NZ618113B2 - Methylphenidate-prodrugs, processes of making and using the same - Google Patents
Methylphenidate-prodrugs, processes of making and using the same Download PDFInfo
- Publication number
- NZ618113B2 NZ618113B2 NZ618113A NZ61811312A NZ618113B2 NZ 618113 B2 NZ618113 B2 NZ 618113B2 NZ 618113 A NZ618113 A NZ 618113A NZ 61811312 A NZ61811312 A NZ 61811312A NZ 618113 B2 NZ618113 B2 NZ 618113B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- methylphenidate
- acid
- mmol
- mph
- present technology
- Prior art date
Links
- 239000000651 prodrug Substances 0.000 title claims abstract description 114
- 229940002612 prodrug Drugs 0.000 title claims abstract description 114
- 238000000034 method Methods 0.000 title description 33
- 230000008569 process Effects 0.000 title description 6
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 claims abstract description 277
- 229960001344 methylphenidate Drugs 0.000 claims abstract description 253
- 239000000203 mixture Substances 0.000 claims abstract description 105
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- -1 edisylate Chemical compound 0.000 claims description 145
- 229940024606 amino acid Drugs 0.000 claims description 63
- 150000001413 amino acids Chemical class 0.000 claims description 59
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 25
- 239000003826 tablet Substances 0.000 claims description 14
- 239000011664 nicotinic acid Substances 0.000 claims description 12
- 239000006188 syrup Substances 0.000 claims description 12
- 235000020357 syrup Nutrition 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 9
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 7
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 6
- 235000001968 nicotinic acid Nutrition 0.000 claims description 6
- 239000010409 thin film Substances 0.000 claims description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 4
- 125000000129 anionic group Chemical group 0.000 claims description 4
- 125000002091 cationic group Chemical group 0.000 claims description 4
- 235000011180 diphosphates Nutrition 0.000 claims description 4
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims description 4
- 229930195712 glutamate Natural products 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 3
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 3
- 239000010408 film Substances 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 3
- ATADHKWKHYVBTJ-UHFFFAOYSA-N hydron;4-[1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol;chloride Chemical compound Cl.CNCC(O)C1=CC=C(O)C(O)=C1 ATADHKWKHYVBTJ-UHFFFAOYSA-N 0.000 claims description 3
- 229940116871 l-lactate Drugs 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 3
- 229940095064 tartrate Drugs 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 3
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims description 2
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 claims description 2
- QCXJEYYXVJIFCE-UHFFFAOYSA-M 4-acetamidobenzoate Chemical compound CC(=O)NC1=CC=C(C([O-])=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-M 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 claims description 2
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims description 2
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 229920002253 Tannate Polymers 0.000 claims description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004473 Threonine Substances 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- HPFVBGJFAYZEBE-XNBTXCQYSA-N [(8r,9s,10r,13s,14s)-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl] 3-cyclopentylpropanoate Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CCC(=O)C=C3CC2)C)CC[C@@]11C)CC1OC(=O)CCC1CCCC1 HPFVBGJFAYZEBE-XNBTXCQYSA-N 0.000 claims description 2
- 229950010741 aceturate Drugs 0.000 claims description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 claims description 2
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 claims description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229940072107 ascorbate Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940050390 benzoate Drugs 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 2
- 239000007894 caplet Substances 0.000 claims description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 2
- 229940120124 dichloroacetate Drugs 0.000 claims description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 2
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 claims description 2
- 229950000206 estolate Drugs 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
