CN104968643B - 位置特异性的非对称氘富集儿茶酚胺衍生物和包含所述化合物的药物 - Google Patents
位置特异性的非对称氘富集儿茶酚胺衍生物和包含所述化合物的药物 Download PDFInfo
- Publication number
- CN104968643B CN104968643B CN201480006672.1A CN201480006672A CN104968643B CN 104968643 B CN104968643 B CN 104968643B CN 201480006672 A CN201480006672 A CN 201480006672A CN 104968643 B CN104968643 B CN 104968643B
- Authority
- CN
- China
- Prior art keywords
- deuterated
- deuterium
- dihydroxyphenyl
- amino
- mol
- 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 - Fee Related
Links
- 239000003814 drug Substances 0.000 title claims description 13
- 229910052805 deuterium Inorganic materials 0.000 title abstract description 49
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 title abstract description 46
- 150000001875 compounds Chemical class 0.000 title abstract description 44
- 150000003943 catecholamines Chemical class 0.000 title abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 238000002360 preparation method Methods 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 208000018737 Parkinson disease Diseases 0.000 claims description 19
- WTDRDQBEARUVNC-QZRTVAIESA-N (2s)-2-amino-2,3,3-trideuterio-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound OC(=O)[C@@]([2H])(N)C([2H])([2H])C1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-QZRTVAIESA-N 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 claims description 16
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 claims description 13
- 229960004205 carbidopa Drugs 0.000 claims description 12
- WTDRDQBEARUVNC-QMUVANLASA-N (2s)-2-amino-2,3-dideuterio-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound OC(=O)[C@@]([2H])(N)C([2H])C1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-QMUVANLASA-N 0.000 claims description 11
- 208000005793 Restless legs syndrome Diseases 0.000 claims description 9
- 208000001089 Multiple system atrophy Diseases 0.000 claims description 8
- 239000002671 adjuvant Substances 0.000 claims description 8
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 8
- 229960000911 benserazide Drugs 0.000 claims description 8
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 claims description 5
- 229960003337 entacapone Drugs 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 13
- 239000001257 hydrogen Substances 0.000 abstract description 13
- 238000002156 mixing Methods 0.000 abstract description 13
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 8
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 7
- 150000002431 hydrogen Chemical class 0.000 abstract description 5
- 230000004962 physiological condition Effects 0.000 abstract description 3
- 230000000648 anti-parkinson Effects 0.000 abstract description 2
- 239000000939 antiparkinson agent Substances 0.000 abstract description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 34
- 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 26
- 239000003826 tablet Substances 0.000 description 23
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 22
- 229960004502 levodopa Drugs 0.000 description 22
- 229960003638 dopamine Drugs 0.000 description 17
- 238000000034 method Methods 0.000 description 14
- 239000007888 film coating Substances 0.000 description 12
- 238000009501 film coating Methods 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 9
- 239000003954 decarboxylase inhibitor Substances 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 208000012661 Dyskinesia Diseases 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000011162 core material Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 7
- 239000002532 enzyme inhibitor Substances 0.000 description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 6
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 6
- 208000014094 Dystonic disease Diseases 0.000 description 6
- 108010051696 Growth Hormone Proteins 0.000 description 6
- 208000005903 Manganese Poisoning Diseases 0.000 description 6
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 6
- 206010060860 Neurological symptom Diseases 0.000 description 6
