NO801209L - R PROCEDURE FOR THE PREPARATION OF ALFA-HALOMETHYLAMINO ACID - Google Patents
R PROCEDURE FOR THE PREPARATION OF ALFA-HALOMETHYLAMINO ACIDInfo
- Publication number
- NO801209L NO801209L NO801209A NO801209A NO801209L NO 801209 L NO801209 L NO 801209L NO 801209 A NO801209 A NO 801209A NO 801209 A NO801209 A NO 801209A NO 801209 L NO801209 L NO 801209L
- Authority
- NO
- Norway
- Prior art keywords
- chain
- acid
- carbon atoms
- branched
- hydrogen
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 39
- 238000000034 method Methods 0.000 title claims description 32
- 238000002360 preparation method Methods 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims description 125
- 125000004432 carbon atom Chemical group C* 0.000 claims description 58
- 239000001257 hydrogen Substances 0.000 claims description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims description 53
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- -1 ketimine salt Chemical class 0.000 claims description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- 150000002431 hydrogen Chemical group 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 230000007062 hydrolysis Effects 0.000 claims description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 150000001413 amino acids Chemical class 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 150000004820 halides Chemical class 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- 239000012024 dehydrating agents Substances 0.000 claims description 5
- GNFVFPBRMLIKIM-UHFFFAOYSA-N 2-fluoroacetonitrile Chemical compound FCC#N GNFVFPBRMLIKIM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 4
- 230000002152 alkylating effect Effects 0.000 claims description 3
- 125000005219 aminonitrile group Chemical group 0.000 claims description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- NRNSHPCDKHOUOE-UHFFFAOYSA-N 2-amino-2-[(3,4-dihydroxyphenyl)methyl]-3-fluoropropanoic acid Chemical compound FCC(N)(C(O)=O)CC1=CC=C(O)C(O)=C1 NRNSHPCDKHOUOE-UHFFFAOYSA-N 0.000 claims description 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 claims description 2
- STVCHNSLSLMIHJ-UHFFFAOYSA-N 2-amino-2-(fluoromethyl)-3-(3-hydroxyphenyl)propanoic acid Chemical compound FCC(N)(C(O)=O)CC1=CC=CC(O)=C1 STVCHNSLSLMIHJ-UHFFFAOYSA-N 0.000 claims 1
- ACIQAJKTARSFHQ-UHFFFAOYSA-N 2-amino-2-(fluoromethyl)-3-(4-hydroxyphenyl)propanoic acid Chemical compound FCC(N)(C(O)=O)CC1=CC=C(O)C=C1 ACIQAJKTARSFHQ-UHFFFAOYSA-N 0.000 claims 1
- 125000004970 halomethyl group Chemical group 0.000 claims 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 38
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 25
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 102000003823 Aromatic-L-amino-acid decarboxylases Human genes 0.000 description 23
- 108090000121 Aromatic-L-amino-acid decarboxylases Proteins 0.000 description 23
- LDCYZAJDBXYCGN-UHFFFAOYSA-N oxitriptan Natural products C1=C(O)C=C2C(CC(N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-UHFFFAOYSA-N 0.000 description 20
- 229940000681 5-hydroxytryptophan Drugs 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 14
- 229960003638 dopamine Drugs 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 13
- 229960004502 levodopa Drugs 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 12
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 12
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 230000002093 peripheral effect Effects 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000006114 decarboxylation reaction Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- DZGWFCGJZKJUFP-UHFFFAOYSA-N tyramine Chemical compound NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 8
- 102000004031 Carboxy-Lyases Human genes 0.000 description 7
- 108090000489 Carboxy-Lyases Proteins 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 230000002427 irreversible effect Effects 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 229930186147 Cephalosporin Natural products 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 6
- 208000018737 Parkinson disease Diseases 0.000 description 6
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 6
- 229940124587 cephalosporin Drugs 0.000 description 6
- 150000001780 cephalosporins Chemical class 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- ARNWQMJQALNBBV-UHFFFAOYSA-N lithium carbide Chemical compound [Li+].[Li+].[C-]#[C-] ARNWQMJQALNBBV-UHFFFAOYSA-N 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 229960002888 oxitriptan Drugs 0.000 description 5
- 239000002831 pharmacologic agent Substances 0.000 description 5
- 235000019260 propionic acid Nutrition 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 208000020925 Bipolar disease Diseases 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- 208000020401 Depressive disease Diseases 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 239000000164 antipsychotic agent Substances 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
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- 239000003954 decarboxylase inhibitor Substances 0.000 description 4
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
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- 229910000104 sodium hydride Inorganic materials 0.000 description 4
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- 229960003732 tyramine Drugs 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 3
- VIYKYVYAKVNDPS-HKGPVOKGSA-N (2s)-2-azanyl-3-[3,4-bis(oxidanyl)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 VIYKYVYAKVNDPS-HKGPVOKGSA-N 0.000 description 3
- UTZABVBAROQQED-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-3-fluoropropan-2-one Chemical compound COC1=CC=C(CC(=O)CF)C=C1OC UTZABVBAROQQED-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
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- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 description 3
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
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- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
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- 239000004480 active ingredient Substances 0.000 description 3
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- 125000003118 aryl group Chemical group 0.000 description 3
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 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
- 231100000252 nontoxic Toxicity 0.000 description 3
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
- A61K31/125—Camphor; Nuclear substituted derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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Description
Foreliggende oppfinnelse angår nye farmasøytisk anvendbare a-halomethylaminosyrederivater som er inhibitorer for aromatiske aminosyredecarboxylase, og fremgansmåter for fremstilling av disse. The present invention relates to new pharmaceutically usable α-halomethylamino acid derivatives which are inhibitors of aromatic amino acid decarboxylase, and processes for their production.
Aminosyrene tryptofan, 5-hydroxytryptofan, 3,4-dihydroxyfenylalanin (DOPA), tyrosin og fenylalanin omdannes metabolisk til tryptamin, 5-hydroxytryptamin, 3,4-dihydroxy-fenethylamin eller dopamin, tyramin og fenethylamin av et aromatisk aminosyredecarboxylase. Det er antatt at det aromatiske aminosyredecarboxylaseenzym er ikke-spesifikk, særlig når det gjelder perifer katalyse. Tegn tyder imidlertid på at i hjernen foreligger spesifikke decarboxyleringsenzymer for hver av DOPA og 5-hydroxytryptofan. The amino acids tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine (DOPA), tyrosine and phenylalanine are metabolically converted to tryptamine, 5-hydroxytryptamine, 3,4-dihydroxy-phenethylamine or dopamine, tyramine and phenethylamine by an aromatic amino acid decarboxylase. It is believed that the aromatic amino acid decarboxylase enzyme is non-specific, particularly in peripheral catalysis. Evidence suggests, however, that specific decarboxylation enzymes exist in the brain for each of DOPA and 5-hydroxytryptophan.
De ovenfor spesifiserte aromatiske aminer er kjent for å være innbefattet i forskjellige patofysiologiske prosesser. Eksempelvis er det funnet at tryptamin, decarboxyleringsproduktet av tryptofan, methyleres enzymatisk til mono-methyltryptamin som i sin tur methyleres enzymatisk til di-methyltryptamin (DMT) i menneskelig røde blodceller, plasma og blodplater. Det methylerende enzym er til stede i mange pattedyrarter og er blitt vist å være produsert i hjernevev i flere arter innbefattet menneske. DMT som har sterk hallu-cinogen eller psykomimetisk egenskap kan spille en rolle i etiologien av schizofreni og andre psykotiske forstyrrelser. Således ville et hvert middel som ville kunne blokkere dannelsen av DMT være anvendbart som et antipsykotisk middel. Blokkering av decarboxyleringen av tryptofan fører til ned-satte konsentrasjoner av tryptamin, og fjerner substratet for DMT-dannelse. Således ville en inhibitor for aromatisk aminosyre decarboxylase som ville kunne blokkere omdannelsen av tryptofan til tryptamin være anvendbart som et antipsykotisk middel. The above specified aromatic amines are known to be involved in various pathophysiological processes. For example, it has been found that tryptamine, the decarboxylation product of tryptophan, is enzymatically methylated to mono-methyltryptamine which in turn is enzymatically methylated to dimethyltryptamine (DMT) in human red blood cells, plasma and platelets. The methylating enzyme is present in many mammalian species and has been shown to be produced in brain tissue in several species, including humans. DMTs that have strong hallucinogenic or psychomimetic properties may play a role in the etiology of schizophrenia and other psychotic disorders. Thus, any agent that could block the formation of DMT would be useful as an antipsychotic agent. Blocking the decarboxylation of tryptophan leads to reduced concentrations of tryptamine, and removes the substrate for DMT formation. Thus, an inhibitor of aromatic amino acid decarboxylase that would block the conversion of tryptophan to tryptamine would be useful as an antipsychotic agent.
Både 5-hydroxytryptanin (5-HT), decarboxyleringsproduktet av 5-hydroxytryptofan, og 3,4-dihydroxyfenethyl-amin (dopamin), decarboxyleringsproduktet av DOPA, er innbefattet i perifere og sentrale fysiologiske prosesser, og midler som er effektive ved kontrollen av nivåer av disse aminer har resultert i anvendbare farmakologiske midler. Both 5-hydroxytryptanin (5-HT), the decarboxylation product of 5-hydroxytryptophan, and 3,4-dihydroxyphenethylamine (dopamine), the decarboxylation product of DOPA, are involved in peripheral and central physiological processes, and agents effective in controlling levels of these amines have resulted in useful pharmacological agents.
Det er blitt vist at sentral- eller hjerne-nivåer av 5-HT og norepinefrin, som dannes metabolsk ved hydroxylering av dopamin, er høyere i pasienter med maniske forstyrrelser enn i individer uten slike forstyrrelser. Det er også blitt vist at midler som nedsetter sentrålnivåer av monoaminer, f.eks. 5-HT og særlig norepinefrin har antimaniske egenska-per når de gies til mennesker, mens legemidler som øker mono-aminnivåer vil kunne fremskynne mania i mottagelige individer. Midler som.blokkerer dannelsen av 5-HT og dopamin, slik som f.eks. ved inhibering av det aromatiske aminosyredecarboxylaseenzym som omdanner 5-hydroxytryptofan og DOPA til 5-HT og dopamin, ville således være nyttig som antipsykotiske midler eller sterke psykosedative ved behandling av maniske forstyrrelser. It has been shown that central or brain levels of 5-HT and norepinephrine, which are formed metabolically by the hydroxylation of dopamine, are higher in patients with manic disorders than in individuals without such disorders. It has also been shown that agents that reduce central levels of monoamines, e.g. 5-HT and especially norepinephrine have antimanic properties when given to humans, while drugs that increase monoamine levels will be able to accelerate mania in susceptible individuals. Agents which block the formation of 5-HT and dopamine, such as e.g. by inhibiting the aromatic amino acid decarboxylase enzyme that converts 5-hydroxytryptophan and DOPA to 5-HT and dopamine, would thus be useful as antipsychotic agents or strong psychosedatives in the treatment of manic disorders.
Det er også blitt vist at midler som er anvendbare ved inhibering av decarboxylering av DOPA til dopamin er anvendbare ved behandling av Parkinsons sykdom når de administreres samtidig med eksogen DOPA eller L-DOPA. Det er antatt at Parkinsons sykdom skyldes, i det minste delvis, nedsatt sentrålnivåer av dopamin da eksogen administrering av DOPA eller L-DOPA er kjent å være et effektivt middel for behandling av Parkinsons sykdom. Da imidlertid eksogent administrerte DOPA lett omdannes.enzymatisk til dopamin perifert, er det nødvendig å administrere store mengder for å oppnå øket absorpsjon sentralt. DOPA penetrerer lett blod-hjerne-barrieren, mens dopamin ikke gjør dette. Administrering av DOPA e ler L-DOPA i forbindelse med en perifert aktiv inhibitor for enzymet som omdanner DOPA til dopamin reduserer mengden av L-DOPA som må administreres for å oppnå adekvate sirkulerende konsentrasjoner for sentralabsorpsjon. Andre fordeler oppnås også ved administrering av en aromatisk aminosyre decarboxylase inhibitor sammen med L-DOPA. Ved å forhindre dannelse av dopamin perifert, kan bivirkninger til-knyttet dopamin slik som hjerte arrhytmia, kvalme og oppkast unngås. Agents useful in inhibiting the decarboxylation of DOPA to dopamine have also been shown to be useful in the treatment of Parkinson's disease when co-administered with exogenous DOPA or L-DOPA. It is believed that Parkinson's disease is due, at least in part, to decreased central levels of dopamine as exogenous administration of DOPA or L-DOPA is known to be an effective means of treating Parkinson's disease. However, since exogenously administered DOPA is easily converted enzymatically to dopamine peripherally, it is necessary to administer large amounts to achieve increased absorption centrally. DOPA easily penetrates the blood-brain barrier, while dopamine does not. Administration of DOPA e ler L-DOPA in conjunction with a peripherally active inhibitor of the enzyme that converts DOPA to dopamine reduces the amount of L-DOPA that must be administered to achieve adequate circulating concentrations for central absorption. Other benefits are also achieved by administering an aromatic amino acid decarboxylase inhibitor together with L-DOPA. By preventing the formation of dopamine peripherally, dopamine-related side effects such as heart arrhythmia, nausea and vomiting can be avoided.
Studier indikerer at nivåer av 5-hydroxytryptamin (5-HT) er lavere i pasienter med depressiv syndromer enn i individer uten slike syndromer. Administrering av eksogen L-5-hydroxytryptofan (L-5-HTP) er effektiv også ved behandling av visse deprimerte pasienter. Da imidlertid L-5-HTP lett metaboliseres perifert til 5-HT, er det som med DOPA, nødvendig å administrere,store mengder av L-5-HTP for å oppnå økede sentrålnivåer av aminosyren. Det er også blitt vist at ved administrering av'en inhibitor for det aromatiske aminosyre decarboxylase enzym som katalyserer dannelsen av. 5-HTP fra 5-HTP.periferisk, er den nødvendige mengde av eksogent 5-HTP for å gi økede sentrålnivåer markert nedsatt. Studies indicate that levels of 5-hydroxytryptamine (5-HT) are lower in patients with depressive syndromes than in individuals without such syndromes. Administration of exogenous L-5-hydroxytryptophan (L-5-HTP) is also effective in the treatment of certain depressed patients. However, since L-5-HTP is easily metabolized peripherally to 5-HT, as with DOPA, it is necessary to administer large amounts of L-5-HTP to achieve increased central levels of the amino acid. It has also been shown that by administering an inhibitor of the aromatic amino acid decarboxylase enzyme that catalyzes the formation of 5-HTP from 5-HTP.peripherally, the required amount of exogenous 5-HTP to produce increased central levels is markedly reduced.
Med andre ord har inhibitorer for aromatiske aminosyre decarboxylase, anvendt i forbindelse med eksogent 5-HTP, vist seg å være nyttig ved behandling av depresjon. In other words, aromatic amino acid decarboxylase inhibitors, used in conjunction with exogenous 5-HTP, have been shown to be useful in the treatment of depression.
Midler som blokkerer perifer omdannelse av 5-HTP til 5-HT kan være nyttige ved behandling av andre tilstander som respons på.økede sentrålnivåer av 5-HTP som et resultat av eksogen administrering av 5-HTP. Det er blitt vist at eksogen L-5-HTP er nyttig ved behandling av myoclonus. Under-søkelser har også fastslått at administrering av eksogen 5-HTP er anvendbare ved behandling av insomnia. Således kan samtidig administrering av 5-HTP og en aromatisk aminosyre decarboxylase inhibitor være gunstig ved behandling av disse tilstander. Agents that block peripheral conversion of 5-HTP to 5-HT may be useful in the treatment of other conditions in response to increased central levels of 5-HTP as a result of exogenous administration of 5-HTP. Exogenous L-5-HTP has been shown to be useful in the treatment of myoclonus. Research has also established that the administration of exogenous 5-HTP is useful in the treatment of insomnia. Thus, simultaneous administration of 5-HTP and an aromatic amino acid decarboxylase inhibitor can be beneficial in the treatment of these conditions.