- 229940110710 fusidate Drugs 0.000 claims description 2
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 claims description 2
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 claims description 2
- 229940114119 gentisate Drugs 0.000 claims description 2
- 229960001731 gluceptate Drugs 0.000 claims description 2
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 claims description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 2
- 229940070765 laurate Drugs 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 2
- QFUDHWDUKUCCHZ-UHFFFAOYSA-M methyl sulfite Chemical compound COS([O-])=O QFUDHWDUKUCCHZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940105132 myristate Drugs 0.000 claims description 2
- 229950005216 napadisilate Drugs 0.000 claims description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 claims description 2
- 239000011833 salt mixture Substances 0.000 claims description 2
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229940071103 sulfosalicylate Drugs 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 claims description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 claims description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 2
- 229960000281 trometamol Drugs 0.000 claims description 2
- 229940075466 undecylenate Drugs 0.000 claims description 2
- 229940070710 valerate Drugs 0.000 claims description 2
- 229940102566 valproate Drugs 0.000 claims description 2
- 229950000339 xinafoate Drugs 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 claims 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-M D-glucopyranuronate Chemical compound OC1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-M 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims 1
- 229940113720 aminosalicylate Drugs 0.000 claims 1
- 229940099584 lactobionate Drugs 0.000 claims 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 claims 1
- 229940049964 oleate Drugs 0.000 claims 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims 1
- 229940042126 oral powder Drugs 0.000 claims 1
- 229940092969 oral strip Drugs 0.000 claims 1
- 229940039748 oxalate Drugs 0.000 claims 1
- 229940068492 thiosalicylate Drugs 0.000 claims 1
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 72
- 238000003786 synthesis reaction Methods 0.000 abstract description 70
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 abstract description 17
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 12
- 238000011282 treatment Methods 0.000 abstract description 8
- 201000010099 disease Diseases 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 153
- 238000005516 engineering process Methods 0.000 description 149
- 239000000562 conjugate Substances 0.000 description 116
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 107
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000007787 solid Substances 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 235000001014 amino acid Nutrition 0.000 description 52
- 239000002904 solvent Substances 0.000 description 47
- 150000004715 keto acids Chemical class 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 235000019439 ethyl acetate Nutrition 0.000 description 42
- 125000003118 aryl group Chemical group 0.000 description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 33
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 229960001033 methylphenidate hydrochloride Drugs 0.000 description 27
- 239000002253 acid Substances 0.000 description 26
- 125000000217 alkyl group Chemical group 0.000 description 25
- 230000002829 reductive effect Effects 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 24
- 241000700159 Rattus Species 0.000 description 23
- 239000012267 brine Substances 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 22
- 229910052739 hydrogen Inorganic materials 0.000 description 22
- 125000005647 linker group Chemical group 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 239000003814 drug Substances 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 20
- 229940079593 drug Drugs 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 20
- 150000001412 amines Chemical class 0.000 description 19
- 125000001072 heteroaryl group Chemical group 0.000 description 19
- 239000001257 hydrogen Substances 0.000 description 19
- 150000001735 carboxylic acids Chemical class 0.000 description 18
- 229920001223 polyethylene glycol Polymers 0.000 description 18
- 150000003573 thiols Chemical class 0.000 description 18
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 17