- 102100024819 Prolactin Human genes 0.000 description 6
- 108010057464 Prolactin Proteins 0.000 description 6
- 102100038803 Somatotropin Human genes 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000001684 chronic effect Effects 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 208000010118 dystonia Diseases 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 239000000122 growth hormone Substances 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 229940097325 prolactin Drugs 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- 239000000600 sorbitol Substances 0.000 description 6
- 235000010356 sorbitol Nutrition 0.000 description 6
- 230000004936 stimulating effect Effects 0.000 description 6
- 229940099362 Catechol O methyltransferase inhibitor Drugs 0.000 description 5
- 229940123736 Decarboxylase inhibitor Drugs 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 229940122439 Hydroxylase inhibitor Drugs 0.000 description 5
- XMRLUNALKLDUPT-UHFFFAOYSA-L calcium;5-butylpyridine-2-carboxylate Chemical compound [Ca+2].CCCCC1=CC=C(C([O-])=O)N=C1.CCCCC1=CC=C(C([O-])=O)N=C1 XMRLUNALKLDUPT-UHFFFAOYSA-L 0.000 description 5
- VIKKBVWEWMBLAT-UHFFFAOYSA-N calcium;pentyl pyridine-2-carboxylate Chemical compound [Ca].CCCCCOC(=O)C1=CC=CC=N1 VIKKBVWEWMBLAT-UHFFFAOYSA-N 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 4
- BUZLUQORXILCMY-LBPRGKRZSA-N (2s)-2-amino-3-(4-hydroxyphenyl)-n'-[(2,3,4-trihydroxyphenyl)methyl]propanehydrazide Chemical compound C([C@H](N)C(=O)NNCC=1C(=C(O)C(O)=CC=1)O)C1=CC=C(O)C=C1 BUZLUQORXILCMY-LBPRGKRZSA-N 0.000 description 4
- BNQDCRGUHNALGH-LURJTMIESA-N (2s)-2-amino-3-hydroxy-n'-[(2,3,4-trihydroxyphenyl)methyl]propanehydrazide Chemical compound OC[C@H](N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-LURJTMIESA-N 0.000 description 4
- VEWUMDXDCNJDHA-UHFFFAOYSA-N 2-amino-n'-[(2,3,4-trihydroxyphenyl)methyl]acetohydrazide Chemical compound NCC(=O)NNCC1=CC=C(O)C(O)=C1O VEWUMDXDCNJDHA-UHFFFAOYSA-N 0.000 description 4
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- 208000027219 Deficiency disease Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-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
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 229920000881 Modified starch Polymers 0.000 description 4
- 102000010909 Monoamine Oxidase Human genes 0.000 description 4
- 108010062431 Monoamine oxidase Proteins 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 108010035075 Tyrosine decarboxylase Proteins 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 229960004596 cabergoline Drugs 0.000 description 4
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 4
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229960001681 croscarmellose sodium Drugs 0.000 description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 4
- -1 deuterium compound Chemical class 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 description 4
- 229960004644 moclobemide Drugs 0.000 description 4
- 229940069328 povidone Drugs 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 230000032258 transport Effects 0.000 description 4
- 229960003741 tranylcypromine Drugs 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 108010015720 Dopamine beta-Hydroxylase Proteins 0.000 description 3
- 102100033156 Dopamine beta-hydroxylase Human genes 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 3
- 230000002688 persistence Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical group C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 3
- 229960003946 selegiline Drugs 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- WTDRDQBEARUVNC-NFFCLGLLSA-N (2s,3s)-2-amino-2,3-dideuterio-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound OC(=O)[C@@]([2H])(N)[C@@H]([2H])C1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-NFFCLGLLSA-N 0.000 description 2
- 102000006378 Catechol O-methyltransferase Human genes 0.000 description 2
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000015592 Involuntary movements Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 2