Blokkerende perifer dannelse av 5-hydroxytryptamin kan resultere i andre gunstige effekter da det er kjent at 5-HT er involvert i etiologien av rheumatoid arthritis og det carcinoide syndrom ved økning av collagennivåene. Det er også rapportert at 5-HT er det primære autocoid som er ansvarlig for anafylactoide reaksjoner i mennesker såvel som bronchoconstriksjon i astmatiske pasienter, og midler som virker som antagonister eller inhiberer dannelsen av 5-HT er nyttige ved behandling av disse tilstander. 5-HT er kjent for for å bevirke blodplateaggregering og har vært implisert som en causal faktor i det post-gastrectomi-styrttømningssyndrom og migrene. Methylsergid, en 5-hydroxytryptarnin antagonist, har vist seg å være effektiv ved behandling av det post-gasteetomi-styrkttømningssyndrom. Blocking peripheral formation of 5-hydroxytryptamine may result in other beneficial effects as 5-HT is known to be involved in the etiology of rheumatoid arthritis and the carcinoid syndrome by increasing collagen levels. It has also been reported that 5-HT is the primary autocoid responsible for anaphylactoid reactions in humans as well as bronchoconstriction in asthmatic patients, and agents that act as antagonists or inhibit the formation of 5-HT are useful in the treatment of these conditions. 5-HT is known to cause platelet aggregation and has been implicated as a causal factor in the post-gastrectomy collapse syndrome and migraine. Methylsergide, a 5-hydroxytryptarnine antagonist, has been shown to be effective in the treatment of the post-gastrectomy wasting syndrome.
Det har vært foreslått at fenethylamin, decarboxyleringsproduktet av fenylalanin, som en endogen forbindelse, bidrar til schizofrene symptomer og utløser migrene. Det har også vært foreslått at endogen tyramin, decarboxyleringsproduktet av tyrosin, bidrar til anfallsforstyrrelser. It has been suggested that phenethylamine, the decarboxylation product of phenylalanine, as an endogenous compound, contributes to schizophrenic symptoms and triggers migraine. It has also been suggested that endogenous tyramine, the decarboxylation product of tyrosine, contributes to seizure disorders.
Det er således klart at midler som er anvendbare ved regulering av nivåene av aromatiske aminosyrer og aminer finner bruk i mange farmakologiske situasjoner. Forbindelsene ifølge oppfinnelsen er inhibitorer av det aromatiske aminosyre decarboxylase som omdanner tryptofan, 5-hydroxytryptofan, 3,4-dihydroxyfenylalanin, tyrosin og fenylalanin til de respektive aminer og utgjør således nyttige farmakologiske midler. It is thus clear that agents useful in regulating the levels of aromatic amino acids and amines find use in many pharmacological situations. The compounds according to the invention are inhibitors of the aromatic amino acid decarboxylase which converts tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine into the respective amines and thus constitute useful pharmacological agents.
Forbindelsene ifølge oppfinnelsen er representert ved følgende generelle formel: The compounds according to the invention are represented by the following general formula:
I den. ovenfor generelle..- formel I er Y FCH2-, F2CE-, C1CH2-eller C^CH-, R-^ er hydrogen, alkylcarbonyl hvori alkyldelen har fra 1 til 4 carbonatomer og er rettkjedet eller forgrenet, alkoxycarbonyl hvori alkoxydelen har fra 1 til 4 carbonatomer og er rettkjedet eller forgrenet, eller hvori R ?7 er hydrogen, en rettkjedet eller forgrenet lavere alkylgruppe med fra 1 til 4 carbonatomer, benzyl eller p-hydroxybenzyl, 1*2 er hydroxy, en rettkjedet eller forgrenet alkoxygruppe med fra 1 til 8 carbonatomer, -^NR^Rg hvori hver av R^og Rg er hydrogen eller en rettk-jedet eller forgrenet alkylgruppe med fra 1 til 4 carbonatomer, eller hvori Rg er hydrogen, en rettkjedet eller forgrenet lavere alkylgruppe med fra 1 til 4 carbonatomer, benzyl eller p-hydroxybenzyl, hver av R^, .R^ r R5'R<*>4°9Rg nar ^e i ^en etterfølgende tabell I angitte betydninger, hvor R^q er hydrogen, en rettkjedet eller forgrenet alkylgruppe med fra 1 til 8 carbonatomer, alkylcarbonyl hvori alkyldelen er rettkjedet eller forgrenet og er fra 1 til 6 .carbonatomer, benzoyl eller fenylalkylencarbonyl hvori alkylendelen er rettkjedet eller forgrenet og har fra 1 til 6 carbonatomer; In the. above general..- formula I is Y FCH2-, F2CE-, C1CH2-or C^CH-, R-^ is hydrogen, alkylcarbonyl in which the alkyl part has from 1 to 4 carbon atoms and is straight-chain or branched, alkoxycarbonyl in which the alkoxy part has from 1 to 4 carbon atoms and is straight-chain or branched, or in which R ?7 is hydrogen, a straight-chain or branched lower alkyl group with from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl, 1*2 is hydroxy, a straight-chain or branched alkoxy group with from 1 to 8 carbon atoms, -^NR^Rg wherein each of R^ and Rg is hydrogen or a straight-chain or branched alkyl group of from 1 to 4 carbon atoms, or wherein Rg is hydrogen, a straight-chain or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl, each of R^, .R^ r R5'R<*>4°9Rg nar ^e in ^a subsequent table I specified meanings, where R^q is hydrogen, a straight-chain or branched alkyl group with from 1 to 8 carbon atoms, alkylcarbonyl in which the alkyl part is straight chain or branched net and is from 1 to 6 carbon atoms, benzoyl or phenylalkylenecarbonyl in which the alkylene moiety is straight-chain or branched and has from 1 to 6 carbon atoms;
Farmasøytisk akseptable salter og individuelle optiske isomerer av forbindelsene av generell formel I innbefattes også innen oppfinnelsens ramme. Pharmaceutically acceptable salts and individual optical isomers of the compounds of general formula I are also included within the scope of the invention.
Forbindelsene av generell formel I er anvendbare som farmakologiske midler ved at forbindelsene er inhibitorer for aromatisk aminosyre decarboxylase, og anvendbare som mellomprodukter ved fremstilling av nyttige farmakologiske midler. The compounds of general formula I are useful as pharmacological agents in that the compounds are inhibitors of aromatic amino acid decarboxylase, and useful as intermediates in the preparation of useful pharmacological agents.
Forbindelsene beskrevet her som generell formel X og fremgangsmåte for fremstilling av disse utgjør også en del. av oppfinnelsen. Forbindelsene av formel X er nyttige som kjemiske mellomprodukter for fremstilling av forbindelser av formel I hvori Y er FCH2-. The compounds described here as general formula X and the method for producing them also form a part. of the invention. The compounds of formula X are useful as chemical intermediates for the preparation of compounds of formula I wherein Y is FCH 2 -.
I den ovenfor angitte generelle • formel I er angi- In the general • formula I indicated above, the
velsen alkylcarbonyl ment å omfatte gruppen alkyl- the choice alkylcarbonyl meant to include the group alkyl-
hvori alkyldelen har fra 1 til 6 carbonatomer og er rettkjedet eller forgrenet. Angivelsen benzoyl som anvendt i generell formel I angir gruppen Angivelsen fenylalkylencarbonyl som anvendt i generell formel I er ment å omfatte gruppen wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight chain or branched. The designation benzoyl as used in general formula I indicates the group The designation phenylalkylenecarbonyl as used in general formula I is intended to include the group
hvori alkylendelen har fra 1 til 6 carbonatomer og er rettkjedet eller forgrenet, eksempelvis methylen, ethylen, iso-propylen og butylen. in which the alkylene part has from 1 to 6 carbon atoms and is straight-chain or branched, for example methylene, ethylene, iso-propylene and butylene.
Illustrative eksempler på rettkjedede eller forgrenede alkoxygrupper med fra 1 til 8 carbonatomer som anvendt her, er methoxyvethoxy, isopropyoxy, n-hexyloxy og n-octyl-oxy. Illustrative examples of straight-chain or branched alkoxy groups having from 1 to 8 carbon atoms as used herein are methoxyvethoxy, isopropyoxy, n-hexyloxy and n-octyloxy.
Illustrative eksempler på rettkjedede eller forgrenede alkylgrupper med fra 1 til 6 carbonatomer er methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl og n-pentyl. Illustrative examples of straight-chain or branched alkyl groups with from 1 to 6 carbon atoms are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and n-pentyl.
Illustrative eksempler på farmasøytisk akseptable salter av forbindelsene ifølge oppfinnelsen innbefatter ikke- toksiske syreaddisjonssalter dannet med uorganiske syrer, slik som saltsyre, hydrobromsyre, svovelsyre og fosforsyre, og organiske syrer slik som methansulfonsyre, salicylsyre, malinsyre, malonsyre, vinsyre, citronsyre og ascorbinsyrer, og ikke-toksiske salter dannet med uorganiske eller organiske baser slik som de med alkalimetaller, for eksempel natrium, kalium og lithium, jordalkalime.taller, for eksempel calcium og magnesium, lette metaller fra gruppe III A, for eksempel alu-minium, organiske aminer slik som primære, sekundære eller tertiære aminer, for eksempel cyclohexylamin, ethylamin,. pyridin, methylaminoethanol, ethanolamin ogpiperazin. Saltene fremstilles etter kjente metoder. Illustrative examples of pharmaceutically acceptable salts of the compounds of the invention include non-toxic acid addition salts formed with inorganic acids, such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as methanesulfonic, salicylic, malic, malonic, tartaric, citric and ascorbic acids, and non-toxic salts formed with inorganic or organic bases such as those with alkali metals, for example sodium, potassium and lithium, alkaline earth metals, for example calcium and magnesium, light metals from group III A, for example aluminium, organic amines such as primary, secondary or tertiary amines, for example cyclohexylamine, ethylamine,. pyridine, methylaminoethanol, ethanolamine and piperazine. The salts are produced according to known methods.
Foretrukne forbindelser ifølge oppfinnelsen er de av generell formel I hvori R-^er hydrogen eller alkylcarbonyl hvori alkyldelen har fra 1 til 4 carbonatomer, og er rettkjedet eller forgrenet, med forbindelser hvori R, er lik hydrogen som mere foretrukne. En annen foretrukket utførelsesform av oppfinnelsen er forbindelsene av generell formel I hvori R2er hydroxy eller en rettkjedet eller forgrenet alkoxygruppe med fra 1 til 8 carbonatomer. Forbindelser hvori R2er hydroxy er mere foretrukne. Forbindelser av generell formel I hvori hver avR^.' R^, R^, R-^og Rg er hydrogen eller Preferred compounds according to the invention are those of general formula I in which R-^ is hydrogen or alkylcarbonyl in which the alkyl part has from 1 to 4 carbon atoms, and is straight-chain or branched, with compounds in which R is equal to hydrogen being more preferred. Another preferred embodiment of the invention is the compounds of general formula I in which R 2 is hydroxy or a straight-chain or branched alkoxy group with from 1 to 8 carbon atoms. Compounds in which R2 is hydroxy are more preferred. Compounds of general formula I wherein each of R^.' R 1 , R 2 , R 2 and R 3 are hydrogen or
OR-^q hvori R^q er hydrogen, representerer en annen foretrukket utførelsesform av oppfinnelsen. Også forbindelser hvori R^ er OH og én av R4, R5, R'4eller Rg er OH, OCH3eller CH3og forbindelser hvori R^ er OH og én av R^ eller R'^er OH, OCH-j eller CH^ er foretrukne utf ørelsesf ormer av oppfinnelsen. Forbindelser av generell formel I hvori Y er FCH.-,- eller F2CH- er også foretrukket. OR-^q in which R^q is hydrogen represents another preferred embodiment of the invention. Also compounds in which R^ is OH and one of R4, R5, R'4 or Rg is OH, OCH3 or CH3 and compounds in which R^ is OH and one of R^ or R'^ is OH, OCH-j or CH^ are preferred embodiments of the invention. Compounds of general formula I in which Y is FCH 1 - or F 2 CH- are also preferred.
Illustrative eksempler på forbindelser av generell formel I er de følgende: 2-difluormethyl-2-amino-3-fenylpropionsyre, Illustrative examples of compounds of general formula I are the following: 2-difluoromethyl-2-amino-3-phenylpropionic acid,
2-difluormethyl-2-amino-3-(3-hydroxyfenyl)propionsyre, 2-difluormethyl-2-amino-3-(3,4-dihydroxyfenyl)propionsyre, 2-difluormethyl-2-amino-3-(4-hydroxyfenyl)propionsyre, 2-fluormethyl-2-amino-3-(4-klor-2-hydroxyfenyl)propionsyre, 2-klormethyl-2-amino-3-(4-klor-3-methoxyfeny1)propionsyre, 2-diklormethyl-2-amino-3-(2-klor-3-benzoyloxyfenyl)-propionsyre , 2-difluoromethyl-2-amino-3-(3-hydroxyphenyl)propionic acid, 2-difluoromethyl-2-amino-3-(3,4-dihydroxyphenyl)propionic acid, 2-difluoromethyl-2-amino-3-(4-hydroxyphenyl) )propionic acid, 2-fluoromethyl-2-amino-3-(4-chloro-2-hydroxyphenyl)propionic acid, 2-chloromethyl-2-amino-3-(4-chloro-3-methoxyphenyl)propionic acid, 2-dichloromethyl-2 -amino-3-(2-chloro-3-benzoyloxyphenyl)-propionic acid,
2-fluormethyl-2-amino-3-(2,4-diklor-3-hydroxyfenyl)propionsyre~2-difluormethyl-2-amino-3-(2-klor-4-hydroxyfenyl)-propionsyre, 2-fluoromethyl-2-amino-3-(2,4-dichloro-3-hydroxyphenyl)propionic acid~2-difluoromethyl-2-amino-3-(2-chloro-4-hydroxyphenyl)-propionic acid,
2-klormethyl-2-amino-3-(2-klor-6-methylfenyl)propionsyre,'2-fluormethyl-2-amino-3-(2,4-diklor-6-methylfenyl)propionsyre, 2-diklormethyl-2-amino-3-(4-klor-6-methylfenyl)propionsyre, 2-diklormethyl-2-amino-3-(2-hydroxy-3,5-dimethylfenyl)-propionsyre, 2-chloromethyl-2-amino-3-(2-chloro-6-methylphenyl)propionic acid,'2-fluoromethyl-2-amino-3-(2,4-dichloro-6-methylphenyl)propionic acid, 2-dichloromethyl-2 -amino-3-(4-chloro-6-methylphenyl)propionic acid, 2-dichloromethyl-2-amino-3-(2-hydroxy-3,5-dimethylphenyl)-propionic acid,
2-klormethyl-2-amino-3-(2-klor-4,6-dimethylfenyl)propionsyre, 2-fluormethyl-2-amino-3-(4-hydroxy-6-methylfenyl)propionsyre, 2-diklormethyl-2-amino-3-(5-ethyl-4-fenylpropionyloxyfenyl)-propionsyre, 2-chloromethyl-2-amino-3-(2-chloro-4,6-dimethylphenyl)propionic acid, 2-fluoromethyl-2-amino-3-(4-hydroxy-6-methylphenyl)propionic acid, 2-dichloromethyl-2- amino-3-(5-ethyl-4-phenylpropionyloxyphenyl)-propionic acid,
2-difluormethyl-2-amino-3-(4,6-diethyl-2-hydroxyfenyl)-propionsyre, 2-difluoromethyl-2-amino-3-(4,6-diethyl-2-hydroxyphenyl)-propionic acid,
2-klormethyl-2-amino-3-(4-klor-6-ethylfenyl)propionsyre, 2-fluormethyl-2-amino-3-(4-klor-6-tert-butylfenyl))propionsyre, 2-chloromethyl-2-amino-3-(4-chloro-6-ethylphenyl)propionic acid, 2-fluoromethyl-2-amino-3-(4-chloro-6-tert-butylphenyl))propionic acid,
2-difluormethyl-2-amino-3-(6-tert-butyl-4-hydroxyfenyl)-propionsyre, .2-diklormethyl-2-(N-ethoxycarbonylamino)3-(4-n-butoxyfenyl)-propionsyre, N,N-di-n-propy1-2-difluormethyl-2-amino-3-(4-acetyloxyfenyl)-propionamid, 2-difluoromethyl-2-amino-3-(6-tert-butyl-4-hydroxyphenyl)-propionic acid, .2-dichloromethyl-2-(N-ethoxycarbonylamino)3-(4-n-butoxyphenyl)-propionic acid, N, N-di-n-propy1-2-difluoromethyl-2-amino-3-(4-acetyloxyphenyl)-propionamide,
2-fluormethyl-2-[N-(2-amino-l-oxoethyl)amino]-3-(3-hydroxy- . fenyl)propionsyre, 2-fluoromethyl-2-[N-(2-amino-1-oxoethyl)amino]-3-(3-hydroxy-.phenyl)propionic acid,
2-f luorme thyl-2-amino-3-'(3 , 4-dihydroxy) f enyl-l-oxopropyl-aminoeddiksyre, 2-fluoroethyl-2-amino-3-(3,4-dihydroxy)phenyl-1-oxopropyl-aminoacetic acid,
2-[(2-difluormethyl-2-amino-l-oxo-3-fenyl)propylamino]-dihydrokanelsyre, 2-difluormethyl-2-(1-oxoethylamino)-3-(4-hydroxy)fenyl-1-oxopropylamino-2-propionsyre, 2-[(2-difluoromethyl-2-amino-1-oxo-3-phenyl)propylamino]-dihydrocinnamic acid, 2-difluoromethyl-2-(1-oxoethylamino)-3-(4-hydroxy)phenyl-1-oxopropylamino- 2-propionic acid,
methyl-2-f luormethyl-2- (1-oxoethylamino) -3- (4-hydroxy)>-f enyl-1- oxopropylaminoacetat, methyl 2-fluoromethyl-2-(1-oxoethylamino)-3-(4-hydroxy)>-phenyl-1-oxopropylaminoacetate,
2- klormethyl-2-amino-3-fenylpropionamid, 2-chloromethyl-2-amino-3-phenylpropionamide,
N,N^dimethyl-2-difluormethyl-2-amino-3-(3-hydroxyfenyl)-propionamid, N,N^dimethyl-2-difluoromethyl-2-amino-3-(3-hydroxyphenyl)-propionamide,
N,N-diethyl-2-diklormethyl-2-amino-3-(3<1>,4'-dimethoxyfenyl)-propionamid, N-n-butyl-2-difluormethyl-2-amino-3-(4-hydroxyfenyl)-propionamid, N,N-diethyl-2-dichloromethyl-2-amino-3-(3<1>,4'-dimethoxyphenyl)-propionamide, N-n-butyl-2-difluoromethyl-2-amino-3-(4-hydroxyphenyl)- propionamide,
methyl-2-klormethyl-2-amino-3-(3-hydroxyfenyl)propionat, isopropyl-2-diklormethyl-2-amino-3-(3,4-dihydroxyfenyl)-propionamid, methyl-2-chloromethyl-2-amino-3-(3-hydroxyphenyl)propionate, isopropyl-2-dichloromethyl-2-amino-3-(3,4-dihydroxyphenyl)-propionamide,
tert-butyl-2-fluormethyl-2-amino-3-(4-hydroxyfenyl)propionat, ethyl-2-difluormethyl-2-amino-3-(4-klor-3-methoxyfenyl)-propionat, tert-butyl-2-fluoromethyl-2-amino-3-(4-hydroxyphenyl)propionate, ethyl-2-difluoromethyl-2-amino-3-(4-chloro-3-methoxyphenyl)-propionate,
.2-fluormethyl-2-amino-3-(4-hydroxyfenyl)propionamid, 2-fluormethyl-2-amino-3-(3-hydroxy-4-methoxyfenyl)propionsyre, 2-fluormethyl-2-amino-3-(3-hydroxy-4-methylfenyl)propionsyre og .2-fluoromethyl-2-amino-3-(4-hydroxyphenyl)propionamide, 2-fluoromethyl-2-amino-3-(3-hydroxy-4-methoxyphenyl)propionic acid, 2-fluoromethyl-2-amino-3-( 3-hydroxy-4-methylphenyl)propionic acid and
2-difluormethyl-2-amino-3-(2-hydroxy-4-methylfenyl)-propionsyre. 2-difluoromethyl-2-amino-3-(2-hydroxy-4-methylphenyl)-propionic acid.
