CA1161451A - .alpha.-ACETYLENIC AMINO ACIDS - Google Patents
.alpha.-ACETYLENIC AMINO ACIDSInfo
- Publication number
- CA1161451A CA1161451A CA000304901A CA304901A CA1161451A CA 1161451 A CA1161451 A CA 1161451A CA 000304901 A CA000304901 A CA 000304901A CA 304901 A CA304901 A CA 304901A CA 1161451 A CA1161451 A CA 1161451A
- Authority
- CA
- Canada
- Prior art keywords
- hydrogen
- straight
- carbon atoms
- acid
- branched
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001413 amino acids Chemical class 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 120
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 239000001257 hydrogen Substances 0.000 claims description 100
- 229910052739 hydrogen Inorganic materials 0.000 claims description 100
- 125000004432 carbon atom Chemical group C* 0.000 claims description 89
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 239000002253 acid Substances 0.000 claims description 48
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 45
- 230000000875 corresponding effect Effects 0.000 claims description 43
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 41
- 150000002431 hydrogen Chemical group 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 35
- 239000000460 chlorine Substances 0.000 claims description 32
- 150000001412 amines Chemical class 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 29
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical class NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 150000004820 halides Chemical class 0.000 claims description 17
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 13
- 230000007062 hydrolysis Effects 0.000 claims description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 12
- 230000002152 alkylating effect Effects 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 125000001475 halogen functional group Chemical group 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 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
- 150000007530 organic bases Chemical class 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 150000008065 acid anhydrides Chemical class 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000012024 dehydrating agents Substances 0.000 claims description 7
- 125000005907 alkyl ester group Chemical group 0.000 claims description 6
- 150000001350 alkyl halides Chemical class 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 239000011260 aqueous acid Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 150000007517 lewis acids Chemical class 0.000 claims description 5
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 4
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000001681 protective effect Effects 0.000 claims 1
- 102000003823 Aromatic-L-amino-acid decarboxylases Human genes 0.000 abstract description 23
- 108090000121 Aromatic-L-amino-acid decarboxylases Proteins 0.000 abstract description 23
- 239000003112 inhibitor Substances 0.000 abstract description 13
- 230000003287 optical effect Effects 0.000 abstract description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 58
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 42
- -1 for ex-ample Chemical compound 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 37
- 229940095574 propionic acid Drugs 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 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
- 235000019260 propionic acid Nutrition 0.000 description 24
- 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 24
- 239000000243 solution Substances 0.000 description 24
- 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 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
- 239000002585 base Substances 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- LDCYZAJDBXYCGN-UHFFFAOYSA-N oxitriptan Natural products C1=C(O)C=C2C(CC(N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-UHFFFAOYSA-N 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 229940000681 5-hydroxytryptophan Drugs 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229960004502 levodopa Drugs 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
- 229960003638 dopamine Drugs 0.000 description 13
- 229940073584 methylene chloride Drugs 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 239000003795 chemical substances by application Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 238000007792 addition Methods 0.000 description 10
- 230000002093 peripheral effect Effects 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 229940086542 triethylamine Drugs 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 238000006114 decarboxylation reaction Methods 0.000 description 8
- 239000000725 suspension Substances 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
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 230000002427 irreversible effect Effects 0.000 description 7
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 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
- 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
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 208000027089 Parkinsonian disease Diseases 0.000 description 6
- 206010034010 Parkinsonism Diseases 0.000 description 6
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-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
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 229960001701 chloroform Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 229910052744 lithium Inorganic materials 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 229960002888 oxitriptan Drugs 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 208000020925 Bipolar disease Diseases 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 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
- 241000282412 Homo Species 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-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
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- DMULVCHRPCFFGV-UHFFFAOYSA-N N,N-dimethyltryptamine Chemical compound C1=CC=C2C(CCN(C)C)=CNC2=C1 DMULVCHRPCFFGV-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
- 239000000164 antipsychotic agent Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 239000002831 pharmacologic agent Substances 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
- 239000002244 precipitate Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 229960003732 tyramine Drugs 0.000 description 4
- 229960004441 tyrosine Drugs 0.000 description 4
- 235000002374 tyrosine Nutrition 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
- 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
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 229940123736 Decarboxylase inhibitor Drugs 0.000 description 3
- 208000020401 Depressive disease Diseases 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 229910021538 borax Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 229920001429 chelating resin Polymers 0.000 description 3
- 239000003954 decarboxylase inhibitor Substances 0.000 description 3
- 229940113088 dimethylacetamide Drugs 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 229960002748 norepinephrine Drugs 0.000 description 3
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- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
ABSTRACT OF DISCLOSURE Novel compounds of the following general structure: and pharmaceutically acceptable salts and individual optical isomers thereof. These compounds are useful as inhibitors of aromatic amino acid decarboxylase.
Description
116~Sl MI-go~
FIELD OF _INVENTION
This invention relates to novel pharmaceutically u 5 e-ful ~-acetylenic amino acid derivatives which are inhibi-tors of aromatic amino acid decarboxylase.
BACKGROUND OF I NVENT I ON
The amino acids tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine (DOPA), tyrosine and phenylalanine are metabolically converted to tryptamine, 5-hydroxy-tryptamine, 3,4-dihydroxyphenethylamine or dopamine, tyra-mine and phenethylamine respectively by an aromatic amino acid decarboxylase. It is believed that the aromatic amino acid decarboxylase enzyme is non-specific, particu-larly, insofar as peripheral catalysis is concerned.
Evidence does exist, however, to indicate that in the brain specific decarboxylation enzymes exist for each of DOPA and 5-hydroxytryptophan.
The above-enumerated aromatic amines are known to be involved in various pathophysiological processes. For example, it has been found that tryptamine, the decarboxy-lation product of tryptophan is enzymatically methylated to monomethyltryptamine which in turn is methylated enzymati-cally to dimethyltryptamine (DMT) in huinan red blood cells, plasma and platelets. The methylating enzyme is present in many mammalian species and has been shown to be produced in brain tissues of several species including man. DMT
which has strong hallucinogenic or psychomimetic properties may play a role in the etiology of schizophrenia and other psychotic disorders. Hence any agent which would block formation of DMT may be useful as an antipsychotic agent.
- 1 - ~r~
~ 45~
Blocking the decarboxylation of tryptophan results in decreased levels of tryptamine, removing the substrate for DMT formation. Hence an inhibitor of aromatic amino acid decarboxylase which would block conversion of tryptophan to tryptamine may be useful as an antipsychotic agent.
Both 5-hydroxytryptamine (5-HT), the decarboxylation product of 5-hydroxytryptophane, and 3,4-dihydroxyphenethyl-amine (dopamine) the decarboxylation product of DOPA are involved in peripheral and cen~tral physiological processes, and agents which are effective in the control of levels of these amines have resulted in useful pharmacological agents.
It has been shown that central or brain levels of 5-HT and norepinephrine, which is formed metabolically by hydroxyla-tion of dopamine, are higher in patients with manic dis-orders than in individuals without such disorders. It hasalso been shown that agents which decrease central levels of monoamines, for example, 5-HT and particularly norepi-nephrine have antimanic properties when given to human sub-jects, whereas drugs that increase monoamine levels could precipitate mania in susceptible individuals. Hence, agents which block format;on of 5-HT and dopamine, such as, for ex-ample, by inhibiting the aromatic amino acid decarboxylase enzyme which converts 5-hydroxytryptophan and DOPA to 5-HT
and dopamine respectively may be useful as antipsychotic agents or major tranquilizers in treating manic disorders.
It has also been shown that agents useful in inhibit-ing the decarboxylation of DOPA to dopamine are useful in the treatment of Parkinsonism when administered concurrent-ly with exogenous DOPA or L-DOPA. It is believed that Parkinsonism is due, at least in part, to decreased 11614sl central levels of dopamine since exogenous administration of DOPA or L-DOPA is known to be an effective means of treat-ing Parkinsonism. However, since exogenously administered DOPA is readily converted enzymatically to dopamine peri-pherally it is necessary to administer large amounts inorder to have increased absorption centrally. DOPA readily penetrates the blood-brain barrier whereas dopamine does not. Administration of DOPA or L-DOPA in conjunction with a peripherally active inhibitor of the enzyme which converts DOPA to dopamine reduces the amount of L-DOPA that must be administered in order to have adequate circulating levels for central absorption. Other advantages are also realized by administration of an aromatic amino acid decarboxylase inhibitor along with L-DOPA. By preventing formation of dopamine peripherally, side effects attributed to dopamine such as, cardiac arrhythmia, nausea and vomiting may be avoided.
Studies indicate that levels of 5-hydroxytryptamine (5-HT) are lower in patients with depressive syndromes than in individuals without such syndromes. Also, administra-tion of exogenous L-5-hydroxytryptophan (L-5-HTP) is effective in treating certain depressed patients. However, as with DOPA, since L-5-HTP is readtly metabolized peri-pherally to 5-HT it is necessary to administer large amounts of L-5-HTP in order to achieve increased central levels of the amino acid. It has been shown that by administering an inhibitor of the aromatic amino acid decarboxylase enzyme that catalyzes the formation of 5-HT
from 5-HTP peripherally the amount of exogenous 5-HTP
required to give increased central levels is markedly 11 6~ ~51 reduced. In other words inhibitors of aromatic amino acid decarboxylase when used in conjunction with exogenous 5-HTP have been shown to be useful in treating depression.
Agents which block peripheral conversion of 5-HTP to 5-HT may be useful in treating other conditions which respond to increased central levels of 5-HTP as a result of exogenous administration of 5-HTP. It has been shown that exogenous L-5-HTP is useful in treating action myoclonus. Also, studies reveal that administration of exogenous 5-HTP is useful in treating insomnia. Hence concurrent administration of 5-HTP and an aromatic amino acid decarboxylase inhibitor may be beneficial in treating these conditions.
Blocking peripheral formation of 5-hydroxytryptamine may result in other beneficial effects since it is known that 5-HT is involved, for example, in the etiology of rheumatoid arthritis and the carcinoid syndrome by in-creasing collagen levels. Also, it is reported that 5-HT
is the primary autocoid responsible for anaphylactoid reactions in human subjects as well as bronchoconstriction in asthmatic human subjects, and agents which antagonize or inhibit formation of 5-HT are useful in treating these conditions. 5-HT is known to cause platelet aggregation and has been implicated as a causal factor in the post-gastrectomy dumping syndrome and migraine headache. Methyl-sergide, a 5-hydroxytryptamine antagonist, has proven e~fective in treating post-gastrectomy dumping syndrome.
It has been suggested that phenethylamine, the de-carboxylation product of phenylalanine, as an endogenous compound contributes to schizophrenic symptoms and triggers Ml-908 1~6~Sl migraine headaches. Also, it has been suggested that endogenous tyramine, the decarboxylation product of tyro-sine, contributes to seizure disorders.
Hence, it is readily evident that agents which are useful in regulating the levels of aromatic amino acids and amines find use in many pharmacological situations.
The compounds of the present invention are inhibitors of the aromatic amino acid decarboxylase which converts tryptophan, 5-hydroxytryptophan~ 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine to the respective amines and hence provide useful pharmacologic agents.
SUMMARY OF INVENTION
The compounds of the present invention are represented by the following general Formula:
R~ R3 f~CH
Rs ~ CH2C-COR2 Formula I
R' 4 ~3 NHRI
In the above general Formula I Rl is selected from hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to ~
carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched and -C-CH-R27 wherein R27 is selected from hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl and p-hydroxybenzyl; ~2 is selected from hydroxyJ a straight or branched alkoxy . group of from 1 to 8 carbon atoms, -NR7R8 wherein each of5 R7 and R8 is hydrogen or a straight or branched alkyl group 11 61 451 Ml-908 of from ~ to 4 carbon atoms, and -NHICH-COOH wherein R9 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl and p-hydroxybenzyl; each of R9, R4, Rs~ R'4 and R~ has the meaning defined in the follow-Ing Table I wherein Rlo is hydrogen, a straight or branched alkyl group of from 1 to 8 carbon atoms, alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 6 carbon atoms, benz~yl or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms:
TABLE I
R 4 Rs ~ R~
H H H H H
H H ORlo H H
H ORlo H H H
H ORlo ORlo H H
OR~o H Cl H H
H ORlo Cl H H
Cl ORlo H H H
Cl ORlo Cl H H
Cl,F H ORlo H H
Cl H H H CH3 Cl H Cl H CH3 H H Cl,F H CH3 OR1o H CH3 H CH3 Cl H CH~ H CH3 H ORIo H CH3 H H ORlo H C2H5 116~451 Ml-908 ORlo H C2Hs H C2Hs H OR1o H OR1o H
OR1o ~R1o OR1o H
H H OH O~H3 H
OR1o ORlo H H H
OR1o H H H H
H H Cl H C2Hs H H Cl H tert-C4Hg H H ORlo H tert-C4H9 Pharmaceutically acceptable salts and individual optical isomers of the compounds of general Formula I are also included within the scope of this invention.
The compounds of general Formula I are useful pharma-cological agents in that said compounds are inhibitors of aromatic amino acid decarboxylase and useful as intermediates in the preparation of useful pharmacological agents.
DE TA I LE D DES C R I PT I ON OF I NVE NT I ON
In the above general Formula I the term alkylcarbonyl is taken to mean the group alkyl-C- wherein the alkyl moiety has from 1 to 6 carbon atoms and is a straight chain or branched chain.
The term benzoyl as used in general Formula I means the group ~ C-.
The term phenylalkylenecarbonyl as used in general Formula I is taken to mean the group ~ lkylene-C-wherein the allcylene moiety has from 1 to 6 carbon atoms and is a straight chain or a branched chain, i11ustra-Ml-908 ~61451 tivelyJ methylene~ ethylene, isopropylene and butylene.
Illustrative examples of straight or branched alkoxy groups having from 1 to ~ carbon atoms as used herein are methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, tert-pentoxy, n-hexyloxy and n-octyloxy.
Illustrative examples of straight or branched alkyl groups having from 1 to 6 carbon atoms are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and n-pentyl.
Illustrative examples of pharmaceutically acceptable salts of the compounds of this invention include non-toxic acid addition salts formed with inorganic acids, such asJ hydrochloric, hydrobromic, sulfuric and phos-phoric acid, and organic acids, such as, methane sulfonic, salicylic, maleic, malonic, tartaricJ citric and ascorbic acids; and non-toxic salts formed with inorganic or or-ganic bases such as those of alkali metals, for example, sodium, potassium and lithium, alkaline earth metals, for example, calcium and magnesium, light metals of Group lll A, for example, aluminum, organic amines, such as, primary, secondary or tertiary amines, for example, cyclohexylamine, ethylamine, pyridine~ methylamino-ethanol, ethanolamine and piperazine. The salts are prepared by conventional means.
Preferred compounds of this invention are those of general Formula I wherein R1 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched with compounds wherein R1 is hydrogen being more preferred. Another preferred embodi-ment of this invention is the compounds of general Formula I
wherein R2 is hydroxy or a straight or branched alkoxy ~1 61 4~ Ml-908 group of from 1 to 8 carbon atoms. Compounds wherein R2 is hydroxy are more preferred. Compounds of general Formula I wherein each of R3, R~, R5, R' 4 and R~ is hydrogen or OR1o wherein Rlo iS hydrogen represent another pre-ferred embodiment of this invention.
Illustrative examples of compounds of general Formula i are the following:
FIELD OF _INVENTION
This invention relates to novel pharmaceutically u 5 e-ful ~-acetylenic amino acid derivatives which are inhibi-tors of aromatic amino acid decarboxylase.
BACKGROUND OF I NVENT I ON
The amino acids tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine (DOPA), tyrosine and phenylalanine are metabolically converted to tryptamine, 5-hydroxy-tryptamine, 3,4-dihydroxyphenethylamine or dopamine, tyra-mine and phenethylamine respectively by an aromatic amino acid decarboxylase. It is believed that the aromatic amino acid decarboxylase enzyme is non-specific, particu-larly, insofar as peripheral catalysis is concerned.
Evidence does exist, however, to indicate that in the brain specific decarboxylation enzymes exist for each of DOPA and 5-hydroxytryptophan.
The above-enumerated aromatic amines are known to be involved in various pathophysiological processes. For example, it has been found that tryptamine, the decarboxy-lation product of tryptophan is enzymatically methylated to monomethyltryptamine which in turn is methylated enzymati-cally to dimethyltryptamine (DMT) in huinan red blood cells, plasma and platelets. The methylating enzyme is present in many mammalian species and has been shown to be produced in brain tissues of several species including man. DMT
which has strong hallucinogenic or psychomimetic properties may play a role in the etiology of schizophrenia and other psychotic disorders. Hence any agent which would block formation of DMT may be useful as an antipsychotic agent.
- 1 - ~r~
~ 45~
Blocking the decarboxylation of tryptophan results in decreased levels of tryptamine, removing the substrate for DMT formation. Hence an inhibitor of aromatic amino acid decarboxylase which would block conversion of tryptophan to tryptamine may be useful as an antipsychotic agent.
Both 5-hydroxytryptamine (5-HT), the decarboxylation product of 5-hydroxytryptophane, and 3,4-dihydroxyphenethyl-amine (dopamine) the decarboxylation product of DOPA are involved in peripheral and cen~tral physiological processes, and agents which are effective in the control of levels of these amines have resulted in useful pharmacological agents.
It has been shown that central or brain levels of 5-HT and norepinephrine, which is formed metabolically by hydroxyla-tion of dopamine, are higher in patients with manic dis-orders than in individuals without such disorders. It hasalso been shown that agents which decrease central levels of monoamines, for example, 5-HT and particularly norepi-nephrine have antimanic properties when given to human sub-jects, whereas drugs that increase monoamine levels could precipitate mania in susceptible individuals. Hence, agents which block format;on of 5-HT and dopamine, such as, for ex-ample, by inhibiting the aromatic amino acid decarboxylase enzyme which converts 5-hydroxytryptophan and DOPA to 5-HT
and dopamine respectively may be useful as antipsychotic agents or major tranquilizers in treating manic disorders.
It has also been shown that agents useful in inhibit-ing the decarboxylation of DOPA to dopamine are useful in the treatment of Parkinsonism when administered concurrent-ly with exogenous DOPA or L-DOPA. It is believed that Parkinsonism is due, at least in part, to decreased 11614sl central levels of dopamine since exogenous administration of DOPA or L-DOPA is known to be an effective means of treat-ing Parkinsonism. However, since exogenously administered DOPA is readily converted enzymatically to dopamine peri-pherally it is necessary to administer large amounts inorder to have increased absorption centrally. DOPA readily penetrates the blood-brain barrier whereas dopamine does not. Administration of DOPA or L-DOPA in conjunction with a peripherally active inhibitor of the enzyme which converts DOPA to dopamine reduces the amount of L-DOPA that must be administered in order to have adequate circulating levels for central absorption. Other advantages are also realized by administration of an aromatic amino acid decarboxylase inhibitor along with L-DOPA. By preventing formation of dopamine peripherally, side effects attributed to dopamine such as, cardiac arrhythmia, nausea and vomiting may be avoided.
Studies indicate that levels of 5-hydroxytryptamine (5-HT) are lower in patients with depressive syndromes than in individuals without such syndromes. Also, administra-tion of exogenous L-5-hydroxytryptophan (L-5-HTP) is effective in treating certain depressed patients. However, as with DOPA, since L-5-HTP is readtly metabolized peri-pherally to 5-HT it is necessary to administer large amounts of L-5-HTP in order to achieve increased central levels of the amino acid. It has been shown that by administering an inhibitor of the aromatic amino acid decarboxylase enzyme that catalyzes the formation of 5-HT
from 5-HTP peripherally the amount of exogenous 5-HTP
required to give increased central levels is markedly 11 6~ ~51 reduced. In other words inhibitors of aromatic amino acid decarboxylase when used in conjunction with exogenous 5-HTP have been shown to be useful in treating depression.
Agents which block peripheral conversion of 5-HTP to 5-HT may be useful in treating other conditions which respond to increased central levels of 5-HTP as a result of exogenous administration of 5-HTP. It has been shown that exogenous L-5-HTP is useful in treating action myoclonus. Also, studies reveal that administration of exogenous 5-HTP is useful in treating insomnia. Hence concurrent administration of 5-HTP and an aromatic amino acid decarboxylase inhibitor may be beneficial in treating these conditions.