- 125000003545 alkoxy group Chemical group 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- 125000000392 cycloalkenyl group Chemical group 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- 125000003107 substituted aryl group Chemical group 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 239000002552 dosage form Substances 0.000 description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 125000000304 alkynyl group Chemical group 0.000 description 15
- 125000000753 cycloalkyl group Chemical group 0.000 description 15
- 125000003342 alkenyl group Chemical group 0.000 description 14
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 14
- 238000002953 preparative HPLC Methods 0.000 description 14
- 201000009032 substance abuse Diseases 0.000 description 14
- 125000003710 aryl alkyl group Chemical group 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 239000002207 metabolite Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid Chemical class OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 11
- 229960003638 dopamine Drugs 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 125000001188 haloalkyl group Chemical group 0.000 description 11
- 150000002431 hydrogen Chemical class 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 230000036470 plasma concentration Effects 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical class C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 10
- 125000005110 aryl thio group Chemical group 0.000 description 10
- DUGOZIWVEXMGBE-CHWSQXEVSA-N dexmethylphenidate Chemical compound C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 DUGOZIWVEXMGBE-CHWSQXEVSA-N 0.000 description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 239000002202 Polyethylene glycol Substances 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000003282 alkyl amino group Chemical group 0.000 description 9
- 125000005210 alkyl ammonium group Chemical group 0.000 description 9
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 9
- 125000005095 alkynylaminocarbonyl group Chemical group 0.000 description 9
- 125000005018 aryl alkenyl group Chemical group 0.000 description 9
- 125000005015 aryl alkynyl group Chemical group 0.000 description 9
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 9
- 125000001769 aryl amino group Chemical group 0.000 description 9
- 125000004350 aryl cycloalkyl group Chemical group 0.000 description 9
- 125000004438 haloalkoxy group Chemical group 0.000 description 9
- 125000001475 halogen functional group Chemical group 0.000 description 9
- 125000004447 heteroarylalkenyl group Chemical group 0.000 description 9
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 9
- 125000005241 heteroarylamino group Chemical group 0.000 description 9
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 9
- 125000005553 heteroaryloxy group Chemical group 0.000 description 9
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 9
- 125000005592 polycycloalkyl group Polymers 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 9
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical class OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 125000005089 alkenylaminocarbonyl group Chemical group 0.000 description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 8
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 8
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 8
- 125000005129 aryl carbonyl group Chemical group 0.000 description 8
- 125000005199 aryl carbonyloxy group Chemical group 0.000 description 8
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 8
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 8
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 8
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 8
- 125000004104 aryloxy group Chemical group 0.000 description 8
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 8
- CGLRXKACBSXHIU-UHFFFAOYSA-N chloromethyl carbamate Chemical compound NC(=O)OCCl CGLRXKACBSXHIU-UHFFFAOYSA-N 0.000 description 8
- 125000000000 cycloalkoxy group Chemical group 0.000 description 8
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 8
- 125000005150 heteroarylsulfinyl group Chemical group 0.000 description 8
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 description 8
- 125000005368 heteroarylthio group Chemical group 0.000 description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
- DUGOZIWVEXMGBE-STQMWFEESA-N methyl (S)-phenyl[(S)-piperidin-2-yl]acetate Chemical compound C([C@H]1[C@@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 DUGOZIWVEXMGBE-STQMWFEESA-N 0.000 description 8