Forbindelsene av generell formel I er irreversible inhibitorer av enzymet som metabolisk katalyserer omdannelsen av tryptofan, 5-hydroxytryptof an, 3 , 4-difty.droxyf enylalanin} tyrosin og fenylalahin til tryptamin,\5-hydroxytryptamin,. 3,4-dihydroxyfenylethylamin, tyramin og fenethylamin. Som Ovenfor angitt har resultater av undersøkelser indikert at enzymet som er ansvarlig for omdannnelsen av de ovenfor angitte aminosyrer til de respektive aminer perifert er et ikke-spesifikt aromatisk aminosyre decarboxylase. For sen-tralomdannelse, har undersøkelser indikert at spesifikke decarboxylaser er ansvarlige for omdannelsen av hver av 5-hydroxytryptofan og 3,4-dihydroxyfenylalanin, mens de gjen-værende ovenfor angitte aminosyrer overføres enzymatisk til de respektive aminer ved en ikke-spesifikk aromatisk aminosyre decarboxylase. Forbindelsen ifølge oppfinnelsen er effektive ved irreversibel inhibering både sentralt og perifert av aktiviteten av ikke-spesifikk aromatisk aminosyre decarboxylase såvel som aktiviteten av 3,4-dihydroxyfenylalanin (DOPA) decarboxylase. Som anvendt her med hensyn til anvendeligheten av forbindelsene ifølge oppfinnelsen henviser uttrykket sentralt til sentralnervesystemet, i første rekke hjernen, mens perifert henvises til andre kroppsvev hvori decarboxylaseenzymet.er tilstede. Den selektive inhibering av aminosyre decarboxylaser sentralt eller perifert ved administrering av forbindelsen av generell formel I er dose-avhengig. The compounds of general formula I are irreversible inhibitors of the enzyme which metabolically catalyzes the conversion of tryptophan, 5-hydroxytryptof an, 3 , 4-difty.droxyf enylalanine} tyrosine and phenylalahine to tryptamine,\5-hydroxytryptamine,. 3,4-dihydroxyphenylethylamine, tyramine and phenethylamine. As indicated above, results of investigations have indicated that the enzyme responsible for the conversion of the above-mentioned amino acids into the respective peripheral amines is a non-specific aromatic amino acid decarboxylase. For central conversion, studies have indicated that specific decarboxylases are responsible for the conversion of each of 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine, while the remaining amino acids listed above are enzymatically transferred to the respective amines by a non-specific aromatic amino acid decarboxylase . The compounds according to the invention are effective by irreversibly inhibiting both centrally and peripherally the activity of non-specific aromatic amino acid decarboxylase as well as the activity of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase. As used here with regard to the applicability of the compounds according to the invention, the term refers centrally to the central nervous system, primarily the brain, while peripherally refers to other body tissues in which the decarboxylase enzyme is present. The selective inhibition of amino acid decarboxylases centrally or peripherally by administration of the compound of general formula I is dose-dependent.
Som irreversible inhibitorer for aromatiske aminosyre decarboxylaser og DOPA decarboxylase har forbindelsene ifølge oppfinnelsen mange farmakologiske anvendelsesmulig-heter. Som perifere irreversible inhibitorer for aromatisk aminosyre decarboxylase, er forbindelsene av generell formel I nyttige ved behandling av Parkinsons sykdom når de gies i forbindelse med 3,4-dihydroxyfenylalanin (DOPA) eller L-3,4-dihydroxyfenylalanin (L-DOPA). DOPA og særlig den aktive isomer L-DOPA er kjent for å være effektive ved behandling av Parkinsons sykdom når de administreres systemisk, vanligvis As irreversible inhibitors of aromatic amino acid decarboxylases and DOPA decarboxylase, the compounds according to the invention have many pharmacological application possibilities. As peripheral irreversible inhibitors of aromatic amino acid decarboxylase, the compounds of general formula I are useful in the treatment of Parkinson's disease when administered in conjunction with 3,4-dihydroxyphenylalanine (DOPA) or L-3,4-dihydroxyphenylalanine (L-DOPA). DOPA and particularly the active isomer L-DOPA are known to be effective in the treatment of Parkinson's disease when administered systemically, usually
i en mengde på fra 0,5 til 1 gram daglig i begynnelsen, hvoretter mengden av administrert forbindelse gradvis økes over en 3 til 7 dagers periode til en maksimal tolerert daglig dose på ca. 8 gram. Ledsagende administrering av en forbindelse av generell formel I og L-DOPA tilveiebringer en forbedret metode for behandling av Parkinsons sykdom ved at forbindelsene av formel I vil blokkere decarboxyleringen av L-DOPA til L-3,4-dihydroxyfenethylamin (L-dopamin) peri-ferisk ved inhibering av aktiviteten av aromatiske aminosyre decarboxylaseenzym, slik at det bibeholdes høye sirkulerende nivåer av L-DOPA for sentral absorpsjon og at det også for-hindres perifer dannelse av økede nivåer av dopamin som er kjent for å føre tii visse uønskede bivirkninger slik som hjerte arrhythmia. Ved ledsagende administrering av en forbindelse av generell formel I og L-DOPA, kan mengden av administrert L-DOPA reduseres to til ti ganger sammenlignet med de mengder som er nødvendig når L-DOPA administreres in an amount of from 0.5 to 1 gram daily initially, after which the amount of administered compound is gradually increased over a 3 to 7 day period to a maximum tolerated daily dose of about 8 grams. Concomitant administration of a compound of general formula I and L-DOPA provides an improved method of treating Parkinson's disease in that the compounds of formula I will block the decarboxylation of L-DOPA to L-3,4-dihydroxyphenethylamine (L-dopamine) peri- ferric by inhibiting the activity of aromatic amino acid decarboxylase enzyme, so that high circulating levels of L-DOPA are maintained for central absorption and that it also prevents peripheral formation of increased levels of dopamine which is known to lead to certain unwanted side effects such as heart arrhythmia. Upon concomitant administration of a compound of general formula I and L-DOPA, the amount of L-DOPA administered can be reduced two to tenfold compared to the amounts required when L-DOPA is administered
alene. Det foretrekkes at forbindelsene ifølge oppfinnelsen administreres før administrering av L-DOPA. Eksempelvis kan en forbindelse av formel I administreres fra 30 minutter til 4 timer før administrering av L-DOPA, avhengig av administre-ringsmåte og tilstanden til den pasient som skal behandles. alone. It is preferred that the compounds according to the invention are administered before the administration of L-DOPA. For example, a compound of formula I can be administered from 30 minutes to 4 hours before the administration of L-DOPA, depending on the method of administration and the condition of the patient to be treated.
Forbindelsene av generell formel I er også nyttige ved behandling av depressive syndromer i pasienter når de gies i forbindelse med 5-hydroxytryptofan (5-HTP) eller særlig den aktive levo isomer som er kjent for å være nyttig ved behandling av depresjon når den administreres systemisk. Forbindelsene av generell formel I vil ved inhibering peri-ferisk'av aktiviteten av aromatisk aminosyre decarboxylase^blokkere omdannelsen av 5-hydroxy-tryptofan til 5-hydroxytryptamin, og således bibeholde høyere sirkulerende nivåer av 5-HTP for sentral absorpsjon. Forbindelsene av generell formel I, når disse administreres samtidig med exogen 5-HTP, er også nyttige ved behandling av myoklonusvirkning som er kjent for effektivt å bli behandlet med økende sentrålnivåer av The compounds of general formula I are also useful in the treatment of depressive syndromes in patients when administered in conjunction with 5-hydroxytryptophan (5-HTP) or particularly the active levo isomer which is known to be useful in the treatment of depression when administered systemically . By peripherally inhibiting the activity of aromatic amino acid decarboxylase, the compounds of general formula I will block the conversion of 5-hydroxytryptophan to 5-hydroxytryptamine, thus maintaining higher circulating levels of 5-HTP for central absorption. The compounds of general formula I, when co-administered with exogenous 5-HTP, are also useful in the treatment of myoclonus which is known to be effectively treated with increasing central levels of
5-HTP.5-HTP.
Forbindelsene av generell formel I er i kraft av deres inhiberende virkning på aromatisk aminosyre decarboxylase perifert, også anvendbare ved behandling av rheumatoid arhtritis, carcinoid syndrome, anaphylactoide reaksjoner i mennesker, bronchokonstruksjon i astmatiske pasienter såvel som andre tilstander kjent å være forårsaket av høye perifere nivåer av 5-hydroxytryptamin. The compounds of general formula I are, by virtue of their inhibitory effect on aromatic amino acid decarboxylase peripherally, also useful in the treatment of rheumatoid arthritis, carcinoid syndrome, anaphylactoid reactions in humans, bronchoconstriction in asthmatic patients as well as other conditions known to be caused by high peripheral levels of 5-hydroxytryptamine.
Som ovenfor angitt er det blitt vist at midler som nedsetter de forhøyede nivåer av 5-HT og norepinefrin, hydroxyleringsproduktet av dopamin, er anvendbare ved behandling av pasienter med maniske forstyrrelser. Som sentral irreversible inhibitorer for aromatisk aminosyre decarboxylase, og DOPA decarboxylase, er således forbindelsene av generell formel I anvendbare ved behandling av maniske forstyrrelser. I tillegg på grunn av den sentral inhiberende virkning av forbindelsene av generell formel I på aromatisk aminosyre decarboxylase, kan forbindelsene også være anvendbare som antipsykotiske midler da sentrålnivåer av tryptamin nedsettes, og anvendbare ved behandling av schizofreni og anfallsforstyrrelser da sentrålnivåer av fenethylamin og tyramin nedsettes ved administrering av en forbindelse av generell formel I. As indicated above, agents which decrease the elevated levels of 5-HT and norepinephrine, the hydroxylation product of dopamine, have been shown to be useful in the treatment of patients with manic disorders. As central irreversible inhibitors of aromatic amino acid decarboxylase and DOPA decarboxylase, the compounds of general formula I are thus useful in the treatment of manic disorders. In addition, due to the central inhibitory effect of the compounds of general formula I on aromatic amino acid decarboxylase, the compounds may also be useful as antipsychotic agents as central levels of tryptamine are reduced, and useful in the treatment of schizophrenia and seizure disorders as central levels of phenethylamine and tyramine are reduced by administration of a compound of general formula I.
Anvendeligheten av forbindelsene av generell formel I som irreversible inhibitorer for aromatiske aminosyre decarboxylase kan vises som følger. En forbindelse av generell formel I ble administrert som en vandig løsning eller suspensjon til rotter eller mus. Ved forskjellige tidsinter-valler etter administrering av forbindelsen fra 1 til 48 timer ble dyrene avlivet ved halshogging og aromatisk aminosyre decarboxylaseaktiviteten ble målt ved en radiometrisk bestemmelse som beskrevet av Christenson et al., Arch. Biochem. Biophys. 141, 356 (1070) i homogenater av nyre, hjerte og hjerne fremstilt ifølge Burkard et al., Arch. Biochem. Biophys. 107, 187 (1964). The utility of the compounds of general formula I as irreversible inhibitors of aromatic amino acid decarboxylase can be shown as follows. A compound of general formula I was administered as an aqueous solution or suspension to rats or mice. At various time intervals after administration of the compound from 1 to 48 hours, the animals were euthanized by decapitation and the aromatic amino acid decarboxylase activity was measured by a radiometric assay as described by Christenson et al., Arch. Biochem. Biophys. 141, 356 (1070) in homogenates of kidney, heart and brain prepared according to Burkard et al., Arch. Biochem. Biophys. 107, 187 (1964).
Forbindelsene ifølge oppfinnelsen kan administreres på forskjellige måter for å oppnå den ønskede effekt. Forbindelsene kan administreres alene eller i form av farmasøy-tiske preparater til den pasient som skal behandles enten oralt eller parenteralt, for eksempel subkutant-, intra-venøst eller intraperitonealt. Forbindelsene kan administreres ved intranasal drypping eller ved påføring til slimhinner slik som den i nesen, svelg og bronkier, for eksempel i et aerosolspray inneholdende små partikler av en ny forbindelse ifølge oppfinnelsen i en sprayløsning eller tørr pulverform. The compounds according to the invention can be administered in different ways to achieve the desired effect. The compounds can be administered alone or in the form of pharmaceutical preparations to the patient to be treated either orally or parenterally, for example subcutaneously, intravenously or intraperitoneally. The compounds can be administered by intranasal drip or by application to mucous membranes such as those in the nose, throat and bronchi, for example in an aerosol spray containing small particles of a new compound according to the invention in a spray solution or dry powder form.