Blocking peripheral formation of 5-hydroxytryptamine may result in other beneficial effects since it is known that 5-HT is involved, for example, in the etiology of rheumatoid arthritis and the carcinoid syndrome by in-creasing collagen levels. Also, it is reported that 5-HT
is the primary autocoid responsible for anaphylactoid reactions in human subjects as well as bronchoconstriction in asthmatic human subjects, and agents which antagonize or inhibit formation of 5-HT are useful in treating these conditions. 5-HT is known to cause platelet aggregation and has been implicated as a causal factor in the post-gastrectomy dumping syndrome and migraine headache. Methyl-sergide, a 5-hydroxytryptamine antagonist, has proven e~fective in treating post-gastrectomy dumping syndrome.
It has been suggested that phenethylamine, the de-carboxylation product of phenylalanine, as an endogenous compound contributes to schizophrenic symptoms and triggers Ml-908 1~6~Sl migraine headaches. Also, it has been suggested that endogenous tyramine, the decarboxylation product of tyro-sine, contributes to seizure disorders.
Hence, it is readily evident that agents which are useful in regulating the levels of aromatic amino acids and amines find use in many pharmacological situations.
The compounds of the present invention are inhibitors of the aromatic amino acid decarboxylase which converts tryptophan, 5-hydroxytryptophan~ 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine to the respective amines and hence provide useful pharmacologic agents.
SUMMARY OF INVENTION
The compounds of the present invention are represented by the following general Formula:
R~ R3 f~CH
Rs ~ CH2C-COR2 Formula I
R' 4 ~3 NHRI
In the above general Formula I Rl is selected from hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to ~
carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched and -C-CH-R27 wherein R27 is selected from hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl and p-hydroxybenzyl; ~2 is selected from hydroxyJ a straight or branched alkoxy . group of from 1 to 8 carbon atoms, -NR7R8 wherein each of5 R7 and R8 is hydrogen or a straight or branched alkyl group 11 61 451 Ml-908 of from ~ to 4 carbon atoms, and -NHICH-COOH wherein R9 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl and p-hydroxybenzyl; each of R9, R4, Rs~ R'4 and R~ has the meaning defined in the follow-Ing Table I wherein Rlo is hydrogen, a straight or branched alkyl group of from 1 to 8 carbon atoms, alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 6 carbon atoms, benz~yl or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms:
TABLE I
R 4 Rs ~ R~
H H H H H
H H ORlo H H
H ORlo H H H
H ORlo ORlo H H
OR~o H Cl H H
H ORlo Cl H H
Cl ORlo H H H
Cl ORlo Cl H H
Cl,F H ORlo H H
Cl H H H CH3 Cl H Cl H CH3 H H Cl,F H CH3 OR1o H CH3 H CH3 Cl H CH~ H CH3 H ORIo H CH3 H H ORlo H C2H5 116~451 Ml-908 ORlo H C2Hs H C2Hs H OR1o H OR1o H
OR1o ~R1o OR1o H
H H OH O~H3 H
OR1o ORlo H H H
OR1o H H H H
H H Cl H C2Hs H H Cl H tert-C4Hg H H ORlo H tert-C4H9 Pharmaceutically acceptable salts and individual optical isomers of the compounds of general Formula I are also included within the scope of this invention.
The compounds of general Formula I are useful pharma-cological agents in that said compounds are inhibitors of aromatic amino acid decarboxylase and useful as intermediates in the preparation of useful pharmacological agents.
DE TA I LE D DES C R I PT I ON OF I NVE NT I ON
In the above general Formula I the term alkylcarbonyl is taken to mean the group alkyl-C- wherein the alkyl moiety has from 1 to 6 carbon atoms and is a straight chain or branched chain.
The term benzoyl as used in general Formula I means the group ~ C-.
The term phenylalkylenecarbonyl as used in general Formula I is taken to mean the group ~ lkylene-C-wherein the allcylene moiety has from 1 to 6 carbon atoms and is a straight chain or a branched chain, i11ustra-Ml-908 ~61451 tivelyJ methylene~ ethylene, isopropylene and butylene.
Illustrative examples of straight or branched alkoxy groups having from 1 to ~ carbon atoms as used herein are methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, tert-pentoxy, n-hexyloxy and n-octyloxy.
Illustrative examples of straight or branched alkyl groups having from 1 to 6 carbon atoms are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and n-pentyl.
Illustrative examples of pharmaceutically acceptable salts of the compounds of this invention include non-toxic acid addition salts formed with inorganic acids, such asJ hydrochloric, hydrobromic, sulfuric and phos-phoric acid, and organic acids, such as, methane sulfonic, salicylic, maleic, malonic, tartaricJ citric and ascorbic acids; and non-toxic salts formed with inorganic or or-ganic bases such as those of alkali metals, for example, sodium, potassium and lithium, alkaline earth metals, for example, calcium and magnesium, light metals of Group lll A, for example, aluminum, organic amines, such as, primary, secondary or tertiary amines, for example, cyclohexylamine, ethylamine, pyridine~ methylamino-ethanol, ethanolamine and piperazine. The salts are prepared by conventional means.
Preferred compounds of this invention are those of general Formula I wherein R1 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched with compounds wherein R1 is hydrogen being more preferred. Another preferred embodi-ment of this invention is the compounds of general Formula I
wherein R2 is hydroxy or a straight or branched alkoxy ~1 61 4~ Ml-908 group of from 1 to 8 carbon atoms. Compounds wherein R2 is hydroxy are more preferred. Compounds of general Formula I wherein each of R3, R~, R5, R' 4 and R~ is hydrogen or OR1o wherein Rlo iS hydrogen represent another pre-ferred embodiment of this invention.
Illustrative examples of compounds of general Formula i are the following:
2-acetylene-2-amino-3-phenylpropionic acid, 2-acetylene-2-amino-3-(3-hydroxyphenyl)propionic acid, 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic acid.
2-acetylene-2-amino-3-(4-hydroxyphenyl)propionic acid, 2-acetylene-2 amino-3-(4-chloro-2-hydroxyphenyl)propionic acid, 2-acetylene-2-amino-3-(4-chloro-3-methoxyphenyl)propionic acid, 2-acetylene-2-amino-3-(2-chloro-3-benzoyloxyphenyl)pro-pionic acid, 2-acetylene-2-amino-3-(2,4-dichloro-3-hydroxyphenyl)-propionic acid, 2-acetylene-2-amino-3-(2-chloro-4-hydroxyphenyl)pro-pionic acid, 2-acetylene-2-amino-3-(2-chloro-6-methylphenyl)propionic acid, 2-acetylene-2-amino-3-(2,4-dichloro-6-methylphenyl)-propionic acid, 2-acetylene-2-amino-3-(4-chloro-6-methylphenyl)propionic acid, 2-acetylene-2-amino-3-(2-hydroxy-4,6-dimethylphenyl)-propionic acid, Ml-908 ~ 5~
2-acetylene-2-amino-3-(2-chloro-4,6-dimethylphenyl)-proptonic acid, 2-acetylene-2-amino-3-(4-hydroxy-6-methylphenyl)propionic acid, 2-acetylene-2-amino-3-(5-ethyl-4-phenylpropionyloxyphenyl)-propionic acid, 2-acetylene-2-amino-3-(4,6-diethyl-2-hydroxyphenyl)-propionic acid, 2-acetylene-2-amino-3-(4-chloro-6-ethylphenyl)propionic acid, 2-acetylene-2-amino-3-(4-chloro-6-tert-butylphenyl~-propionic acid, 2-acetylene-2-amino-3-(6-tert-butyl-4-hydroxyphenyl)-propionic acid, 2-acetylene-2-(N-ethoxycarbonylamino)-3-(4-n-butoxyphenyl)-propionic acid, N,N-di-n-propyl 2-acetylene-2-amino-3-(4-acetyloxyphenyl)-propionamide, 2~acetylene-2-[N-(2-amino-1-oxoethyl)amino]-3-(3-hydroxy-phenyl)propionic acid, 2-acetylene-2-amino-3-(3,4-dihydroxy)phenyl-1-oxopropyl-aminoacetic acid, 2-[(2-acetylene-2-amino-1-oxo-3-phenyl)propylamino)di-hydrocinnamic acid, 2-acetylene-2-(1-oxoethylamino)-3-(4-hydroxy)phenyl-1-oxopropylamino-2-propionic acid, methyl 2-acetylene-2-(1-oxoethylamino)-3-(4-hydroxy)-phenyl-1-oxopropylaminoacetate, 2-acetylene-2-amino-3-phenylpropionamide, N,N-dimethyl 2-acetylene-2-amino-3-(3-hydroxyphenyl)-Ml-908 116~451 propionamide, N,N-diethyl 2-acetylene-2-amino-~-(3',4'-dimethoxyphenyl)-propionamide, N-n-butyl 2-acetylene-2-amino-3-(4-hydroxyphenyl)propiona-mide,methyl 2-acetylene-2-amino-3-~3-hydroxyphenyl)propionate, isopropyl 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)-propionate, tert-butyl 2-acetylene-2-amino-3-(4-hydroxyphenyl)propionate, ethyl-2-acetylene~2-amino-3-(4-chloro-3-methoxyphenyl)-propionate, and 2-acetylene-2-amino-3-(4-hydroxyphenyl)propionamide.
The compounds of general Formula I are irreversible inhibitors of the enzyme which metabolically catalyzes the conversion of tryptophan, 5-hydroxytryptophan, 3,4-di-hydroxyphenylalanine, tyrosine and phenylalanine to trypta-mine, 5-hydroxytryptamine, 3,4-dihydroxyphenylethylamine, tyramine and phenethylamine respectively. As indicated hereinabove results of studies indicate that the enzyme responsible for the conversion of the above-enumerated amino acids to the respective amines peripherally is a non-specific aromatic amino acid decarboxylase. For central conversion studies indicate that specific decarboxylases are responsible for the conversion of each of 5-hydroxy-tryptophan and 3J4-dihydroxyphenylalanine whereas the remaining above-enumerated amino acids are enzymatically transformed to the respective amines by a non-specific aromatic amino acid decarboxylase. The compounds of the present invention are effective in irreversibly inhibiting both centrally and peripherally the activity of non-specific Ml-908 4Sl aromatic amino acid decarboxylase as well as the activity of
2-acetylene-2-amino-3-(4-hydroxyphenyl)propionic acid, 2-acetylene-2 amino-3-(4-chloro-2-hydroxyphenyl)propionic acid, 2-acetylene-2-amino-3-(4-chloro-3-methoxyphenyl)propionic acid, 2-acetylene-2-amino-3-(2-chloro-3-benzoyloxyphenyl)pro-pionic acid, 2-acetylene-2-amino-3-(2,4-dichloro-3-hydroxyphenyl)-propionic acid, 2-acetylene-2-amino-3-(2-chloro-4-hydroxyphenyl)pro-pionic acid, 2-acetylene-2-amino-3-(2-chloro-6-methylphenyl)propionic acid, 2-acetylene-2-amino-3-(2,4-dichloro-6-methylphenyl)-propionic acid, 2-acetylene-2-amino-3-(4-chloro-6-methylphenyl)propionic acid, 2-acetylene-2-amino-3-(2-hydroxy-4,6-dimethylphenyl)-propionic acid, Ml-908 ~ 5~
2-acetylene-2-amino-3-(2-chloro-4,6-dimethylphenyl)-proptonic acid, 2-acetylene-2-amino-3-(4-hydroxy-6-methylphenyl)propionic acid, 2-acetylene-2-amino-3-(5-ethyl-4-phenylpropionyloxyphenyl)-propionic acid, 2-acetylene-2-amino-3-(4,6-diethyl-2-hydroxyphenyl)-propionic acid, 2-acetylene-2-amino-3-(4-chloro-6-ethylphenyl)propionic acid, 2-acetylene-2-amino-3-(4-chloro-6-tert-butylphenyl~-propionic acid, 2-acetylene-2-amino-3-(6-tert-butyl-4-hydroxyphenyl)-propionic acid, 2-acetylene-2-(N-ethoxycarbonylamino)-3-(4-n-butoxyphenyl)-propionic acid, N,N-di-n-propyl 2-acetylene-2-amino-3-(4-acetyloxyphenyl)-propionamide, 2~acetylene-2-[N-(2-amino-1-oxoethyl)amino]-3-(3-hydroxy-phenyl)propionic acid, 2-acetylene-2-amino-3-(3,4-dihydroxy)phenyl-1-oxopropyl-aminoacetic acid, 2-[(2-acetylene-2-amino-1-oxo-3-phenyl)propylamino)di-hydrocinnamic acid, 2-acetylene-2-(1-oxoethylamino)-3-(4-hydroxy)phenyl-1-oxopropylamino-2-propionic acid, methyl 2-acetylene-2-(1-oxoethylamino)-3-(4-hydroxy)-phenyl-1-oxopropylaminoacetate, 2-acetylene-2-amino-3-phenylpropionamide, N,N-dimethyl 2-acetylene-2-amino-3-(3-hydroxyphenyl)-Ml-908 116~451 propionamide, N,N-diethyl 2-acetylene-2-amino-~-(3',4'-dimethoxyphenyl)-propionamide, N-n-butyl 2-acetylene-2-amino-3-(4-hydroxyphenyl)propiona-mide,methyl 2-acetylene-2-amino-3-~3-hydroxyphenyl)propionate, isopropyl 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)-propionate, tert-butyl 2-acetylene-2-amino-3-(4-hydroxyphenyl)propionate, ethyl-2-acetylene~2-amino-3-(4-chloro-3-methoxyphenyl)-propionate, and 2-acetylene-2-amino-3-(4-hydroxyphenyl)propionamide.
The compounds of general Formula I are irreversible inhibitors of the enzyme which metabolically catalyzes the conversion of tryptophan, 5-hydroxytryptophan, 3,4-di-hydroxyphenylalanine, tyrosine and phenylalanine to trypta-mine, 5-hydroxytryptamine, 3,4-dihydroxyphenylethylamine, tyramine and phenethylamine respectively. As indicated hereinabove results of studies indicate that the enzyme responsible for the conversion of the above-enumerated amino acids to the respective amines peripherally is a non-specific aromatic amino acid decarboxylase. For central conversion studies indicate that specific decarboxylases are responsible for the conversion of each of 5-hydroxy-tryptophan and 3J4-dihydroxyphenylalanine whereas the remaining above-enumerated amino acids are enzymatically transformed to the respective amines by a non-specific aromatic amino acid decarboxylase. The compounds of the present invention are effective in irreversibly inhibiting both centrally and peripherally the activity of non-specific Ml-908 4Sl aromatic amino acid decarboxylase as well as the activity of
3,4-dihydroxyphenylalanine (DOPA) decarboxylase. As used herein with regard to the utility of the compounds of the present invention the term central refers to the central nervous system, primarily the brain, whereas peripheral refers to other body tissues wherein the decarboxylase enzyme is present. Selectivity of inhibition of the amino acid decarboxylases centrally or peripherally by admini-stering compounds of general Formula I is dose dependent.
As irreversible inhibitors of aromatic amino acid decarboxylase, and DOPA decarboxylase the compounds of the present invention possess many pharmacological utilities.
As peripheral irreversible inhibitors of aromatic amino acid decarboxylase the compounds of general Formula I are useful in the treatment of Parkinsonism when given in conjunction with 3,4-dihydroxyphenylalanine (DOPA) or L-3,4-dihydroxyphenylalanine (L-DOPA). DOPA and more particularly the active isomer L-DOPA are known to be effective in treating Parkinsonism when administered systemically, usually in an amount from 0.5 to 1 gram daily initially after which the amount administered is gradually increased over a 3 to 7 day period to a maximally tolera-ted daily dose of about 8 grams. Concurrent administra-tion of a compound of general Formula I and L-DOPA provides an improved method of treating Parkinsonism in that the compounds of Formula I will block the decarboxylation of L-DOPA to L-3,4-dihydroxyphenethylamine (L-dopamine) peripherally by inhibiting the activity of aromatic amino acid decarboxylase enzyme, thus retaining high circulatlng levels of L-DOPA for central absorpt;on and also preventing 116145~ Ml-9o8 peripheral formation of increased levels of dopamine which is known to result in certain undesirable side effects such as cardiac arrhythmia. By concurrently administering a compound of general Formula I and L-DOPA the amount of 5 L-DOPA administered may be reduced 2 to 10-fold as com-pared to amounts required for utility when L-DOPA is administered alone. It is preferred that the compounds of this invention be administered prior to administration of L-DOPA. For example, a compound of Formula I may be administered from 30 minutes to 4 hours prior to admini-stration of L-DOPA depending on the route of administration and condition of the patient to be treated.
The compounds of general Formula I are also useful in treating depressive syndromes in individuals when given in conjunction with 5-hydroxytryptophan (5-HTP) or more particularly the active levo isomer which is known to be useful in the treatment of depression when adminis-tered systemically. The compounds of general Formula I, by inhibiting peripherally the activity of aromatic amino acid decarboxyla,e will block the conversion of 5-hydroxy-tryptophan to 5-hydroxytryptamine thus retaining higher circulating levels of 5-~TP for central absorption. The compounds of general Formula I when administered con-currently with exogenous 5-HTP are also useful in treating action myoclonus which is known to be effectively treated by increasing central levels of 5-HTP.
The compounds of general Formula I, by virtue of their inhibitory action on aromatic amino acid decarboxylase peripherally are also useful in the treatment of rheumatoid arthritis, carcinoid syndrome, anaphylactoid reactions in 11 61 ~5~ Ml-908 .
humans~ bronchoconstriction in asthamatic humans as well as other conditions known to be caused by high peripheral levels of 5-hydroxytryptamine.
As indicated hereinabove it has been shown that agents which decrease the elevated levels of 5-HT and norepi-nephrine, the hydroxylation product of dopamine, are useful in treating patients with manic disorders. Hence, as central irreversible inhibitors of aromatic amino acid decarboxylase, and DOPA decarboxylase the compounds of general Formula I are useful in treating manic disorders.
Additionally, by virtue of the central inhibitory action of the compounds of general Formula I on aromatic amino acid decarboxylase said compounds may also be useful as antipsychotic agents, since central levels of tryptamine are decreased, and useful in the treatment of schizophrenia and seizure disorders since central levels of phenethylamine and tyramine are decreased by administration of a compound of general Formula lo The utility of the compounds of general Formula I as irreversible inhibitors of aromatic amino acid decarboxylase may be demonstrated as follows. A compound of general Formula I is administered as an aqueous solution or sus-pension to rats or mice. At different time intervals after administration of the compound from 1 to 48 hours the animals are sacrificed by decapitation and aromatic amino acid decarboxylase activity is measured by a radiometric assay as described by Christenson et al., Arch. Biochem.
Biophys. 141, ~56 (1970) in homogenates of kidney, heart and brain prepared according to Burkard et al., Arch.
Biochem. Biophys. 107~ 187 (1964~.
1~ 6~ 4s~ Ml-908 The compounds of this invention can be administered in various manners to achieve the desired effect. The compounds can be administered alone or in the form of pharmaceutical preparations to the patient being treated either orally or parenterally, for example, subcutaneously, intravenously or intraperitoneally. The compounds can be administered by intranasal instillation or by application to mucous membranes such as that of the nose~ throat and bronchial tubes, for examp1e, in an aerosol spray con-taining small particles of a novel compound of thisinvention in a spray solution or dry powder form.
The amount of novel compound administered will vary and can be any effective amount. Depending on the patient, the condition being treated and the mode of administration, the quantity of novel compound adminis-tered may 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 affect a peripheral .
_ 3o - ~1 6i ~5~ Ml-908 irreversible inhibition or aromatic decarboxylase the effective amount of compound administered will vary from about 0.1 mg/kg (milli~rams per kilogram) to 100 mg/kg of body weight of the patient per dose and preferably from about 5 mg/kg to 25 mg/kg. For example, the desired peri-pheral effect can be obtained by consumption of a unit dosage form, such as, for example, a tablet containing from 10 to 250 mg of a novel compound of this invention taken 1 to 4 times daily. When the compounds of general Formula I are administered to achieve a central irreversi-ble inhibition of aromatic decarboxylase or 3,4-dihydroxy-phenylalanine decarboxylase the effective amount of com-pound administered will vary from about 100 mg/kg to 500 mg/kg of body weight of the patient per day and pre-ferably from about 150 mg/kg to 300 mg/kg. For example, the desired central effect can be achieved by consumption of a unit dosage form, such as, for example, a tablet containing from about 350 mg to 500 mg of a novel com-pound of this invèntion taken from 1 to 4 times daily.