- 210000001577 neostriatum Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- IVTMXOXVAHXCHI-YXLMWLKOSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;(2s)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 IVTMXOXVAHXCHI-YXLMWLKOSA-N 0.000 description 1
- UPJSKSFDCCZYFM-JLPAGWDYSA-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.OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 UPJSKSFDCCZYFM-JLPAGWDYSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 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 1
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010054089 Depressive symptom Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 239000004129 EU approved improving agent Substances 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- 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 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- 206010030312 On and off phenomenon Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010067206 Postural reflex impairment Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010071390 Resting tremor Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960001335 benserazide hydrochloride Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960000632 dexamfetamine Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical class CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 150000002483 hydrogen compounds Chemical class 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000003483 hypokinetic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- XBBDACCLCFWBSI-MSDKDVFUSA-N methyl (2S)-2-amino-2,3,3-trideuterio-3-(3,4-dihydroxyphenyl)propanoate Chemical compound COC([C@@](C(C1=CC(=C(C=C1)O)O)([2H])[2H])([2H])N)=O XBBDACCLCFWBSI-MSDKDVFUSA-N 0.000 description 1
- XBBDACCLCFWBSI-XCHUINSUSA-N methyl (2S)-2-amino-2,3-dideuterio-3-(3,4-dihydroxyphenyl)propanoate Chemical compound [2H]C(c1ccc(O)c(O)c1)[C@]([2H])(N)C(=O)OC XBBDACCLCFWBSI-XCHUINSUSA-N 0.000 description 1
- IYETZZCWLLUHIJ-UHFFFAOYSA-N methyl-(1-phenylpropan-2-yl)-prop-2-ynylazanium;chloride Chemical compound Cl.C#CCN(C)C(C)CC1=CC=CC=C1 IYETZZCWLLUHIJ-UHFFFAOYSA-N 0.000 description 1
- 230000001095 motoneuron effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229960003678 selegiline hydrochloride Drugs 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000015883 synaptic transmission, dopaminergic Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2813—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Psychology (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明描述了通式(I)的氘化的儿茶酚胺衍生物以及其生理学上可接受的盐和其在光学上纯的形式的立体异构体、对映异构体或非对映异构体
其中R1为氘，R2,和R3独立地选自氢和氘，和其中R2和R3中的至少一个具有0.02mol％至100mol％氘范围内的氘富集，和其中R2和R3的氘富集彼此不同，和R2和R3的氘富集之间的差异为至少5个百分点，R4为氢、氘、C1至C6‑烷基或C5至C6‑环烷基、氘化的C1至C6‑烷基或C5至C6‑环烷基，或在生理条件下容易地被水解或酶裂解的基团。所述化合物可以通过将氘化的和非氘化的化合物以预定义的比例混合来简单地制备。所述化合物在较低的剂量显示抗‑帕金森的疗效，且显示较低的副作用。
Description
本发明涉及位置特异性的非对称氘富集的儿茶酚胺衍生物,它们的制备方法，和包含所述化合物的药物，以及它们在治疗帕金森疾病中的用途。
已知代表性的儿茶酚胺类例如L-DOPA(左旋多巴)以及它们的羧酸酯尤其被用于治疗帕金森病和不宁腿综合症。包含左旋多巴的药物为，例如，左旋多巴
L-DOPA作用于脑神经元中的多巴胺浓度。与多巴胺本身不同，L-DOPA能够通过血脑屏障并在脑中被转化为多巴胺。
另外，在药物中将左旋多巴与活性添加剂联合给药。左旋多巴的联合与外周脱羧酶抑制剂、酶儿茶酚-O-甲基转移酶(COMT)抑制剂、酶单胺氧化酶(MAO)抑制剂和多巴胺β-羟化酶抑制剂一起使用。
就此而论，使用的所述脱羧酶抑制剂为,例如:D,L-丝氨酸-2-(2,3,4-三羟基苄基)酰肼(苄丝肼),(-)-L-α-肼基-3,4-二羟基-α-甲基氢化桂皮酸(卡比多巴),L-丝氨酸-2-(2,3,4-三羟基苄基)酰肼,甘氨酸-2-(2,3,4-三羟基苄基)酰肼和L-酪氨酸-2-(2,3,4-三羟基苄基)酰肼。左旋多巴和脱羧酶抑制剂的联合制剂的示例包括:美多芭
(左旋多巴和盐酸苄丝肼)以及
(左旋多巴和卡比多巴)等。
COMT抑制剂的示例为恩他卡朋
和卡麦角林,和经常使用的MAO抑制剂为盐酸司来吉兰、吗氯贝胺和反苯环丙胺。
吡啶甲酸5-丁酯钙(calcium 5-butyl picolinate)和吡啶甲酸5-戊酯钙(calcium 5-pentyl picolinate)被记载为多巴胺-β-羟化酶的抑制剂(DE-A 2 049 115)。
帕金森病为神经变性的疾病，其具有缓慢的发展过程，其特征在于 可能在疾病的发展中出现或发展的不同症状和征兆。核心症状为运动机能减退和至少一种以下症状：休息性震颤、肌僵硬和姿势反射病损。可能在疾病发展中出现的其他症状为自主神经机能紊乱(autonomic disturbance)、睡眠障碍、嗅觉感觉或温度感觉的障碍，以及抑郁症状和认识功能障碍。
目前药物治疗的要点为通过施用L-DOPA改善病损的多巴氨能神经传递。晚期帕金森病的患者需要更高剂量的多巴胺能药，但是这受到例如波动和不自主运动的运动并发症(称为左旋多巴诱导的运动障碍,LIDs)的限制。特别是在晚期帕金森病的患者(也被称为“帕金森患者”)中，波动可能是由多巴胺的较短的纹状体的持续(半衰期)引起的。已经建立的临床上用于延长纹状体的多巴胺持续的方法为阻断多巴胺的主要代谢分解途径的MAO-B抑制剂的共给药。LIDs的诱发在很多患者中与大剂量L-DOPA所产生的更高的CNS多巴胺水平有关。目前存在正在研发中的用于治疗现有LIDs的不同的药理学方法。
α,β,β-D3-L-DOPA显示比L-DOPA更高的更持久的纹状体的多巴胺水平。相对于纹状体中增加的多巴胺可用度，在一些帕金森模型中，α,β,β-D3-L-DOPA对比L-DOPA显示了改善的运动活性(Malmlof等,Exp Neurol,2008,538-542；