Mengden av administrert ny forbindelse vil variere og kan være en hvilken som helst effektiv mengde. Avhengig av pasienten, den tilstand som skal behandles og administre-ringsmåte, kan mengden av administrert ny forbindelse variere over et vidt område for å gi en effektiv mengde i en enhets-doseringsform. Når forbindelsene av generell formel I administreres for å bevirke en perifer irreversibel inhibering av aromatisk decarboxylase, vil den effektive mengde av administrert forbindelse variere fra 0,1 mg/kg til 100 mg/kg kroppsvekt av pasienten pr. dose og fortrinnsvis fra 5 mg/kg til 25 mg/kg. Eksempelvis kan denønskede perifere effekt erholdes ved forbruk av en enhetsdoseform slik som for eksempel en tablett inneholdende fra 10 til 250 mg av en ny forbindelse ifølge oppfinnelsen tatt 1 til 4 ganger daglig. Når forbindelsen av generell formel I administreres for å oppnå en sentral irreversibel inhibering av aromatisk decarboxylase eller 3,4-dihydroxyfenylalanin decarboxylase, vil den effektive mengde av administrert forbindelse variere fra 25 mg/kg til 500 mg/kg kroppsvekt av pasienten pr. dag, og fortrinnsvis fra 50 mg/kg til 300 mg/kg. Eksempelvis kan den ønskede sentrale effekt oppnås ved forbruk av en enhetsdoseform slik som f.eks. en tablett inneholdende fra 350 mg til 500 mg av en ny forbindelse ifølge oppfinnelsen tatt fra én til ti ganger The amount of novel compound administered will vary and may be any effective amount. Depending on the patient, the condition to be treated and the mode of administration, the amount of novel compound administered can vary over a wide range to provide an effective amount in a unit dosage form. When the compounds of general formula I are administered to effect a peripheral irreversible inhibition of aromatic decarboxylase, the effective amount of compound administered will vary from 0.1 mg/kg to 100 mg/kg body weight of the patient per dose and preferably from 5 mg/kg to 25 mg/kg. For example, the desired peripheral effect can be obtained by consuming a unit dosage form such as, for example, a tablet containing from 10 to 250 mg of a new compound according to the invention taken 1 to 4 times a day. When the compound of general formula I is administered to achieve a central irreversible inhibition of aromatic decarboxylase or 3,4-dihydroxyphenylalanine decarboxylase, the effective amount of compound administered will vary from 25 mg/kg to 500 mg/kg body weight of the patient per day, and preferably from 50 mg/kg to 300 mg/kg. For example, the desired central effect can be achieved by consuming a unit dosage form such as e.g. a tablet containing from 350 mg to 500 mg of a new compound according to the invention taken from one to ten times
daglig.daily.
Som anvendt her menes med uttrykket pasient varmblodige dyr slik som pattedyr, f.eks. katter, hunner, rotter,, mus, marsvin, sauer, hester, kveg og mennesker. As used here, the term patient means warm-blooded animals such as mammals, e.g. cats, females, rats, mice, guinea pigs, sheep, horses, cattle and humans.
De faste ehhetsdoseringsformer kan være av konven-sjonell type. Således kan den faste form være en kapsel som kan være av vanlig gelatintype inneholdende en ny forbindelse ifølge oppfinnelsen og en bærer, smøremiddel og inerte fyll-stoffer slik som lactose, sucrose og maisstivelse. I en annen utførelsesform tabletteres de nye forbindelser med konvensjo-nelle tablettbaser slik som lactose, sucrose eller maisstivelse i kombinasjon med bindemidler slik som acacis, maisstivelse eller gelatin, oppløsnende midler slik som maisstivelse, potetstivelse eller alginsyre, og et smøremiddel slik som stearinsyre eller magnesiumstearat. The solid unit dosage forms can be of the conventional type. Thus, the solid form can be a capsule which can be of the usual gelatin type containing a new compound according to the invention and a carrier, lubricant and inert fillers such as lactose, sucrose and corn starch. In another embodiment, the new compounds are tableted with conventional tablet bases such as lactose, sucrose or corn starch in combination with binders such as acacia, corn starch or gelatin, dissolving agents such as corn starch, potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate .
For parenteral administrering kan forbindelsene administreres som injiserbare doser av en løsning eller suspensjon av forbindelsen i et fysiologisk akseptabelt fortyn-ningsmiddel med en farmasøytisk bærer som kan være en steril væske slik som vann og oljer med eller uten tilsetning av et overflateaktivt middel og andre farmasøytisk akseptable hjelpe-stoffer. Illustrative eksempler på oljer som kan anvendes i disse preparater er oljer fra petroleum, oljer av animalsk, vegetabilsk eller syntetisk opprinnelse, f.eks. peanøttolje, soyabønneolje og mineralolje. Generelt er vann, fysiologisk saltvann, vandig dextrose og beslektede sukkerløsninger, ethanoler og glycoler slik som propylenglycol eller poly-ethylenglycol foretrukne flytende bærere, i særdeleshet for injiserbare løsninger. For parenteral administration, the compounds may be administered as injectable doses of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically acceptable excipients. Illustrative examples of oils that can be used in these preparations are oils from petroleum, oils of animal, vegetable or synthetic origin, e.g. peanut oil, soybean oil and mineral oil. In general, water, physiological saline, aqueous dextrose and related sugar solutions, ethanols and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
Forbindelsene kan administreres i form av en depot injeksjon eller implantat preparat som kan formuleres på en slik måte at det tillates en forlenget frigivelse av aktiv bestanddel. Den aktive bestanddel kan være sammenpresset i pellets eller små sylindere og implanteres subcutant eller intramuskulært som depot injeksjoner eller implantater. Implantater kan.anvende inerte materialer slik som bionedbryt-bare polymerer eller syntetiske siliconer, for eksempel Silastic silicongummi fremstilt av Dow-corning Corporation. The compounds can be administered in the form of a depot injection or implant preparation which can be formulated in such a way that a prolonged release of the active ingredient is permitted. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may use inert materials such as biodegradable polymers or synthetic silicones, for example Silastic silicone rubber manufactured by Dow-corning Corporation.
For bruk som aerosoler kan de nye forbindelser i løsning eller suspensjon pakkes i en komprimert aerosolbehol-der med et gassformig eller flytende drivmiddel, f.eks. diklordifluormethan, diklordifluormethan med diklordifluorethan, carbohdioxyd, nitrogen eller propan, med de vanlige hjelpe- stoffer slik som coløsningsmidler, og fuktemidler som kan være nødvendig eller ønskelig. Forbindelsene kan også administreres i en ikke-komprimert form slik som en forstøver eller atomiser. For use as aerosols, the new compounds in solution or suspension can be packaged in a compressed aerosol container with a gaseous or liquid propellant, e.g. dichlorodifluoromethane, dichlorodifluoromethane with dichlorodifluoroethane, carbon dioxide, nitrogen or propane, with the usual auxiliary substances such as co-solvents, and wetting agents that may be necessary or desirable. The compounds can also be administered in a non-compressed form such as a nebulizer or atomizer.
Som ovenfor angitt finner de nye forbindelser av generell formel I særlig anvendelse når de administreres sammen med exogent L-DOPA i hvilket tilfelle individuelle formuleringer av en forbindelse av generell formel I og L-DOPA kan administreres, eller begge bestanddeler kan formuleres i en enkel kombinasjon av en farmasøytisk formulering. I hver-administreringsmåte vil mengden av forbindelse av generell formel I sammenlignet med mengden av L-DOPA variere fra 1:1 til 1:10. En kombinasjonsformulering kan inneholde en indre del inneholdende L-DOPA og en ytre del inneholdende en forbindelse av generell formel I, idet hver aktiv bestanddel er egnet formulert. En særlig egnet kombinasjbnsformulering kan fremstilles ved sammenpressing av L-DOPA, eventuelt med egnede bærere, til en kjerne, hvilken kjerne utstyres med et laminert belegg som er resistent overfor mavesaft, hvoretter det over den belagte kjerne påføres et ytre lag som inneholder en forbindelse av generell formel I egnet formulert. Ved anvendelse av en slik kombinasjonsformulering frigis decarboxylase inhibitoren, dvs. en forbindelse av generell formel I fortrinnsvis 30 til 60 minutter før L-DOPA. Det laminerte belegg kan være dannet ved bruk av en ikke-vandig løsning av glycerider eller en vann-løselig polymer slik som ethylcel-lulose eller celluloseacetatfthalat. Formulering hvori L-DOPA er enterisk belagt ved bruk av blandinger av shellac og shellac-derivater og celiuloseacetat fthalater kan også anvendes. As indicated above, the novel compounds of general formula I find particular utility when administered together with exogenous L-DOPA in which case individual formulations of a compound of general formula I and L-DOPA may be administered, or both components may be formulated in a simple combination of a pharmaceutical formulation. In each mode of administration, the amount of compound of general formula I compared to the amount of L-DOPA will vary from 1:1 to 1:10. A combination formulation may contain an inner part containing L-DOPA and an outer part containing a compound of general formula I, each active ingredient being suitably formulated. A particularly suitable combination formulation can be prepared by compressing L-DOPA, possibly with suitable carriers, into a core, which core is equipped with a laminated coating that is resistant to gastric juice, after which an outer layer containing a compound of general formula I suitably formulated. When using such a combination formulation, the decarboxylase inhibitor, i.e. a compound of general formula I, is preferably released 30 to 60 minutes before L-DOPA. The laminated coating may be formed using a non-aqueous solution of glycerides or a water-soluble polymer such as ethyl cellulose or cellulose acetate phthalate. Formulations in which L-DOPA is enterically coated using mixtures of shellac and shellac derivatives and cellulose acetate phthalates can also be used.
I de spesifikke eksempler innbefattet- senere, er illustrative eksempler på egnede farmasøytiske formuleringer beskrevet. In the specific examples included later, illustrative examples of suitable pharmaceutical formulations are described.
I tillegg til å være nyttige . farmakologiske midler,' er forbindelsene av formel I også nyttige som mellomprodukter for fremstilling av anvendbare cefalosporin antibioticaer. Forbindelser av generell formel I hvori er hydroxy er nyttige ved fremstilling av cefalosporinderivater av følgen-de generelle formel II: In addition to being useful. pharmacological agents,' the compounds of formula I are also useful as intermediates for the preparation of useful cephalosporin antibiotics. Compounds of general formula I in which is hydroxy are useful in the preparation of cephalosporin derivatives of the following general formula II:
I den ovenfor angitte generelle formel II har Y, R-^.R^, , R^, R'4og Rg de tidligere angitte betydninger, M er hydrogen eller en negativ ladning, og X er hydrogen eller acetoxy. In the general formula II set forth above, Y, R-^, R^, , R^, R'4 and Rg have the previously indicated meanings, M is hydrogen or a negative charge, and X is hydrogen or acetoxy.
Forbindelsene av generell formel II og de farmasøy-tisk akseptable salter og individuelle optiske isomerer derav, er nye forbindelser anvendbare som antibiotica, og kan administreres på lignende måte som mange velkjente cefalosporinderivater, f.eks. cefalexin, cefalothin eller cefaloglycin. Forbindelsene av generell formel II og farmasøytisk akseptable salter og isomerer derav kan administreres alene eller i form av farmasøytiske preparater enten oralt eller parenteralt og topisk til varmblodige dyr, dvs. fugler og pattedyr, f.eks. katter, hunder, kveg, sauger, hester og mennesker. The compounds of general formula II and the pharmaceutically acceptable salts and individual optical isomers thereof are new compounds useful as antibiotics, and can be administered in a similar manner to many well-known cephalosporin derivatives, e.g. cephalexin, cephalothin or cephaloglycin. The compounds of general formula II and pharmaceutically acceptable salts and isomers thereof can be administered alone or in the form of pharmaceutical preparations either orally or parenterally and topically to warm-blooded animals, i.e. birds and mammals, e.g. cats, dogs, cattle, sheep, horses and humans.
For oral administrering kan forbindelsene administreres i form av tabletter, kapsler eller piller i form av eliksirer eller suspensjoner. For parenteral administrering kan forbindelsene best brukes i form av en steril vandig løsning som kan inneholde andre oppløste bestanddeler, for eksempel nok. fysiologisk saltvann eller glycose til å gjøre løsningen iso-tonisk. For topisk administrering kan forbindelsene av generell formel II, salter og isomerer derav, inkorporeres i kremer eller salver. For oral administration, the compounds may be administered in the form of tablets, capsules or pills in the form of elixirs or suspensions. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other dissolved constituents, for example NOK. physiological saline or glucose to make the solution isotonic. For topical administration, the compounds of general formula II, salts and isomers thereof, may be incorporated into creams or ointments.
Illustrative eksempler på bakterier overfor hvilke forbindelsene av generell formel II og de farmasøytisk akseptable salter og individuelle optiske isomerer er aktive overfor er Staphylococcus aureaus, Salmonella schotmuehleri, Klebsiella pneumoniae, Diplococcus pneumoniae og Streptococcus pyrogenes. Illustrative examples of bacteria against which the compounds of general formula II and the pharmaceutically acceptable salts and individual optical isomers are active are Staphylococcus aureaus, Salmonella schotmuehleri, Klebsiella pneumoniae, Diplococcus pneumoniae and Streptococcus pyrogenes.
Illustrative farmasøytisk akseptable ikke-toksiske uorganiske syreaddisjonssalter av forbindelsene av generell formel II er mineralsyreaddisjonssalter, for eksempel hydrogenklorid, hydrogenbromid, sulfater, sulfamater, fosfat, og organiske syreaddisjonssalter er for eksempel maleat, acetat, citrat, oxalat, succinat, benzoat, tartrat, fumarat, malat og ascorbat. Disse salter kan dannes på kjent måte. Illustrative pharmaceutically acceptable non-toxic inorganic acid addition salts of the compounds of general formula II are mineral acid addition salts, for example hydrogen chloride, hydrogen bromide, sulfates, sulfamates, phosphate, and organic acid addition salts are for example maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate , malate and ascorbate. These salts can be formed in a known manner.
Illustrative eksempler på cefalosporinderivater. som representert ved generell formel III er 7-[[2-acetylen-2-amino-3-fenylpropionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylsyre, 7-[[2-acetylen-2-amino-3-(3-hydroxyfenyl)propionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-en-2-carboxylsyre, 7-[[2-acetylen-2-amino-3-(3,4-dihydroxyfenyl)propionyl]-amino]-3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylsyre og 7-[[2-acetylen-2-amino-3-(4-hydroxyfenyl)-propionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-l-aza-bicyclo-[4.2.0]oct-2-en-2-carboxylsyre. Illustrative examples of cephalosporin derivatives. as represented by general formula III is 7-[[2-acetylene-2-amino-3-phenylpropionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2- ene-2-carboxylic acid, 7-[[2-acetylene-2-amino-3-(3-hydroxyphenyl)propionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo[4.2.0] -oct-2-ene-2-carboxylic acid, 7-[[2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionyl]-amino]-3-acetyloxymethyl-8-oxo-5-thia- l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 7-[[2-acetylene-2-amino-3-(4-hydroxyphenyl)-propionyl]amino]-3-acetyloxymethyl-8-oxo -5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylic acid.
Forbindelsene av generell formel II hvori R^- er hydrogen, fremstilles ved kobling av 7-aminocefalosporansyre eller et derivat derav av formel The compounds of general formula II in which R^- is hydrogen are prepared by coupling 7-aminocephalosporanic acid or a derivative thereof of formula
hvori X og M har de tidligere angitte betydninger, med en syre av'formelen: wherein X and M are as previously defined, with an acid of the formula:
eller et funksjonelt derivat derav slik som syreklorid eller syreanhydrid, og i nærvær av et dehydratiseringsmiddel. slik som dicyclohexylcarbodiimid, når den fri syre anvendes, hvori R^, R^, Rj., R'4 og Rg har de i generell formel II angitte betydninger, og hvor aminogruppen er beskyttet med en egnet blokkerende gruppe slik som tert-butoxycarbony1, etterfulgt av syrehydrolyse for å fjerne de aminobeskyttende grupper. or a functional derivative thereof such as acid chloride or acid anhydride, and in the presence of a dehydrating agent. such as dicyclohexylcarbodiimide, when the free acid is used, wherein R^, R^, Rj., R'4 and Rg have the meanings given in general formula II, and where the amino group is protected with a suitable blocking group such as tert-butoxycarbony1, followed by acid hydrolysis to remove the amino protecting groups.
Koblingsreaksjonen utføres generelt i et løsnings-middel slik som f.eks. ethylacetat, dioxan, kloroform eller tetrahydrofuran i -nærvær av en base slik som alkalibicarbonat. Temperaturen i reaksjonen kan variere fra -10 til 100° C og reaksjonstiden kan variere fra 1/2 time til 10 timer. Cefalosporinproduktene isoleres etter kjente metoder. Forbindelsene av generell formel IV fremstilles ved prosedyrer'beskrevet ovenfor, og forbindelsene av formel III er kommer-sielt tilgjengelige eller kan fremstilles etter vel kjente metoder innen faget. The coupling reaction is generally carried out in a solvent such as e.g. ethyl acetate, dioxane, chloroform or tetrahydrofuran in the presence of a base such as alkali bicarbonate. The temperature in the reaction can vary from -10 to 100° C and the reaction time can vary from 1/2 hour to 10 hours. The cephalosporin products are isolated according to known methods. The compounds of general formula IV are prepared by procedures described above, and the compounds of formula III are commercially available or can be prepared by methods well known in the art.