As used herein the term patient is taken to mean warm blooded animals such as mammals, for example, cats, dogs, ratsJ mice, guinea pigs, sheep, horses, bovine cows, and humans.
The solid unit dosage forms can be of the conven-tional type. Thus, the solid form can be a capsule which ca~ be of the ordinary gelatin type containing a novel compound of this invention and a carrier, for example, lubricant and inert fillers such as lactose, sucrose and corn starch. In another èmbodiment, the novel compounds 11 6~ 45~ MI-908 are tableted with conventional tablet bases such as lac-tose, sucrose or corn starch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents such as corn starch, potato starch, or alsinic acid, and a lubricant such as stearic acid, or magnesium stearate.
For parenteral administration the compounds may be administered as injectable dosages of a solution or sus-pension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative of oils which can be employed in these preparations are those of petroleumJ
animal, vegeta61e or synthetic origin, for example, peanut Oj1J soybean Oj1J and mineral oil~ In general waterJ salineJ aqueous dextroseJ and related sugar solu-tionsJ ethanols and glycols such as propylene glycol or polyethjlene glycol are preferred liquid carriersJ par-ticularly for injectable solutions.
The compounds can be administered in the form of adepot injection or implant preparation which may be form-ulated in such a manner as to permit a sustained release of the active ingredtent. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, *Silastic, silicone rubber manufactured by the Dow-Corning Corporation.
." . * Trade Mark 1~ 61 ~51 For use as aerosols the novel compounds in solution or suspension may be packaged in a pressurized aerosol container together with a gaseous or liquified propellant, for example, dichlorodifluoromethane, dichlorodifluoro-methane with dichlorodifluoroethane, carbon dioxide,nitrogen or propane, with the usual adjuvants such as cosolvents, and wetting agents, as may be necessary or desirable. The compounds may also be administered in a non-pressurized form such as in a nebulizer or atomizer.
As indicated hereinabove the 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 ad-ministered, or both active ingredients may be formulated into a single combination pharmaceutical formulation. In either mode of administration the amount of compound of general Formula I as compared to the amount of L-DOPA
administered wil1 vary from about 1:~ to 1:10. A combi-nation formulation may contain an internal portion con-taining L-DOPA and an outer portion containing a compound of general Formula I, each active ingredient being suit-ably formulated. A particularly suitable combination formulation may be prepared by compressing L-DOPA, optionally with suitable carriers, to a core, providing said core with a laminated coating that is resistant to gastric juice, and applying over the coated core an external layer that contains a compound of general Formula I suitably formulated. Using such a combination formulation the decarboxylase inhibitor, that is, a compound of General Formula I is released, preferably 1~1451 MI-~08 30 to 60 minutes prior to the L-DOPA. The laminated coating may be formed by use of a nonaqueous solution of - glycerides or a water-insoluble polymer such as ethyl cellulose or cellulose acetate phthalate. Formulation wherein the L-DOPA is enteric coated by use of mixtures of shellacs and shellac derivatives and cellulose acetate phthalates may also be enployed.
In the specific examples included hereinbelow illustrative examples of suitable pharmaceutical formu-lations are described.
In addition to being useful pharmacological agentscompounds of general Formula I are also useful as inter-med1ates for the preparatîon of useful cephalosporin anti-biotics. Compounds of general Formula I wherein R~ is hydroxy are useful in the preparation of cephalosporin derivatives of the fol!owing general Formula II:
R4 R3 C~CH
R5 ~CH2 C CONH I ~ ~
R' R IHR ~ N ~ CH2X Formula II
COOM
In the above general Formula II, R1, R3, R4, R5, R~ and RB
have the meanings defined in general Formula I; M is hydrogen or a negative charge; and X is hydrogen or acetoxy.
The compounds of general Formula II and the pharma-ceutically acceptable salts and individual optical iso-mers thereof are novel compoùnds useful as antibiotics and can be administered in a manner similar to that of many well known cephalosporin derivatives, for example, Ml-908 ~L1614S~.
cephalexin, cephalothin, or cephaloglycine. The com-pounds of general Formula ll and pharmaceutically accept-able 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, that is, birds and mammals, for example, cats, dogs, bovine cows, sheep, horses and humans. For oral administration the compounds can be administered in the form of tablets, capsules or pills or in the form of elTxirs or suspensions. For parenteral administration, the compounds may best be used in the form of a sterile aqueous solution which may contain other solutes, for example, enough saline or glucose to make the solution isotonic. For topical administration the compounds of general Formula ll, salts and isomers thereof may be Tncorporated intG creams or ointments.
Illustrative examples of bacteria against which the compounds of general Formula ll and the pharmaceutically acceptable salts and individual optical isomers thereof are active are Staphylococcus aureus, Salmonella schot-mueh!eri, Klebsiella pneumoniae, Diplococcus pneumoniae and Streptococcus pyoqenes.
Illustrative pharmaceutically acceptable non-toxic inorganic acid additions salts of the compounds of general Formula ll are mineral acid addition salts, for example, hydrogen chloride, hydrogen bromide, sulfates, sul~amates, phosphate, and organic acid addition salts are, for ex-ample, maleate, acetate, citrate, oxalate3 succinate~
~enzoate, tartrate, fumarate, malate and ascorbate. The salts can be formed by conventional means.
1~ 6~ Ml-go~
Illustrative examples of cephalosporin derivatives as represented by general Formula ll are 7-[[2-acetylene-2-amino-3-phenylpropionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-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-1-azabicyclo[4.2.o]-oct-2-ene-2-carboxylic acid, 7-[[2-acetylene-2-amino-~-(3,4-dihydroxyphenyl)propionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and 7-[[~-acetylene-2-amino-3-(4-hydroxyphenyl)-propionyl]amino]-~-acetyloxymethyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
The compounds of general Formula ll wherein R1 is hydrogen are prepared by coupling 7-aminocephalosporanic acid or a derivative thereof having the formula H2N ~ ~
N ~ CH2X Formula lll COOM
wherein X and M have the meanings defined in general Formula ll with an acid of the formula R 5 ~ C H2 -C -C OOH Formula IV
R' 4 R6 NH2 or a functional derivative thereof such as the acid chloride or an acid anhydride and in the presence of a dehy-drating agent such as dicyclohexylcarbodiimide, when the ~ree acid is used, wherein R3, R4, R5, R' 4, and R6 have the ~eanings defined in general Formula ll and the amino group is 1~ 61 ~5~ Ml-908 protected with a suitable blocking group such as tertbutoxy-carbonyl followed by acid hydrolysis to remove the amino protecting groups.
The coupling reaction is generally carried out in a solvent, such as, ethyl acetate~ dioxane, chloroform or tetrahydrofuran in the presence of a base, such as, alka-line bicarbonate. The temperature of the reaction may vary from about -10C to 100C and the reaction time may vary from about 1/2 hour to 10 hours. The cephalosporin products are isolated by conventional procedures. The compounds of general Formula IV are prepared by procedures described hereinabove and the compounds of Formula iII are commercially available or are made by procedures well known in the art.
The compounds of general Formula Il wherein R1 is other than hydrogen are prepared from the corresponding derivatives wherein Rl is hydrogen by the general proce-dures set forth hereinbelow for compounds of general Formula I wherein R1 is other than hydrogen.
The compounds of general Formula I wherein R2 is hydroxy~ R1 is hydrogen and both R3 and R4 are OR1o wherein R~o is hydrogen or both R4 and Rs are ORlo wherein Rlo is hydrogen, both R4 and R5 together are -0-CH2-0-, or wherein each of R3, R~) Rs, R'4 and R~ has the meanings defined in Table I except Rlo is methyl are prepared by treating a suitably protected propargylamine derivative with a strong base to form a protected propargylamine carbanion inter-mediate which is alkylated respectively when R3 and R~ are both OR1o and Rlo is hydrogen with 2~3-isopropylidenedioxy-~0 benzylhalide and, when R4 and R5 are both ORlo and Rlo i$
Ml-908 ~1 6~ ~51 hydrogen, with ~,4-isopropylidenedioxybenzylhalide, and when R4 and R5 together are -O-CH2-O- with 3,4-methylenedioxy-benzylhalide wherein halide is, for example, chloride or bromide, and, when R3 to R~ and R'~ are as otherwise described above, with a compound of the formula:
Rl~l 1 R1 ~ CH2Y Formula V
R~ 12 R14 wherein Y is a halogen atom, for example, chlorine or bromine and each of R11, R12, R13, R' 12 and R14 has the meanings defined in the following Table ll wherein R1s Is methyl:
TABLE ll Rll R12 Rl3 R' 12 H H H H H
H H OR1s H H
H OR1s OR1s H H
OR1s H Cl H H
OR1s Cl H H
C1 OR1s H H H
Cl OR1s Cl H H
Cl,F H OR1s H H
Cl H H H CH3 Cl H Cl H CH3 H H Cl,F H CH3 Cl H CH3 H CH~
H H OR1s H CH3 1~6i45~ Ml-908 H H ORl5 H C2Hs OR15 H C2Hs H C2H5 tt ORls H ORl5 H
H . ORls OR15 OR15 H
H H OCH3 OCH2Ph H
H H OCHzPh OCH3 H
ORls OR15 H H H
ORls H H H H
H H Cl H C2H5 H H Cl H tert-C4Hg H H OR15 H tert-C4H9 The thus formed alkylated propargyiamine derivative is treated with a strong base to form an alkylated propar-gylamine carbanion, said second carbanion intermediate is ~:5 treated with an acylating reagent with subsequent removal of the protecting groups as represented by the following reaction sequence:
(R1~)3-Si-C-C~CH2 strong ~(R1~)9-Si-C-C-CH( ) b f R base ? IN=F-R17' R~ , R
compounds 1 ~Rl9Y
1 ;R~)3-Si-C_C-C(-) I strong (R1~)3-Si-C--C-CH
1 1 I base , N=l-Rl7l N=f-R17 L Rl8 1. R~8 _ _ _ _ compounds 2 acylating reagent 145~
~ I - 9~8 Rsa R'4a ~ R4a R1s R6a ~ R3a I CHz (R1~)3-Si-C-C-C-R20 deprotection N=C-R17 HC-C-C-COOH
Rl~ NH2 Formula Vll In the above reaction scheme R16 represents a straTght or branched lower alkyl group having from 1 to 4 carbon atoms, such as, methyl, ethyl, n-propyl and tert-butyl;
R~7 is phenyl, tert-butyl or triethylmethyl, 1-adamantanyl or 2-furyl; R18 is hydrogen, methoxy or ethoxy with the proviso that when R17 is 1-adamantanyl or 2-furyl, R1~ is not hydrogen; R19Y represents the alkylating reagents of Formula V or 2,~-isopropylidenedioxybenzylhalide, 3,4-iso-propylidenedioxybenzylhalide or 3,4-methylenedioxybenzyl~
halide; Ph represents phenyl; R20 is a carboxy anion, a carboxylic acid ester, a carboxamide, a nitrile or other group capable of being hydrolyzed to a carboxylic acid functîon which varies with the acylating reagent employed;
and each of R3a, R4a, R5a, R'4a and R6a respectively has the meaning defined for R3, R47 Rs~ R'4 and R6 in Table I
except R1o is methyl, or both of R3a and R4a are OR1o and R1o is hydrogen, or both R4a and R5a represent OR1o wherein Rlo is hydrogen.
Suitable strong bases which may be employed in the above reaction to form each carbanion are those which will abstract a proton from the carbon atom adjacent to the 45~
Ml-908 acetylene moiety, such as, alkyl lithium, for example, butyl lithium or phenyl lithium, lithium di-alkylamide, for example, lithium diisopropylamide, lithium amide, tertiary potassium butylate or sodium amideO
The alkylating reagents employed in the above reaction sequence are known in the art or can be prepared by proce-dures known in the art. For example, 2,3-isopropylidene-dioxy benzyl halide may be obtained from 2,3-dihydroxy-toluene by treatment with acetone in the presence of phos-phorus pentoxide followed by treatment with bromosuccin-imide by the general procedure of K. Ogura and G. Tsuchi-hashi, Tetrahedron Letters lC~71, ~151.
Suitable acylating reagents which may be employed in the above reaction are halo-formates, such as chloro-methyl formate or chloro ethylformate, azido tert-butyl-formate, cyanogen bromide, carbon dioxide, diethylcarbon-ate, phenylisocyanate, triethoxymethylium tetrafluoro-borate, N,N-dimethylcarbamoyl chloride, 2-methylthio-1,3-dithiolinium iodide, ethylene carbonate or ethylene tri-thiocarbona~e. When 2-methylthio~ -dithiolinium iodide is employecl the additional step of alcoholysis with a lower a1cohol, for example ethanol or isopropyl alcohol is required prior to deprotection by hydrolysis.
The alkylating reaction and the acylating reaction may be carried out in an aprotic solvent, for example, benzene, toluene, ethers, tetrahydrofuran/ dimethylsul-foxide, hexamethyl phosphortriamide. For each reaction the temperature varies from -120C to about 25C, a pre-ferred reaction temperature being about -70C, and the reaction time varies from about 1~2 hour to 24 hours.
11 ~1 45~ Ml-908 Removal of the protecting groups is achieved by treatment with aqueous base, for example, sodium or potas-sium hydroxide or use of hydrazine or phenylhydrazine followed by acid hydrolysis with, for example~ hydrochloric acid when the alkylating reagent is 3,4-isopropylidene-dioxybenzyl halide or 2,3-isopropylidenedioxybenzyl halide, and when the alkylating reagent contains a benzyloxy group base hydrolysis is followed by treatment with lithium amide or sodium amide in ammonia followed by the addition of lithium or sodium metal until the blue color persists for about 15 minutes.
The propargylamine derivatives wherein R1~ is hydrogen are prepared by the addition of protecting groups on the acetylene function and the nitrogen function of propargyl-amineO Protection of the nitrogen function of the propar-gylamine is accomplishe~d by forming in a known manner a Schiff's base with a nonenolizable carbonyl bearing com-pound selected from benzaldehyde, 2,2-dimethylpropanal and 2,2-diethylbutanal. Protection of the acetylenic function is accomplished by reactiny the above-described Schiff's base with a trialkylsilylchloride wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, for example, trimethylsilylchloride or triethylsilylchloride forming in a known manner the corresponding trialkylsilyl derivative.
The propargylamine derivatives wherein R18 is methoxy or ethoxy are prepared by reacting propargylamine wherein the acetylene function is protected by a trialkylsilyl group, wherein the alkyl moiety has from 1 to 4 carbon ~0 atoms, wi~h benzoyl chloride, pivalic acid chloride, 2,2-116145~ Ml-908 diethylbutyric acid chloride, 2-furoic acid chloride or 1-adamantane carboxylic acid chloride at 0C in diethyl ether, dioxane, tetrahydrofuran, chloroform, methylene-chloride, dimethylformamide, dimethylacetamide, or chloro-benzene in the presence of an organic base such as tri-ethylamine or pyridine after which the react iOil mixture is allowed to warm to about 25C for one hour. The resulting amide derivative is combined with an alkylating reagent, such as, methylfluorosulfonate, dîmethylsulfate, methyliodide, methyl p-toluenesulfonate or trimethyl-oxonium hexafluorophosphate when Rl8 is methoxy and tri-ethyloxonium tetrafluoroborate when R18 is ethoxy at about 25C in a chlorinated hydrocarbon solvent such as methylene chloride, chlorobenzene or chloroform, and the reaction mixture is refluxed for about 12 to 20 hours.
The mixture is then cooled to about 25C and an organic base such as triethylamine or pyridine is added, after which the solution is extracted with brine and the product Tsolated.
The protected propargylamine starting material is obtained by treating a ~-trialkylsilylprop-2-ynyl-1-imino-benzyl derivative with hydrazine or phenylhydrazine at about 25C for about 1/2 hour after which the mixture is diluted with, for example, petroleum ether, benzene or toluene and the protected propargylamine derivative iso-lated. Alternatively treatment with 0.5 to 1 N HCl gives the hydrochloride.
The compounds of general Formula V are known in the art or may be prepared from the corresponding appropriately substituted benzoic acid or benzaldehyde derivatives which 1~16:145i M I - ~o8 are known in the art. For example, the benzylhalides of Formula V may be prepared from the corresponding benzalde-hyde by reduction with sodium borohydride, lithium alumi-num hydride or by catalytic red~ction or from the corres-ponding benzoic acid ester by reduction with lithiumaluminum hydride or borane or reduction of the corres-ponding benzoic acid derivative with lithium hydride and treating the thus formed benzy1 alcohol derivative with, for example, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide or phos-phorus pentachlorideO
The compounds of general Formula I wherein Rl is hydrogen, R2 is hydroxy and either of R3, R4, Rs or R' 4 is OR1o wherein R1o is hydrogen are prepared from the corresponding derivative wherein either of R3, R4, R5 or R' 4 is OR1o and R1o is methyl by treatment of said deriva-tive with a lower alcohol, such as, methanol saturated with anhydrous HCl for about 15 hours at about 25C to form the lower alkyl ester, for example, the methyl ester which is suspended in methylene chloride, dimethylformamide, dimethyl-acetamideJ chlorobenzene or an ether such as diethyl ether, dioxane or tetrahydrofuran and treated with benzoyl chloride followed by treatment with an organic base such as triethyl-amine or pyridine with stirring for about 24 hours at about 25C to give the lower alkyl ester derivative wherein the amino group is protected with phenylcarbonyl which is sub-sequently trea~ed with a Lewis acid, such as, boron tri-bromide, boron trichloride or boron trifluoride then an aqueous acidS for example, hydrochloric acid.
Compounds of general Formula I wherein R1 is hydrogen, -2g~
1~ 61 ~5~ 908 Rz is hydroxy and any of R3, R~, Rs or R' 4 is ORlo and R1o is a straight or branched alkyl group of from 1 to 8 carbon atoms may be prepared by alky!ating the corresponding com-pounds wherein R1o is hydrogen with an alkyl halide of the formula R21Y2 wherein R21 is a straight 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 as methanol or ethanol or hydrocarbon solvents such as benzene or ~oluene in the presence of an organic base such as triethylamine or pyridine or in an aprotic so1vent such as dimethylformamide, dimethylacetamide or dimethyl-sulfoxide in the presence of sodium hydride for about 1 to 24 hours at a temperaturè of about 25C to 85C followed by hydrolysis with aqueous base with the proviso that prior to the alkylation reaction the ~-amino group of the hydroxy substituted starting material is protected with a suitable protecting group such as tert-butoxycarbonyl which is subsequently removed by tr~atment with acid, such as, trifluoroacetic acid. The alkyl halides employed in the above reaction are known in the art or can be prepared by procedures well known in Lhe artO
The compounds of general Formula I wherein R2 is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms, R1 is hydrogen and any of R3, R~, R5 or R' 4 is ORlo and Rlo is alkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched, benzoyl, or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms are prepared by treating the corresponding deriva-~0 tives wherein ~10 is hydrogen with an acid anhydride of the 3o-~ 45~ Ml-908 formula (R~2-C-)20 or an acid halide of the formula R22-C-halo wherein halo is chlorine or bromine and R22 is a straight or branched alkyl group of from 1 to 6 carbon atoms, phenyl or phenylalkylene wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms in the presence of an organic base such as pyridine, quino-line or triethylamine, which base serves as the solvent, for about 1 to 24 hours at a temperature of about 25C to 100C with the proviso that prior to the reaction the ~-amino group of the hydroxy substituted startlng materialis protected with a suitable blocking group, such as, tert-butoxycarbonyl which is subsequently removed by treatment with acid, for example, trifluoroacetic acid.
The acid anhydride and acid halide reactants employed in the above reaction are known in the art or can be pre-pared from the appropriate acids by procedures well known in the art.
