2 are independently selected from the group consisting of: A) hydrogen, cycloalkyl, phenyl or a group R7 wherein R7, R8 and R9 are selected Rd-C-R9 independently from the group consisting of hydrogen, lower alkyl , lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, phenoxy-lower alkyl and heteroaryl selected from 2-thienyl, 3-thienyl, 2-furyl, 3-furyl , imidazolyl, oxazolyl, pyrazolyl, pyrimidinyl, pyrrolyl, thiazolyl, 1,4-triazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, any phenyl or heteroaryl group optionally present which is substituted with one or more substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulfonyl, lower alkyl, or dialkylamino (lower), cyano, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfonyloxy and fe nyl which again can be substituted with halogen, methyl, methoxy or trifluoromethyl; and any alkyl group present which is, optionally substituted with one to three hydroxy groups which are again optionally esterified with a carboxylic acid of B) a group of the general formula Y- (CH2) r- (CHR11) s- (CH2 ) t- where Y is selected from the following groups (1) - (5): wherein U is CHR10b, NR10b, O or S, U1 is NR10b, 0 or S; p is 0 or 1; q is 0 or 1; V is C or N and the dotted line represents a link when V is C and no link when V is N; A is 0, S, CH2, (CH2) 2, CH = CH-CH2,. { CH2) 3, CH = CH or 0-CH2; Ra and R each represent one or more substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulfonyl, lower alkyl or di (lower alkyl) amino, cyano, trifluoromethyl, trifluoromethylsulfo-nyloxy and trifluoromethylthio. r and t are independently 0, 1, 2 or 3, s is 0 or 1, with the proviso that when Y is a group (1) where U is NR1 ^, oo S or a group (4), then r + s + t is at least 2; and when Y is a group (3) or a group (5) where V is N, then r + s + t is at least 1; R7b, Rb and R9 * 3 are as defined for R7, R8 and R9 in A) with the proviso that they are not at the same time selected from hydrogen, lower alkyl, lower alkenyl and lower alkynyl; R 10"and R 11 are independently hydrogen, lower alkyl, lower alkenyl or lower alkynyl; C) a group of the general formula YC- (CH2) -W- (CH2) m- wherein n is 1, 2 or 3, m is 2 or 3; W is 0 or S; and Yc is a group (1) - (5) as defined in B) with the proviso that n may not be 1, when Y is a group (1) or (4) where U or U1, respectively, is NR10b , S or O; D) a group of the general formula Rlld Y * d- (CH2) k-C lH- (CH2) 1- where k is 0, 1, 2 or 3; 1 is 0, 1, 2 or 3; Rlld is defined R11 in B) above; and Y is selected from groups (2) and (5) as defined in B) above and the following groups (6) - (10): R7d R lOd R7d R7d l I RM-C- CH C = N-RM-C-CH * N- l R9d (6) •, (7) ¡9d (8). wherein p, q, Ra, Rb and A are as defined in B) and R7b-Rlld are as defined for R7tD-R10b and R11, respectively under B) or R1 and R2 together designate the alkylene thereby forming a ring containing nitrogen of 4-8 members; or one of R1 and R2 is a group R2 'OCO where R2' is phenyl, or heteroaryl as defined in A) above or phenyl or such heteroaryl substituted with one or more substituents selected from halogen, lower alkyl, lower alkoxy, hydroxy, nitro, lower alkylthio, lower alkylsulfonyl, lower alkyl or dialkylamino (lower), cyano, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfonyloxy, phenyl and phenyl substituted with halogen, methyl, methoxy or trifluoromethyl; R ^ - R6 are independently selected from hydrogen, hydroxy and lower alkyl, any alkyl group optionally being substituted with one or more hydroxy groups; X is oxygen or sulfur; P is hydrogen or a group ZR where Z is CO, CS, S02 or CRtRu, Rt and Ru being hydrogen, hydroxy or lower alkyl and if Z is CO or CS, then R is selected from the groups consisting of: i) hydrogen, C 1 -C 18 alkyl, C 1 -C 18 alkenyl, C 3 -Cg cycloalkyl, C 3 -Cg cycloalkenyl or C 4 -C 8 cycloalk (en) yl-alk (en) yl optionally substituted with one or more hydroxy groups, or phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, C -, - C4 alkyl, C - ^^ alkoxy, C - j - C4 alkylthio, acyloxy of - | _ -C5, or cyano; or ii) QRV wherein Q is 0 or S and Rv is selected from the substituents defined for R under i) above; and iii) NRXRY, wherein Rx and RY independently are selected from the substituents defined by R under i) above or Rx and RY are combined to form a four- to eight-membered heterocyclic ring containing from one to three nitrogen atoms and zero to three oxygen or sulfur atoms, or if Z is CRtR11, R is selected from the groups consisting of: iv) a QRV group as defined in ii); v) an NRXRY group as defined in iii); or vi) a group OC (0) Rz, SC (0) Rz, or SC (S) RZ where Rz is selected from the substituents defined for R under i) above; if Z is 02, R is selected from the group of i) defined in the above; with the proviso that P can not be hydrogen, when R1 to R6 are all hydrogen, X is oxygen and the compound exists as a racemic mixture; or pharmaceutically acceptable salts thereof.
2. The compound according to claim 1, characterized in that X is oxygen.
3. The compound according to claim 2, characterized in that R1 is a lower alkyl (ene / ino) yl optionally substituted with hydroxy, which can be esterified with a C2_2 carboxylic acid or phenyl or phenyl-lower alkyl, optionally substituted with halogen, lower alkyl, lower alkoxy or trifluoromethyl, R1 which is preferably methyl, ethyl or phenylbutyl.