Forbindelsene av generell formel II hvori R-^er forskjellig fra hydrogen, fremstilles fra tilsvarende derivater hvori R^er hydrogen, ved den generelle prosedyre som er beskrevet i det etterfølgende for forbindelser av generell, formel I hvori R-^er forskjellig fra hydrogen. The compounds of general formula II wherein R-^ is different from hydrogen are prepared from corresponding derivatives wherein R^ is hydrogen, by the general procedure described below for compounds of general formula I wherein R-^ is other than hydrogen.
Forbindelsene av generell formel I hvori R^ er hydrogen, R2er hydroxy, både R^og R^er OR-^q hvori rj_q er hydrogen eller hvor både R^og R,- er OR^q hvori R-^q er hydrogen eller både R^og R^sammen er -0-CH2-0- eller hvori hver av R^, R4, R,-, R'4og Rg har de i tabell I angitte betydninger unntatt R^q er methyl, fremstilles ved behandling av et egnet beskyttet fenylpropionat av formelen The compounds of general formula I wherein R^ is hydrogen, R2 is hydroxy, both R^ and R^ are OR-^q wherein rj_q is hydrogen or where both R^ and R^- are OR^q wherein R-^q is hydrogen or both R^ and R^ together are -0-CH2-0- or in which each of R^, R4, R1-, R'4 and Rg have the meanings given in Table I except R^q is methyl, is prepared by treatment of a suitable protected phenylpropionate of the formula
med en sterk base for å danne et carbanion som behandles med et'egnet halomethylalkylerende reagens, etterfulgt av syrehydrolyse. I den ovenfor generelle formel V er R en rettkjedet eller forgrenet alkoxygruppe med fra 1 til 8 carbonatomer, Rtø er hydrogen, fenyl, en rettkjedet eller forgrenet alkylgruppe med fra 1 til 8 carbonatomer, methoxy eller ethoxy, Rcer fenyl eller en rettkjedet eller forgrenet alkylgruppe med fra 1 til 8 carbonatomer, eller R^. og Rcsammen danner en alkylengruppe med fra 5 til 7 carbonatomer, with a strong base to form a carbanion which is treated with a suitable halomethylalkylating reagent, followed by acid hydrolysis. In the above general formula V, R is a straight-chain or branched-chain alkoxy group of from 1 to 8 carbon atoms, Rtø is hydrogen, phenyl, a straight-chain or branched-chain alkyl group of from 1 to 8 carbon atoms, methoxy or ethoxy, Rcer is phenyl or a straight-chain or branched-chain alkyl group having from 1 to 8 carbon atoms, or R^. and Rc together form an alkylene group with from 5 to 7 carbon atoms,
dvs. -CH^-(CH0) -C<H>0<->hvori m er et helt tall fra 3 til 5.i.e. -CH^-(CH0) -C<H>0<->wherein m is an integer from 3 to 5.
Z ZmZZ ZmZ
Illustrative eksempler på rettkjedede eller forgrenede alkylgruppe r med fra 1 til 8 carbonatomer som R, og Rckan repre-sentere, er methyl, ethyl, n-prdpyl, isopropyl, n-butyl, tert-butyl, n-hexyl, n-octyl og nedpentyl. Hver av r-q'R12'<R>13'<R>'l2 °^ R14 ^ar ^e i etter^ølgende tabell II angitte betydninger: Illustrative examples of straight-chain or branched alkyl groups with from 1 to 8 carbon atoms that R and R can represent are methyl, ethyl, n-prdpyl, isopropyl, n-butyl, tert-butyl, n-hexyl, n-octyl and down pentyl. Each of r-q'R12'<R>13'<R>'l2 °^ R14 ^are ^e in the following table II indicated meanings:
Egnede sterke baser som kan anvendes i den ovenfor angitte reaksjonssekvens under dannelse av carbanionmellom-• . produktet er de som vil trekke et proton fra carbonatomet i a-stilling til carboxygruppen, slik. som alkyllithium, f.eks. butyllithium eller fenyllithium, lithiumdialkylamin, f.eks. lithiumdiisopropylamid, eller lithiumamid, tertiært kaliumbutylat, natriumamid, metallhydrider, f.eks. natriumhydrid eller kaliumhydrid, tertiære aminer, slik som triethylamin, lithiumacetylid eller dilithiumacetylid. Lithiumacetylid, dilithiumacetylid, natriumhydrid og lithiumdiisopropylamid er særlig foretrukne baser. Suitable strong bases which can be used in the above-mentioned reaction sequence during the formation of carbanion intermediate-• . the product are those that will withdraw a proton from the carbon atom in the a-position to the carboxy group, like this. such as alkyllithium, e.g. butyllithium or phenyllithium, lithiumdialkylamine, e.g. lithium diisopropylamide, or lithium amide, tertiary potassium butylate, sodium amide, metal hydrides, e.g. sodium hydride or potassium hydride, tertiary amines, such as triethylamine, lithium acetylide or dilithium acetylide. Lithium acetylide, dilithium acetylide, sodium hydride and lithium diisopropylamide are particularly preferred bases.
Egnede halomethylalkylerende reagenser som kan anvendes i den ovenfor angitte reaksjon er illustrativt kloro-fluormethan, bromfluormethan, fluorjodmethan, klordifluor-methan, bromdifluormethan, difluorjodmethan, bromklormethan, diklormethan, klorjodmethan, bromdiklormethan og diklorjod-methan. Halomethylalkylerende reagenser er kjent innen faget. Suitable halomethylalkylating reagents that can be used in the above reaction are illustratively chlorofluoromethane, bromofluoromethane, fluoroiodomethane, chlorodifluoromethane, bromodifluoromethane, difluoroiodomethane, bromochloromethane, dichloromethane, chloroiodomethane, bromodichloromethane and dichloroiodomethane. Halomethylalkylating reagents are known in the art.
Alkyleringsreaksjonen kan utføres i et aprotisk løsningsmiddel^f.eks. benzen, toluen, ethere, tetrahydrofuran, dimethylsulfoxid eller hexamethylfosfortriamid. Reak-sjonstemperaturen kan variere fra -120 til 65° C, en foretrukket reaksjonstemperatur er 40° C. Reaksjonstiden vil variere fra 1/2 time til 24 timer. The alkylation reaction can be carried out in an aprotic solvent^e.g. benzene, toluene, ethers, tetrahydrofuran, dimethylsulfoxide or hexamethylphosphoric triamide. The reaction temperature can vary from -120 to 65° C, a preferred reaction temperature is 40° C. The reaction time will vary from 1/2 hour to 24 hours.
Syrehydrolyse for å fjerne et hvert uomsatt utgangsmateriale og beskyttende grupper kan oppnås i et trinn eller trinnvis. I en én-trinns hydrolyseprosedyre vil, konsentra- sjonen av anvendt syre selvsagt variere med varigheten av hydrolysetrinnet og den anvendte temperatur. Eksempelvis kan en éntrinns hydrolyse oppnås ved behandling med konsentrert saltsyre i 1 - 4 dager ved 25 - 120° C. Trinnvis hydrolyse kan utføres ved behandling med fortynnet syre i fra 1/2 time til 6 timer ved 25° C for å fjerne uomsatt utgangsmateriale hvoretter behandlingen gjentas med fortynnet syre for å fjerne enhver aminbeskyttende gruppe, etterfulgt av behandling med konsentrert syre i 1 - 3 dager ved 25 - 125° C for å fjerne enhver ester eller ethergrupper. Trinnvis hydrolyse foretrekkes. Acid hydrolysis to remove each unreacted starting material and protecting groups can be accomplished in one step or stepwise. In a one-step hydrolysis procedure, the concentration of acid used will of course vary with the duration of the hydrolysis step and the temperature used. For example, a one-step hydrolysis can be achieved by treatment with concentrated hydrochloric acid for 1 - 4 days at 25 - 120° C. Stepwise hydrolysis can be carried out by treatment with dilute acid for from 1/2 hour to 6 hours at 25° C to remove unreacted starting material after which treatment is repeated with dilute acid to remove any amine protecting groups, followed by treatment with concentrated acid for 1 - 3 days at 25 - 125°C to remove any ester or ether groups. Stepwise hydrolysis is preferred.
Forbindelsene av generell formel I hvori Y er FCf^-, 1*2er hydroxy, R-^ er hydrogen, både R^ og R^ er OR^g hvori R^g er hydrogen, eller både R^og R^ er OR-^g hvori R^.g er hydrogen, eller hvor både R^og R^ sammen er -0-CH2-0~eller hvori hver av R^, R^, R^, R'4og Rg har de i tabell I angitte betydninger unntagen R^g er lik methyl. eller hydrogen, fremstilles også ved den prosedyre som er angitt i følgende reak-sjonsskjema: The compounds of general formula I wherein Y is FCf^-, 1*2 is hydroxy, R-^ is hydrogen, both R^ and R^ are OR^g wherein R^g is hydrogen, or both R^ and R^ are OR- ^g in which R^.g is hydrogen, or where both R^ and R^ together are -0-CH2-O~or in which each of R^, R^, R^, R'4 and Rg have those in Table I meanings except R^g is equal to methyl. or hydrogen, is also produced by the procedure indicated in the following reaction scheme:
I den ovenfor angitte reaksjonssekvens er Xa klor eller brom, R<->^i'<R>12'<R>13'<R>'l2°^R14^ar cS'e i takell 11 angitte betydninger, og R^, R^, R^, R'^og Rg har de i tabell I angitte betydninger unntatt R^q er lik methyl eller hydrogen . In the reaction sequence indicated above, Xa is chlorine or bromine, R<->^i'<R>12'<R>13'<R>'l2°^R14^are cS'e in takell 11 indicated meanings, and R^ , R^, R^, R'^ and Rg have the meanings given in Table I except R^q is equal to methyl or hydrogen.
I den ovenfor angitte reaksjonssekvens tilsettes et benzylhalogenid av formel VII meget langsomt til magnesiumringer i et egnet etherløsningsmiddel slik som tetrahydrofuran, diethylether eller blandinger derav, og reaksjonen tillates å forløpe i fra 30 minutter til 24 timer ved en temperatur fra -20 til 70° C, fortrinnsvis ved ca. 25° C til løsningsmidlets kokepunkt. Ved begynnelsen av reaksjonen tilsettes spor av methyljodid. Hvis enten R^ eller R^er methoxy, initieres reaksjonen i tetrahydrofuran. In the above reaction sequence, a benzyl halide of formula VII is added very slowly to magnesium rings in a suitable ether solvent such as tetrahydrofuran, diethyl ether or mixtures thereof, and the reaction is allowed to proceed for from 30 minutes to 24 hours at a temperature from -20 to 70°C , preferably at approx. 25° C to the boiling point of the solvent. At the beginning of the reaction, traces of methyl iodide are added. If either R 1 or R 2 is methoxy, the reaction is initiated in tetrahydrofuran.
Til det således dannede Grignard-reagens, dvs. forbindelser av formel VIII, tilsettes fluoracetonitril i et forhold som kan variere fra 0,5 til 3, i et aprotisk løs-ningsmiddel slik som tetrahydrofuran, diethylether, dioxan, benzen, dimethoxymethan eller dimethoxyethan eller blandinger derav. Temperaturen på reaksjonen vil variere fra -20 til To the thus formed Grignard reagent, i.e. compounds of formula VIII, fluoroacetonitrile is added in a ratio which can vary from 0.5 to 3, in an aprotic solvent such as tetrahydrofuran, diethyl ether, dioxane, benzene, dimethoxymethane or dimethoxyethane or mixtures thereof. The temperature of the reaction will vary from -20 to
-70° C, fortrinnsvis fra -20 til -25° C, og reaksjonstiden vil variere fra 10 minutter til 12 timer, fortrinnsvis fra -70° C, preferably from -20 to -25° C, and the reaction time will vary from 10 minutes to 12 hours, preferably from
10 minutter til 1 time. Det således dannede ketiminsalt,10 minutes to 1 hour. The ketimin salt thus formed,
dvs. forbindelser av formel IX, hydrolyseres med syre til ketonet. Syrehydrolyse kan utføres ved å helle ketiminsal-tet over i vann og konsentrert HC1 og opprettholde et sterkt surt medium. Ketonet av formel X isoleres på kjent måte, f.eks. ved ekstraksjon med petroleumether eller pentan eller hexan, og deretter med ethere slik som diethylether. i.e. compounds of formula IX, are hydrolyzed with acid to the ketone. Acid hydrolysis can be carried out by pouring the ketimine salt into water and concentrated HCl and maintaining a strongly acidic medium. The ketone of formula X is isolated in a known manner, e.g. by extraction with petroleum ether or pentane or hexane, and then with ethers such as diethyl ether.
Ketonet omdannes til aminonitrilet av formel IX under.betingelser for en Strecker-reaksjon ved behandling med 1-10 ekvivalenter natriumcyanid og 1 - 10 ekvivalenter av et ammoniumsalt, f.eks. zmmoniumklorid i enten et basisk medium under anvendelse av vandig ammoniumhydroxyd (1 molar til konsentrert) i en lavere alkohol slik som methanol eller ethanol, eller et nøytralt medium under anvendelse av vann og en lavere alkohol. The ketone is converted to the aminonitrile of formula IX under Strecker reaction conditions by treatment with 1-10 equivalents of sodium cyanide and 1-10 equivalents of an ammonium salt, e.g. zmmonium chloride in either a basic medium using aqueous ammonium hydroxide (1 molar to concentrated) in a lower alcohol such as methanol or ethanol, or a neutral medium using water and a lower alcohol.
Hydrolyse av aminonitrilet under dannelse av aminosyren av formel XII kan oppnås på forskjellige måter. Hydrolysis of the aminonitrile to form the amino acid of formula XII can be achieved in various ways.
Eksempelvis kan hydrolyse utføres ved behandling med hydrogenbromid ved 25 - 100° C i. fra 1/2 time til 24 timer. Når imidlertid hydrogenbromid anvendes, vil R-^Q i formel XII være hydrogen. Hydrolyse kan også utføres under anvendelse av svovelsyre ved generelt kjente metoder. Hydrolyse kan også oppnås ved behandling med en lavere alkohol slik som methanol mettet med vannfritt hydrogenklorid i 1 - 24 timer, fortrinnsvis 10 timer, ved 0 - 50° C, fortrinnsvis 25° C, under dannelse av det tilsvarende aminoamid som hydrolyseres ved behandling med vandig saltsyre eller 50 % vandig svovelsyre i fra 2 til 6 timer ved 60 - 100° C, fortrinnsvis 95° C, med etterfølgende nøytralisering under anvendelse av barium-hydroxyd når svovelsyre anvendes. For example, hydrolysis can be carried out by treatment with hydrogen bromide at 25 - 100° C. from 1/2 hour to 24 hours. However, when hydrogen bromide is used, R-^Q in formula XII will be hydrogen. Hydrolysis can also be carried out using sulfuric acid by generally known methods. Hydrolysis can also be achieved by treatment with a lower alcohol such as methanol saturated with anhydrous hydrogen chloride for 1 - 24 hours, preferably 10 hours, at 0 - 50° C, preferably 25° C, forming the corresponding aminoamide which is hydrolyzed by treatment with aqueous hydrochloric acid or 50% aqueous sulfuric acid for from 2 to 6 hours at 60 - 100° C, preferably 95° C, with subsequent neutralization using barium hydroxide when sulfuric acid is used.
Den nærmest kjente teknikk når det gjelder fremstilling av ketonene av formel X er den kjente prosedyre for fremstilling av fluormethyl m-tolylketon, E.D. Bergmann et al., J. Chem. Soc. 1961, 3452. Metoden beskrevet i den ovenfor angitte reaksjonssekvens kan skilles fra teknikkens stand, og gir også visse fordeler overfor teknikkens stand. I den ovenfor beskrevne prosedyre, er for det første Grignard-reagensene benzylreagenser, dernest må temperaturen på reaksjonsblandingen under Grignard-tilsetningen opprettholdes ved en temperatur på -20° C eller lavere, og for det tredje er fluoracetonitrilreagenset anvendt i foreliggende fremgangsmåte meget mindre toksisk enn de monofluoreddiksyrederi-vater som er blitt anvendt innen teknikkens stand for å fremstille fluormethylbenzylketon. The closest known technique for the preparation of the ketones of formula X is the known procedure for the preparation of fluoromethyl m-tolyl ketone, E.D. Bergmann et al., J. Chem. Soc. 1961, 3452. The method described in the reaction sequence indicated above can be distinguished from the state of the art, and also provides certain advantages over the state of the art. In the procedure described above, firstly, the Grignard reagents are benzyl reagents, secondly, the temperature of the reaction mixture during the Grignard addition must be maintained at a temperature of -20°C or lower, and thirdly, the fluoroacetonitrile reagent used in the present method is much less toxic than the monofluoroacetic acid derivatives which have been used in the prior art to prepare fluoromethylbenzyl ketone.