The compounds of general Formula I wherein R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms are prepared by treating the corresponding deriva~
tives wherein R2 is hydroxy with thionyl chloride to form the acid chloride which is reacted with an alcohol of the formula R23-OH, wherein R23 is a straight or branched alkyl group of from 1 to 8 carbon atoms, such as, methyl, ethyl, n-propyl, isopropyl, n-butyl, hexyl, or octyl, at about 25C
for from about 4 to 12 hours.
The compounds of general Formula I wherein R2 is -NR7R~ wherein each of R7 and R~ is hydrogen or a straight 1161 ~51 Ml-908 or branched lower alkyl of 1 to 4 carbon atoms are prepared by an acylation reaction of an acid halide, for examplej an acid chloride, or the corresponding compound wherein R2 is hydroxy and Rl has the meaning defined in Formula I with the proviso that any free amino group is pr-otected with a suitable protecting groupJ for example, carbobenzyloxy or tert-butoxycarbonyl and when any of R3, R4, R5 or R' 4 is ORlo and R1o is hydrogen said groups are protected as the corresponding alkylcarbonyloxy group, with an excess of an appropriate amine which may be`represented as NHR7R8o The reaction is carried out in methylene chloride, chloroform, d1methylformamide, ethers such as tetrahydrofuran or dioxane or benzene at about 25C for about 1 to 4 hoursO Suitable amines are, for example, ammonia, or a compound which is a potential source of ammonia, for example, hexamethylene-tetramine; primary amines, for example, methylamine, ethyl-amine, or n-propylamine; and secondary amines such as dimethylamine, diethylamine or di-n-butylamine. Following the acylation reaction the amino protecting group is removed by treatment with acid or hydrogen bromide in dioxane, and the hydroxy protecting group when appropriate is removed by base or acid hydrolysis.
The compounds of general Formula I wherein R2 is -NH-IH-COOH are prepared by reacting the corresponding derivative wherein R2 is hydroxy or a functional derivative thereof such as an acid anhydride and R, has the meaning defined in Formula I with the proviso that any free amino group is protected with a suitable blocking group, such as benzyloxycarbonyl or tert-butoxycarbonyl with a compound of ~16145~
Ml-908 the formula N~2-CH-COOR24 wherein R9 has the meaning defined R~
in general Formula I and R24 is a lower alkyl group, for example, methyl or ethyl in an ~ther, such as, tetrahydro-furan or dioxane at 0 to about 50C for about 1 to 24 hours followed by acid hydrolysis to remove the protecting group, with the proviso that when the amine protected free acid is employed the reaction is carried out using a dehydrating agent such as dicyclohexylcarbodiimide.
The compounds of general Formula I wherein R1 is alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 4 carbon atoms are prepared by treating the corresponding derivatives wherein R1 is hydrogen and R2 is hydroxy with an acid halide of the formula R2s-c-halo wherein halo Is a halogen atom, for example, chlorine or bromine and R2s is a straight 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 0C to 25C for from 1/2 hour to 6 hours. These compounds may also be prepared from the ester derivative, that is, compounds of general Formula I wherein Rl is hydrogen and R2 is an alkoxy group of from 1 to 8 carbon atoms by treatment with 1l the acid halide, R25-C-halo, described above, in water, methylene chloride, chloroform or dimethyl acetamide in the presence of a base such as sodium hydroxide~ potassium hydroxide or excess triethylamine at a temperature of from about 0C to 25C for from about 1/2 hour to 2~ hours.
~33-6~ ~S~
Ml-908 The compounds of general Formula I wherein R1 is alkoxy carbonyl wherein the alkoxy moiety is straight or branched and has from 1 to 4 carbon atoms are prepared by treating the corresponding derivative wherein R1 is hydro-~en and R2 is hydroxy with an alkyl haloformate of the formula halo-C-OR2~ wherein halo is a halogen atom such as chlorine or bromine and R2~ is a straight 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 about 0C to 25C for from about 1/2 hour to 6 hours.
The compounds of general Formula I wherein R1 is 1l -C-fH-R27 wherein R27 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl are prepared by treating the corresponding derivative wherein R1 is hydrogen and R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms with an acid of the formula HOOC-CH-R27 or an anhydride thereof wherein the amino group is protected with a suitable blocking group such as benzyloxycarbonyl or tert-butoxy-carbonyl and R27 has the meaning defined hereinabove 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 employed, at a temperature of from about 0C to ~5C for about 1 to 12 hours followed by acid and base hydrolysis to remove the protecting groups.
-~4-6~ ~51 Ml-908 The individual optical isomers of the compounds of general Formula I wherein R1 is H and Rz is OH may be sepa-rated by using a (+) of (-) binaphthylphosphoric acid salt by the method of R. Viterbo et al., Tetrahedron Letters 48, 4617 (1971)o Other resolving agents such as (+) camphor-10-sulfonic acid may also be employedO The individual optical isomers of compounds of Formula I wherein R1 and R2 are other than H and OH may be obtained as described herein for the racemate only starting with the resolved amino acid.
The following Example 1 illustrates the use of a compound of general Formula I wherein R2 is hydroxy as a chemical intermediate in the preparation of a cephalosporin of Formula ll.
7-~2-Acetylene-2-amino-3-phenylpro ionyl]amino]-3-acetyl-oxymethyl-c.-oxo-5-thia-1-azabicyclo~4.2.0Joct-2-ene-2-~carboxylic acid A mixture of 1 9 of 3-acetyloxy-7-amino-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 9 of 2-acetylene-2-amino-3-phenylpropionic acid chloride wherein the free amino group is protected with tert-butoxycarbonyl in 50 ml of ethyl acetate is refluxed for 2 hours after whTch the solvent is removed leaving a residue which is treated with mild acid and chromatographed on silica gel using benzene-acetone as the eluant to give 7-[[2-acetyl-ene-2-amino-3-phenylpropionyl]amino~-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
The following Examples 2 to 4 are illustrative of pharmaceutical preparations of the compounds of this invention~
~~5-11 61 ~Si Ml-908 An illustrative composition for hard gelatin capsules is as follows:
(a) 2-acet~lene-2-amino-3-(3-hydroxy- 20 mg phenyl propionic acid (b) talc 5 mg (c) la~tose 90 mg The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into hard gelatin capsules at a net fill of 115 mg per capsule~
An illustrative composition for tablets is as follows:
(a) 2-acetylene-2-amino-3-(3,4- 20 mg dihydroxyphenyl)propionic acid (b) starch 43 mg (c) lactose 45 mg (d) magnesium stearate 2 mg The granulation obtained upon mixing the lactose with the compound (a) and part of the starch and granulated with starch paste is dried, screened, and mixed with the magnesium stearate. The mixture is compressed into tablets weighing 110 mg each.
An illustrative composition for an injectable suspen-sion is the fo1lowing 1 ml ampul for an intramuscular injection~
Wei~ht per cent (a) 2-acetylene-2-amino-3-(4- 1.0 hydroxyphenyl)propionic acid (b) polyvinylpyrrolidone 0.5 ~ 51 Ml-908 (c) 1ecithin 0.25 (d) water for injection to make 100~0 The materials (a)-(d) are mixed, homogenized, and filled into 1 ml ampuls which are sealed and autoclaved 20 minut~s at 121C. Each ampul contains 10 mg per ml of novel compound (a).
The following Examples further illustrate the com-pounds of general Formula 1.
2-Acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic acid (A) A solution of 32.4 9 (0.15 M) of 3-trimethyl-silylprop-2-ynyl-1-iminobenzyl in 20 ml of tetrahydrofuran is added to lithium diisopropylamide, prepared from 21 ml (0015 M) of diisopropylamide and 73.2 ml of a 2005 M
solution of n-butyllithium (0.15 M), in 1 liter of tetra-hydrofuran at -78C. After 15 minutes 32.7 9 (1.35 M) of 3,4-isopropylidenedioxybenzylbromide in 20 ml of tetra-hydrofuran is added, and the mixture is maintained at -78C
for 2 hours a~ter which 7302 ml of a 2.05 M solution (0.15 M) of n-butyllithium is added followed by the addition of 14.2 9, 11.6 ml (0015 M) of methyl chloroformate. After an additional 30 minutes at -78C the reaction mixture is treated with brine and extracted with ether. The ether extract is evaporated leaving a residue which is dissolved in 300 ml of petroleum ether, bop~ 30-60C, and treated with 16.2 9 (0.15 M) of phenylhydrazine at 25C for 2 hours.
The precipitate is filtered off and the petroleum ether evaporated leaving a residue which is treated with 40 9 of potassium hydroxide in 300 ml of ethanol and 300 ml of water at 25C for about 15 hours. The ethanol Ts evapo-37~
6~ ~51 Ml-908 .
rated, and the aqueous solution is washed well with methyl-ene chloride, then acidified and rewashed with methylene chloride. The water ;s evaporated, and the remaining solid residue is triturated with ethanol, filtered and the fil-trate evaporated leaving a residue which is dissolved in water. The pH of the water solution is adjusted to 6 and applied to a column of Amberlite resin 120 H+ and eluting wlth 2 M ammonium hydroxide solution affords 2-acetylene-2-amino-3~,4'-isopropylidenedioxyphenylpropionic acid after recrystallization from water-ethanol.
(B) 3 9 (0.13 M) of 2-acetylene-2-amino-3,4-isoPropyl-ldenedioxyphenylpropionic acid is heated at reflux with 200 ml of 6 N hydrochloric acid for 2 hours after which the solvent is evaporated. The resulting residue is taken up in water and the pH is adjusted to 6 by careful addition of hydraztne hydrate. On cooling the solution to 0C a precipitate forms which is collected and recrystallized (charcoal) from water to afford 2-acetylene-2-amino-~-(3,4-dlhydroxyphenyl)propionic acid.
~XAMPLE 6 2-Acetylene-2-amino-~ -methoxyphenyl)propionic acid -When in the procedure of Example 5 (A) 25.8 9 (0.12 M) of 3-trimethylsilylprop-2-ynyl-1-iminobenzyl is used instead of 32.4 9 (0.15 M) and 20.1 9 (0.1 M) of 1-bromomethyl-~-methoxybenzene is used in place of 5-bromomethyl-1,~-benzodioxoleg upon recrystallization from water, 2-acetyl-ene-2-amino-~ -me-thoxyphenyl)propionic acid is obtained.
2-Acety!ene-2-amino-3-(~-hydroxyphenyl)propionic acid ~0 A suspension of 2.0 9 (9.1 mM) of 2-acetylene-2-~, . .
* Trade Mark ` Ml-908 amino-3~(3-methoxyphenyl)propionic acid in 20 ml of methanol saturated with anhydrous HCl is stirred for about 15 hours at 25C after which the solvent is evaporated. The resulting methyl ester derivative is suspended in 50 ml of methylene chloride and treated with 1.26 9 of benzoyl chloride followed by treatment with 3.6 9 of triethylamine.
The mixture is stirred for 24 hours then washed with water, dried and evaporated. The resul~ing residue is recrystal-lized from methanol to give the methyl ester derivative whereTn the amino ~roup is protected with phenylcarbonyl.
A so1ution of 1.2 9 (~.5 mM) of the amine protected methyl ester in 50 ml of methyl~ne chloride at 25C is treated with 0.9 9 of boron tribromide. The mixture is stirred for about 15 hours at 25C after which 10 ml of methanol is added and the solvents evaporated. The resulting residue is heated to reflux with 50 ml of 6 N
hydrochloric acid for 5 hours. The solution is concen-trated, the pH adjusted to 6 and applied to a column of Amberlite 120 H~. Eluting with 1 M ammonium hydroxide affords 2-acetylene-2-amino-3-(~-hydroxyphenyl)propionic acid after recrystallization from water-ethanol.
When in the procedure of Example 5 an appropriate amount of benzylchloride, 4-chloro-2-methoxybenzyl-chloride, 2-chloro-6-methylbenzylchloride, 2,4-dichloro-6-methylbenzylchloride, 4-methoxy-6-methylbenzylchloride, or 6-tert-butyl-4-chlorobenzylchloride is substituted for 3',4'-isopropylidenedioxybenzylbromide the following products are obtained:
2~acetylene-2-amino-3-phenylpropionic acid, 2-acetylene-2-amino-3-(4-chloro-2-methoxyphenyl)propionic acid, 2-* Trade Mark S~
Ml-908 acetylene-2-amino-~-(2-chloro-6-methylphenyl)propionic acid, 2-acetylene-2-amino-3-(2J4-dichloro-6-methylphenyl)-propionic acid, 2-acetylene-2-amino-3-(4-methoxy-6-methyl) phenyl)propionic acid and 2-acetylene-2-amino-3-(6-tert-butyl-4-chlorophenyl)propionic acid.
Ethyl 2-acetylene-?-amino-3-(3,4-dihydroxyph~nyl)pro-pionate ydroc orIde A suspension of 2.2 9 (10 mM) of 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic acid in 30 ml of ethanol is saturated with anhydrous HCl, and the resulting solution allowed to stand at 25C for 24 hours. The sol-vent is evaporated leaving a residue which is recrystal-llzed from ethanol-ether to give ethyl 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic hydrochloride.
2-Acetylene-3-(3,4-diacetyloxyphenyl)-2-(tert-but carbonylamino)propionic acid 2 N Aqueous sodium hydroxide and acetic anhydride (3.5 g) are added simultaneously during 1/2 hour to a solution of 2-acetylene-2-(tert-butoxycarbonylamino)-3-~3,4-dihydroxyphenylpropionic acid (6 9) prepared from 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic acid and tert-butyl azidoformate, in 30 ml of 1 N sodium hydroxide under argon so that the pH is maintained between 6.5 and 7.5. After 1 hour at 25C the pH is adjusted to 1 using 6 N sulfuric acid then extracted with methylene chloride. The organic phase is dried and concentrated to give 2-acetylene-3-(3,4-diacetyloxyphenyl)-2-tert-butoxycarbonylamino)propionic acid.
116~4S~ Ml-908 2-Acetylene-2-(acety!amino)-3-(3,4-dihydroxyphenyl)pro-P!onlc aci To a stirred suspension of 6.8 g (10 mM) of borax in 10 ml of water is added 2.2 g (10 mM) of 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic acid under argon.
After 15 minutes the pH is adjusted to 9 by the addition of 2 N sodium hydroxide then treated dropwise with 780 mg of acetyl chloride, maintaining the pH between 9.0 and 9.5. The aqueous solution is washed with ether~ adjusted to a pH of 1 using 6 ~ sulfuric acid and extracted with methylene chloride. The organic phase is dried and con-centrated to afford 2-acetylene-2-(acetylamino)-3-(3,4-dihydroxyphenyl)propionic acid, which may be treated with ethanolic HCl to afford the ethyl esterO
~5 EXAMPLE 11 ~2-Acetylene-2-amino-3-(3,4-diacetyloxyphenyl)-1-oxo-propy aminoJpropionic aci A solution of 404 g (10 mM) of 2-acetylene-2-carbobenzyloxyamino)-3-(3,4-diacetyloxyphenyl)propionic acid, prepared from 2-acety1ene-2-amino-3-(3,4-diacetyloxy-phenyl)propionic acid and benzyl chloroformate, in 50 mlof ether is treated with 1.0 g (10 mM) of triethylamine fol10wed by 1.08 g (10 mM) of ethyl chloroformate. After 1 hour at 25~C the precipitate is filtered off and to the ether solution is added a solution of alanine benzyloxy ester (10 mM) in 30 ml of etherO The solution is main-talned at 25C overnight then evaporated to drynessO The residue is treated wi~h H~r in dioxane (40~ w/w, 20 ml) for 30 minutes at 25C. Ether is then added and the precipi-tated hydrobromide filtered off to ~ive 2-[2-acetylene^2-61 ~51 Ml-908 amino-3-(3,1~-diacetyloxyphenyl)-l-oxopropylamino]propionic acid.
2hAcel)ylene.2-~2-amidohldoxopropylamino)-~ 4-dihydr p eny ~roplonlc acl y roc orl e A suspension of 3.3 9 (10 mM) of benzyl 2-acetylene-2-amTno-~-(3,4-dihydroxyphenyl)propionate in 50 ml of methylene chloride is treated with 1 9 (10 mM) of tri-ethylamine afterwhich 10 mM of N-carbobenzyloxyalanine wherein the acid function is activated by ethoxycarbonyl in 20 ml of methylene chloride is added. The mixture is stirred at 25C for about 16 hours then washed with water.
The organic layer is dried and evaporated.-The residue is taken up in ether and the ether solution coo1ed to 0C.
A vigorous stream of HCl gas is bubbled through the solu-tion for 3 hours after which the ether solution is washed with water. The aqueo~us phase is evaporated to afford 2-acetylene-2-(2-amino-1-oxopropylamino)~ ,4-dihydroxy-; phenyl)propionic acid hydrochloride as a gumO
EXAMPLE 1~
2-Acetylene-2-amino-3-(4-hydroxy-3-methoxyphenyl)propionic aci A solution of 3.25 9 (10 mM) of 2-acetylene-2-amino-3-(4-benzyloxy-3-methoxyphenyl)prop70nic acid in 20 ml of tetrahydrofuran is added to 100 ml of ammonia at -~0C
containing 0.5 9 ot lithium amide. After 1 hour lithium metal is added until the blue color persists for 2~ minutes then ammonium chloride is added, and the ammonia allowed to evaporate. The residue is dissolved in water, the pH ad-justed to 6 and applied to an Amberlite 120 Hl resin.
* Trade Mark ~61451 Ml -908 Elution with 1 M ammonium hydroxide affords 2-acetylene-2-amino-3-(4-hydroxy-~-methoxyphenyl)propionic acid which is recrystal l ized from water.
As irreversible inhibitors of aromatic amino acid decarboxylase, and DOPA decarboxylase the compounds of the present invention possess many pharmacological utilities.
As peripheral irreversible inhibitors of aromatic amino acid decarboxylase the compounds of general Formula I are useful in the treatment of Parkinsonism when given in conjunction with 3,4-dihydroxyphenylalanine (DOPA) or L-3,4-dihydroxyphenylalanine (L-DOPA). DOPA and more particularly the active isomer L-DOPA are known to be effective in treating Parkinsonism when administered systemically, usually in an amount from 0.5 to 1 gram daily initially after which the amount administered is gradually increased over a 3 to 7 day period to a maximally tolera-ted daily dose of about 8 grams. Concurrent administra-tion of a compound of general Formula I and L-DOPA provides an improved method of treating Parkinsonism in that the compounds of Formula I will block the decarboxylation of L-DOPA to L-3,4-dihydroxyphenethylamine (L-dopamine) peripherally by inhibiting the activity of aromatic amino acid decarboxylase enzyme, thus retaining high circulatlng levels of L-DOPA for central absorpt;on and also preventing 116145~ Ml-9o8 peripheral formation of increased levels of dopamine which is known to result in certain undesirable side effects such as cardiac arrhythmia. By concurrently administering a compound of general Formula I and L-DOPA the amount of 5 L-DOPA administered may be reduced 2 to 10-fold as com-pared to amounts required for utility when L-DOPA is administered alone. It is preferred that the compounds of this invention be administered prior to administration of L-DOPA. For example, a compound of Formula I may be administered from 30 minutes to 4 hours prior to admini-stration of L-DOPA depending on the route of administration and condition of the patient to be treated.
The compounds of general Formula I are also useful in treating depressive syndromes in individuals when given in conjunction with 5-hydroxytryptophan (5-HTP) or more particularly the active levo isomer which is known to be useful in the treatment of depression when adminis-tered systemically. The compounds of general Formula I, by inhibiting peripherally the activity of aromatic amino acid decarboxyla,e will block the conversion of 5-hydroxy-tryptophan to 5-hydroxytryptamine thus retaining higher circulating levels of 5-~TP for central absorption. The compounds of general Formula I when administered con-currently with exogenous 5-HTP are also useful in treating action myoclonus which is known to be effectively treated by increasing central levels of 5-HTP.
The compounds of general Formula I, by virtue of their inhibitory action on aromatic amino acid decarboxylase peripherally are also useful in the treatment of rheumatoid arthritis, carcinoid syndrome, anaphylactoid reactions in 11 61 ~5~ Ml-908 .
humans~ bronchoconstriction in asthamatic humans as well as other conditions known to be caused by high peripheral levels of 5-hydroxytryptamine.