等,Exp Neurol,2010,225:408-415)。α,β,β-D3-L-DOPA对比L-DOPA的相等有效剂量为约60％。所观察到的多巴胺的更久的纹状体持续使得可以作出波动可能会被减少的假设。
S/S-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸(α,β-D2-L-DOPA)和L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸(α,β,β-D3-L-DOPA)显示了其比L-DOPA显著更多地增加和延长纹状体多巴胺的输出量(WO-A 2004/056724和WO-A 2007/093450)。
在α,β-D2-L-DOPA给药后发现了最高纹状体多巴胺浓度。那些多巴胺水平甚至高于在三氘化α,β,β-D3-L-DOPA(其包含与二氘化L-DOPA相同的氘化的位置)给药后得到的那些多巴胺水平。
相等有效剂量(与L-DOPA相同的纹状体多巴胺水平和相同的运动效 应)的α,β,β-D3-L-DOPA引起的运动障碍显著地少于L-DOPA(
等,Exp Neurol,2010,225:408-415)。
本发明解决的问题为改善已知α,β,β-D3-L-DOPA的活性。
本发明中所使用的“氘化”的含义延伸至部分或完全氘化的化合物。“完全氘化”的化合物为这样的化合物：在该化合物中，至少98mol％的氘存在于其各自的位置(分析测量的偏差和实验误差导致至100Mol％的偏差)。这意味着：在各自位置已经达到氘的富集和氢已经被替换。所述各自的富集可以通过使用氘化的起始物质或已经通过混合各自的化合物完成氢/氘的交换的化学反应进行。
因此“氘化”不涉及任何在氢化合物中天然存在的氘。如所知的，氘以至0.015mol％的程度的天然丰度在氢中存在。任何高于0.02mol％的丰度或富集都被认为是本发明意义上的“氘化”。
通过提供通式I的氘化的儿茶酚胺衍生物以及其生理学上可接受的盐和其光学上纯的形式的立体异构体、对映异构体或非对映异构体来解决本发明的问题
其中
R1为氘,
R2,和R3独立地选自氢和氘，和
其中R2和R3中的至少一个具有在0.02mol％至100mol％氘范围内的氘富集，和
其中R2和R3的氘富集彼此不相同，和R2和R3的氘富集之间的差异为至少5个百分点,
R4为氢,氘,C1至C6-烷基或C5至C6-环烷基,氘化的C1至C6-烷基或C5至C6-环烷基,或在生理条件下容易地被水解或酶裂解的基团。
优选根据本发明的氘化的儿茶酚胺衍生物，其中R2和R3的氘富集之间的差异为至少7个百分点。
优选根据本发明的氘化的儿茶酚胺衍生物，其中R2和R3的氘富集之间的差异为至少10个百分点。
优选根据本发明的氘化的儿茶酚胺衍生物，其中R2和R3的氘富集之间的差异为至少15个百分点。
优选根据本发明的氘化的儿茶酚胺衍生物，其中R2和R3的氘富集之间的差异为至少20个百分点。
优选根据本发明的氘化的儿茶酚胺衍生物，其中R4选自以下：氢、氘、甲基、全氘化甲基、乙基、全氘化乙基、丙基、全氘化丙基、丁基、全氘化丁基、可为支链或非支链的C1至C6-烷基，或C5至C6-环烷基,可为支链或非支链的氘化的或部分氘化的C1至C6-烷基,或氘化的或部分氘化的C5至C6-环烷基。
优选根据本发明的氘化的儿茶酚胺衍生物，其中R4选自以下：氢、氘、甲基、全氘化甲基、乙基、全氘化乙基、丙基、全氘化丙基、环己基和全氘化环己基。
优选根据本发明的氘化的儿茶酚胺衍生物，其中R4为氢。
优选根据本发明的氘化的儿茶酚胺衍生物，其中R4为甲基。
优选根据本发明的氘化的儿茶酚胺衍生物，其中R4为乙基。
根据本发明特别优选的为L-2-氨基-2,3,3*-三氘化-3-(3,4-二羟基苯基)丙酸(α,β,β*-D3-L-DOPA),其中3*表明在一个β-位置中的氘富集为约90mol％。该化合物根据本发明的定义在β-位置的氘富集具有约8至10个百分点的差异。另外的带有氘的位置被完全氘化，并显示至少98mol％的氘富集。该化合物在本发明说明书的表1和2中被命名为测试物D。
本发明的问题也可以通过提供氘化的儿茶酚胺衍生物来解决，所述儿茶酚胺衍生物可通过将通式II的化合物以及其生理学上可接受的盐和 光学上纯的形式的立体异构体、对映异构体或非对映异构体与
通式III的化合物或通式IV的化合物以及其生理学上可接受的盐和光学上纯的形式的立体异构体、对映异构体或非对映异构体混合获得
其中，在通式II,III,或IV中,
R4为氢、氘、C1至C6-烷基或C5至C6-环烷基，氘化的C1至C6-烷基或C5至C6-环烷基，或在生理条件下容易地被水解或酶裂解的基团，
上述混合以一定比例，该比例将通式I中的R2或R3位置的氘富集调节至0.02mol％至100mol％氘的预定义的范围。
根据本发明优选的为氘化的儿茶酚胺衍生物，其中根据通式II的化合物选自以下:
L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸,
L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸甲酯,
L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸乙酯,
L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸丙酯,
L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸环己酯,
L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸全氘化甲酯,
L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸全氘化乙酯,
L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸全氘化丙基乙酯,
L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸全氘化环己酯,以及其生理学上可接受的盐和其光学上纯的形式的立体异构体、对映异构体或非对映异构体,其中根据通式III或IV的化合物选自以下:
L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸,
L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸甲酯,
L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸乙酯,
L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸丙酯,
L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸环己酯,
L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸全氘化甲酯,
L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸全氘化乙酯,
L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸全氘化丙基乙酯,
L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸全氘化环己酯,以及其生理学上可接受的盐和其光学上纯的形式的立体异构体、对映异构体或非对映异构体。
特别优选氘化的儿茶酚胺衍生物，其中根据通式II的化合物的百分比在0.1mol％至99.9mol％的范围中,优选5mol％至95mol％的范围,特别优选78mol％至95mol％的范围。最优选的为本说明书中的氘化的儿茶酚胺衍生物,其中根据通式II的化合物的百分比在88mol％至92mol％的范围中。最优选的也为本说明书中的氘化的儿茶酚胺衍生物，其中根据通式II的化合物的百分比在78mol％至82mol％的范围中。
因此，根据本发明优选的混合物为：在其中将90mol％的L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸与10mol％的L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸混合,或将80mol％的L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸与20mol％的L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸混合,或将85mol％的L-2-氨基-2,3,3-三氘化 -3-(3,4-二羟基苯基)丙酸与15mol％的L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸混合,或将70mol％的L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸与30mol％的L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸混合。
本发明另外的主题为制备本发明的氘化的儿茶酚胺衍生物的方法，所述方法通过将以下混合：
(i)通式I的化合物以及其生理学上可接受的盐和其光学上纯的形式的立体异构体、对映异构体或非对映异构体
其中