4. The compound according to claim 3, characterized in that R2 is hydrogen, lower alkyl or a group R2 'OCO where R2' is as defined in claim 1.
5. The compound according to claim 2 or 4, characterized in that P is not hydrogen, P is preferably a group ZR as defined in claim 1, wherein Z is CH2 and R is a group 0C (0) Rz, as is defined in vi) in claim 1.
6. The compound according to claim 5, characterized in that R4-R6 are hydrogen and R3 is hydrogen or lower alkyl, preferably hydrogen or methyl.
7. The compound according to claim 6, characterized in that this is a compound of the formula la.
8. The compound according to claim 2, characterized in that R1 is a group as defined under B), C) or D).
9. The compound according to claim 8, characterized in that R1 is a group as defined in B), wherein Y is a group of the formula (1), (2) or (3), wherein R7b and R8b are phenyl , heteroaryl or substituted phenyl or heteroaryl, preferably a group of the formula (1) or (2) wherein u is CH2 or 0.
10. The compound according to claim 9, characterized in that R9b is hydrogen or lower alkyl, preferably hydrogen.
11. The compound according to claim 10, characterized in that R7b and R8b are independently phenyl, phenyl substituted with halogen, lower alkyl, lower alkoxy or trifluoromethyl, 2-thienyl, 2-thienyl substituted with methyl, pyrrolyl or pyrrolyl substituted with methyl or ethyl .
12. The compound according to claim 11, characterized in that Y is a group of the formula (1), (2) or (3), wherein U is CH2 or 0 and s is 0 and r + t is 0-5, preference 1-3, more preferred 2.
13. The compound according to claim 12, characterized in that R4-R6 are hydrogen and R3 is hydrogen or lower alkyl, preferably hydrogen or methyl.
14. The compound according to claim 8, characterized in that R ^ is a group as defined in B) wherein Y is a group of the formula (4) or (5).
15. The compound according to claim 14, characterized in that r + t is 0-5, preferably 1-3, more preferably 2.
16. The compound according to claim 15, characterized in that R1 is a group of the formula (5) wherein p and q are 0, A is sulfur or -CH2CH2- and Ra and Rb are hydrogen.
17. The compound according to claim 16, characterized in that R4-R6 are hydrogen and R3 is hydrogen or lower alkyl, preferably hydrogen or methyl.
18. The compound according to claim 8, characterized in that R1 is a group as defined in C), preferably such a group wherein Yc is a group of the formula (1) wherein U is CH2 or a group of the formula (2) ) wherein the formulas R7b and R8b are phenyl, heteroaryl or phenyl or substituted heteroaryl.
19. The compound according to claim 18, characterized in that R b is hydrogen or lower alkyl, preferably hydrogen.
20. The compound according to claim 8, characterized in that R1 is a group as defined in C) wherein Yc is a group of the formula (5).
21. The compound according to claim 8, characterized in that R1 is a group as defined in D) wherein Yd is a group of the formula (2), (5), (6), (7), (8), (9) or (10).
22. The compound according to claim 21, characterized in that Yd is a group of the formula (6), (7) or (8), R9d is hydrogen or lower alkyl, preferably hydrogen, R ^ -Od and Rlld are hydrogen and R d and R d are phenyl, phenyl substituted with halogen, lower alkyl, lower alkoxy or trifluoromethyl, 2-thienyl, 2-thienyl substituted with lower alkyl, pyrrolyl or pyrrolyl substituted with methyl or ethyl.
23. The compound according to claim 22, characterized in that k + 1 is 0-4, preferably 1-3.
24. The compound according to any of claims 8-23, characterized in that R2 is hydrogen, lower alkyl or a group R2 '-O-CO- wherein R2' is defined as in claim 1.
25. The compound according to claim 24, characterized in that R 2 is hydrogen or lower alkyl, preferably hydrogen or methyl.
26. The compound according to any of claims 8-25, characterized in that P is hydrogen.
27. The compound according to any of claims 8-25, characterized in that it is a compound of the formula la and that P is a group ZR as defined in claim 1, wherein Z is CH2 and R is a group OC (0) Rz, as defined in vi) in claim 1, preferably pivaloyloxy or benzoyloxy.
28. A pharmaceutical composition, characterized in that it comprises at least one novel 4-amino-tetrahydrobenzisoxazole or isothiazole according to any one of claims 1-27 in a therapeutically effective amount together with a pharmaceutically acceptable carrier and / or diluent.
29. The use of a 4-aminotetrahydrobenzisoxazole or isothiazole according to any of claims 1-27, for the manufacture of a pharmaceutical preparation for the treatment of diseases associated with neurotransmission of GABA.
30. The use of a 4-aminotetrahydrobenzisoxazole or isothiazole according to any of claims 1 - 27 for the manufacture of a pharmaceutical preparation for the treatment of analgesia, psychosis, seizures, epilepsy, anxiety, muscular and movement disorders, spasmodic disorders or symptoms of Huntington's disease or Parkinson's disease, preferably seizures.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK0207/95 | 1995-02-28 | ||
DK20795 | 1995-02-28 |
Publications (2)
Publication Number | Publication Date |
---|---|
MX9706280A MX9706280A (en) | 1998-06-30 |
MXPA97006280A true MXPA97006280A (en) | 1998-10-30 |
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