Forbindelsene av generell formel I hvori R-|_ er hydrogen, R2er hydroxy og hvilke som helst av R^, R^, R'4eller R5er OR-^g, og R^g er hydrogen, fremstilles fra det tilsvarende derivat hvori hvilke som helst av R^, R^, R'4eller R^er OR-^q og R^g er methyl, ved behandling av deriva-tet med hydrogenbromid i vann eller eddiksyre ved en temperatur på 25 til 125° C i fra 4 til 24 timer. The compounds of general formula I wherein R-|_ is hydrogen, R2 is hydroxy and any of R^, R^, R'4 or R5 is OR-^g, and R^g is hydrogen, are prepared from the corresponding derivative wherein which preferably of R^, R^, R'4 or R^ is OR-^q and R^g is methyl, by treating the derivative with hydrogen bromide in water or acetic acid at a temperature of 25 to 125° C. in from 4 to 24 hours.
Forbindelser av generell formel I hvori R^ er hydrogen,<R>2er hydroxy og hvilke som helst av R3, R4, R'4eller R5er OR-^g og R^Qer rettkjedet eller forgrenet alkyl med fra 1 til 8 carbonatomer, kan fremstilles ved alkylering av de tilsvarende forbindelser hvori R-^g er hydrogen, med et alkylhalogenid av formel R2lY2nvor R21er en rettkjec^et eller forgrenet alkylgruppe med fra 1 til 8 carbonatomer og Y2er halogen, for eksempel brom eller jod, i et lavere alkoholisk løsningsmiddel slik som methanol eller ethanol, eller hydrocarbonløsningsmidler slik som benzen eller toluen i nærvær av en organisk base slik som triethylamin eller pyridin, eller i et aprotisk løsningsmiddel slik som dimethylformamid, dimethylacetamid eller dimethylsulfoxyd i nærvær av natriumhydrid i fra 1 til 24 timer ved eh temperatur på fra 25 til 85° C, etterfulgt av hydrolyse med vandig base, forutsatt at a-aminogruppen og eventuelt carboxylgruppen i det hydroxysubstituerte utgangsmateriale før alkyleringsreaksjonen beskyttes med en egnet beskyttende gruppe slik som tert-butoxycarbonyl eller benzyloxycarbonyl og benzyl som deretter fjernes ved hydrogenolyse eller ved behandling med syre slik som trifluoreddiksyre. Alkylhalogenidene som anvendes i denne prosedyre er kjent innen faget eller kan fremstilles etter velkjente metoder. Compounds of general formula I in which R^ is hydrogen, <R>2 is hydroxy and any of R3, R4, R'4 or R5 is OR-^g and R^Q is straight or branched chain alkyl of from 1 to 8 carbon atoms can be prepared by alkylation of the corresponding compounds in which R-^g is hydrogen, with an alkyl halide of the formula R2lY2where R21 is a straight-chain or branched alkyl group of from 1 to 8 carbon atoms and Y2 is halogen, for example bromine or iodine, in a lower alcoholic solvent such such as methanol or ethanol, or hydrocarbon solvents such as benzene or toluene in the presence of an organic base such as triethylamine or pyridine, or in an aprotic solvent such as dimethylformamide, dimethylacetamide or dimethylsulfoxide in the presence of sodium hydride for from 1 to 24 hours at eh temperature of from 25 to 85° C, followed by hydrolysis with an aqueous base, provided that the α-amino group and optionally the carboxyl group in the hydroxy-substituted starting material before the alkylation reaction be is protected with a suitable protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl and benzyl which is then removed by hydrogenolysis or by treatment with an acid such as trifluoroacetic acid. The alkyl halides used in this procedure are known in the art or can be prepared by well-known methods.
Forbindelsene av generell formel I hvori R2 er hydroxy, R^er hydrogen og hvilke som helst av , R^ r R'4eller R,, er 0R^Qog R^q er alkylcarbonyl hvori alkyldelen har fra 1 til 6 carbonatomer og er rettkje!det eller forgrenet, benzoyl, eller fenylalkylencarbonyl hvori alkylendelen er rettkjedet eller forgrenet og har fra 1 til 6 carbonatomer, fremstilles ved behandling av de tilsvarende derivater hvori R,q er hydrogen, med et syreanhydrid av formelen The compounds of general formula I in which R2 is hydroxy, R2 is hydrogen and any of the or branched, benzoyl, or phenylalkylenecarbonyl in which the alkylene moiety is straight-chain or branched and has from 1 to 6 carbon atoms, is prepared by treating the corresponding derivatives in which R,q is hydrogen, with an acid anhydride of the formula
eller et syrehalogenid av formel or an acid halide of formula
hvori in which
halo er klor eller brom og R22er en rettkjedet eller forgrenet alkylgruppe med fra 1 til 6 carbonatomer, fenyl eller halo is chlorine or bromine and R22 is a straight-chain or branched alkyl group of from 1 to 6 carbon atoms, phenyl or
fenylalkylen, hvori alkylendelen er rettkjedet eller forgrenet og har fra 1 til 6 carbonatomer, i nærvær av en organisk base slik som pyridin, kinolin eller triethylamin, hvilken base tjener som løsningsmiddel., i fra 1 til 24 timer ved en temperatur på fra 25 til 100° C, forutsatt at a-aminogruppen og eventuelt carboxylgruppen i det hydroxy-substituerte utgangsmateriale før reaksjonen beskyttes med en egnet blokkerende gruppe slik som tert-butoxycarbonyl eller benzyloxycarbonyl og benzyl som deretter fjernes ved behandling med phenylalkylene, in which the alkylene moiety is straight chain or branched and has from 1 to 6 carbon atoms, in the presence of an organic base such as pyridine, quinoline or triethylamine, which base serves as a solvent., for from 1 to 24 hours at a temperature of from 25 to 100° C, provided that the α-amino group and possibly the carboxyl group in the hydroxy-substituted starting material are protected before the reaction with a suitable blocking group such as tert-butoxycarbonyl or benzyloxycarbonyl and benzyl which are then removed by treatment with
syre, f.eks. trifluoreddiksyre og hydrogenolyse. Syreanhydrid og syrehalogenidreaktantene anvendt i denne prosedyre er kjent innen faget eller kan fremstilles fra egnede syrer etter velkjente metoder.- acid, e.g. trifluoroacetic acid and hydrogenolysis. Acid anhydride and the acid halide reactants used in this procedure are known in the art or can be prepared from suitable acids by well-known methods.
Forbindelsene av formel I hvori R2er en. rettkjedet eller forgrenet alkoxygruppe med fra 1 til 8 carbonatomer, fremstilles ved behandling av de tilsvarende derivater hvori R2er hydroxy med thionylklorid under dannelse av syreklori-det, som omsettes med alkohol av formel R23~OH, hvori R23er en rettkjedet eller forgrenet alkylgruppe med fra 1 til 8 carbonatomer, slik som methyl, ethyl, n-propyl, isopropyl, n-butyl, hexyl eller octyl, ved ca. 25° C i fra 4 til 12 timer. The compounds of formula I wherein R 2 is one. straight-chain or branched alkoxy group with from 1 to 8 carbon atoms, is produced by treating the corresponding derivatives in which R2 is hydroxy with thionyl chloride to form the acid chloride, which is reacted with alcohol of formula R23~OH, in which R23 is a straight-chain or branched alkyl group with from 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, hexyl or octyl, at approx. 25° C for from 4 to 12 hours.
Forbindelsene av generell formel I hvori R2er The compounds of general formula I in which R 2 is
-NR^Rg, hvori hver av R^og Rg er hydrogen eller en rettkjedet eller forgrenet lavere alkylgruppe med 1 til 4 carbonatomer, fremstilles ved en acyleringsreaksjon av et syrehalogenid, f.eks. et syreklorid, av den tilsvarende forbindelse hvori R2er hydroxy og R^har den i formel I angitte betydning, forutsatt at enhver fri aminogruppe er beskyttet med en egnet beskyttende gruppe, f.eks. carbobenzyloxy eller tert-butoxycarbonyl, og når enhver av R^, R^, R^ eller R<1>^-NR^Rg, in which each of R^ and Rg is hydrogen or a straight-chain or branched lower alkyl group of 1 to 4 carbon atoms, is prepared by an acylation reaction of an acid halide, e.g. an acid chloride, of the corresponding compound in which R 2 is hydroxy and R 1 has the meaning given in formula I, provided that any free amino group is protected with a suitable protecting group, e.g. carbobenzyloxy or tert-butoxycarbonyl, and when any of R^, R^, R^ or R<1>^
er OR-^q og R-^q ér hydrogen, at angitte grupper er beskyttet som den tilsvarende alkylcarbonyloxygruppe, med et overskudd av et egnet amin som kan representeres som HNR_,Rg. Reaksjonen utføres i methylenklorid, kloroform, dimethylformamid, ethere slik som tetrahydrofuran eller dioxan eller benzen ved ca. 25° C i 1 4 timer. Egnede aminer er for eksempel ammoniakk eller en forbindelse som er en potensiell ammoniakk-kilde, f.eks. hexamethylentetramin, primære aminer, f.eks. methylamin, ethylamin eller n-propylamin, og sekundære aminer slik som dimethylamin, diethylamin eller di-n-butylamin. Etter acyleringsreaksjonen fjernes de aminobeskyttende grupper ved behandling med syre, f.eks. hydrogenbromid i dioxan eller hydrogenolyse, og den hydroxybeskyttende gruppe, når en slik er hensiktsmessig, fjernes ved base eller syrehydrolyse. is OR-^q and R-^q is hydrogen, that indicated groups are protected as the corresponding alkylcarbonyloxy group, with an excess of a suitable amine which can be represented as HNR_,Rg. The reaction is carried out in methylene chloride, chloroform, dimethylformamide, ethers such as tetrahydrofuran or dioxane or benzene at approx. 25° C for 1 4 hours. Suitable amines are, for example, ammonia or a compound which is a potential ammonia source, e.g. hexamethylenetetramine, primary amines, e.g. methylamine, ethylamine or n-propylamine, and secondary amines such as dimethylamine, diethylamine or di-n-butylamine. After the acylation reaction, the amino protecting groups are removed by treatment with acid, e.g. hydrogen bromide in dioxane or hydrogenolysis, and the hydroxy protecting group, when appropriate, is removed by base or acid hydrolysis.
Forbindelsene av generell formel I hvori R- er The compounds of general formula I in which R- is
fremstilles ved omsetning av det tilsvarende produced by the sale of the equivalent
derivat hvor R2er hydroxy eller en funksjonelt derivat derav slik som et syreanhydrid og hvor R, har den i formel I angitte betydning, forutsatt at enhver fri aminogruppe er beskyttet med en egnet blokkerende gruppe slik som benzyloxycarbonyl leier tert-butoxycarbonyl, med en forbindelse av derivative where R2 is hydroxy or a functional derivative thereof such as an acid anhydride and where R has the meaning given in formula I, provided that any free amino group is protected with a suitable blocking group such as benzyloxycarbonyl or tert-butoxycarbonyl, with a compound of
formelen the formula
hvor Rg har den i formel I angitte betydning og R24er en lavere alkylgruppe, f .eks. methyl eller ethyl, i en egnet ether slik som tetrahydrofuran eller dioxan ved 0 til 50° C i fra 1 til 24 timer, etterfulgt av syrehydrolyse for å fjerne den beskyttende gruppe, forutsatt at når den amin-beskyttede fri syre anvendes, utføres reaksjonen under anvendelse av et dehydratiseringsmiddel slik som dicyclohexylcarbodiimid. Forbindelsene av generell formel I hvori R^er alkylcarbonyl hvori alkyldelen er rettkjedet eller forgrenet og har fra 1 til 4 carbonatomer, fremstilles ved behandling av de tilsvarende derivater hvori R^er hydrogen og R2 er hydroxy, med et syrehalogenid av formelen hvori halo er et halogenatom, f .eks. klor eller brom, og R2^er en rettkjedet eller forgrenet alkylgruppe med fra 1 til 4 carbonatomer, i vann i nærvær'.av en base slik som natriumhydroxyd eller natriumborat ved en temperatur på fra 0 til 25° C i fra 1/2 time til 6 timer. Disse forbindelser kan også fremstilles fra esterderivatet, dvs. forbindelser av generell formel I hvori R-^ er hydrogen og R2er en alkoxygruppe med fra 1 til 8 carbonatomer, ved behandling med syrehalogenidet, where Rg has the meaning given in formula I and R24 is a lower alkyl group, e.g. methyl or ethyl, in a suitable ether such as tetrahydrofuran or dioxane at 0 to 50° C. for from 1 to 24 hours, followed by acid hydrolysis to remove the protecting group, provided that when the amine-protected free acid is used, the reaction is carried out under using a dehydrating agent such as dicyclohexylcarbodiimide. The compounds of general formula I in which R^ is alkylcarbonyl in which the alkyl part is straight-chain or branched and has from 1 to 4 carbon atoms, are prepared by treating the corresponding derivatives in which R^ is hydrogen and R2 is hydroxy, with an acid halide of the formula in which halo is a halogen atom, e.g. chlorine or bromine, and R 2 is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms, in water in the presence of a base such as sodium hydroxide or sodium borate at a temperature of from 0 to 25° C. for from 1/2 hour to 6 hours. These compounds can also be prepared from the ester derivative, i.e. compounds of general formula I in which R-^ is hydrogen and R2 is an alkoxy group with from 1 to 8 carbon atoms, by treatment with the acid halide,
beskrevet ovenfor, i described above, i
vann, methylenklorid, kloroform eller dimethylacetamid, i nærvær av en base slik som natriumhydroxyd, kaliumhydroxyd eller overskudd triethylamin ved en temperatur på fra 0 til 25° C i fra 1/2 time til 24 timer. water, methylene chloride, chloroform or dimethylacetamide, in the presence of a base such as sodium hydroxide, potassium hydroxide or excess triethylamine at a temperature of from 0 to 25° C. for from 1/2 hour to 24 hours.
Forbindelsene av generell formel I hvori R^ er alkoxycarbonyl hvori alkoxydelen er rettkjedet eller forgrenet og har fra 1 til 4 carbonatomer, fremstilles ved behandling av det tilsvarende derivat hvori R-^ er hydrogen og R2er hydroxy, med et alkyl haloformiat av formel The compounds of general formula I in which R^ is alkoxycarbonyl in which the alkoxy part is straight-chain or branched and has from 1 to 4 carbon atoms, are prepared by treating the corresponding derivative in which R-^ is hydrogen and R2 is hydroxy, with an alkyl haloformate of formula
hvori halo er et halogenatom slik som klor eller brom, og R2g er en rettkjedet eller forgrenet alkylgruppe med fra 1 til-4 carbonatomer, i vann i nærvær av en base slik som natriumhydroxyd eller natriumborat ved en temperatur fra 0 til 25° C i fra 1/2 time til 6 timer. Forbindelsene av generell formel I hvori R^ 'er hvori R^- j er hydrogen, en rettkjedet eller forgrenet lavere alkylgruppe med fra 1 til 4 carbonatomer, benzyl eller p-hydroxybenzyl, fremstilles ved behandling av det tilsvarende derivat hvori R^ er hydrogen og R^er en rettkjedet eller forgrenet alkoxygruppe med fra 1 til 8 carbonatomer, med en syre av formelen wherein halo is a halogen atom such as chlorine or bromine, and R2g is a straight-chain or branched alkyl group having from 1 to -4 carbon atoms, in water in the presence of a base such as sodium hydroxide or sodium borate at a temperature of from 0 to 25° C. in from 1/2 hour to 6 hours. The compounds of general formula I in which R^ is in which R^-j is hydrogen, a straight-chain or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl, are prepared by treating the corresponding derivative in which R^ is hydrogen and R^ is a straight-chain or branched alkoxy group of from 1 to 8 carbon atoms, with an acid of the formula
eller et anhydrid or an anhydride
derav, hvori aminogruppen er beskyttet med en egnet blokkerende gruppe slik som benzyloxycarbonyl eller tert-butoxycarbonyl, og R27har den ovenfor angitte betydning, i en e.ther slik som tetrahydrofuran eller dioxan, methylenklorid eller kloroform og i nærvær av et dehydratiseringsmiddel når den fri syre anvendes, ved en temperatur fra 0 til 35° C i fra 1 til 12 timer, etterfulgt av syre og basehydrolyse for å fjerne de beskyttende grupper. Eventuelt kan basehydrolyse elimineres under dannelse av esterpeptidderivatet. thereof, in which the amino group is protected with a suitable blocking group such as benzyloxycarbonyl or tert-butoxycarbonyl, and R27 has the above meaning, in an ether such as tetrahydrofuran or dioxane, methylene chloride or chloroform and in the presence of a dehydrating agent when the free acid is used, at a temperature from 0 to 35° C for from 1 to 12 hours, followed by acid and base hydrolysis to remove the protective groups. Optionally, base hydrolysis can be eliminated to form the ester peptide derivative.