R1,R2,R3,和R4具有如上定义的含义,
其中R2和R3的氘富集彼此不同，R2和R3的氘富集之间的差异具有第一预定义的值,
与
(ii)至少一种通式I的化合物以及其生理学上可接受的盐和其光学上纯的形式的立体异构体、对映异构体或非对映异构体
其中
R1,R2,R3,和R4具有如上定义的含义,其中R2和R3的氘富集彼此不同， R2和R3的氘富集之间的差异具有第二预定义的值,
(iii)上述混合以一定比例，该比例产生R2和R3的氘富集之间的预定义的差异，其在至少5到至少20个百分点的范围。
本发明的另一个主题为根据本发明的氘化的儿茶酚胺衍生物以及其生理学上可接受的盐的以下用途：治疗多巴胺缺乏疾病，或基于中断的酪氨酸转运或中断的酪氨酸脱羧酶的疾病，例如帕金森病、不宁腿综合征、张力失调；抑制泌乳刺激素分泌；刺激生长激素的释放；治疗慢性锰中毒的神经学上的症状、肌萎缩侧索硬化和多系统萎缩。
优选的为本发明的氘化的儿茶酚胺衍生物，以及其生理学上可接受的盐与一种或几种酶抑制剂的联合的以下用途：治疗多巴胺缺乏疾病，或基于中断的酪氨酸转运或中断的酪氨酸脱羧酶的疾病，例如帕金森病、不宁腿综合征、张力失调；抑制泌乳刺激素分泌；刺激生长激素的释放；治疗慢性锰中毒的神经学上的症状、肌萎缩侧索硬化和多系统萎缩。
优选的为本发明的氘化的儿茶酚胺衍生物，以及其生理学上可接受的盐的用途，其特征还在于一种或几种酶抑制剂或酶抑制剂包括脱羧酶抑制剂，和/或儿茶酚O-甲基转移酶抑制剂，和/或单胺氧化酶抑制剂，和/或β-羟化酶抑制剂。
优选的为本发明的氘化的儿茶酚胺衍生物以及其生理学上可接受的盐的用途，其特征还在于脱羧酶抑制剂选自D,L-丝氨酸-2-(2,3,4-三羟基苄基)酰肼(苄丝肼),(-)-L-α-肼基-3,4二羟基-α-甲基氢化桂皮酸(卡比多巴),L-丝氨酸-2-(2,3,4-三羟基苄基)酰肼,甘氨酸-2-(2,3,4-三羟基苄基)酰肼和L-酪氨酸-2-(2,3,4-三羟基苄基)酰肼以及其生理学上可接受的盐。
优选的为本发明的氘化的儿茶酚胺衍生物，以及其生理学上可接受的盐的用途，其特征还在于儿茶酚O-甲基转移酶抑制剂选自恩他卡朋和卡麦角林以及其生理学上可接受的盐。
优选的为本发明的氘化的儿茶酚胺衍生物，以及其生理学上可接受的盐的用途，其特征还在于单胺氧化酶抑制剂选自司来吉兰、吗氯贝胺和反苯环丙胺以及其生理学上可接受的盐。
优选的为本发明的氘化的儿茶酚胺衍生物，以及其生理学上可接受的盐的用途，其特征还在于β-羟化酶抑制剂选自吡啶甲酸5-丁酯钙和吡啶甲酸5-戊酯钙以及其生理学上可接受的盐。
优选的为本发明的氘化的儿茶酚胺衍生物，以及其生理学上可接受的盐的用于制备用于治疗帕金森病、不宁腿综合征、肌萎缩侧索硬化和多系统萎缩的药物的用途。
本发明的另一个主题为药物组合物，其除了包含药学上可接受的佐剂和添加剂之外，还包含本发明氘化的儿茶酚胺以及其生理学上可接受的盐，其用于治疗帕金森病、不宁腿综合征、张力失调，抑制泌乳刺激素分泌，刺激生长激素的释放，治疗慢性锰中毒的神经学上的症状、肌萎缩侧索硬化和多系统萎缩。
优选的为药物组合物，其除了包含药学上可接受的佐剂和添加剂之外，还包含本发明的氘化的儿茶酚胺以及其生理学上可接受的盐，其用于治疗帕金森病、不宁腿综合征、张力失调，抑制泌乳刺激素分泌，刺激生长激素的释放，治疗慢性锰中毒的神经学上的症状、肌萎缩侧索硬化和多系统萎缩，以及一种或多种酶抑制剂。
优选的为药物组合物，其包含本发明氘化的儿茶酚胺，其特征还在于酶抑制剂包含脱羧酶抑制剂和/或儿茶酚O-甲基转移酶抑制剂和/或单胺氧化酶抑制剂和/或β-羟化酶抑制剂。
优选的为药物组合物，其包含本发明氘化的儿茶酚胺，其特征还在于脱羧酶抑制剂选自以下：D,L-丝氨酸-2-(2,3,4-三羟基苄基)酰肼(苄丝肼),(-)-L-α-肼基-3,4-二羟基-α-甲基氢化桂皮酸(卡比多巴),L-丝氨酸-2-(2,3,4-三羟基苄基)酰肼,甘氨酸-2-(2,3,4-三羟基苄基)酰肼和L-酪氨酸-2-(2,3,4-三羟基苄基)酰肼以及其生理学上可接受的盐。
优选的为药物组合物，其包含本发明氘化的儿茶酚胺，其特征还在于儿茶酚O-甲基转移酶抑制剂选自恩他卡硼和卡麦角林以及其生理学上可接受的盐。
优选的为药物组合物，其包含本发明氘化的儿茶酚胺，其特征还在于所述单胺氧化酶抑制剂选自司来吉兰,吗氯贝胺和反苯环丙胺以及其 生理学上可接受的盐。
优选的为药物组合物，其包含本发明氘化的儿茶酚胺，其特征还在于β-羟化酶抑制剂选自吡啶甲酸5-丁酯钙和吡啶甲酸5-戊酯钙以及其生理学上可接受的盐。
本发明的另一个主题为药物组合物，其除了任选地包含药学上可接受的佐剂和添加剂，还包含药理学活性剂量的以下混合物：10mol％的L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸以及其生理学上可接受的盐和90mol％的L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸以及其生理学上可接受的盐。
优选的为药物组合物，其中该组合物进一步地包含药理学活性剂量的卡比多巴,苄丝肼或恩他卡朋或所述化合物的混合物。
因为本发明的药物组合物的非对称位置特异性的氘富集能够调节位置特异性的氘化的L-DOPA的已知效应，所以所述药物组合物非常强效地治疗帕金森病。这提供了根据在疾病发展中变化的症状和副作用来调节治疗的强效工具。
根据各个个体中的帕金森病的阶段，本领域人员能够使用具有按被治疗患者所需调节的氘富集的化合物。这提供了根据患者定制或特制的药物的新机会。
本发明的另一个主题为用于以下的方法：治疗多巴胺缺乏疾病或者基于中断的酪氨酸转运或中断的酪氨酸脱羧酶的疾病，例如帕金森病,不宁腿综合征,张力失调；抑制泌乳刺激素分泌；刺激生长激素的释放；治疗慢性锰中毒的神经学上的症状、肌萎缩侧索硬化和多系统萎缩。上述治疗的接受者为被确定为需要以下的患者：治疗多巴胺缺乏疾病或者基于中断的酪氨酸转运或中断的酪氨酸脱羧酶的疾病，例如帕金森病,不宁腿综合征,张力失调；抑制泌乳刺激素分泌、刺激生长激素的释放；治疗慢性锰中毒的神经学上的症状、肌萎缩侧索硬化和多系统萎缩。所述方法包括向个体施用如本发明给出的通式的氘化的儿茶酚胺衍生物以及其生理学上可接受的盐。
优选的为一种方法，其中将上述本发明的氘化的儿茶酚胺衍生物以 及其生理学上可接受的盐与一种或几种酶抑制剂联合施用于患者。
优选的为一种方法，其中一种或几种酶抑制剂包括脱羧酶抑制剂和/或儿茶酚O-甲基转移酶抑制剂和/或单胺氧化酶抑制剂和/或β-羟化酶抑制剂。
优选的为一种方法，其中脱羧酶抑制剂选自D,L-丝氨酸-2-(2,3,4-三羟基苄基)酰肼(苄丝肼),(-)-L-α-肼基-3,4二羟基-α-甲基氢化桂皮酸(卡比多巴),L-丝氨酸-2-(2,3,4-三羟基苄基)酰肼,甘氨酸-2-(2,3,4-三羟基苄基)酰肼和L-酪氨酸-2-(2,3,4-三羟基苄基)酰肼以及其生理学上可接受的盐。
优选的为一种方法，其中儿茶酚-O-甲基转移酶抑制剂选自恩他卡朋和卡麦角林以及其生理学上可接受的盐。
优选的为一种方法，其中单胺氧化酶抑制剂选自司来吉兰、吗氯贝胺和反苯环丙胺以及其生理学上可接受的盐。
优选的为一种方法，其中β-羟化酶抑制剂选自吡啶甲酸5-丁酯钙和吡啶甲酸5-戊酯钙以及其生理学上可接受的盐。
本发明氘化的儿茶酚胺衍生物的制备可以通过至少两种最主要的方法进行。一种方法为将具有一定的氘富集的化合物与只具有氢或者只具有在一定位置的高富集(>98％D)氘取代的化合物混合。通过混合至少这两种化合物就能够得到在任何位置所需的任何氘富集水平。另一种制备方法为将特定氘富集的起始物质加入至本发明化合物制备方法的某一步骤中。
在WO-A 2004/056724和WO-A 2007/093450中已知氘富集儿茶酚胺衍生物的制备。在这些文献中公开了选择性的氘化的DOPA衍生物的制备，所述衍生物在至少98％的分子内的各自位置具有氘富集。
一种优选的合成途径如方案1中所示。
方案1
氘化的儿茶酚胺衍生物的合成途径
根据本发明，优选通过加入非-氘化的起始物3a和/或4和/或5至各自的氘化的化合物中制备本发明的化合物。将氘化和非氘化的化合物的比例按照能够在最终产物得到所期望的比例的方法调节。该制备方法具有不需要另外的混合步骤的优势。该所得化合物根据定义不再是混合物。
为了制备本发明的氘化的儿茶酚胺衍生物的生理学上可接受的盐，可以使用通常的生理学上可接受的无机和有机酸，例如氢氯酸、氢溴酸、磷酸、硫酸、草酸、马来酸、富马酸、乳酸、酒石酸、苹果酸、柠檬酸、水杨酸、己二酸、和苯甲酸。例如在Fortschritte derArzneimittelforschung,第10卷,第224-225页,
出版商,Basel和Stuttgart,1966,和Journal of Pharmaceutical Sciences,第66卷,第1-5页(1977)中记载了其他能够使用的酸。
通常通过在有机溶剂中将游离碱或其溶液与对应的酸或其溶液混合获得酸的加成盐，所述有机溶剂为例如，低级醇，例如甲醇、乙醇、正-丙醇或异-丙醇，或者低级酮，例如丙酮、甲基乙基酮或甲基异丁基酮，或醚，例如乙醚、四氢呋喃或二噁烷。也能够使用上述溶剂的混合物来得到更好的结晶沉淀。另外，本发明使用的化合物的酸加成盐的生理学上可接受的水溶液可以从酸的水溶液中制备。
本发明的化合物的酸加成盐可通过已知方法转化为其自身中的游离碱或其自身的游离碱，例如通过碱或离子交换剂。可通过与无机或有机酸(特别是那些适用于形成可以在治疗上使用的盐的酸)的反应，由游离碱获得加成盐。本发明化合物的这些或者其他盐，例如苦味酸盐，也可能用于纯化游离碱的目的(通过将游离碱转化为盐，分离该盐，然后由该盐释放该碱)。