As indicated hereinabove it has been shown that agents which decrease the elevated levels of 5-HT and norepi-nephrine, the hydroxylation product of dopamine, are useful in treating patients with manic disorders. Hence, as central irreversible inhibitors of aromatic amino acid decarboxylase, and DOPA decarboxylase the compounds of general Formula I are useful in treating manic disorders.
Additionally, by virtue of the central inhibitory action of the compounds of general Formula I on aromatic amino acid decarboxylase said compounds may also be useful as antipsychotic agents, since central levels of tryptamine are decreased, and useful in the treatment of schizophrenia and seizure disorders since central levels of phenethylamine and tyramine are decreased by administration of a compound of general Formula lo The utility of the compounds of general Formula I as irreversible inhibitors of aromatic amino acid decarboxylase may be demonstrated as follows. A compound of general Formula I is administered as an aqueous solution or sus-pension to rats or mice. At different time intervals after administration of the compound from 1 to 48 hours the animals are sacrificed by decapitation and aromatic amino acid decarboxylase activity is measured by a radiometric assay as described by Christenson et al., Arch. Biochem.
Biophys. 141, ~56 (1970) in homogenates of kidney, heart and brain prepared according to Burkard et al., Arch.
Biochem. Biophys. 107~ 187 (1964~.
1~ 6~ 4s~ Ml-908 The compounds of this invention can be administered in various manners to achieve the desired effect. The compounds can be administered alone or in the form of pharmaceutical preparations to the patient being treated either orally or parenterally, for example, subcutaneously, intravenously or intraperitoneally. The compounds can be administered by intranasal instillation or by application to mucous membranes such as that of the nose~ throat and bronchial tubes, for examp1e, in an aerosol spray con-taining small particles of a novel compound of thisinvention in a spray solution or dry powder form.
The amount of novel compound administered will vary and can be any effective amount. Depending on the patient, the condition being treated and the mode of administration, the quantity of novel compound adminis-tered may 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 affect a peripheral .
_ 3o - ~1 6i ~5~ Ml-908 irreversible inhibition or aromatic decarboxylase the effective amount of compound administered will vary from about 0.1 mg/kg (milli~rams per kilogram) to 100 mg/kg of body weight of the patient per dose and preferably from about 5 mg/kg to 25 mg/kg. For example, the desired peri-pheral effect can be obtained by consumption of a unit dosage form, such as, for example, a tablet containing from 10 to 250 mg of a novel compound of this invention taken 1 to 4 times daily. When the compounds of general Formula I are administered to achieve a central irreversi-ble inhibition of aromatic decarboxylase or 3,4-dihydroxy-phenylalanine decarboxylase the effective amount of com-pound administered will vary from about 100 mg/kg to 500 mg/kg of body weight of the patient per day and pre-ferably from about 150 mg/kg to 300 mg/kg. For example, the desired central effect can be achieved by consumption of a unit dosage form, such as, for example, a tablet containing from about 350 mg to 500 mg of a novel com-pound of this invèntion taken from 1 to 4 times daily.
As used herein the term patient is taken to mean warm blooded animals such as mammals, for example, cats, dogs, ratsJ mice, guinea pigs, sheep, horses, bovine cows, and humans.
The solid unit dosage forms can be of the conven-tional type. Thus, the solid form can be a capsule which ca~ be of the ordinary gelatin type containing a novel compound of this invention and a carrier, for example, lubricant and inert fillers such as lactose, sucrose and corn starch. In another èmbodiment, the novel compounds 11 6~ 45~ MI-908 are tableted with conventional tablet bases such as lac-tose, sucrose or corn starch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents such as corn starch, potato starch, or alsinic acid, and a lubricant such as stearic acid, or magnesium stearate.
For parenteral administration the compounds may be administered as injectable dosages of a solution or sus-pension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative of oils which can be employed in these preparations are those of petroleumJ
animal, vegeta61e or synthetic origin, for example, peanut Oj1J soybean Oj1J and mineral oil~ In general waterJ salineJ aqueous dextroseJ and related sugar solu-tionsJ ethanols and glycols such as propylene glycol or polyethjlene glycol are preferred liquid carriersJ par-ticularly for injectable solutions.
The compounds can be administered in the form of adepot injection or implant preparation which may be form-ulated in such a manner as to permit a sustained release of the active ingredtent. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, *Silastic, silicone rubber manufactured by the Dow-Corning Corporation.
." . * Trade Mark 1~ 61 ~51 For use as aerosols the novel compounds in solution or suspension may be packaged in a pressurized aerosol container together with a gaseous or liquified propellant, for example, dichlorodifluoromethane, dichlorodifluoro-methane with dichlorodifluoroethane, carbon dioxide,nitrogen or propane, with the usual adjuvants such as cosolvents, and wetting agents, as may be necessary or desirable. The compounds may also be administered in a non-pressurized form such as in a nebulizer or atomizer.
As indicated hereinabove the 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 ad-ministered, or both active ingredients may be formulated into a single combination pharmaceutical formulation. In either mode of administration the amount of compound of general Formula I as compared to the amount of L-DOPA
administered wil1 vary from about 1:~ to 1:10. A combi-nation formulation may contain an internal portion con-taining L-DOPA and an outer portion containing a compound of general Formula I, each active ingredient being suit-ably formulated. A particularly suitable combination formulation may be prepared by compressing L-DOPA, optionally with suitable carriers, to a core, providing said core with a laminated coating that is resistant to gastric juice, and applying over the coated core an external layer that contains a compound of general Formula I suitably formulated. Using such a combination formulation the decarboxylase inhibitor, that is, a compound of General Formula I is released, preferably 1~1451 MI-~08 30 to 60 minutes prior to the L-DOPA. The laminated coating may be formed by use of a nonaqueous solution of - glycerides or a water-insoluble polymer such as ethyl cellulose or cellulose acetate phthalate. Formulation wherein the L-DOPA is enteric coated by use of mixtures of shellacs and shellac derivatives and cellulose acetate phthalates may also be enployed.
In the specific examples included hereinbelow illustrative examples of suitable pharmaceutical formu-lations are described.
In addition to being useful pharmacological agentscompounds of general Formula I are also useful as inter-med1ates for the preparatîon of useful cephalosporin anti-biotics. Compounds of general Formula I wherein R~ is hydroxy are useful in the preparation of cephalosporin derivatives of the fol!owing general Formula II:
R4 R3 C~CH
R5 ~CH2 C CONH I ~ ~
R' R IHR ~ N ~ CH2X Formula II
COOM
In the above general Formula II, R1, R3, R4, R5, R~ and RB
have the meanings defined in general Formula I; M is hydrogen or a negative charge; and X is hydrogen or acetoxy.
The compounds of general Formula II and the pharma-ceutically acceptable salts and individual optical iso-mers thereof are novel compoùnds useful as antibiotics and can be administered in a manner similar to that of many well known cephalosporin derivatives, for example, Ml-908 ~L1614S~.
cephalexin, cephalothin, or cephaloglycine. The com-pounds of general Formula ll and pharmaceutically accept-able 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, that is, birds and mammals, for example, cats, dogs, bovine cows, sheep, horses and humans. For oral administration the compounds can be administered in the form of tablets, capsules or pills or in the form of elTxirs or suspensions. For parenteral administration, the compounds may best be used in the form of a sterile aqueous solution which may contain other solutes, for example, enough saline or glucose to make the solution isotonic. For topical administration the compounds of general Formula ll, salts and isomers thereof may be Tncorporated intG creams or ointments.
Illustrative examples of bacteria against which the compounds of general Formula ll and the pharmaceutically acceptable salts and individual optical isomers thereof are active are Staphylococcus aureus, Salmonella schot-mueh!eri, Klebsiella pneumoniae, Diplococcus pneumoniae and Streptococcus pyoqenes.
Illustrative pharmaceutically acceptable non-toxic inorganic acid additions salts of the compounds of general Formula ll are mineral acid addition salts, for example, hydrogen chloride, hydrogen bromide, sulfates, sul~amates, phosphate, and organic acid addition salts are, for ex-ample, maleate, acetate, citrate, oxalate3 succinate~
~enzoate, tartrate, fumarate, malate and ascorbate. The salts can be formed by conventional means.
1~ 6~ Ml-go~
Illustrative examples of cephalosporin derivatives as represented by general Formula ll are 7-[[2-acetylene-2-amino-3-phenylpropionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-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-1-azabicyclo[4.2.o]-oct-2-ene-2-carboxylic acid, 7-[[2-acetylene-2-amino-~-(3,4-dihydroxyphenyl)propionyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and 7-[[~-acetylene-2-amino-3-(4-hydroxyphenyl)-propionyl]amino]-~-acetyloxymethyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
The compounds of general Formula ll wherein R1 is hydrogen are prepared by coupling 7-aminocephalosporanic acid or a derivative thereof having the formula H2N ~ ~
N ~ CH2X Formula lll COOM
wherein X and M have the meanings defined in general Formula ll with an acid of the formula R 5 ~ C H2 -C -C OOH Formula IV
R' 4 R6 NH2 or a functional derivative thereof such as the acid chloride or an acid anhydride and in the presence of a dehy-drating agent such as dicyclohexylcarbodiimide, when the ~ree acid is used, wherein R3, R4, R5, R' 4, and R6 have the ~eanings defined in general Formula ll and the amino group is 1~ 61 ~5~ Ml-908 protected with a suitable blocking group such as tertbutoxy-carbonyl followed by acid hydrolysis to remove the amino protecting groups.
The coupling reaction is generally carried out in a solvent, such as, ethyl acetate~ dioxane, chloroform or tetrahydrofuran in the presence of a base, such as, alka-line bicarbonate. The temperature of the reaction may vary from about -10C to 100C and the reaction time may vary from about 1/2 hour to 10 hours. The cephalosporin products are isolated by conventional procedures. The compounds of general Formula IV are prepared by procedures described hereinabove and the compounds of Formula iII are commercially available or are made by procedures well known in the art.
The compounds of general Formula Il wherein R1 is other than hydrogen are prepared from the corresponding derivatives wherein Rl is hydrogen by the general proce-dures set forth hereinbelow for compounds of general Formula I wherein R1 is other than hydrogen.
The compounds of general Formula I wherein R2 is hydroxy~ R1 is hydrogen and both R3 and R4 are OR1o wherein R~o is hydrogen or both R4 and Rs are ORlo wherein Rlo is hydrogen, both R4 and R5 together are -0-CH2-0-, or wherein each of R3, R~) Rs, R'4 and R~ has the meanings defined in Table I except Rlo is methyl are prepared by treating a suitably protected propargylamine derivative with a strong base to form a protected propargylamine carbanion inter-mediate which is alkylated respectively when R3 and R~ are both OR1o and Rlo is hydrogen with 2~3-isopropylidenedioxy-~0 benzylhalide and, when R4 and R5 are both ORlo and Rlo i$
Ml-908 ~1 6~ ~51 hydrogen, with ~,4-isopropylidenedioxybenzylhalide, and when R4 and R5 together are -O-CH2-O- with 3,4-methylenedioxy-benzylhalide wherein halide is, for example, chloride or bromide, and, when R3 to R~ and R'~ are as otherwise described above, with a compound of the formula:
Rl~l 1 R1 ~ CH2Y Formula V
R~ 12 R14 wherein Y is a halogen atom, for example, chlorine or bromine and each of R11, R12, R13, R' 12 and R14 has the meanings defined in the following Table ll wherein R1s Is methyl:
TABLE ll Rll R12 Rl3 R' 12 H H H H H
H H OR1s H H
H OR1s OR1s H H
OR1s H Cl H H
OR1s Cl H H
C1 OR1s H H H
Cl OR1s Cl H H
Cl,F H OR1s H H
Cl H H H CH3 Cl H Cl H CH3 H H Cl,F H CH3 Cl H CH3 H CH~
H H OR1s H CH3 1~6i45~ Ml-908 H H ORl5 H C2Hs OR15 H C2Hs H C2H5 tt ORls H ORl5 H
H . ORls OR15 OR15 H
H H OCH3 OCH2Ph H
H H OCHzPh OCH3 H
ORls OR15 H H H
ORls H H H H
H H Cl H C2H5 H H Cl H tert-C4Hg H H OR15 H tert-C4H9 The thus formed alkylated propargyiamine derivative is treated with a strong base to form an alkylated propar-gylamine carbanion, said second carbanion intermediate is ~:5 treated with an acylating reagent with subsequent removal of the protecting groups as represented by the following reaction sequence:
(R1~)3-Si-C-C~CH2 strong ~(R1~)9-Si-C-C-CH( ) b f R base ? IN=F-R17' R~ , R
compounds 1 ~Rl9Y
1 ;R~)3-Si-C_C-C(-) I strong (R1~)3-Si-C--C-CH
1 1 I base , N=l-Rl7l N=f-R17 L Rl8 1. R~8 _ _ _ _ compounds 2 acylating reagent 145~
~ I - 9~8 Rsa R'4a ~ R4a R1s R6a ~ R3a I CHz (R1~)3-Si-C-C-C-R20 deprotection N=C-R17 HC-C-C-COOH
Rl~ NH2 Formula Vll In the above reaction scheme R16 represents a straTght or branched lower alkyl group having from 1 to 4 carbon atoms, such as, methyl, ethyl, n-propyl and tert-butyl;
R~7 is phenyl, tert-butyl or triethylmethyl, 1-adamantanyl or 2-furyl; R18 is hydrogen, methoxy or ethoxy with the proviso that when R17 is 1-adamantanyl or 2-furyl, R1~ is not hydrogen; R19Y represents the alkylating reagents of Formula V or 2,~-isopropylidenedioxybenzylhalide, 3,4-iso-propylidenedioxybenzylhalide or 3,4-methylenedioxybenzyl~
halide; Ph represents phenyl; R20 is a carboxy anion, a carboxylic acid ester, a carboxamide, a nitrile or other group capable of being hydrolyzed to a carboxylic acid functîon which varies with the acylating reagent employed;
and each of R3a, R4a, R5a, R'4a and R6a respectively has the meaning defined for R3, R47 Rs~ R'4 and R6 in Table I
except R1o is methyl, or both of R3a and R4a are OR1o and R1o is hydrogen, or both R4a and R5a represent OR1o wherein Rlo is hydrogen.
Suitable strong bases which may be employed in the above reaction to form each carbanion are those which will abstract a proton from the carbon atom adjacent to the 45~
Ml-908 acetylene moiety, such as, alkyl lithium, for example, butyl lithium or phenyl lithium, lithium di-alkylamide, for example, lithium diisopropylamide, lithium amide, tertiary potassium butylate or sodium amideO
The alkylating reagents employed in the above reaction sequence are known in the art or can be prepared by proce-dures known in the art. For example, 2,3-isopropylidene-dioxy benzyl halide may be obtained from 2,3-dihydroxy-toluene by treatment with acetone in the presence of phos-phorus pentoxide followed by treatment with bromosuccin-imide by the general procedure of K. Ogura and G. Tsuchi-hashi, Tetrahedron Letters lC~71, ~151.
Suitable acylating reagents which may be employed in the above reaction are halo-formates, such as chloro-methyl formate or chloro ethylformate, azido tert-butyl-formate, cyanogen bromide, carbon dioxide, diethylcarbon-ate, phenylisocyanate, triethoxymethylium tetrafluoro-borate, N,N-dimethylcarbamoyl chloride, 2-methylthio-1,3-dithiolinium iodide, ethylene carbonate or ethylene tri-thiocarbona~e. When 2-methylthio~ -dithiolinium iodide is employecl the additional step of alcoholysis with a lower a1cohol, for example ethanol or isopropyl alcohol is required prior to deprotection by hydrolysis.
The alkylating reaction and the acylating reaction may be carried out in an aprotic solvent, for example, benzene, toluene, ethers, tetrahydrofuran/ dimethylsul-foxide, hexamethyl phosphortriamide. For each reaction the temperature varies from -120C to about 25C, a pre-ferred reaction temperature being about -70C, and the reaction time varies from about 1~2 hour to 24 hours.
11 ~1 45~ Ml-908 Removal of the protecting groups is achieved by treatment with aqueous base, for example, sodium or potas-sium hydroxide or use of hydrazine or phenylhydrazine followed by acid hydrolysis with, for example~ hydrochloric acid when the alkylating reagent is 3,4-isopropylidene-dioxybenzyl halide or 2,3-isopropylidenedioxybenzyl halide, and when the alkylating reagent contains a benzyloxy group base hydrolysis is followed by treatment with lithium amide or sodium amide in ammonia followed by the addition of lithium or sodium metal until the blue color persists for about 15 minutes.
The propargylamine derivatives wherein R1~ is hydrogen are prepared by the addition of protecting groups on the acetylene function and the nitrogen function of propargyl-amineO Protection of the nitrogen function of the propar-gylamine is accomplishe~d by forming in a known manner a Schiff's base with a nonenolizable carbonyl bearing com-pound selected from benzaldehyde, 2,2-dimethylpropanal and 2,2-diethylbutanal. Protection of the acetylenic function is accomplished by reactiny the above-described Schiff's base with a trialkylsilylchloride wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, for example, trimethylsilylchloride or triethylsilylchloride forming in a known manner the corresponding trialkylsilyl derivative.
The propargylamine derivatives wherein R18 is methoxy or ethoxy are prepared by reacting propargylamine wherein the acetylene function is protected by a trialkylsilyl group, wherein the alkyl moiety has from 1 to 4 carbon ~0 atoms, wi~h benzoyl chloride, pivalic acid chloride, 2,2-116145~ Ml-908 diethylbutyric acid chloride, 2-furoic acid chloride or 1-adamantane carboxylic acid chloride at 0C in diethyl ether, dioxane, tetrahydrofuran, chloroform, methylene-chloride, dimethylformamide, dimethylacetamide, or chloro-benzene in the presence of an organic base such as tri-ethylamine or pyridine after which the react iOil mixture is allowed to warm to about 25C for one hour. The resulting amide derivative is combined with an alkylating reagent, such as, methylfluorosulfonate, dîmethylsulfate, methyliodide, methyl p-toluenesulfonate or trimethyl-oxonium hexafluorophosphate when Rl8 is methoxy and tri-ethyloxonium tetrafluoroborate when R18 is ethoxy at about 25C in a chlorinated hydrocarbon solvent such as methylene chloride, chlorobenzene or chloroform, and the reaction mixture is refluxed for about 12 to 20 hours.
The mixture is then cooled to about 25C and an organic base such as triethylamine or pyridine is added, after which the solution is extracted with brine and the product Tsolated.
The protected propargylamine starting material is obtained by treating a ~-trialkylsilylprop-2-ynyl-1-imino-benzyl derivative with hydrazine or phenylhydrazine at about 25C for about 1/2 hour after which the mixture is diluted with, for example, petroleum ether, benzene or toluene and the protected propargylamine derivative iso-lated. Alternatively treatment with 0.5 to 1 N HCl gives the hydrochloride.
The compounds of general Formula V are known in the art or may be prepared from the corresponding appropriately substituted benzoic acid or benzaldehyde derivatives which 1~16:145i M I - ~o8 are known in the art. For example, the benzylhalides of Formula V may be prepared from the corresponding benzalde-hyde by reduction with sodium borohydride, lithium alumi-num hydride or by catalytic red~ction or from the corres-ponding benzoic acid ester by reduction with lithiumaluminum hydride or borane or reduction of the corres-ponding benzoic acid derivative with lithium hydride and treating the thus formed benzy1 alcohol derivative with, for example, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide or phos-phorus pentachlorideO
The compounds of general Formula I wherein Rl is hydrogen, R2 is hydroxy and either of R3, R4, Rs or R' 4 is OR1o wherein R1o is hydrogen are prepared from the corresponding derivative wherein either of R3, R4, R5 or R' 4 is OR1o and R1o is methyl by treatment of said deriva-tive with a lower alcohol, such as, methanol saturated with anhydrous HCl for about 15 hours at about 25C to form the lower alkyl ester, for example, the methyl ester which is suspended in methylene chloride, dimethylformamide, dimethyl-acetamideJ chlorobenzene or an ether such as diethyl ether, dioxane or tetrahydrofuran and treated with benzoyl chloride followed by treatment with an organic base such as triethyl-amine or pyridine with stirring for about 24 hours at about 25C to give the lower alkyl ester derivative wherein the amino group is protected with phenylcarbonyl which is sub-sequently trea~ed with a Lewis acid, such as, boron tri-bromide, boron trichloride or boron trifluoride then an aqueous acidS for example, hydrochloric acid.