De individuelle optiske isomerer av forbindelsene av generell formel I hvori R-^er H og R2er OH, kan separe-res ved anvendelse av (+) eller (-) binafthylfosforsyresalt ved den metode som er beskrevet av R. Viterbo et al., Tetrahedron Letters 48, 4617 (1971). Andre oppløsende midler slik som (+) kamfer-10-sulfonsyre kan også anvendes. De individuelle optiske isomerer av forbindelser av formel I hvori R-^og R2er forskjellige fra H og OH, kan erholdes som beskrevet heri for racematet ved å starte den oppløste aminosyre . The individual optical isomers of the compounds of general formula I in which R₂ is H and R₂ is OH can be separated using (+) or (-) binaphthylphosphoric acid salt by the method described by R. Viterbo et al., Tetrahedron Letters 48, 4617 (1971). Other solvents such as (+) camphor-10-sulfonic acid can also be used. The individual optical isomers of compounds of formula I in which R 1 and R 2 are different from H and OH can be obtained as described herein for the racemate by starting with the dissolved amino acid.
Forbindelsene av generell formel V kan fremstilles ved behandling av én ekvivalent av et glycinat av formel: The compounds of general formula V can be prepared by treating one equivalent of a glycinate of formula:
hvori R , R^og Rc'har de i formel V angitte betydninger, med én ekvivalent av en sterk base, slik som alkyllithium, f.eks. butyllithium eller fenyllithium, lithium-di-alkylamid, f.eks. lithiumdiisopropylamid, eller lithiumamid, tertiær kaliumbutylat, natriumamid, metallhydrider slik som natriumhydrid, tertiære aminer slik som triethylamin, lithiumacetylid eller dilithiumacetylid, etterfulgt av behandling med et alkylerende reagens av formel wherein R, R^ and Rc' have the meanings given in formula V, with one equivalent of a strong base, such as alkyllithium, e.g. butyllithium or phenyllithium, lithium dialkylamide, e.g. lithium diisopropylamide, or lithium amide, tertiary potassium butylate, sodium amide, metal hydrides such as sodium hydride, tertiary amines such as triethylamine, lithium acetylide or dilithium acetylide, followed by treatment with an alkylating reagent of the formula
hvori R^ i' R12'<R>13'<R>'l2 °^<R>14 ^ar ^e ketYdninger som er angitt i formel V, og hvor Xaer et halogenatom, f.eks. klor eller brom. Alkyleringen kan utføres i et aprotisk løsnings-middel, f.eks. benzen, ethere, tetrahydrofuran, dimethyl- . sulfoxyd eller hexamethylfosfortriamid. Reaksjonstiden varierer.fra 1/2 time til 24 timer og temperaturen varierer fra -120 til 25° C. wherein R^ i' R12'<R>13'<R>'12 °^<R>14 ^are ^e ketYdations which are indicated in formula V, and where Xa is a halogen atom, e.g. chlorine or bromine. The alkylation can be carried out in an aprotic solvent, e.g. benzene, ethers, tetrahydrofuran, dimethyl- . sulfoxide or hexamethylphosphoric triamide. The reaction time varies from 1/2 hour to 24 hours and the temperature varies from -120 to 25° C.
Forbindelsene av generell formel VI fremstilles ved behandling av et egnet alkylglycinat med en carbonylbærende forbindelse under dannelse av en Schiff-base på generelt kjent måte, spesielt (a) når R^ er hydrogen, ved behandling av den egnede aminosyreester med benzaldehyd eller et alkanal med fra 1 til 9 carbonatomer og som er rettkjedet eller forgrenet, f.eks. 1-propanal, 1-butanal, 2,2-dimethylpropan-l-al eller 2,2-diethylbutan-l-al, The compounds of general formula VI are prepared by treating a suitable alkylglycinate with a carbonyl-bearing compound to form a Schiff base in a generally known manner, in particular (a) when R^ is hydrogen, by treating the appropriate amino acid ester with benzaldehyde or an alkane with from 1 to 9 carbon atoms and which is straight-chain or branched, e.g. 1-propanal, 1-butanal, 2,2-dimethylpropan-1-al or 2,2-diethylbutan-1-al,
(b) når R^ er fenyl, ved behandling av den egnede aminosyreester med benzofenon eller fenylalkylketon hvori alkyldelen har fra 1 til 8 carbonatomer og er rettkjedet eller forgrenet, f.eks. fenylmethylketon, fenylethylketon, fenylisopropyl- (b) when R 1 is phenyl, by treating the appropriate amino acid ester with benzophenone or phenyl alkyl ketone in which the alkyl moiety has from 1 to 8 carbon atoms and is straight chain or branched, e.g. phenylmethyl ketone, phenylethyl ketone, phenylisopropyl-
keton, feny1-n-butylketon eller fenyl-tert-butylketon, og (c) når R, er rettkjedet eller forgrenet alkylgruppe med fra 1 til 8 carbonatomer, at den egnede aminosyreester behandles med et fenylalkylketon som beskrevet ovenfor, med et di-alkylketon hvori hver alkyldel har fra 1 til 8 carbonatomer og er rettkjedet eller forgrenet, f.eks. dimethylisopropyl-keton, di-n-butylketon eller methyl-tert-butylketon. 'De carbonyl-bærende forbindelser er kjent innen faget eller kan fremstilles etter velkjente metoder. ketone, phenyl-n-butyl ketone or phenyl-tert-butyl ketone, and (c) when R is a straight-chain or branched alkyl group having from 1 to 8 carbon atoms, that the appropriate amino acid ester is treated with a phenylalkyl ketone as described above, with a di-alkyl ketone wherein each alkyl moiety has from 1 to 8 carbon atoms and is straight or branched, e.g. dimethylisopropyl ketone, di-n-butyl ketone or methyl tert-butyl ketone. The carbonyl-bearing compounds are known in the art or can be prepared according to well-known methods.
Når R, er methoxy eller ethoxy i forbindelser av formel VI, omsettes et egnet alkylglycinat med benzoylhalo-genid, f.eks. klorid eller et alkansyrehalogenid, f.eks. klorid hvori alkansyren har fra 1 til 9 carbonatomer og kan være rettkjedet eller forgrenet, slik som acetylklorid, propionylklorid, butyrylklorid, tert-butyrylklorid, 2,2-diethylsmørsyreklorid eller valerylklorid ved 0° C i ethere, methylenklorid, dimethylformamid, dimethylacetamid eller klorbenzen, i nærvær av en organisk base slik som triethylamin eller pyridin, hvoretter reaksjonsblandingen tillates å oppvarmes til ca. 25° Ci 1 time. Det resulterende amid-derivat kombineres med et alkylerende reagens slik som methylfluorsulfonat, dimethylsulfat, methyljodid, methyl-p-toluensulfonat eller trimethyloxonium-hexafluorfosfat når R^er methoxy eller triethyloxonium-tetrafluorborat når R^er ethoxy ved ca. 25° C i et klorert hydrocarbonløsningsmiddel slik som methylenklorid, klorbenzen eller kloroform, og reaksjonsblandingen kokes under tilbakeløpskjøling i fra 12 til 20 timer. Blandingen avkjøles deretter til ca. 25° C, og en organisk base slik som triethylamin eller pyridin tilsettes, hvoretter løsningen ekstraheres med saltvann og produktet isoleres. When R, is methoxy or ethoxy in compounds of formula VI, a suitable alkyl glycinate is reacted with benzoyl halide, e.g. chloride or an alkanoic acid halide, e.g. chloride in which the alkanoic acid has from 1 to 9 carbon atoms and can be straight-chain or branched, such as acetyl chloride, propionyl chloride, butyryl chloride, tert-butyryl chloride, 2,2-diethylbutyric acid chloride or valeryl chloride at 0° C in ethers, methylene chloride, dimethylformamide, dimethylacetamide or chlorobenzene, in the presence of an organic base such as triethylamine or pyridine, after which the reaction mixture is allowed to warm to approx. 25°C 1 hour. The resulting amide derivative is combined with an alkylating reagent such as methyl fluorosulfonate, dimethyl sulfate, methyl iodide, methyl p-toluenesulfonate or trimethyloxonium hexafluorophosphate when R^ is methoxy or triethyloxonium tetrafluoroborate when R^ is ethoxy at about 25° C. in a chlorinated hydrocarbon solvent such as methylene chloride, chlorobenzene or chloroform, and the reaction mixture is refluxed for 12 to 20 hours. The mixture is then cooled to approx. 25° C, and an organic base such as triethylamine or pyridine is added, after which the solution is extracted with salt water and the product is isolated.
Når i forbindelsene av formel VI R, b og ^ R c sammen danner en alkylengruppe med fra 5 til 7 carbonatomer, erholdes angitte aminosyreesterderivater ved behandling av amino-syreesteren med et cyklisk alkanon valgt fra cyclopentanon, cyclohexanon og cycloheptanon under dannelse av en Schiff-base ved generelt kjente metoder. When in the compounds of formula VI R, b and ^ R c together form an alkylene group with from 5 to 7 carbon atoms, indicated amino acid ester derivatives are obtained by treating the amino acid ester with a cyclic alkane selected from cyclopentanone, cyclohexanone and cycloheptanone to form a Schiff- base by generally known methods.
Alkylglycinatene erholdes ved behandling av glycin The alkyl glycinates are obtained by treating glycine
med en alkohol av formelen RH hvori R3 har den i formel VI with an alcohol of the formula RH wherein R 3 has that of formula VI
3. ei angitte betydning, mettet med HCl-gass ved ca. 25° C i fra 12 til 36 timer, eller forbindelsene kan erholdes fra kommer-sielle kilder.3. a specified value, saturated with HCl gas at approx. 25° C. for from 12 to 36 hours, or the compounds may be obtained from commercial sources.
Forbindelsene av generell formel VII er kjent innen faget ellerkan fremstilles fra den tilsvarende egnede substituerte benzoesyre eller benzaldenydderivat som er kjent innen faget. For eksempel kan benzylhalogenider av formel VII fremstilles fra det tilsvarende benzaldehyd ved reduksjon med natriumborhydrid, lithiumaluminiumhydrid eller ved kataly-tisk reduksjon, eller fra den tilsvarende benzoesyreester ved reduksjon med lithiumaluminiumhydrid eller boran eller reduksjon ved av det tilsvarende benzoesyrederivat med lithium-hydrid og behandling av det således dannede benzylalkohol-derivat med f .eks. thionylklorid, fosforoxyklorid, fosfortri-klorid, fosfortribromid eller fosforpentaklorid. The compounds of general formula VII are known in the art or can be prepared from the correspondingly suitable substituted benzoic acid or benzaldehyde derivative known in the art. For example, benzyl halides of formula VII can be prepared from the corresponding benzaldehyde by reduction with sodium borohydride, lithium aluminum hydride or by catalytic reduction, or from the corresponding benzoic acid ester by reduction with lithium aluminum hydride or borane or reduction by of the corresponding benzoic acid derivative with lithium hydride and treatment of the benzyl alcohol derivative thus formed with e.g. thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride.
Visse forbindelser av generell formel V kan erholdes direkte fra den egnede aminosyre ved omdannelse av angitte syrer til en egnet ester og deretter beskyttelse av a-aminogruppen etter generelt kjente prosedyrer tidligere beskrevet for beskyttelse av alkylglycinataminogruppen. Eksempelvis kan det aminobeskyttede esterderivat av tyrosin eller fenylalanin erholdes på slik måte. Denne prosedyre kan ikke anvendes for å fremstille forbindelser av formel V hvori den aromatiske ring inneholder en hydroxygruppe i meta-stilling. Certain compounds of general formula V can be obtained directly from the suitable amino acid by conversion of indicated acids to a suitable ester and then protection of the α-amino group according to generally known procedures previously described for protection of the alkyl glycinate amino group. For example, the amino-protected ester derivative of tyrosine or phenylalanine can be obtained in this way. This procedure cannot be used to prepare compounds of formula V in which the aromatic ring contains a hydroxy group in the meta position.
Det etterfølgende eksempel 1 illustrerer anvendelsen av en forbindelse av generell formel I hvori R2er hydroxy, som et kjemisk utgangsmateriale ved fremstilling av et cefalosporin av formel II. The following Example 1 illustrates the use of a compound of general formula I in which R 2 is hydroxy, as a chemical starting material in the preparation of a cephalosporin of formula II.
Eksempel 1 Example 1
7-[[ 2- difiuormethyl- 2- amino- 3- fenylpropionyl] amino]- 3- acetyl-oxyemthyl- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- en- 2- carboxylsyre 7-[[ 2- difluoromethyl- 2- amino- 3- phenylpropionyl] amino]- 3- acetyl-oxyemthyl- 8- oxo- 5- thia- l- azabicyclo[ 4. 2. 0] oct- 2- en- 2 - carboxylic acid
En blanding av 1 g 3-acetyloxy-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-en-2-carboxylsyre og 1 g 2-difluor-methyl-2-amino-3-fenylpropionsyreklorid hvor den fri aminogruppe er beskyttet med tert-butoxycarbonyl i 50 ml ethylacetat ble kokt under tilbakeløpskjøling i 2 timer, hvoretter løsningsmidlet ble fjernet under dannelse av et residuum som ble 'behandlet med mild syre og kromatografert på siiicagel under anvendelse av benzen-aceton som elueringsmiddel under dannelse av 7-[[2-difluormethyl-2-amino-3-fenylpropionyl]-amino]-3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-en-2-carboxylsyre.■ A mixture of 1 g of 3-acetyloxy-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid and 1 g of 2-difluoro-methyl-2-amino -3-phenylpropionic acid chloride in which the free amino group is protected by tert-butoxycarbonyl in 50 ml of ethyl acetate was refluxed for 2 hours, after which the solvent was removed to give a residue which was treated with mild acid and chromatographed on silica gel using benzene -acetone as eluent during formation of 7-[[2-difluoromethyl-2-amino-3-phenylpropionyl]-amino]-3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct- 2-ene-2-carboxylic acid.■
De etterfølgende eksempler 2-4 illustrerer farma-søytiske preparater av forbindelsene .ifølge oppfinnelsen. The following examples 2-4 illustrate pharmaceutical preparations of the compounds according to the invention.
Eksempel 2Example 2
En illustrativ sammensetning for harde gelatinkapsler er som følger: An illustrative composition for hard gelatin capsules is as follows:
Formuleringen fremstilles ved å føre de tørre pulve-re av (a) og (b) gjennom en fin sikt og blande disse godt. Pulveret fylles deretter i harde gelatinkapsler til en netto-fyllihg på 115 mg pr. kapsel. The formulation is prepared by passing the dry powders of (a) and (b) through a fine sieve and mixing them well. The powder is then filled into hard gelatin capsules to a net filling of 115 mg per capsule.
Eksempel 3 Example 3
En illustrativ sammensetning for tabletter er som følger: An illustrative composition for tablets is as follows:
Granuleringen erholdt ved blanding av lactosen med forbindelse (a) og en del av stivelsen, og granulert med stivelsespasta tørkes, siktes og blandes med magnesiumsteara-tet. Blandingen presses til tabletter som hver veier 490 mg. The granulation obtained by mixing the lactose with compound (a) and part of the starch, and granulated with starch paste is dried, sieved and mixed with the magnesium stearate. The mixture is pressed into tablets each weighing 490 mg.
Eksempel 4Example 4
En illustrativ sammensetning for en injiserbar suspensjon er følgende 1 ml<1>s ampulle for en intramuskulær injeksjon. An illustrative composition for an injectable suspension is the following 1 ml<1>s ampoule for an intramuscular injection.
Materialene (a) - (d) blandes, homogeniseres og fylles i 1 ml's ampuller som forsegles og autoklaveres i 20 minutter ved 121° C. Hver ampulle inneholder 10 mg pr. ml av den nye forbindelse (a). The materials (a) - (d) are mixed, homogenized and filled in 1 ml ampoules which are sealed and autoclaved for 20 minutes at 121° C. Each ampoule contains 10 mg per ml of the new compound (a).
De etterfølgende eksempler illustrerer fremstilling av forbindelser av generell formel I. The following examples illustrate the preparation of compounds of general formula I.