本发明的主题也为用于口服、口腔、舌下、鼻、直肠、皮下、静脉或肌肉应用以及用于吸入的药物，所述药物除包含常规的载体和稀释剂外，也包含作为活性成分的通式I的化合物或其酸加成盐。
按照已知的方法通过合适的剂量、使用常见的固体或液体载体物质或稀释剂和所期望的应用类型对应的常用的药物-技术的佐剂来制备本发明的药物。优选的制剂包括适合口服应用的给药剂型，其包括，例如,片剂、吸入片剂(sucking tablets)、膜片剂、糖衣丸剂、胶囊剂、丸剂、粉末剂、溶液剂、气雾剂或混悬剂或缓慢释放剂型。
当然，也考虑了例如注射溶液的肠胃外制剂。另外，例如栓剂也已经被命名为制剂。对应的片剂可以通过，例如将活性物质与以下物质混合得到：已知的佐剂，例如惰性稀释剂例如葡萄糖、糖、山梨醇、甘露醇、聚乙烯吡咯烷酮，崩解剂例如玉米淀粉或海藻酸，粘合剂例如淀粉或明胶，润滑剂例如硬脂酸镁或滑石，和/或用于达到缓慢释放效应的试剂例如羧聚乙烯、羧甲基纤维素、邻苯二甲酸乙酸纤维素或聚乙酸乙酯。该片剂也可能由几层构成。
通过将类似于片剂所产生的片芯物质用糖锭剂包衣常用的试剂(例如聚乙烯吡咯烷酮或者虫胶，阿拉伯树胶、滑石、二氧化钛或者糖)包衣，也能够相应地将糖锭剂制备为控制或延迟释放形式的剂型。所述糖锭剂包膜也可以由几层构成，其中可以使用上述片剂的例子中所述的佐剂。
包含本发明使用的活性物质的溶液或悬浮物可以另外地包含改进味道的试剂，例如糖精、甜蜜素或糖，以及，例如，增味剂例如香草和橘子提取物。它们也可能包含例如羧甲纤维素钠的悬浮佐剂，或例如对- 羟苯酸酯的防腐剂。包含活性物质的胶囊可以通过，例如，将活性物质与例如乳糖或山梨醇的惰性载体混合，并将该混合物装入明胶胶囊中来制备。合适的栓剂可以通过，例如，将由此提供的例如天然脂肪或聚乙二醇或其衍生物的载体剂混合制备。
本发明的药物制剂的制备在现有技术中已知，并被记载在本领域技术人员已知的手册中，例如Hager's Handbuch[手册](第5版)2,622-1045；List等,Arzneiformenlehre[Instructions for Drug Forms],Stuttgart:Wiss.Verlagsges.1985；Sucker等,Pharmazeutische Technologie[Pharmaceutical Technology],Stuttgart:Thieme 1991；Ullmann's
[Encyclopedia](第5版)A 19,241-271；Voigt,Pharmazeutische Technologie[Pharmaceutical Technology],Berlin:Ullstein Mosby1995。
以下实施例将解释本发明。应该将以下实施例仅仅理解为本发明的优选实施方式。其并非旨在将本发明限定于给出的实施例的范围内。
实施例1
在6-羟基多巴胺(6-OHDA)啮齿目动物的帕金森病模型中，将在支链的特定位置具有不同氘化富集的氘化的L-DOPA衍生物给药后，对于所述每种衍生物对运动表现的效应和运动失调的发展，在彼此之间以及与L-DOPA进行了对比。表1显示了受测试的化合物和这些化合物的特定的氘富集。
表1测试物
(3*或β*,分别表明该位置没有完全氘化)
(βR和βS涉及常用的表明在光学活性化合物中的相对位置的R/S命名法。)
将体重约225g的雌性Sprague-Dawley大鼠置于12小时的亮/黑循环中，并保持标准实验室饮食和无限制的水。向所述大鼠单侧注射神经毒素6-OHDA来造成损伤。在腹膜腔内注射2.5mg/kg D-苯丙胺后通过测量旋转活性验证该损伤。
通过测量药物引起的对侧的旋转来评估抗-帕金森效应(对于运动表现的效应)。建立了一种剂量效应来确定等效(同等效应)剂量。
通过对动物的异常的不自主运动评分来评估重复治疗后的运动失调。由不了解实验设计的观测者对于大鼠的肢、轴的和口舌的不自主运动评分。
表2给出等效剂量(以L-DOPA剂量的百分比表示的)，所述等效剂量这些剂量重复给药后导致对于运动表现和运动失调上观察到的相同效应。
表2结果
如较低的等效剂量所反映的，α,βD2-L-DOPA[B]在运动表现上的效应比α,β,βD3-L-DOPA[C]和L-DOPA[A]要显著地强得多。然而，对比等效剂量的L-DOPA，施用α,βD2-L-DOPA[B]后没有降低运动失调，而α,β,βD3-L-DOPA[C]相比等效剂量的L-DOPA显著地降低了运动失调。
令人惊讶得是，测试物D(在α和βS位置有几乎100％的氘富集，和在βR有90％的氘富集)与二-氘化α,βD2-L-DOPA[B]具有同等的运动效应，同时如三-氘化α,β,βD3-L-DOPA[C]一样地降低了运动失调。
因此测试物D为患有症状波动(motor fluctuation)和LIDs及需要高剂量L-DOPA的晚期帕金森患者的最佳治疗。
化合物D的例子表明非对称、位置特异性的氘富集能够调节位置特异性的氘化的L-DOPA的已知效应。这提供了一种根据在疾病发展中变化的症状和副作用来调整治疗的强效工具。
根据各个个体的帕金森病的阶段，本领域人员能够使用具有按治疗中的患者需要所调节的氘富集的化合物。这提供了为患者特制或定制药物的新机会。
实施例2
表1中测试物D的制备
L-2-氨基-2,3,3*-三氘化-3-(3,4-二羟基苯基)丙酸
(α,β,β*-D3-L-DOPA)
测试物D在βR具有90％的氘富集。
通过将10mol％L-2-氨基-2,3(S)-二氘化-3-(3,4-二羟基苯基)丙酸与90mol％L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸(在全部3个位置上，氘富集>98％)混合来获得D。
C9H8.1 2H2.9NO4的实验数据
理论值:H 6.95 C 54.05 N 7.00 O 32.00
实测值:H 7.00 C 54.02 N 7.00 O 31.98
也已经通过NMR谱仪来确定氘化的程度。为了该目的，使用500MHz谱仪记录NMR谱。使用的溶剂为d6-DMSO。下面表3显示了测试物D的化合物中各自的位置，和反映了各自位置的氢含量的已记录的谱的积分(AUC＝曲线下的面积)。
表3NMR结果
| 位置 | 积分(AUC) |
| 环 | 3.02 |
| α | 0.02 |
| β | 0.01 |
| β* | 0.10 |
WO-A 2004/056724中记载了起始物L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸的制备，WO-A 2007/093450中记载了起始物L-2-氨基-2,3(S)-二氘化-3-(3,4-二羟基苯基)丙酸的制备。
如下列实施例中给出的，将化合物混合后，可以进一步地处理所得混合物以得到用于帕金森病药物治疗的合适的药物产品。
实施例3
带有膜包衣和包含α,β,β*-D3-L-DOPA的片剂
片芯的组成:
膜包衣:
制备:
将α,β,β*-D3-L-DOPA(测试物D)和高度分散的二氧化硅在强制式搅拌器其中与聚维酮和山梨醇的溶液颗粒化。将颗粒干燥、过筛并与预胶化淀粉、交联羧甲基纤维素-钠、羧甲基纤维素-钠和微晶纤维素混合，然后与硬脂酸镁合并，并压缩成片剂。将所述片剂用羟丙基甲基纤维素、聚乙二醇、氧化钛和滑石膜包衣。
实施例4
带有膜包衣和包含α,β,β*-D3-L-DOPA和卡比多巴的片剂
片芯的组成:
膜包衣:
制备:
将α,β,β*-D3-L-DOPA(测试物D),卡比多巴和高度分散的二氧化硅 在强制式搅拌器中与聚维酮和山梨醇的溶液颗粒化。将颗粒干燥、过筛并与预胶化淀粉、交联羧甲基纤维素-钠、羧甲基纤维素-钠和微晶纤维素混合，然后与硬脂酸镁合并，并压缩成片剂。将所述片剂用羟丙基甲基纤维素、聚乙二醇、氧化钛和滑石膜包衣。
实施例5
具有膜包衣和包含装入微胶囊的α,β,β*-D3-L-DOPA和卡比多巴的片剂
片芯的组成:
膜包衣:
制备:
将α,β,β*-D3-L-DOPA(测试物D),卡比多巴,山梨醇和丙烯酸树脂 Eudragit装入微胶囊，并在转筒式混合器中与酒石酸、高度分散的二氧化硅、聚维酮、预胶化淀粉、交联羧甲基纤维素-钠、羧甲基纤维素-钠和微晶纤维素均匀化，然后与硬脂酸镁合并，并压缩成片剂。将所述片剂用羟丙基甲基纤维素、聚乙二醇、氧化钛和滑石膜包衣。
实施例6
具有膜包衣和包含装入微胶囊的α,β,β*-D3-L-DOPA和苄丝肼的片剂
片芯的组成:
膜包衣:
实施例5给出了膜包衣片剂的制备。
实施例7
具有膜包衣和包含α,β,β*-D3-L-DOPA和苄丝肼的片剂
片芯的组成:
膜包衣:
制备:
将α,β,β*-D3-L-DOPA(测试物D),卡比多巴和高度分散的二氧化硅在强制式搅拌器中与聚维酮和山梨醇的溶液颗粒化。将颗粒干燥、过筛并与预胶化淀粉、交联羧甲基纤维素-钠、羧甲基纤维素-钠和微晶纤维素混合，然后与硬脂酸镁合并，并压缩成片剂。将所述片剂用羟丙基甲基纤维素、聚乙二醇、氧化钛和滑石膜包衣。
实施例8
具有膜包衣和包含α,β,β*-D3-L-DOPA和卡比多巴和恩他卡朋的片剂
片芯的组成:
膜包衣:
按照实施例3的记载进行膜包衣片剂的制备。
Claims (10)
1.药物组合物，其包含：
90mol％的L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸或其生理学上可接受的盐，和
10mol％的L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸或其生理学上可接受的盐。