Compounds of general Formula I wherein R1 is hydrogen, -2g~
1~ 61 ~5~ 908 Rz is hydroxy and any of R3, R~, Rs or R' 4 is ORlo and R1o is a straight or branched alkyl group of from 1 to 8 carbon atoms may be prepared by alky!ating the corresponding com-pounds wherein R1o is hydrogen with an alkyl halide of the formula R21Y2 wherein R21 is a straight 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 as methanol or ethanol or hydrocarbon solvents such as benzene or ~oluene in the presence of an organic base such as triethylamine or pyridine or in an aprotic so1vent such as dimethylformamide, dimethylacetamide or dimethyl-sulfoxide in the presence of sodium hydride for about 1 to 24 hours at a temperaturè of about 25C to 85C followed by hydrolysis with aqueous base with the proviso that prior to the alkylation reaction the ~-amino group of the hydroxy substituted starting material is protected with a suitable protecting group such as tert-butoxycarbonyl which is subsequently removed by tr~atment with acid, such as, trifluoroacetic acid. The alkyl halides employed in the above reaction are known in the art or can be prepared by procedures well known in Lhe artO
The compounds of general Formula I wherein R2 is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms, R1 is hydrogen and any of R3, R~, R5 or R' 4 is ORlo and Rlo is alkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched, benzoyl, or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms are prepared by treating the corresponding deriva-~0 tives wherein ~10 is hydrogen with an acid anhydride of the 3o-~ 45~ Ml-908 formula (R~2-C-)20 or an acid halide of the formula R22-C-halo wherein halo is chlorine or bromine and R22 is a straight or branched alkyl group of from 1 to 6 carbon atoms, phenyl or phenylalkylene wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms in the presence of an organic base such as pyridine, quino-line or triethylamine, which base serves as the solvent, for about 1 to 24 hours at a temperature of about 25C to 100C with the proviso that prior to the reaction the ~-amino group of the hydroxy substituted startlng materialis protected with a suitable blocking group, such as, tert-butoxycarbonyl which is subsequently removed by treatment with acid, for example, trifluoroacetic acid.
The acid anhydride and acid halide reactants employed in the above reaction are known in the art or can be pre-pared from the appropriate acids by procedures well known in the art.
The compounds of general Formula I wherein R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms are prepared by treating the corresponding deriva~
tives wherein R2 is hydroxy with thionyl chloride to form the acid chloride which is reacted with an alcohol of the formula R23-OH, wherein R23 is a straight or branched alkyl group of from 1 to 8 carbon atoms, such as, methyl, ethyl, n-propyl, isopropyl, n-butyl, hexyl, or octyl, at about 25C
for from about 4 to 12 hours.
The compounds of general Formula I wherein R2 is -NR7R~ wherein each of R7 and R~ is hydrogen or a straight 1161 ~51 Ml-908 or branched lower alkyl of 1 to 4 carbon atoms are prepared by an acylation reaction of an acid halide, for examplej an acid chloride, or the corresponding compound wherein R2 is hydroxy and Rl has the meaning defined in Formula I with the proviso that any free amino group is pr-otected with a suitable protecting groupJ for example, carbobenzyloxy or tert-butoxycarbonyl and when any of R3, R4, R5 or R' 4 is ORlo and R1o is hydrogen said groups are protected as the corresponding alkylcarbonyloxy group, with an excess of an appropriate amine which may be`represented as NHR7R8o The reaction is carried out in methylene chloride, chloroform, d1methylformamide, ethers such as tetrahydrofuran or dioxane or benzene at about 25C for about 1 to 4 hoursO Suitable amines are, for example, ammonia, or a compound which is a potential source of ammonia, for example, hexamethylene-tetramine; primary amines, for example, methylamine, ethyl-amine, or n-propylamine; and secondary amines such as dimethylamine, diethylamine or di-n-butylamine. Following the acylation reaction the amino protecting group is removed by treatment with acid or hydrogen bromide in dioxane, and the hydroxy protecting group when appropriate is removed by base or acid hydrolysis.
The compounds of general Formula I wherein R2 is -NH-IH-COOH are prepared by reacting the corresponding derivative wherein R2 is hydroxy or a functional derivative thereof such as an acid anhydride and R, has the meaning defined in Formula I with the proviso that any free amino group is protected with a suitable blocking group, such as benzyloxycarbonyl or tert-butoxycarbonyl with a compound of ~16145~
Ml-908 the formula N~2-CH-COOR24 wherein R9 has the meaning defined R~
in general Formula I and R24 is a lower alkyl group, for example, methyl or ethyl in an ~ther, such as, tetrahydro-furan or dioxane at 0 to about 50C for about 1 to 24 hours followed by acid hydrolysis to remove the protecting group, with the proviso that when the amine protected free acid is employed the reaction is carried out using a dehydrating agent such as dicyclohexylcarbodiimide.
The compounds of general Formula I wherein R1 is alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 4 carbon atoms are prepared by treating the corresponding derivatives wherein R1 is hydrogen and R2 is hydroxy with an acid halide of the formula R2s-c-halo wherein halo Is a halogen atom, for example, chlorine or bromine and R2s is a straight 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 0C to 25C for from 1/2 hour to 6 hours. These compounds may also be prepared from the ester derivative, that is, compounds of general Formula I wherein Rl is hydrogen and R2 is an alkoxy group of from 1 to 8 carbon atoms by treatment with 1l the acid halide, R25-C-halo, described above, in water, methylene chloride, chloroform or dimethyl acetamide in the presence of a base such as sodium hydroxide~ potassium hydroxide or excess triethylamine at a temperature of from about 0C to 25C for from about 1/2 hour to 2~ hours.
~33-6~ ~S~
Ml-908 The compounds of general Formula I wherein R1 is alkoxy carbonyl wherein the alkoxy moiety is straight or branched and has from 1 to 4 carbon atoms are prepared by treating the corresponding derivative wherein R1 is hydro-~en and R2 is hydroxy with an alkyl haloformate of the formula halo-C-OR2~ wherein halo is a halogen atom such as chlorine or bromine and R2~ is a straight 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 about 0C to 25C for from about 1/2 hour to 6 hours.
The compounds of general Formula I wherein R1 is 1l -C-fH-R27 wherein R27 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl are prepared by treating the corresponding derivative wherein R1 is hydrogen and R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms with an acid of the formula HOOC-CH-R27 or an anhydride thereof wherein the amino group is protected with a suitable blocking group such as benzyloxycarbonyl or tert-butoxy-carbonyl and R27 has the meaning defined hereinabove 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 employed, at a temperature of from about 0C to ~5C for about 1 to 12 hours followed by acid and base hydrolysis to remove the protecting groups.
-~4-6~ ~51 Ml-908 The individual optical isomers of the compounds of general Formula I wherein R1 is H and Rz is OH may be sepa-rated by using a (+) of (-) binaphthylphosphoric acid salt by the method of R. Viterbo et al., Tetrahedron Letters 48, 4617 (1971)o Other resolving agents such as (+) camphor-10-sulfonic acid may also be employedO The individual optical isomers of compounds of Formula I wherein R1 and R2 are other than H and OH may be obtained as described herein for the racemate only starting with the resolved amino acid.
The following Example 1 illustrates the use of a compound of general Formula I wherein R2 is hydroxy as a chemical intermediate in the preparation of a cephalosporin of Formula ll.
7-~2-Acetylene-2-amino-3-phenylpro ionyl]amino]-3-acetyl-oxymethyl-c.-oxo-5-thia-1-azabicyclo~4.2.0Joct-2-ene-2-~carboxylic acid A mixture of 1 9 of 3-acetyloxy-7-amino-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 9 of 2-acetylene-2-amino-3-phenylpropionic acid chloride wherein the free amino group is protected with tert-butoxycarbonyl in 50 ml of ethyl acetate is refluxed for 2 hours after whTch the solvent is removed leaving a residue which is treated with mild acid and chromatographed on silica gel using benzene-acetone as the eluant to give 7-[[2-acetyl-ene-2-amino-3-phenylpropionyl]amino~-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
The following Examples 2 to 4 are illustrative of pharmaceutical preparations of the compounds of this invention~
~~5-11 61 ~Si Ml-908 An illustrative composition for hard gelatin capsules is as follows:
(a) 2-acet~lene-2-amino-3-(3-hydroxy- 20 mg phenyl propionic acid (b) talc 5 mg (c) la~tose 90 mg The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into hard gelatin capsules at a net fill of 115 mg per capsule~
An illustrative composition for tablets is as follows:
(a) 2-acetylene-2-amino-3-(3,4- 20 mg dihydroxyphenyl)propionic acid (b) starch 43 mg (c) lactose 45 mg (d) magnesium stearate 2 mg The granulation obtained upon mixing the lactose with the compound (a) and part of the starch and granulated with starch paste is dried, screened, and mixed with the magnesium stearate. The mixture is compressed into tablets weighing 110 mg each.
An illustrative composition for an injectable suspen-sion is the fo1lowing 1 ml ampul for an intramuscular injection~
Wei~ht per cent (a) 2-acetylene-2-amino-3-(4- 1.0 hydroxyphenyl)propionic acid (b) polyvinylpyrrolidone 0.5 ~ 51 Ml-908 (c) 1ecithin 0.25 (d) water for injection to make 100~0 The materials (a)-(d) are mixed, homogenized, and filled into 1 ml ampuls which are sealed and autoclaved 20 minut~s at 121C. Each ampul contains 10 mg per ml of novel compound (a).
The following Examples further illustrate the com-pounds of general Formula 1.
2-Acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic acid (A) A solution of 32.4 9 (0.15 M) of 3-trimethyl-silylprop-2-ynyl-1-iminobenzyl in 20 ml of tetrahydrofuran is added to lithium diisopropylamide, prepared from 21 ml (0015 M) of diisopropylamide and 73.2 ml of a 2005 M
solution of n-butyllithium (0.15 M), in 1 liter of tetra-hydrofuran at -78C. After 15 minutes 32.7 9 (1.35 M) of 3,4-isopropylidenedioxybenzylbromide in 20 ml of tetra-hydrofuran is added, and the mixture is maintained at -78C
for 2 hours a~ter which 7302 ml of a 2.05 M solution (0.15 M) of n-butyllithium is added followed by the addition of 14.2 9, 11.6 ml (0015 M) of methyl chloroformate. After an additional 30 minutes at -78C the reaction mixture is treated with brine and extracted with ether. The ether extract is evaporated leaving a residue which is dissolved in 300 ml of petroleum ether, bop~ 30-60C, and treated with 16.2 9 (0.15 M) of phenylhydrazine at 25C for 2 hours.
The precipitate is filtered off and the petroleum ether evaporated leaving a residue which is treated with 40 9 of potassium hydroxide in 300 ml of ethanol and 300 ml of water at 25C for about 15 hours. The ethanol Ts evapo-37~
6~ ~51 Ml-908 .
rated, and the aqueous solution is washed well with methyl-ene chloride, then acidified and rewashed with methylene chloride. The water ;s evaporated, and the remaining solid residue is triturated with ethanol, filtered and the fil-trate evaporated leaving a residue which is dissolved in water. The pH of the water solution is adjusted to 6 and applied to a column of Amberlite resin 120 H+ and eluting wlth 2 M ammonium hydroxide solution affords 2-acetylene-2-amino-3~,4'-isopropylidenedioxyphenylpropionic acid after recrystallization from water-ethanol.
(B) 3 9 (0.13 M) of 2-acetylene-2-amino-3,4-isoPropyl-ldenedioxyphenylpropionic acid is heated at reflux with 200 ml of 6 N hydrochloric acid for 2 hours after which the solvent is evaporated. The resulting residue is taken up in water and the pH is adjusted to 6 by careful addition of hydraztne hydrate. On cooling the solution to 0C a precipitate forms which is collected and recrystallized (charcoal) from water to afford 2-acetylene-2-amino-~-(3,4-dlhydroxyphenyl)propionic acid.
~XAMPLE 6 2-Acetylene-2-amino-~ -methoxyphenyl)propionic acid -When in the procedure of Example 5 (A) 25.8 9 (0.12 M) of 3-trimethylsilylprop-2-ynyl-1-iminobenzyl is used instead of 32.4 9 (0.15 M) and 20.1 9 (0.1 M) of 1-bromomethyl-~-methoxybenzene is used in place of 5-bromomethyl-1,~-benzodioxoleg upon recrystallization from water, 2-acetyl-ene-2-amino-~ -me-thoxyphenyl)propionic acid is obtained.
2-Acety!ene-2-amino-3-(~-hydroxyphenyl)propionic acid ~0 A suspension of 2.0 9 (9.1 mM) of 2-acetylene-2-~, . .
* Trade Mark ` Ml-908 amino-3~(3-methoxyphenyl)propionic acid in 20 ml of methanol saturated with anhydrous HCl is stirred for about 15 hours at 25C after which the solvent is evaporated. The resulting methyl ester derivative is suspended in 50 ml of methylene chloride and treated with 1.26 9 of benzoyl chloride followed by treatment with 3.6 9 of triethylamine.
The mixture is stirred for 24 hours then washed with water, dried and evaporated. The resul~ing residue is recrystal-lized from methanol to give the methyl ester derivative whereTn the amino ~roup is protected with phenylcarbonyl.
A so1ution of 1.2 9 (~.5 mM) of the amine protected methyl ester in 50 ml of methyl~ne chloride at 25C is treated with 0.9 9 of boron tribromide. The mixture is stirred for about 15 hours at 25C after which 10 ml of methanol is added and the solvents evaporated. The resulting residue is heated to reflux with 50 ml of 6 N
hydrochloric acid for 5 hours. The solution is concen-trated, the pH adjusted to 6 and applied to a column of Amberlite 120 H~. Eluting with 1 M ammonium hydroxide affords 2-acetylene-2-amino-3-(~-hydroxyphenyl)propionic acid after recrystallization from water-ethanol.
When in the procedure of Example 5 an appropriate amount of benzylchloride, 4-chloro-2-methoxybenzyl-chloride, 2-chloro-6-methylbenzylchloride, 2,4-dichloro-6-methylbenzylchloride, 4-methoxy-6-methylbenzylchloride, or 6-tert-butyl-4-chlorobenzylchloride is substituted for 3',4'-isopropylidenedioxybenzylbromide the following products are obtained:
2~acetylene-2-amino-3-phenylpropionic acid, 2-acetylene-2-amino-3-(4-chloro-2-methoxyphenyl)propionic acid, 2-* Trade Mark S~
Ml-908 acetylene-2-amino-~-(2-chloro-6-methylphenyl)propionic acid, 2-acetylene-2-amino-3-(2J4-dichloro-6-methylphenyl)-propionic acid, 2-acetylene-2-amino-3-(4-methoxy-6-methyl) phenyl)propionic acid and 2-acetylene-2-amino-3-(6-tert-butyl-4-chlorophenyl)propionic acid.
Ethyl 2-acetylene-?-amino-3-(3,4-dihydroxyph~nyl)pro-pionate ydroc orIde A suspension of 2.2 9 (10 mM) of 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic acid in 30 ml of ethanol is saturated with anhydrous HCl, and the resulting solution allowed to stand at 25C for 24 hours. The sol-vent is evaporated leaving a residue which is recrystal-llzed from ethanol-ether to give ethyl 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic hydrochloride.
2-Acetylene-3-(3,4-diacetyloxyphenyl)-2-(tert-but carbonylamino)propionic acid 2 N Aqueous sodium hydroxide and acetic anhydride (3.5 g) are added simultaneously during 1/2 hour to a solution of 2-acetylene-2-(tert-butoxycarbonylamino)-3-~3,4-dihydroxyphenylpropionic acid (6 9) prepared from 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic acid and tert-butyl azidoformate, in 30 ml of 1 N sodium hydroxide under argon so that the pH is maintained between 6.5 and 7.5. After 1 hour at 25C the pH is adjusted to 1 using 6 N sulfuric acid then extracted with methylene chloride. The organic phase is dried and concentrated to give 2-acetylene-3-(3,4-diacetyloxyphenyl)-2-tert-butoxycarbonylamino)propionic acid.
116~4S~ Ml-908 2-Acetylene-2-(acety!amino)-3-(3,4-dihydroxyphenyl)pro-P!onlc aci To a stirred suspension of 6.8 g (10 mM) of borax in 10 ml of water is added 2.2 g (10 mM) of 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic acid under argon.
After 15 minutes the pH is adjusted to 9 by the addition of 2 N sodium hydroxide then treated dropwise with 780 mg of acetyl chloride, maintaining the pH between 9.0 and 9.5. The aqueous solution is washed with ether~ adjusted to a pH of 1 using 6 ~ sulfuric acid and extracted with methylene chloride. The organic phase is dried and con-centrated to afford 2-acetylene-2-(acetylamino)-3-(3,4-dihydroxyphenyl)propionic acid, which may be treated with ethanolic HCl to afford the ethyl esterO
~5 EXAMPLE 11 ~2-Acetylene-2-amino-3-(3,4-diacetyloxyphenyl)-1-oxo-propy aminoJpropionic aci A solution of 404 g (10 mM) of 2-acetylene-2-carbobenzyloxyamino)-3-(3,4-diacetyloxyphenyl)propionic acid, prepared from 2-acety1ene-2-amino-3-(3,4-diacetyloxy-phenyl)propionic acid and benzyl chloroformate, in 50 mlof ether is treated with 1.0 g (10 mM) of triethylamine fol10wed by 1.08 g (10 mM) of ethyl chloroformate. After 1 hour at 25~C the precipitate is filtered off and to the ether solution is added a solution of alanine benzyloxy ester (10 mM) in 30 ml of etherO The solution is main-talned at 25C overnight then evaporated to drynessO The residue is treated wi~h H~r in dioxane (40~ w/w, 20 ml) for 30 minutes at 25C. Ether is then added and the precipi-tated hydrobromide filtered off to ~ive 2-[2-acetylene^2-61 ~51 Ml-908 amino-3-(3,1~-diacetyloxyphenyl)-l-oxopropylamino]propionic acid.
2hAcel)ylene.2-~2-amidohldoxopropylamino)-~ 4-dihydr p eny ~roplonlc acl y roc orl e A suspension of 3.3 9 (10 mM) of benzyl 2-acetylene-2-amTno-~-(3,4-dihydroxyphenyl)propionate in 50 ml of methylene chloride is treated with 1 9 (10 mM) of tri-ethylamine afterwhich 10 mM of N-carbobenzyloxyalanine wherein the acid function is activated by ethoxycarbonyl in 20 ml of methylene chloride is added. The mixture is stirred at 25C for about 16 hours then washed with water.
The organic layer is dried and evaporated.-The residue is taken up in ether and the ether solution coo1ed to 0C.
A vigorous stream of HCl gas is bubbled through the solu-tion for 3 hours after which the ether solution is washed with water. The aqueo~us phase is evaporated to afford 2-acetylene-2-(2-amino-1-oxopropylamino)~ ,4-dihydroxy-; phenyl)propionic acid hydrochloride as a gumO
EXAMPLE 1~
2-Acetylene-2-amino-3-(4-hydroxy-3-methoxyphenyl)propionic aci A solution of 3.25 9 (10 mM) of 2-acetylene-2-amino-3-(4-benzyloxy-3-methoxyphenyl)prop70nic acid in 20 ml of tetrahydrofuran is added to 100 ml of ammonia at -~0C
containing 0.5 9 ot lithium amide. After 1 hour lithium metal is added until the blue color persists for 2~ minutes then ammonium chloride is added, and the ammonia allowed to evaporate. The residue is dissolved in water, the pH ad-justed to 6 and applied to an Amberlite 120 Hl resin.
* Trade Mark ~61451 Ml -908 Elution with 1 M ammonium hydroxide affords 2-acetylene-2-amino-3-(4-hydroxy-~-methoxyphenyl)propionic acid which is recrystal l ized from water.