Eksempel 5 1- fluor- 3-( 3, 4- dimethoxyfenyl)- 2- propanon Example 5 1-fluoro-3-(3,4-dimethoxyphenyl)-2-propanone
Under nitrogenatmosfære ble 12,20 g 3,4-dimethoxy-benzylklorid i 90 ml tetrahydrofuran (THF) langsomt tilsatt (innen 1 time) til 3,0 g magnesiumringer i.50 ml THF, hvorved kolben ble dyppet i et bad inneholdende vann ved romtemperatur.. Omrøring ble fortsatt i 1 time, hvoretter Grignard-reagenset ble fraskilt fra overskudd Mg, overført til en annen kolbe under nitrogen og avkjølt til -20° C. 10,0 g CH2FCN Under a nitrogen atmosphere, 12.20 g of 3,4-dimethoxy-benzyl chloride in 90 ml of tetrahydrofuran (THF) was slowly added (within 1 hour) to 3.0 g of magnesium rings in 50 ml of THF, whereby the flask was immersed in a bath containing water at room temperature.. Stirring was continued for 1 hour, after which the Grignard reagent was separated from excess Mg, transferred to another flask under nitrogen and cooled to -20° C. 10.0 g CH2FCN
i 25 ml THF ble tilsatt fra en dråpetrakt med en slik hastig-het at temperaturen ble holdt mellom -25 og -20° C. Etter at tilsetningen var.full ført, ble omrøringen fortsatt i 1 time ved -20° C, hvoretter løsningen ble heldt over på en blanding av 200 g is og 240 ml vann og 120 ml konsentrert HC1 og ekstrahert med petroleumether (2 x 100 ml) og diethylether (4 x 100 ml). Tørking (Na-jSO^) og fordampning av etherekstraktet ga 4,53 g (33 %) av rent keton med k.p. in 25 ml of THF was added from a dropping funnel at such a rate that the temperature was kept between -25 and -20° C. After the addition was complete, stirring was continued for 1 hour at -20° C, after which the solution was poured onto a mixture of 200 g ice and 240 ml water and 120 ml concentrated HCl and extracted with petroleum ether (2 x 100 ml) and diethyl ether (4 x 100 ml). Drying (Na-SO4) and evaporation of the ether extract gave 4.53 g (33%) of pure ketone, b.p.
100° C/0,35 mm Hg. 100° C/0.35 mm Hg.
Eksempel 6 Example 6
2- amino- 2- fluormethyl- 3-( 3, 4- dimethoxyfenyl) propionitril2-amino-2-fluoromethyl-3-(3,4-dimethoxyphenyl)propionitrile
Til en suspensjon av 31,5 g (0,149 mol) l-fluor-3-(3,4-dimethoxyfenyl)-2-propanon og 9,57 g (0,179 mol) ammo-niumklorid i en løsning av 28 % vandig ammoniakk (170 ml) ble tilsatt 8,77 g (0,179 mol) natriumcyanid. Reaksjonsblandingen ble omrørt ved romtemperatur under nitrogen i 20 timer. Det faste materiale som ble utskilt ble filtrert fra på sin-tret glass, deretter vasket med 50 ml 28 %-ig vandig ammoniakk. Det faste materiale ble løst i 1,3 liter éther, og den organiske fase ble vasket med vann, deretter med saltvann og .tørket over MgSO^. Ved konsentrering av løsningsmidlet ble . det utkrystallisert 21,8 g 2-amino-2-fluormethyl-3-(3,4-dimethoxyfenyl)propionitril med sm.p. 76° C. To a suspension of 31.5 g (0.149 mol) of 1-fluoro-3-(3,4-dimethoxyphenyl)-2-propanone and 9.57 g (0.179 mol) of ammonium chloride in a solution of 28% aqueous ammonia ( 170 ml) was added 8.77 g (0.179 mol) of sodium cyanide. The reaction mixture was stirred at room temperature under nitrogen for 20 hours. The solid material that separated was filtered off on sintered glass, then washed with 50 ml of 28% aqueous ammonia. The solid material was dissolved in 1.3 liters of ether, and the organic phase was washed with water, then with brine and dried over MgSO 4 . By concentrating the solvent, . the crystallized 21.8 g of 2-amino-2-fluoromethyl-3-(3,4-dimethoxyphenyl)propionitrile with m.p. 76° C.
Eksempel 7 Example 7
2- f luorme thyl- 2- ami- no- 3-( 3, 4- dihydroxyfenyl) propionsyre2- fluoroethyl- 2- amino- 3-( 3, 4- dihydroxyphenyl) propionic acid
En løsning av 20,7 g (0,086 mol) 2-amino-2-fluormethyl-3- (3,4-dimethoxyfenyl)propionitril i 300 ml 47 %-ig vandig hydrobromsyre ble oppvarmet under nitrogen til 100° C A solution of 20.7 g (0.086 mol) of 2-amino-2-fluoromethyl-3-(3,4-dimethoxyphenyl)propionitrile in 300 ml of 47% aqueous hydrobromic acid was heated under nitrogen to 100° C.
1 3 2 timer. Konsentrering av løsningsmidlet under redusert trykk ga et residuum som ble løst i 300 ml isopropanol. Løsningen fikk stå i 12 timer ved 4° C. Ammoniumbromidet som utskiltes ble filtrert fra og vasket med isopropanol (3 x 40 ml). Filtratet ble nøytralisert med 16 g triethylamin i isopropanol inntil pH på løsningen nådde 4,5 - 5. Bunnfallet som ble dannet ble oppsamlet og vasket grundig med kloroform. 19,4 g residuum ble løst i 500 ml vann og behandlet med kull. Ved konsentrering ble 13 g a-fluormethy1 DOPA utkrystallisert.. Fra modervæsken ble en annen sats (1,2 g) 2-fluormethyl-2-amino-3-(3,4-dihydroxyfenyl)propionsyre erholdt med sm.p. 2 30° C. 1 3 2 hours. Concentration of the solvent under reduced pressure gave a residue which was dissolved in 300 ml of isopropanol. The solution was allowed to stand for 12 hours at 4° C. The ammonium bromide which separated was filtered off and washed with isopropanol (3 x 40 ml). The filtrate was neutralized with 16 g of triethylamine in isopropanol until the pH of the solution reached 4.5 - 5. The precipitate that formed was collected and washed thoroughly with chloroform. 19.4 g of residue was dissolved in 500 ml of water and treated with charcoal. By concentration, 13 g of α-fluoromethyl DOPA was crystallized. From the mother liquor, another batch (1.2 g) of 2-fluoromethyl-2-amino-3-(3,4-dihydroxyphenyl)propionic acid was obtained with m.p. 2 30° C.
Eksempel 8 ' Example 8'
2- amino- 2- fluormethyl- 3-( p- methoxyfenyl) propionitril2-amino-2-fluoromethyl-3-(p-methoxyphenyl)propionitrile
Når det i fremgangsmåten ifølge eksempel 5 anvendes en egnet mengde p-methoxybenzylbromid i stedet for 3,4-dimethoxybenzylklorid, erholdes l-fluor-3-(p-methoxyfenyl)-2- propan som deretter anvendes i en egnet mengde i stedet for 1- fluor-3-(3,4-dimethoxyfenyl)-2-propanon, i fremgangsmåten ifølge eksempel 6, under dannelse av 2-amino-2-fluormethyl-3- (p-methoxyfenyl)propionitril. When, in the method according to example 5, a suitable amount of p-methoxybenzyl bromide is used instead of 3,4-dimethoxybenzyl chloride, 1-fluoro-3-(p-methoxyphenyl)-2-propane is obtained, which is then used in a suitable amount instead of 1 - fluoro-3-(3,4-dimethoxyphenyl)-2-propanone, in the method according to example 6, forming 2-amino-2-fluoromethyl-3-(p-methoxyphenyl)propionitrile.
Eksempel 9 2- fluormethyl- 2- amino- 3-( p- methoxyfenyl) propionsyre Example 9 2-fluoromethyl-2-amino-3-(p-methoxyphenyl)propionic acid
En løsning av 1 g 2-amino-2-fluormethyl-3-(p-methoxyfenyl)propionitril-hydroklorid i 40 ml vannfri methanol ble mettet med tørr HC1 under isavkjøling. Blandingen fikk stå over natten ved romtemperatur. Fordampning av løs-ningsmidlet ga det tilsvarende amid-hydroklorid i kvantita- A solution of 1 g of 2-amino-2-fluoromethyl-3-(p-methoxyphenyl)propionitrile hydrochloride in 40 ml of anhydrous methanol was saturated with dry HCl under ice-cooling. The mixture was allowed to stand overnight at room temperature. Evaporation of the solvent gave the corresponding amide hydrochloride in quantity
tivt utbytte. Nmr (D90) J ppm: 6,88 (4H, AB, J,,- = 9 Hz), tive dividend. Nmr (D90) J ppm: 6.88 (4H, AB, J,,- = 9 Hz),
AB AB
4,76 (2H, 2AB, JAD= 11 Hz, J = 46 Hz) , 3,64 (3H, s) ,4.76 (2H, 2AB, JAD= 11 Hz, J = 46 Hz) , 3.64 (3H, s) ,
Ad lirAd lir
3,08 (2H, AB, JAT3 14 Hz).3.08 (2H, AB, JAT3 14 Hz).
AB AB
6 00 mg av det således erholdte amidhydroklorid,600 mg of the amide hydrochloride thus obtained,
løst i 3N NaOH (50 ml) og ekstrahert med Et20. (3 x 50 ml) ga det fri amid (420 mg), nmr (CDCl3) J ppm: 6,94 (4H, AB, dissolved in 3N NaOH (50 mL) and extracted with Et 2 O. (3 x 50 mL) gave the free amide (420 mg), nmr (CDCl3) J ppm: 6.94 (4H, AB,
JAB= 9Hz) ; 4,56 (2H, 2AB, JAB9 Hz, J RF<=>47 Hz); JAB= 9Hz) ; 4.56 (2H, 2AB, JAB9 Hz, J RF<=>47 Hz);
3,80 (3H, s) , 3,0 (2H, AB, J = 14 Hz) , 1,68 (2H, bred s) . 3.80 (3H, s) , 3.0 (2H, AB, J = 14 Hz) , 1.68 (2H, wide s) .
920 mg av det fri amid og 50 vol% vandig H2SO4920 mg of the free amide and 50 vol% aqueous H2SO4
(7 ml) ble oppvarmet til-95° C i 2 timer. Blandingen ble-fortynnet med vann til et volum på 50 ml og nøytralisert med en Ba(0H)2løsning (totalt volum ble da ca. 150 ml). Et likt volum av 0,2 NH^SO^ ble tilsatt, og BaSO^ fjernet ved filtrering over celite. Filtratet ble ført over en Amberlite Amberlite. R J ) harpikskolonne (ca. 50 ml), H<+>form), og har-piksen ble vasket nøytralt med. vann og eluert med 3 N NH^OH (150 ml). Ved fordampning av ommoniofraksjonen ble 2-fluormethyl-2-amino-3-(p-methoxyfenyl)propionsyre erholdt (390 mg), (7 mL) was heated to -95° C. for 2 hours. The mixture was diluted with water to a volume of 50 ml and neutralized with a Ba(OH) 2 solution (total volume was then approx. 150 ml). An equal volume of 0.2 NH^SO^ was added, and BaSO^ removed by filtration over celite. The filtrate was passed over an Amberlite Amberlite. R J ) resin column (approx. 50 ml), H<+>form), and the resin peak was washed neutral with. water and eluted with 3 N NH^OH (150 mL). By evaporation of the ammonio fraction, 2-fluoromethyl-2-amino-3-(p-methoxyphenyl)propionic acid was obtained (390 mg),
nmr (D00/DC1) J ppm: 7,0 (4H, AB, J,_ = 9.Hz), 4,80 (2H,nmr (D00/DC1) J ppm: 7.0 (4H, AB, J,_ = 9.Hz), 4.80 (2H,
Z. AB Z. AB
2AB, JAD= 11 Hz, J„_ 46 Hz), 3,80 (3H, s), 3,20 (2H,2AB, JAD= 11 Hz, J„_ 46 Hz), 3.80 (3H, s), 3.20 (2H,
Ari rirAri rides
AB, JAB= 14 Hz) .. AB, JAB= 14 Hz) ..
Claims (7)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3371979A | 1979-04-26 | 1979-04-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO801209L true NO801209L (en) | 1980-10-27 |
Family
ID=21872052
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO801209A NO801209L (en) | 1979-04-26 | 1980-04-25 | R PROCEDURE FOR THE PREPARATION OF ALFA-HALOMETHYLAMINO ACID |
Country Status (14)
Country | Link |
---|---|
JP (1) | JPS55145647A (en) |
AU (1) | AU5774180A (en) |
BE (1) | BE882105R (en) |
CH (1) | CH646939A5 (en) |
DE (3) | DE3012641A1 (en) |
DK (1) | DK180880A (en) |
ES (2) | ES8201533A1 (en) |
GB (1) | GB2050356B (en) |
IE (1) | IE49522B1 (en) |
IT (1) | IT1143940B (en) |
NL (1) | NL8002417A (en) |
NO (1) | NO801209L (en) |
SE (1) | SE8003116L (en) |
ZA (1) | ZA801118B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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DE4101873C2 (en) | 1991-01-23 | 1993-12-09 | Isis Pharma Gmbh | Orally administrable drug form for the treatment of central dopamine deficiency states |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE47542B1 (en) * | 1977-06-01 | 1984-04-18 | Merck & Co Inc | Di-and tri-fluoromethyl amino acids and amines,compositions and processes for preparing said compounds |
FR2392958A1 (en) * | 1977-06-01 | 1978-12-29 | Merck & Co Inc | NEW FLUORINE AMINO ACIDS USEFUL AS A MEDICINAL PRODUCT |
ZA783273B (en) * | 1977-07-11 | 1979-06-27 | Merrell Toraude & Co | A-halomethyl amino acids |
AU3872678A (en) * | 1977-09-01 | 1980-02-14 | Merrell Toraude & Co | Alpha-halomethyl amines |
ATE3282T1 (en) * | 1978-07-24 | 1983-05-15 | Merck & Co. Inc. | ALPHA-DIFLUOROMETHYL-ALPHA-AMINO ACIDS AND PHARMACEUTICAL COMPOSITION CONTAINING THEM. |
-
1980
- 1980-02-26 IE IE382/80A patent/IE49522B1/en not_active IP Right Cessation
- 1980-02-27 ZA ZA00801118A patent/ZA801118B/en unknown
- 1980-03-06 BE BE0/199691A patent/BE882105R/en not_active IP Right Cessation
- 1980-03-18 CH CH213680A patent/CH646939A5/en not_active IP Right Cessation
- 1980-04-01 DE DE19803012641 patent/DE3012641A1/en not_active Withdrawn
- 1980-04-01 DE DE19803012581 patent/DE3012581A1/en not_active Withdrawn
- 1980-04-01 DE DE19803012602 patent/DE3012602A1/en not_active Withdrawn
- 1980-04-10 ES ES490441A patent/ES8201533A1/en not_active Expired
- 1980-04-10 ES ES490442A patent/ES8201534A1/en not_active Expired
- 1980-04-22 IT IT48484/80A patent/IT1143940B/en active
- 1980-04-23 AU AU57741/80A patent/AU5774180A/en not_active Abandoned
- 1980-04-24 SE SE8003116A patent/SE8003116L/en not_active Application Discontinuation
- 1980-04-25 NL NL8002417A patent/NL8002417A/en not_active Application Discontinuation
- 1980-04-25 NO NO801209A patent/NO801209L/en unknown
- 1980-04-25 GB GB8013819A patent/GB2050356B/en not_active Expired
- 1980-04-25 DK DK180880A patent/DK180880A/en unknown
- 1980-04-25 JP JP5442780A patent/JPS55145647A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
DK180880A (en) | 1980-10-27 |
IE49522B1 (en) | 1985-10-16 |
IT1143940B (en) | 1986-10-29 |
ES490442A0 (en) | 1982-01-01 |
IE800382L (en) | 1980-10-26 |
DE3012581A1 (en) | 1980-11-13 |
CH646939A5 (en) | 1984-12-28 |
ZA801118B (en) | 1981-02-25 |
DE3012641A1 (en) | 1980-11-06 |
JPS55145647A (en) | 1980-11-13 |
ES490441A0 (en) | 1982-01-01 |
DE3012602A1 (en) | 1980-11-06 |
GB2050356B (en) | 1983-05-18 |
AU5774180A (en) | 1980-10-30 |
IT8048484A0 (en) | 1980-04-22 |
ES8201533A1 (en) | 1982-01-01 |
GB2050356A (en) | 1981-01-07 |
NL8002417A (en) | 1980-10-28 |
SE8003116L (en) | 1980-10-27 |
ES8201534A1 (en) | 1982-01-01 |
BE882105R (en) | 1980-07-01 |
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