2.根据权利要求1所述的药物组合物，其中L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸具有下式：
3.根据权利要求1所述的药物组合物，其中L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸具有下式：
或其组合。
4.根据权利要求1所述的药物组合物，其中L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸具有下式：
5.根据权利要求1所述的药物组合物，其中L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸具有下式：
6.根据权利要求1所述的药物组合物，其包含90mol％的L-2-氨基-2,3,3-三氘化-3-(3,4-二羟基苯基)丙酸和10mol％的L-2-氨基-2,3-二氘化-3-(3,4-二羟基苯基)丙酸。
7.根据权利要求1的药物组合物，还包括药学上可接受的佐剂或添加剂。
8.根据权利要求1的药物组合物，进一步包含卡比多巴、苄丝肼或恩他卡朋或其混合物。
9.根据权利要求1的药物组合物在制备药物中的用途，所述药物用于治疗帕金森病、不宁腿综合征、肌萎缩侧索硬化或多系统萎缩。
10.根据权利要求9的用途，所述药物用于治疗帕金森病。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361760738P | 2013-02-05 | 2013-02-05 | |
| US61/760,738 | 2013-02-05 | ||
| EP13182708 | 2013-09-02 | ||
| EP13182708.1 | 2013-09-02 | ||
| PCT/EP2014/052267 WO2014122184A1 (en) | 2013-02-05 | 2014-02-05 | Position-specific asymmetric deuterium enriched catecholamine derivatives and medicaments comprising said compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104968643A CN104968643A (zh) | 2015-10-07 |
| CN104968643B true CN104968643B (zh) | 2020-03-03 |
Family
ID=49084847
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201480006672.1A Expired - Fee Related CN104968643B (zh) | 2013-02-05 | 2014-02-05 | 位置特异性的非对称氘富集儿茶酚胺衍生物和包含所述化合物的药物 |
Country Status (14)
| Country | Link |
|---|---|
| US (2) | US9567289B2 (zh) |
| EP (1) | EP2953926B1 (zh) |
| JP (1) | JP6704252B2 (zh) |
| KR (1) | KR20150115807A (zh) |
| CN (1) | CN104968643B (zh) |
| AU (2) | AU2014214055A1 (zh) |
| BR (1) | BR112015016889A8 (zh) |
| CA (1) | CA2897132C (zh) |
| EA (1) | EA028931B1 (zh) |
| ES (1) | ES2901752T3 (zh) |
| HK (2) | HK1214241A1 (zh) |
| IL (2) | IL239733A0 (zh) |
| MX (1) | MX370884B (zh) |
| WO (1) | WO2014122184A1 (zh) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2918266A1 (en) | 2014-03-11 | 2015-09-16 | CDRD Berolina AB | Composition comprising a dopamine agonist and an L-DOPA derivative for treating Parkinson's disease |
| WO2017060870A1 (en) | 2015-10-09 | 2017-04-13 | Hermann Russ | Combination of deuterated levodopa with carbidopa and opicapone for the treatment of parkinson`s disease |
| ES2942468T3 (es) * | 2018-10-18 | 2023-06-01 | Oncopeptides Ab | Compuestos que contienen deuterio |
| US20220024858A1 (en) * | 2018-12-06 | 2022-01-27 | Intrabio Ltd. | Deuterated analogs of acetyl-leucine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101384545A (zh) * | 2006-02-17 | 2009-03-11 | 比罗利纳创新研究与发展服务药物有限公司 | 氘化的儿茶酚胺衍生物及包含所述化合物的药物 |
| CN100584807C (zh) * | 2002-12-19 | 2010-01-27 | Bdd贝罗琳纳药品发展有限公司 | 氘化的儿茶酚胺衍生物以及含有该化合物的药物 |
| WO2010103273A2 (en) * | 2009-03-12 | 2010-09-16 | Amarin Neuroscience Limited | Essential fatty acid compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2049115C3 (de) | 1970-10-06 | 1981-07-30 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai, Tokyo | Verwendung von Calcium-5-butylpicolinat und/oder Calcium-5-pentylpicolinat bei der Bekämpfung des Parkinsonismus mit 3-(3,4-Dihydroxyphenyl)-L-alanin (L-Dopa) |
-
2014
- 2014-02-05 CA CA2897132A patent/CA2897132C/en active Active
- 2014-02-05 AU AU2014214055A patent/AU2014214055A1/en not_active Abandoned
- 2014-02-05 CN CN201480006672.1A patent/CN104968643B/zh not_active Expired - Fee Related
- 2014-02-05 BR BR112015016889A patent/BR112015016889A8/pt not_active Application Discontinuation
- 2014-02-05 JP JP2015555754A patent/JP6704252B2/ja active Active
- 2014-02-05 EA EA201500739A patent/EA028931B1/ru not_active IP Right Cessation
- 2014-02-05 KR KR1020157021874A patent/KR20150115807A/ko not_active Application Discontinuation
- 2014-02-05 EP EP14707659.0A patent/EP2953926B1/en active Active
- 2014-02-05 MX MX2015010087A patent/MX370884B/es active IP Right Grant
- 2014-02-05 US US14/765,430 patent/US9567289B2/en active Active
- 2014-02-05 ES ES14707659T patent/ES2901752T3/es active Active
- 2014-02-05 WO PCT/EP2014/052267 patent/WO2014122184A1/en active Application Filing
-
2015
- 2015-07-01 IL IL239733A patent/IL239733A0/en unknown
-
2016
- 2016-02-26 HK HK16102244.2A patent/HK1214241A1/zh unknown