- 239000011570 nicotinamide Substances 0.000 description 8
- 229960003966 nicotinamide Drugs 0.000 description 8
- 229960002748 norepinephrine Drugs 0.000 description 8
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 8
- 230000000144 pharmacologic effect Effects 0.000 description 8
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 7
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 7
- 229940025084 amphetamine Drugs 0.000 description 7
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 150000001991 dicarboxylic acids Chemical class 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 230000004060 metabolic process Effects 0.000 description 7
- 229960005190 phenylalanine Drugs 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 239000000021 stimulant Substances 0.000 description 7
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 6
- 125000004423 acyloxy group Chemical group 0.000 description 6
- 125000002877 alkyl aryl group Chemical group 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229960001042 dexmethylphenidate Drugs 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N DL-isoserine Natural products NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 5
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 125000004043 oxo group Chemical group O=* 0.000 description 5
- 235000011007 phosphoric acid Nutrition 0.000 description 5
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 5
- 229920000136 polysorbate Polymers 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 5
- 150000003628 tricarboxylic acids Chemical class 0.000 description 5
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- GPVDHNVGGIAOQT-UHFFFAOYSA-N 2,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 4
- KWCCUYSXAYTNKA-UHFFFAOYSA-N 3-O-methylgallic acid Chemical compound COC1=CC(C(O)=O)=CC(O)=C1O KWCCUYSXAYTNKA-UHFFFAOYSA-N 0.000 description 4
- UBXDWYFLYYJQFR-UHFFFAOYSA-N 4-O-Methylgallic acid Chemical compound COC1=C(O)C=C(C(O)=O)C=C1O UBXDWYFLYYJQFR-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 4
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 125000005164 aryl thioalkyl group Chemical group 0.000 description 4
- 125000002843 carboxylic acid group Chemical group 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000013985 cinnamic acid Nutrition 0.000 description 4
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 208000013403 hyperactivity Diseases 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
- 229940011051 isopropyl acetate Drugs 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 4
- 230000000670 limiting effect Effects 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
- 230000037353 metabolic pathway Effects 0.000 description 4
- 229940060942 methylin Drugs 0.000 description 4
- 201000003631 narcolepsy Diseases 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229910052711 selenium Inorganic materials 0.000 description 4
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 4
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 3
- QRRRYDFIETVYRZ-UHFFFAOYSA-N 2-amino-2-[(2-methylpropan-2-yl)oxycarbonyl]hexanoic acid Chemical compound CCCCC(N)(C(O)=O)C(=O)OC(C)(C)C QRRRYDFIETVYRZ-UHFFFAOYSA-N 0.000 description 3
- YQUVCSBJEUQKSH-UHFFFAOYSA-N 3,4-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 3
- IWPZKOJSYQZABD-UHFFFAOYSA-N 3,5-dimethoxybenzoic acid Chemical compound COC1=CC(OC)=CC(C(O)=O)=C1 IWPZKOJSYQZABD-UHFFFAOYSA-N 0.000 description 3
- CURRPCDEHZEVEU-UHFFFAOYSA-N 3-(hydroxymethoxy)benzoic acid Chemical compound OCOC1=CC=CC(C(O)=O)=C1 CURRPCDEHZEVEU-UHFFFAOYSA-N 0.000 description 3
- IZZIWIAOVZOBLF-UHFFFAOYSA-N 5-methyloxysalicylic acid Natural products COC1=CC=C(O)C(C(O)=O)=C1 IZZIWIAOVZOBLF-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 241001539473 Euphoria Species 0.000 description 3
- 206010015535 Euphoric mood Diseases 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 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 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 3
- 229960003767 alanine Drugs 0.000 description 3
- 150000001414 amino alcohols Chemical class 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 208000029560 autism spectrum disease Diseases 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 3