Claims (10)
1. A process for preparing a compound of the formula wherein R1 is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched or wherein R27 is hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms; R2 is hydroxy, a straight or branched alkoxy group of from 1 to 8 carbon atoms, -NR7R8 wherein each of R7 and R8 is hydrogen or a straight or branched alkyl group of from 1 to 4 carbon atoms, or wherein R9 is hydrogen or a straight or bran-ched lower alkyl group of from 1 to 4 carbon atoms; each of R3, R4, R5, R'4 and R6 has the meaning defined in Table I
wherein R10 is hydrogen, a straight or branched alkyl group of from 1 to 8 carbon atoms or an alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 6 carbon atoms;
TABLE I
or a pharmaceutically acceptable salt thereof which com-prises either (a) when R1 is hydrogen, R2 is hydroxy and both R3 and R4 are OR10 wherein R10 is hydrogen, both R4 and R5 are OR10 wherein R10 is hydrogen, both R4 and R5 together are -O-CH2-O-, or wherein each of R3, R4, R5, R'4 and R6 have the meanings defined hereinabove except R10 is methyl, treat-ing a suitably protected propargylamine derivative with a suitable strong base to form a protected propargylamine car-banion intermediate which is alkylated respectively, when R3 and R4 are both OR10 and R10 is hydrogen with 2,3-isopropyl-idenedioxybenzylhalide when R4 and R5 are both OR10 and R10 is hydrogen, with 3,4-isopropylidenedioxybenzylhalide, when R4 and R5 together are -O-CH2-O- with 3,4-methylenedioxy-halide, and when R3 to R6 are as otherwise described above, with a compound of the formula wherein Y is a halogen atom, and each of R11 to R14 have the meanings defined in Table II wherein R15 is methyl, treating the thus formed alkylated propargylamine deriva-tive with a suitable strong base to form an alkylated pro-pargylamine carbanion, reacting said second carbanion in-termediate with a suitable acylating reagent followed by hydrolysis, said alkylating and acylating reactions being carried out in a suitable solvent for about 1/2 hour to 24 hours at about -120°C. to 25°C.;
or (b) when R1 is hydrogen, R2 is hydroxy and either of R3, R4, R5 or R'4 is OR10 wherein R10 is hydrogen, treating the corresponding amine protected lower alkyl ester deriva-tive wherein R10 is methyl with a Lewis acid in a suitable solvent for about 4 to 18 hours at about 0° to 50°C.
followed by treatment with aqueous acid;
or (c) when R1 is hydrogen, R2 is hydroxy and any of R3, R4, R5 or R'4 is OR10 and R10 is a straight or branched alkyl group of from 1 to 8 carbon atoms, treating the cor-responding amine protected derivatives wherein R10 is Ml-908 Ca.
hydrogen with an alkyl halide of the formula R21Y2 wherein R21 is a straight or branched alkyl group of from 1 to 8 carbon atoms and Y2 is halogen in a suitable solvent in the presence of an organic amine for about 1 to 24 hours at about 25°C to 85°C followed by base and acid hydrolysis;
(d) when R1 is hydrogen, R2 is hydroxy or a straight or branched alkoxy group of 1 to 8 carbon atoms and any of R3, R4, R5 or R'4 is OR10 and R10 is alkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched, benzoyl or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms treating the corresponding amine protected derivatives wherein R10 is hydrogen with an acid anhydride of the formula (R22-?-)2O or an acid halide of the formula R22-?-halo wherein halo is chlorine or bromine and R22 is a straight or branched alkyl group of from 1 to 6 carbon atoms, phenyl or phenylalkylene wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms, in the presence of an organic base which serves as the solvent for about 1 to 24 hours at about 25°
to 100°C followed by acid hydrolysis;
(e) when R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms, reacting the corresponding derivative wherein R2 is hydroxy with thionyl chloride Ml-908 Ca.
followed by treatment with an alcohol of the formula R23-OH
wherein R23 is a straight or branched alkyl group of from 1 to o carbon atoms at about 25°C for about 4 to 12 hours;
(f) when R2 is -NR7R8 wherein each of R7 and R8 has the meaning defined in claim 1 treating an acid halide of the corresponding derivative wherein R2 is hydroxy and R1 has the meaning defined in claim 1 with the proviso that any free amino group is protected with a suitable protect-ing group, and when any of R3, R4, R5 or R'4 is OR10 and R10 is hydrogen said groups are protected as the corres-ponding alkylcarbonyloxy group with an excess of an appropriate amine of the formula NHR7R8 wherein R7 and R8 have the meanings defined above in an appropriate solvent at about 25°C for about 1 to 4 hours, followed by acid or base hydrolysis;
(g) when R2 is wherein R9 has the meaning defined in claim 1, treating the corresponding derivative wherein R2 is hydroxy or a functional derivative thereof and R1 has the meaning defined in claim 1 with the proviso that any free amino group is suitably protected with a compound of the formula wherein R9 has the meaning defined in claim 1 and R24 is a lower alkyl group in a suitable solvent at about 0° to 50°C for about 1 to 24 hours followed by acid hydrolysis with the proviso that Ml-908 Ca.
when the amine protected free acid is employed the reaction is carried out in the presence of a dehydrating agent;
(h) when R1 is alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen, and R2 is hydroxy with an acid halide of the formula R25-?-halo wherein halo is a halogen atom and R25 is a straight or branched alkyl group of from 1 to 4 carbon atoms in a suitable solvent in the presence of a base at a temperature of from about 0°C to 25°C for from about 1/2 hour to 24 hours;
(i) when R1 is alkoxycarbonyl wherein the alkoxy moiety has 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen and R2 is hydroxy with a halo alkylformate of the formula halo-?-OR26 wherein halo is a halogen atom and R26 is a straight or branched alkyl group having from 1 to 4 carbon atoms in water in the presence of a base at a temp-erature of from about 0°C to 25°C for from about 1/2 hour to 6 hours;
(j) when R1 is wherein R27 has the meaning defined in claim 1, treating the corresponding derivative, Ml-908 Ca.
wherein R1 is hydrogen and R2 is a straight or branched alkoxy of from 1 to 8 carbon atoms with an acid of the formula or an anhydride thereof wherein R27 has the meaning defined above and the amino group is suit-ably protected, in a suitable solvent and in the presence of a dehydrating agent when the free acid is employed, at a temperature of about 0°C to 35°C for about 1 to 12 hours followed by acid and base hydrolysis; and (k) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharmaceutically acceptable acid or base.
wherein R10 is hydrogen, a straight or branched alkyl group of from 1 to 8 carbon atoms or an alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 6 carbon atoms;
TABLE I
or a pharmaceutically acceptable salt thereof which com-prises either (a) when R1 is hydrogen, R2 is hydroxy and both R3 and R4 are OR10 wherein R10 is hydrogen, both R4 and R5 are OR10 wherein R10 is hydrogen, both R4 and R5 together are -O-CH2-O-, or wherein each of R3, R4, R5, R'4 and R6 have the meanings defined hereinabove except R10 is methyl, treat-ing a suitably protected propargylamine derivative with a suitable strong base to form a protected propargylamine car-banion intermediate which is alkylated respectively, when R3 and R4 are both OR10 and R10 is hydrogen with 2,3-isopropyl-idenedioxybenzylhalide when R4 and R5 are both OR10 and R10 is hydrogen, with 3,4-isopropylidenedioxybenzylhalide, when R4 and R5 together are -O-CH2-O- with 3,4-methylenedioxy-halide, and when R3 to R6 are as otherwise described above, with a compound of the formula wherein Y is a halogen atom, and each of R11 to R14 have the meanings defined in Table II wherein R15 is methyl, treating the thus formed alkylated propargylamine deriva-tive with a suitable strong base to form an alkylated pro-pargylamine carbanion, reacting said second carbanion in-termediate with a suitable acylating reagent followed by hydrolysis, said alkylating and acylating reactions being carried out in a suitable solvent for about 1/2 hour to 24 hours at about -120°C. to 25°C.;
or (b) when R1 is hydrogen, R2 is hydroxy and either of R3, R4, R5 or R'4 is OR10 wherein R10 is hydrogen, treating the corresponding amine protected lower alkyl ester deriva-tive wherein R10 is methyl with a Lewis acid in a suitable solvent for about 4 to 18 hours at about 0° to 50°C.
followed by treatment with aqueous acid;
or (c) when R1 is hydrogen, R2 is hydroxy and any of R3, R4, R5 or R'4 is OR10 and R10 is a straight or branched alkyl group of from 1 to 8 carbon atoms, treating the cor-responding amine protected derivatives wherein R10 is Ml-908 Ca.
hydrogen with an alkyl halide of the formula R21Y2 wherein R21 is a straight or branched alkyl group of from 1 to 8 carbon atoms and Y2 is halogen in a suitable solvent in the presence of an organic amine for about 1 to 24 hours at about 25°C to 85°C followed by base and acid hydrolysis;
(d) when R1 is hydrogen, R2 is hydroxy or a straight or branched alkoxy group of 1 to 8 carbon atoms and any of R3, R4, R5 or R'4 is OR10 and R10 is alkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched, benzoyl or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms treating the corresponding amine protected derivatives wherein R10 is hydrogen with an acid anhydride of the formula (R22-?-)2O or an acid halide of the formula R22-?-halo wherein halo is chlorine or bromine and R22 is a straight or branched alkyl group of from 1 to 6 carbon atoms, phenyl or phenylalkylene wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms, in the presence of an organic base which serves as the solvent for about 1 to 24 hours at about 25°
to 100°C followed by acid hydrolysis;
(e) when R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms, reacting the corresponding derivative wherein R2 is hydroxy with thionyl chloride Ml-908 Ca.
followed by treatment with an alcohol of the formula R23-OH
wherein R23 is a straight or branched alkyl group of from 1 to o carbon atoms at about 25°C for about 4 to 12 hours;
(f) when R2 is -NR7R8 wherein each of R7 and R8 has the meaning defined in claim 1 treating an acid halide of the corresponding derivative wherein R2 is hydroxy and R1 has the meaning defined in claim 1 with the proviso that any free amino group is protected with a suitable protect-ing group, and when any of R3, R4, R5 or R'4 is OR10 and R10 is hydrogen said groups are protected as the corres-ponding alkylcarbonyloxy group with an excess of an appropriate amine of the formula NHR7R8 wherein R7 and R8 have the meanings defined above in an appropriate solvent at about 25°C for about 1 to 4 hours, followed by acid or base hydrolysis;
(g) when R2 is wherein R9 has the meaning defined in claim 1, treating the corresponding derivative wherein R2 is hydroxy or a functional derivative thereof and R1 has the meaning defined in claim 1 with the proviso that any free amino group is suitably protected with a compound of the formula wherein R9 has the meaning defined in claim 1 and R24 is a lower alkyl group in a suitable solvent at about 0° to 50°C for about 1 to 24 hours followed by acid hydrolysis with the proviso that Ml-908 Ca.
when the amine protected free acid is employed the reaction is carried out in the presence of a dehydrating agent;
(h) when R1 is alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen, and R2 is hydroxy with an acid halide of the formula R25-?-halo wherein halo is a halogen atom and R25 is a straight or branched alkyl group of from 1 to 4 carbon atoms in a suitable solvent in the presence of a base at a temperature of from about 0°C to 25°C for from about 1/2 hour to 24 hours;
(i) when R1 is alkoxycarbonyl wherein the alkoxy moiety has 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen and R2 is hydroxy with a halo alkylformate of the formula halo-?-OR26 wherein halo is a halogen atom and R26 is a straight or branched alkyl group having from 1 to 4 carbon atoms in water in the presence of a base at a temp-erature of from about 0°C to 25°C for from about 1/2 hour to 6 hours;
(j) when R1 is wherein R27 has the meaning defined in claim 1, treating the corresponding derivative, Ml-908 Ca.
wherein R1 is hydrogen and R2 is a straight or branched alkoxy of from 1 to 8 carbon atoms with an acid of the formula or an anhydride thereof wherein R27 has the meaning defined above and the amino group is suit-ably protected, in a suitable solvent and in the presence of a dehydrating agent when the free acid is employed, at a temperature of about 0°C to 35°C for about 1 to 12 hours followed by acid and base hydrolysis; and (k) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharmaceutically acceptable acid or base.
2. A compound of the formula where in R1, R2, R3, R4, R5, R'4 and R6 have the meanings defined in claim 1 or a pharmaceutically acceptable salt thereof when prepared by the process of claim 1.
3. The process of claim 1 wherein R1 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched which comprises (a) when R1 is hydrogen, R2 is hydroxy and both R3 and R4 are OR10 wherein R10 is hydrogen, both R4 and R5 Ml-908 Ca.
are OR10 wherein R10 is hydrogen, both R4 and R5 together are -O-CH2-O-, or wherein each of R3, R4, R5, R'4 and R6 have the meanings defined in claim 1 except R10 is methyl, treating a suitably protected propargylamine derivative with a suitable strong base to form a protected propar-gylamine carbanion intermediate which is alkylated respec-tively, when R3 and R4 are both OR10 and R10 is hydrogen with 2,3-isopropylidenedioxybenzylhalide when R4 and R5 are both OR10 and R10 is hydrogen, with 3,4-isopropylidene-dioxybenzylhalide, when R4 and R5 together are -O-CH2-O-with 3,4-methylenedioxyhalide, and when R3 to R6 are as otherwise described above, with a compound of the formula wherein Y is a halogen atom, and each of R11 to R14 have the meanings defined in claim 1 wherein R15 is methyl, treating the thus formed alkylated propargylamine deriva-tive with a suitable strong base to form an alkylated propargylamine carbanion, reacting said second carbanion intermediate with a suitable acylating reagent followed by hydrolysis, said alkylating and acylating reactions being carried out in a suitable solvent for about 1/2 hour to 24 hours at about -120°C to 25°C;
(b) when R1 is hydrogen, R2 is hydroxy and either Ml-908 Ca.
of R3, R4, R5 or R'4 is OR10 wherein R10 is hydrogen, treating the corresponding amine protected lower alkyl ester derivative wherein R10 is methyl with a Lewis acid in a suitable solvent for about 4 to 18 hours at about 0° to 50°C followed by treatment with aqueous acid;
(c) when R1 is hydrogen, R2 is hydroxy and any of R3, R4, R5 or R'4 is OR10 and R10 is a straight or branched alkyl group of from 1 to 8 carbon atoms, treating the corresponding amine protected derivatives wherein R10 is hydrogen with an alkyl halide of the formula R21Y2 wherein R21 is a straight or branched alkyl group of from 1 to 8 carbon atoms and Y2 is halogen in a suitable solvent in the presence of an organic amine for about 1 to 24 hours at about 25°C to 85°C followed by base and acid hydrolysis;
(d) when R1 is hydrogen, R2 is hydroxy or a straight or branched alkoxy group of 1 to 8 carbon atoms and any of R3, R4, R5 or R'4 is OR10 and R10 is alkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched, benzoyl or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms, treating the corresponding amine protected derivatives wherein R10 is hydrogen with an acid anhydride of the formula (R22-?-)20 or an acid halide of the formula R22-?-halo wherein halo is chlorine or bromine Ml-908 Ca.
and R22 is a straight or branched alkyl group of from 1 to 6 carbon atoms, phenyl or phenylalkylene wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms, in the presence of an organic base which serves as the solvent for about 1 to 24 hours at about 25°
to 100°C followed by acid hydrolysis;
(e) when R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms, reacting the corresponding derivative wherein R2 is hydroxy with thionyl chloride followed by treatment with an alcohol of the formula R23-OH
wherein R23 is a straight or branched alkyl group of from 1 to 8 carbon atoms at about 25°C for about 4 to 12 hours;
(f) when R2 is -NR7R8 wherein each of R7 and R8 has the meaning defined in claim 1 treating an acid halide of the corresponding derivative wherein R2 is hydroxy and R1 has the meaning defined in claim 1 with the proviso that any free amino group is protected with a suitable protect ing group, and when any of R3, R4, R5 or R'4 is OR10 and R10 is hydrogen said groups are protected as the corres-ponding alkylcarbonyloxy group with an excess of an appropriate amine of the formula NHR7R8 wherein R7 and R8 have the meanings defined above in an appropriate solvent at about 25°C for about 1 to 4 hours, followed by acid or base hydrolysis;
(g) when R2 is wherein R9 has the meaning Ml-908 Ca.
defined in claim 1, treating the corresponding derivative wherein R2 is hydroxy or a functional derivative thereof and R1 has the meaning defined in claim 1 with the proviso that any free amino group is suitably protected with a compound of the formula wherein R9 has the meaning defined in claim 1 and R24 is a lower alkyl group in a suitable solvent at about 0° to 50°C for about 1 to 24 hours followed by acid hydrolysis with the proviso that when the amine protected free acid is employed the reaction is carried out in the presence of a dehydrating agent;
(h) when R1 is alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen, and R2 is hydroxy with an acid halide of the formula R25-?-halo wherein halo is a halogen atom and R25 is a straight or branched alkyl group of from 1 to 4 carbon atoms in a suitable solvent in the presence of a base at a temperature of from about 0°C to 25°C for from about 1/2 hour to 24 hours; and (k) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharma-ceutically acceptable acid or base.
are OR10 wherein R10 is hydrogen, both R4 and R5 together are -O-CH2-O-, or wherein each of R3, R4, R5, R'4 and R6 have the meanings defined in claim 1 except R10 is methyl, treating a suitably protected propargylamine derivative with a suitable strong base to form a protected propar-gylamine carbanion intermediate which is alkylated respec-tively, when R3 and R4 are both OR10 and R10 is hydrogen with 2,3-isopropylidenedioxybenzylhalide when R4 and R5 are both OR10 and R10 is hydrogen, with 3,4-isopropylidene-dioxybenzylhalide, when R4 and R5 together are -O-CH2-O-with 3,4-methylenedioxyhalide, and when R3 to R6 are as otherwise described above, with a compound of the formula wherein Y is a halogen atom, and each of R11 to R14 have the meanings defined in claim 1 wherein R15 is methyl, treating the thus formed alkylated propargylamine deriva-tive with a suitable strong base to form an alkylated propargylamine carbanion, reacting said second carbanion intermediate with a suitable acylating reagent followed by hydrolysis, said alkylating and acylating reactions being carried out in a suitable solvent for about 1/2 hour to 24 hours at about -120°C to 25°C;
(b) when R1 is hydrogen, R2 is hydroxy and either Ml-908 Ca.
of R3, R4, R5 or R'4 is OR10 wherein R10 is hydrogen, treating the corresponding amine protected lower alkyl ester derivative wherein R10 is methyl with a Lewis acid in a suitable solvent for about 4 to 18 hours at about 0° to 50°C followed by treatment with aqueous acid;
(c) when R1 is hydrogen, R2 is hydroxy and any of R3, R4, R5 or R'4 is OR10 and R10 is a straight or branched alkyl group of from 1 to 8 carbon atoms, treating the corresponding amine protected derivatives wherein R10 is hydrogen with an alkyl halide of the formula R21Y2 wherein R21 is a straight or branched alkyl group of from 1 to 8 carbon atoms and Y2 is halogen in a suitable solvent in the presence of an organic amine for about 1 to 24 hours at about 25°C to 85°C followed by base and acid hydrolysis;
(d) when R1 is hydrogen, R2 is hydroxy or a straight or branched alkoxy group of 1 to 8 carbon atoms and any of R3, R4, R5 or R'4 is OR10 and R10 is alkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched, benzoyl or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms, treating the corresponding amine protected derivatives wherein R10 is hydrogen with an acid anhydride of the formula (R22-?-)20 or an acid halide of the formula R22-?-halo wherein halo is chlorine or bromine Ml-908 Ca.
and R22 is a straight or branched alkyl group of from 1 to 6 carbon atoms, phenyl or phenylalkylene wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms, in the presence of an organic base which serves as the solvent for about 1 to 24 hours at about 25°
to 100°C followed by acid hydrolysis;
(e) when R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms, reacting the corresponding derivative wherein R2 is hydroxy with thionyl chloride followed by treatment with an alcohol of the formula R23-OH
wherein R23 is a straight or branched alkyl group of from 1 to 8 carbon atoms at about 25°C for about 4 to 12 hours;
(f) when R2 is -NR7R8 wherein each of R7 and R8 has the meaning defined in claim 1 treating an acid halide of the corresponding derivative wherein R2 is hydroxy and R1 has the meaning defined in claim 1 with the proviso that any free amino group is protected with a suitable protect ing group, and when any of R3, R4, R5 or R'4 is OR10 and R10 is hydrogen said groups are protected as the corres-ponding alkylcarbonyloxy group with an excess of an appropriate amine of the formula NHR7R8 wherein R7 and R8 have the meanings defined above in an appropriate solvent at about 25°C for about 1 to 4 hours, followed by acid or base hydrolysis;
(g) when R2 is wherein R9 has the meaning Ml-908 Ca.
defined in claim 1, treating the corresponding derivative wherein R2 is hydroxy or a functional derivative thereof and R1 has the meaning defined in claim 1 with the proviso that any free amino group is suitably protected with a compound of the formula wherein R9 has the meaning defined in claim 1 and R24 is a lower alkyl group in a suitable solvent at about 0° to 50°C for about 1 to 24 hours followed by acid hydrolysis with the proviso that when the amine protected free acid is employed the reaction is carried out in the presence of a dehydrating agent;
(h) when R1 is alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen, and R2 is hydroxy with an acid halide of the formula R25-?-halo wherein halo is a halogen atom and R25 is a straight or branched alkyl group of from 1 to 4 carbon atoms in a suitable solvent in the presence of a base at a temperature of from about 0°C to 25°C for from about 1/2 hour to 24 hours; and (k) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharma-ceutically acceptable acid or base.