- 2016-03-10 HK HK16102797.3A patent/HK1214810A1/zh unknown
-
2018
- 2018-06-13 IL IL260018A patent/IL260018B/en active IP Right Grant
- 2018-10-09 AU AU2018247203A patent/AU2018247203A1/en not_active Abandoned
-
2019
- 2019-07-16 US US16/512,684 patent/US20200163918A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100584807C (zh) * | 2002-12-19 | 2010-01-27 | Bdd贝罗琳纳药品发展有限公司 | 氘化的儿茶酚胺衍生物以及含有该化合物的药物 |
| CN101384545A (zh) * | 2006-02-17 | 2009-03-11 | 比罗利纳创新研究与发展服务药物有限公司 | 氘化的儿茶酚胺衍生物及包含所述化合物的药物 |
| WO2010103273A2 (en) * | 2009-03-12 | 2010-09-16 | Amarin Neuroscience Limited | Essential fatty acid compounds |
Non-Patent Citations (1)
| Title |
|---|
| Stereo-divergent synthesis of L-threo- and L-erythro-[2,3-2H2]amino acids using optically active dioxopiperazine as a chiral template;Makoto Oba等;《J. Chem. Soc., Perkin Trans. 1》;19980101(第7期);第1275-1281页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| IL260018B (en) | 2020-01-30 |
| KR20150115807A (ko) | 2015-10-14 |
| CA2897132A1 (en) | 2014-08-14 |
| IL260018A (en) | 2018-07-31 |
| WO2014122184A1 (en) | 2014-08-14 |
| MX370884B (es) | 2020-01-09 |
| ES2901752T3 (es) | 2022-03-23 |
| MX2015010087A (es) | 2016-04-21 |
| EA201500739A1 (ru) | 2015-11-30 |
| AU2014214055A1 (en) | 2015-07-16 |
| EP2953926B1 (en) | 2021-10-20 |
| HK1214241A1 (zh) | 2016-07-22 |
| EP2953926A1 (en) | 2015-12-16 |
| US20150376117A1 (en) | 2015-12-31 |
| US9567289B2 (en) | 2017-02-14 |
| JP2016513084A (ja) | 2016-05-12 |
| CA2897132C (en) | 2021-05-25 |
| IL239733A0 (en) | 2015-08-31 |
| US20200163918A1 (en) | 2020-05-28 |
| BR112015016889A8 (pt) | 2018-01-23 |
| AU2018247203A1 (en) | 2018-11-01 |
| CN104968643A (zh) | 2015-10-07 |
| BR112015016889A2 (pt) | 2017-07-11 |
| HK1214810A1 (zh) | 2016-08-05 |
| EA028931B1 (ru) | 2018-01-31 |
| JP6704252B2 (ja) | 2020-06-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8524695B2 (en) | Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same | |
| CN107106529A (zh) | 神经衰减性氯胺酮和去甲氯胺酮化合物、其衍生物和方法 | |
| US20200163918A1 (en) | Position-specific asymmetric deuterium enriched catecholamine derivatives and medicaments comprising said compounds | |
| US20080132578A1 (en) | Dosage forms of O-desmethylvenlafaxine | |
| JP2003524613A (ja) | （−）−ベンラファキシン誘導体並びにその製造方法および使用方法 | |
| JP2003501344A (ja) | （＋）−ベンラファキシン誘導体並びにその製造方法および使用方法 | |
| IL169203A (en) | History of catecholamines that have passed through the deuterium, pharmaceutical preparations containing them and drugs containing them or their mixtures together with enzyme inhibitors | |
| JP2018530612A (ja) | パーキンソン病の治療のための重水素化レボドパとカルビドパおよびオピカポンとの組合せ | |
| US20130296414A1 (en) | 1-Phenyl-2-Dimethylaminomethyl Cyclohexane Compounds And Therapies For Depressive Symptoms, Pain and Incontinence | |
| US20190381028A1 (en) | Pharmaceutical composition for the treatment of parkinson's disease | |
| US9763904B2 (en) | Position-specific asymmetric deuterium enriched catecholamine derivatives and medicaments comprising said compounds | |
| US20210094904A1 (en) | Position-specific asymmetric deuterium enriched catecholamine derivatives and medicaments comprising said compounds | |
| CA2513077A1 (en) | Use of l-dopa, derivatives thereof and medicaments comprising said compounds for the prophylaxis of psychotic diseases | |
| US20070082953A1 (en) | Use of l-dopa, derivatives thereof and medicaments comprising said compounds for the prophylaxis of psychotic diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1214241 Country of ref document: HK |
|
| TA01 | Transfer of patent application right |
Effective date of registration: 20170531 Address after: Switzerland Jonathan Applicant after: Teva Pharmaceuticals International GmbH Address before: Ulm Applicant before: Weisuo Fan Co.,Ltd. Effective date of registration: 20170531 Address after: Ulm Applicant after: Weisuo Fan Co.,Ltd. Address before: Berlin Applicant before: Imoffel AG |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200303 Termination date: 20210205 |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1214241 Country of ref document: HK |