- 229930016911 cinnamic acid Natural products 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 235000013681 dietary sucrose Nutrition 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000013265 extended release Methods 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 125000004404 heteroalkyl group Chemical group 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- DUGOZIWVEXMGBE-QWHCGFSZSA-N methyl (R)-phenyl[(S)-piperidin-2-yl]acetate Chemical compound C([C@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 DUGOZIWVEXMGBE-QWHCGFSZSA-N 0.000 description 3
- 229960003512 nicotinic acid Drugs 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229940049953 phenylacetate Drugs 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229940099204 ritalin Drugs 0.000 description 3
- IWOLVLSIZCEOHM-UHFFFAOYSA-M silver;dibenzyl phosphate Chemical compound [Ag+].C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 IWOLVLSIZCEOHM-UHFFFAOYSA-M 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 208000011117 substance-related disease Diseases 0.000 description 3
- 229940014800 succinic anhydride Drugs 0.000 description 3
- 229960004793 sucrose Drugs 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- CCVYRRGZDBSHFU-UHFFFAOYSA-N (2-hydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1O CCVYRRGZDBSHFU-UHFFFAOYSA-N 0.000 description 2
- IEXRKQFZXJSHOB-UHFFFAOYSA-N (4-nitrophenyl) formate Chemical compound [O-][N+](=O)C1=CC=C(OC=O)C=C1 IEXRKQFZXJSHOB-UHFFFAOYSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- GFAZGHREJPXDMH-UHFFFAOYSA-N 1,3-dipalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCC GFAZGHREJPXDMH-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- BRRSNXCXLSVPFC-UHFFFAOYSA-N 2,3,4-Trihydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C(O)=C1O BRRSNXCXLSVPFC-UHFFFAOYSA-N 0.000 description 2
- GPDXFYPVHRESMA-UHFFFAOYSA-N 2,4,5-trihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=C(O)C=C1O GPDXFYPVHRESMA-UHFFFAOYSA-N 0.000 description 2
- MBIZFBDREVRUHY-UHFFFAOYSA-N 2,6-Dimethoxybenzoic acid Chemical compound COC1=CC=CC(OC)=C1C(O)=O MBIZFBDREVRUHY-UHFFFAOYSA-N 0.000 description 2
- WFVBGDQDYLTEJX-UHFFFAOYSA-N 2,6-dihydroxycinnamic acid Natural products OC(=O)C=CC1=C(O)C=CC=C1O WFVBGDQDYLTEJX-UHFFFAOYSA-N 0.000 description 2
- OYIFNHCXNCRBQI-UHFFFAOYSA-N 2-aminoadipic acid Chemical compound OC(=O)C(N)CCCC(O)=O OYIFNHCXNCRBQI-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- AAUQLHHARJUJEH-UHFFFAOYSA-N 2-hydroxy-5-methoxybenzoic acid Natural products COC1=CC=CC(O)=C1C(O)=O AAUQLHHARJUJEH-UHFFFAOYSA-N 0.000 description 2
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 description 2
- CFFZDZCDUFSOFZ-UHFFFAOYSA-N 3,4-Dihydroxy-phenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C(O)=C1 CFFZDZCDUFSOFZ-UHFFFAOYSA-N 0.000 description 2
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-UHFFFAOYSA-N 0.000 description 2
- CJBDUOMQLFKVQC-UHFFFAOYSA-N 3-(2-hydroxyphenyl)propanoic acid Chemical compound OC(=O)CCC1=CC=CC=C1O CJBDUOMQLFKVQC-UHFFFAOYSA-N 0.000 description 2
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 2
- LBKFGYZQBSGRHY-UHFFFAOYSA-N 3-hydroxy-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1O LBKFGYZQBSGRHY-UHFFFAOYSA-N 0.000 description 2
- IJFXRHURBJZNAO-UHFFFAOYSA-N 3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC(O)=C1 IJFXRHURBJZNAO-UHFFFAOYSA-N 0.000 description 2
- BRARRAHGNDUELT-UHFFFAOYSA-N 3-hydroxypicolinic acid Chemical compound OC(=O)C1=NC=CC=C1O BRARRAHGNDUELT-UHFFFAOYSA-N 0.000 description 2
- AUZQQIPZESHNMG-UHFFFAOYSA-N 3-methoxysalicylic acid Chemical compound COC1=CC=CC(C(O)=O)=C1O AUZQQIPZESHNMG-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- NGSWKAQJJWESNS-UHFFFAOYSA-N 4-coumaric acid Chemical compound OC(=O)C=CC1=CC=C(O)C=C1 NGSWKAQJJWESNS-UHFFFAOYSA-N 0.000 description 2
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 2
- MRIXVKKOHPQOFK-UHFFFAOYSA-N 4-methoxysalicylic acid Chemical compound COC1=CC=C(C(O)=O)C(O)=C1 MRIXVKKOHPQOFK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CQUUHDQRJWXDPY-UHFFFAOYSA-N 6-Hydroxykynurenic acid Chemical compound C1=C(O)C=CC2=NC(C(=O)O)=CC(O)=C21 CQUUHDQRJWXDPY-UHFFFAOYSA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- HCJMNOSIAGSZBM-UHFFFAOYSA-N 6-methylsalicylic acid Chemical compound CC1=CC=CC(O)=C1C(O)=O HCJMNOSIAGSZBM-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- RYFFRLPDQKMWST-UHFFFAOYSA-N COC(C(C(CCCC1)N1C(OCI)=O)=O)C1=CC=CC=C1 Chemical compound COC(C(C(CCCC1)N1C(OCI)=O)=O)C1=CC=CC=C1 RYFFRLPDQKMWST-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 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 2
- 239000004472 Lysine Substances 0.000 description 2