4. A compound of the formula Ml-908 Ca.
wherein R1 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched and R2, R3, R4, R5, R'4 and R6 have the meanings defined in claim 1 or a pharmaceutically acceptable salt thereof when prepared by the process of claim 3.
wherein R1 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched and R2, R3, R4, R5, R'4 and R6 have the meanings defined in claim 1 or a pharmaceutically acceptable salt thereof when prepared by the process of claim 3.
5. The process of claim 1 wherein R2 is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms which comprises (a) when R1 is hydrogen, R2 is hydroxy and both R9 and R4 are OR10 wherein R10 is hydrogen, both R4 and R5 are OR10 wherein R10 is hydrogen, both R4 and R5 together are -O-CH2-O-, or wherein each of R9, R4, R5, R'4 and R6 have the meanings defined in claim 1 except R10 is methyl, treating a suitably protected propargylamine derivative with a suitable strong base to form a protected propar-gylamine carbanion intermediate which is alkylated respec-tively, when R3 and R4 are both OR10 and R10 is hydrogen with 2,3-isopropylidenedioxybenzylhalide when R4 and R5 are both OR10 and R10 is hydrogen, with 3,4-isopropylidene-dioxybenzylhalide, when R4 and R5 together are -O-CH2-O-with 3,4-methylenedioxyhalide, and when R3 to R5 are as otherwise described above, with a compound of the formula Ml-908 Ca.
wherein Y is a halogen atom, and each of R11 to R14 have the meanings defined in claim 1 wherein R15 is methyl, treating the thus formed alkylated propargylamine deriva-tive with a suitable strong base to form an alkylated propargylamine carbanion, reacting said second carbanion intermediate with a suitable acylating reagent followed by hydrolysis, said alkylating and acylating reactions being carried out in a suitable solvent for about 1/2 hour to 24 hours at about -120°C to 25°C;
(b) when R1 is hydrogen, R2 is hydroxy and either of R3, R4, R5 or R'4 is OR10 wherein R10 is hydrogen, treating the corresponding amine protected lower alkyl ester derivative wherein R10 is methyl with a Lewis acid in a suitable solvent for about 4 to 18 hours at about 0 to 50°C followed by treatment with aqueous acid;
(c) when R1 is hydrogen, R2 is hydroxy and any of R3, R4, R5 or R'4 is OR10 and R10 is a straight or branched alkyl group of from 1 to 8 carbon atoms, treating the corresponding amine protected derivatives wherein R10 is hydrogen with an alkyl halide of the formula R21Y2 wherein R21 is a straight or branched alkyl group of from 1 to 8 carbon atoms and Y2 is halogen in a suitable solvent in Ml-908 Ca.
the presence of an organic amine for about 1 to 24 hours at about 25°C to 85°C followed by base and acid hydrolysis;
(d) when R1 is hydrogen, R2 is hydroxy or a straight or branched alkoxy group of 1 to 8 carbon atoms and any of R3, R4, R5 or R'4 is OR10 and R10 is alkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched, benzoyl or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms, treating the corresponding amine protected derivatives wherein R10 is hydrogen with an acid anhydride of the formula (R22-?-)2O or an acid halide of the formula R22-?-halo wherein halo is chlorine or bromine and R22 is a straight or branched alkyl group of from 1 to 6 carbon atoms, phenyl or phenylalkylene wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms, in the presence of an organic base which serves as the solvent for about 1 to 24 hours at about 25°
to 100°C followed by acid hydrolysis;
(e) when R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms, reacting the corresponding derivative wherein R2 is hydroxy with thionyl chloride followed by treatment with an alcohol of the formula R23-OH
wherein R23 is a straight or branched alkyl group of from 1 to 8 carbon atoms at about 25°C for about 4 to 12 hours;
Ml-908 Ca.
(f) when R1 is alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen, and R2 is hydroxy with an acid halide of the formula R25-?-halo wherein halo is a halogen atom and R25 is a straight or branched alkyl group of from 1 to 4 carbon atoms in a suitable solvent in the presence of a base at a temperature of from about 0°C to 25°C for from about 1/2 hour to 24 hours;
(g) when R1 is alkoxycarbonyl wherein the alkoxy moiety has 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen and R2 is hydroxy with a halo alkylformate of the formula halo-?-OR26 wherein halo is a halogen atom and R26 is a straight or branched alkyl group having from 1 to 4 carbon atoms in water in the presence of a base at a temp-erature of from about 0°C to 25°C for from about 1/2 hour to 6 hours;
(h) when R1 is wherein R27 has the meaning defined in claim 1, treating the corresponding derivative, wherein R1 is hydrogen and R2 is a straight or branched alkoxy of from 1 to 8 carbon atoms with an acid of the Ml-908 Ca.
formula or an anhydride thereof wherein R27 has the meaning defined above and the amino group is suit-ably protected, in a suitable solvent and in the presence of a dehydrating agent when the free acid is employed, at a temperature of about 0°C to 35°C for about 1 to 12 hours followed by acid and base hydrolysis; and (i) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharma-ceutically acceptable acid or base.
wherein Y is a halogen atom, and each of R11 to R14 have the meanings defined in claim 1 wherein R15 is methyl, treating the thus formed alkylated propargylamine deriva-tive with a suitable strong base to form an alkylated propargylamine carbanion, reacting said second carbanion intermediate with a suitable acylating reagent followed by hydrolysis, said alkylating and acylating reactions being carried out in a suitable solvent for about 1/2 hour to 24 hours at about -120°C to 25°C;
(b) when R1 is hydrogen, R2 is hydroxy and either of R3, R4, R5 or R'4 is OR10 wherein R10 is hydrogen, treating the corresponding amine protected lower alkyl ester derivative wherein R10 is methyl with a Lewis acid in a suitable solvent for about 4 to 18 hours at about 0 to 50°C followed by treatment with aqueous acid;
(c) when R1 is hydrogen, R2 is hydroxy and any of R3, R4, R5 or R'4 is OR10 and R10 is a straight or branched alkyl group of from 1 to 8 carbon atoms, treating the corresponding amine protected derivatives wherein R10 is hydrogen with an alkyl halide of the formula R21Y2 wherein R21 is a straight or branched alkyl group of from 1 to 8 carbon atoms and Y2 is halogen in a suitable solvent in Ml-908 Ca.
the presence of an organic amine for about 1 to 24 hours at about 25°C to 85°C followed by base and acid hydrolysis;
(d) when R1 is hydrogen, R2 is hydroxy or a straight or branched alkoxy group of 1 to 8 carbon atoms and any of R3, R4, R5 or R'4 is OR10 and R10 is alkylcarbonyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched, benzoyl or phenylalkylenecarbonyl wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms, treating the corresponding amine protected derivatives wherein R10 is hydrogen with an acid anhydride of the formula (R22-?-)2O or an acid halide of the formula R22-?-halo wherein halo is chlorine or bromine and R22 is a straight or branched alkyl group of from 1 to 6 carbon atoms, phenyl or phenylalkylene wherein the alkylene moiety is straight or branched and has from 1 to 6 carbon atoms, in the presence of an organic base which serves as the solvent for about 1 to 24 hours at about 25°
to 100°C followed by acid hydrolysis;
(e) when R2 is a straight or branched alkoxy group of from 1 to 8 carbon atoms, reacting the corresponding derivative wherein R2 is hydroxy with thionyl chloride followed by treatment with an alcohol of the formula R23-OH
wherein R23 is a straight or branched alkyl group of from 1 to 8 carbon atoms at about 25°C for about 4 to 12 hours;
Ml-908 Ca.
(f) when R1 is alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen, and R2 is hydroxy with an acid halide of the formula R25-?-halo wherein halo is a halogen atom and R25 is a straight or branched alkyl group of from 1 to 4 carbon atoms in a suitable solvent in the presence of a base at a temperature of from about 0°C to 25°C for from about 1/2 hour to 24 hours;
(g) when R1 is alkoxycarbonyl wherein the alkoxy moiety has 1 to 4 carbon atoms and is straight or branched, treating the corresponding derivative wherein R1 is hydro-gen and R2 is hydroxy with a halo alkylformate of the formula halo-?-OR26 wherein halo is a halogen atom and R26 is a straight or branched alkyl group having from 1 to 4 carbon atoms in water in the presence of a base at a temp-erature of from about 0°C to 25°C for from about 1/2 hour to 6 hours;
(h) when R1 is wherein R27 has the meaning defined in claim 1, treating the corresponding derivative, wherein R1 is hydrogen and R2 is a straight or branched alkoxy of from 1 to 8 carbon atoms with an acid of the Ml-908 Ca.
formula or an anhydride thereof wherein R27 has the meaning defined above and the amino group is suit-ably protected, in a suitable solvent and in the presence of a dehydrating agent when the free acid is employed, at a temperature of about 0°C to 35°C for about 1 to 12 hours followed by acid and base hydrolysis; and (i) when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharma-ceutically acceptable acid or base.
6. A compound of the formula wherein R2 is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms and R1, R3, R3, R5, R'4 and R'3 have the meanings defined in claim 1 or a pharma-ceutically acceptable salt thereof when prepared by the process of claim 5.
7. The process of claim 1 wherein each of R3, R4, R5, R'4 and R6, is hydrogen or OR10 wherein R10 is hydrogen or a straight or branched alkyl group of from 1 to carbon atoms, R2 is hydroxy and R1 is hydrogen which comprises Ml-908 Ca.
(a) when both R2 and R4 are OR10 wherein R10 is hydrogen, both R4 and R5 are OR10 wherein R10 is hydrogen, or wherein each of R3, R4, R5, R'4 and R6 is hydrogen or OR10 wherein R10 is methyl, treating a suitably protected propargylamine derivative with a suitable strong base to form a protected propargylamine carbanion intermediate which is alkylated respectively, when R3 and R4 are both OR10 and R10 is hydrogen with 2,3-isopropylidenedioxy-benzylhalide when R4 and R5 are both OR10 and R10 is hydro-gen, with 3,4-isopropylidenedioxybenzylhalide, and when R3 to R6 are hydrogen or OR10 wherein R10 is methyl, with a compound of the formula wherein Y is a halogen atom, and each of R11 to R14 have the meanings defined below wherein R15 is methyl, treating the thus formed alkylated propargylamine derivative with a suitable strong base to form an alkylated propargylamine carbanion, reacting said second carbanion intermediate with a suitable acylating reagent followed by hydrolysis, said alkylating and acylating reactions being carried out in a suitable solvent for about 1/2 hour to 24 hours at about -120°C to 25°C;
Ml-908 Ca.
(b) when either of R3, R4, R5 or R'4 is OR10 wherein R10 is hydrogen, treating the corresponding amine protected lower alkyl ester derivative wherein R10 is methyl with a Lewis acid in a suitable solvent for about 4 to 18 hours at about 0° to 50°C followed by treatment with aqueous acid;
(c) when any of R3, R4, R5 or R'4 is OR10 and R10 is a straight or branched alkyl group of from 1 to 8 carbon atoms, treating the corresponding amine protected deriva-tives wherein R10 is hydrogen with an alkyl halide of the formula R21Y2 wherein R21 is a straight or branched alkyl group of from 1 to 8 carbon atoms and Y2 is halogen in a suitable solvent in the presence of an organic amine for about 1 to 24 hours at about 25°C to 85°C followed by base and acid hydrolysis; and (d) when a pharmaceutically acceptable salt is Ml-908 Ca.
desired, reacting the thus obtained compound with a pharma-ceutically acceptable acid or base.
(a) when both R2 and R4 are OR10 wherein R10 is hydrogen, both R4 and R5 are OR10 wherein R10 is hydrogen, or wherein each of R3, R4, R5, R'4 and R6 is hydrogen or OR10 wherein R10 is methyl, treating a suitably protected propargylamine derivative with a suitable strong base to form a protected propargylamine carbanion intermediate which is alkylated respectively, when R3 and R4 are both OR10 and R10 is hydrogen with 2,3-isopropylidenedioxy-benzylhalide when R4 and R5 are both OR10 and R10 is hydro-gen, with 3,4-isopropylidenedioxybenzylhalide, and when R3 to R6 are hydrogen or OR10 wherein R10 is methyl, with a compound of the formula wherein Y is a halogen atom, and each of R11 to R14 have the meanings defined below wherein R15 is methyl, treating the thus formed alkylated propargylamine derivative with a suitable strong base to form an alkylated propargylamine carbanion, reacting said second carbanion intermediate with a suitable acylating reagent followed by hydrolysis, said alkylating and acylating reactions being carried out in a suitable solvent for about 1/2 hour to 24 hours at about -120°C to 25°C;
Ml-908 Ca.
(b) when either of R3, R4, R5 or R'4 is OR10 wherein R10 is hydrogen, treating the corresponding amine protected lower alkyl ester derivative wherein R10 is methyl with a Lewis acid in a suitable solvent for about 4 to 18 hours at about 0° to 50°C followed by treatment with aqueous acid;
(c) when any of R3, R4, R5 or R'4 is OR10 and R10 is a straight or branched alkyl group of from 1 to 8 carbon atoms, treating the corresponding amine protected deriva-tives wherein R10 is hydrogen with an alkyl halide of the formula R21Y2 wherein R21 is a straight or branched alkyl group of from 1 to 8 carbon atoms and Y2 is halogen in a suitable solvent in the presence of an organic amine for about 1 to 24 hours at about 25°C to 85°C followed by base and acid hydrolysis; and (d) when a pharmaceutically acceptable salt is Ml-908 Ca.
desired, reacting the thus obtained compound with a pharma-ceutically acceptable acid or base.
8. A compound of the formula wherein each of R3, R4, R5, R'4 and R6 is hydrogen or OR10 wherein R10 is hydrogen or a straight or branched alkyl group of From 1 to 8 carbon atoms, R2 is hydroxy and R1 is hydrogen or a pharmaceutically acceptable salt thereof when prepared by the process of claim 7.
9. A process for preparing 2-acetylene-2-amino-3-(3,4-dihydroxyphenyl)propionic acid or a pharmaceutically acceptable salt thereof which comprises treating a suit-ably protected propargylamine derivative with a suitable strong base to form a protective propargylamine carbanion intermediate which is alkylated with 3,4-isopropylidene-dioxybenzylhalide, treating the thus formed alkylated propargylamine derivative with a suitable strong base to form an alkylated propargylamine carbanion, reacting said second carbanion intermediate with a suitable acylating reagent followed by hydrolysis, said alkylating and acylating reactions being carried out in a suitable solvent for about 1/2 hour to 24 hours at about -120° to 25°C.; and when a pharmaceutically acceptable salt is desired, reacting the thus obtained compound with a pharmaceutically acceptable acid or base.
10. The compound 2-acetylene-2-amino-3-(3,4-dihydroxy-phenyl)propionic acid or a pharmaceutically acceptable salt thereof when prepared by the process of claim 9.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US81205877A | 1977-07-01 | 1977-07-01 | |
US812,058 | 1977-07-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1161451A true CA1161451A (en) | 1984-01-31 |
Family
ID=25208370
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000304901A Expired CA1161451A (en) | 1977-07-01 | 1978-06-06 | .alpha.-ACETYLENIC AMINO ACIDS |
Country Status (16)
Country | Link |
---|---|
JP (1) | JPS5414937A (en) |
AU (1) | AU521142B2 (en) |
BE (1) | BE868596A (en) |
CA (1) | CA1161451A (en) |
CH (1) | CH641150A5 (en) |
DE (1) | DE2827824A1 (en) |
DK (1) | DK299478A (en) |
FR (1) | FR2401133A1 (en) |
GB (1) | GB2001060B (en) |
IE (1) | IE47082B1 (en) |
IL (1) | IL54918A0 (en) |
IT (1) | IT1107978B (en) |
NL (1) | NL7807089A (en) |
NZ (1) | NZ187541A (en) |
SE (1) | SE7807359L (en) |
ZA (1) | ZA783354B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK309579A (en) * | 1978-07-24 | 1980-02-22 | Merck & Co Inc | PROCESS FOR THE PREPARATION OF ALPHETHYNYLAMINO ACIDS AND ESTERS THEREOF |
US4720489A (en) * | 1984-10-15 | 1988-01-19 | Douglas Shander | Hair growth modification with ornithine decarboxylase inhibitors |
DE10261808A1 (en) * | 2002-12-19 | 2004-07-08 | Turicum Drug Development Ag | Use of L-DOPA, its derivatives and medicaments containing these compounds for the prophylaxis of psychotic diseases |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3959356A (en) * | 1975-03-18 | 1976-05-25 | Richardson-Merrell Inc. | Acetylene derivatives of amino acids |
US4401676A (en) * | 1977-06-01 | 1983-08-30 | Merck & Co., Inc. | Novel α-amino acids |
-
1978
- 1978-06-06 CA CA000304901A patent/CA1161451A/en not_active Expired
- 1978-06-06 IE IE1147/78A patent/IE47082B1/en not_active IP Right Cessation
- 1978-06-12 ZA ZA00783354A patent/ZA783354B/en unknown
- 1978-06-13 NZ NZ187541A patent/NZ187541A/en unknown
- 1978-06-15 IL IL7854918A patent/IL54918A0/en not_active IP Right Cessation
- 1978-06-21 AU AU37325/78A patent/AU521142B2/en not_active Expired
- 1978-06-24 DE DE19782827824 patent/DE2827824A1/en not_active Withdrawn
- 1978-06-27 GB GB7827973A patent/GB2001060B/en not_active Expired
- 1978-06-28 FR FR7819346A patent/FR2401133A1/en active Granted
- 1978-06-29 CH CH710478A patent/CH641150A5/en not_active IP Right Cessation
- 1978-06-29 BE BE188956A patent/BE868596A/en not_active IP Right Cessation
- 1978-06-29 SE SE7807359A patent/SE7807359L/en unknown
- 1978-06-29 IT IT50102/78A patent/IT1107978B/en active
- 1978-06-30 NL NL7807089A patent/NL7807089A/en not_active Application Discontinuation
- 1978-06-30 DK DK299478A patent/DK299478A/en not_active Application Discontinuation
- 1978-07-01 JP JP7926878A patent/JPS5414937A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
GB2001060A (en) | 1979-01-24 |
FR2401133A1 (en) | 1979-03-23 |
GB2001060B (en) | 1982-02-24 |
NZ187541A (en) | 1982-11-23 |
IT1107978B (en) | 1985-12-02 |
IE47082B1 (en) | 1983-12-14 |
DK299478A (en) | 1979-01-02 |
IE781147L (en) | 1979-01-01 |
JPS6334145B2 (en) | 1988-07-08 |
IL54918A0 (en) | 1978-08-31 |
AU521142B2 (en) | 1982-03-18 |
CH641150A5 (en) | 1984-02-15 |
JPS5414937A (en) | 1979-02-03 |
DE2827824A1 (en) | 1979-01-18 |
NL7807089A (en) | 1979-01-03 |
ZA783354B (en) | 1979-06-27 |
AU3732578A (en) | 1980-01-03 |
SE7807359L (en) | 1979-01-02 |
FR2401133B1 (en) | 1981-12-11 |
IT7850102A0 (en) | 1978-06-29 |
BE868596A (en) | 1978-10-16 |
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