- DATAGRPVKZEWHA-YFKPBYRVSA-N N(5)-ethyl-L-glutamine Chemical compound CCNC(=O)CC[C@H]([NH3+])C([O-])=O DATAGRPVKZEWHA-YFKPBYRVSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 206010033557 Palpitations Diseases 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000001871 Tachycardia Diseases 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 2
- AKZWRTCWNXHHFR-PDIZUQLASA-N [(3S)-oxolan-3-yl] N-[(2S,3S)-4-[(5S)-5-benzyl-3-[(2R)-2-carbamoyloxy-2,3-dihydro-1H-inden-1-yl]-4-oxo-3H-pyrrol-5-yl]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound NC(=O)O[C@@H]1Cc2ccccc2C1C1C=N[C@](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)(Cc2ccccc2)C1=O AKZWRTCWNXHHFR-PDIZUQLASA-N 0.000 description 2
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 229960002684 aminocaproic acid Drugs 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 229960003121 arginine Drugs 0.000 description 2
- 125000000732 arylene group Chemical group 0.000 description 2
- 229940009098 aspartate Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- QMKYBPDZANOJGF-UHFFFAOYSA-N benzene-1,3,5-tricarboxylic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC(C(O)=O)=C1 QMKYBPDZANOJGF-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229960003920 cocaine Drugs 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000007891 compressed tablet Substances 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000001177 diphosphate Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229940053650 focalin Drugs 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940049906 glutamate Drugs 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- IGMNYECMUMZDDF-UHFFFAOYSA-N homogentisic acid Chemical compound OC(=O)CC1=CC(O)=CC=C1O IGMNYECMUMZDDF-UHFFFAOYSA-N 0.000 description 2
- QRMZSPFSDQBLIX-UHFFFAOYSA-N homovanillic acid Chemical compound COC1=CC(CC(O)=O)=CC=C1O QRMZSPFSDQBLIX-UHFFFAOYSA-N 0.000 description 2
- WUAXWQRULBZETB-UHFFFAOYSA-N homoveratric acid Chemical compound COC1=CC=C(CC(O)=O)C=C1OC WUAXWQRULBZETB-UHFFFAOYSA-N 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- BTNMPGBKDVTSJY-UHFFFAOYSA-N keto-phenylpyruvic acid Chemical compound OC(=O)C(=O)CC1=CC=CC=C1 BTNMPGBKDVTSJY-UHFFFAOYSA-N 0.000 description 2
- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- KEMQGTRYUADPNZ-UHFFFAOYSA-N n-heptadecanoic acid Natural products CCCCCCCCCCCCCCCCC(O)=O KEMQGTRYUADPNZ-UHFFFAOYSA-N 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 230000001561 neurotransmitter reuptake Effects 0.000 description 2
- 230000019818 neurotransmitter uptake Effects 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- INGSNVSERUZOAK-UHFFFAOYSA-N ritalinic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)C1CCCCN1 INGSNVSERUZOAK-UHFFFAOYSA-N 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000006748 scratching Methods 0.000 description 2
- 230000002393 scratching effect Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- LMEWRZSPCQHBOB-UHFFFAOYSA-M silver;2-hydroxypropanoate Chemical compound [Ag+].CC(O)C([O-])=O LMEWRZSPCQHBOB-UHFFFAOYSA-M 0.000 description 2
- PCMORTLOPMLEFB-ONEGZZNKSA-N sinapic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC(OC)=C1O PCMORTLOPMLEFB-ONEGZZNKSA-N 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 231100000736 substance abuse Toxicity 0.000 description 2
- 125000005017 substituted alkenyl group Chemical group 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000004426 substituted alkynyl group Chemical group 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- JMSVCTWVEWCHDZ-UHFFFAOYSA-N syringic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1O JMSVCTWVEWCHDZ-UHFFFAOYSA-N 0.000 description 2
- 230000006794 tachycardia Effects 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- RQCVJYHIRCKECA-UHFFFAOYSA-N tert-butyl 2-[[2-(pyridine-3-carbonylamino)acetyl]amino]propanoate Chemical compound CC(C)(C)OC(=O)C(C)NC(=O)CNC(=O)C1=CC=CN=C1 RQCVJYHIRCKECA-UHFFFAOYSA-N 0.000 description 2
- JDUFHJZHJNEQBU-UHFFFAOYSA-N tert-butyl 3-methyl-2-(pyridine-3-carbonylamino)butanoate Chemical compound CC(C)(C)OC(=O)C(C(C)C)NC(=O)C1=CC=CN=C1 JDUFHJZHJNEQBU-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 description 2
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 description 2
- 238000011277 treatment modality Methods 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- ITYNGVSTWVVPIC-DHGKCCLASA-N (-)-allo-Aromadendrene Chemical compound C([C@@H]1[C@H]2C1(C)C)CC(=C)[C@@H]1[C@H]2[C@H](C)CC1 ITYNGVSTWVVPIC-DHGKCCLASA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- IQVLXQGNLCPZCL-ZDUSSCGKSA-N (2,5-dioxopyrrolidin-1-yl) (2s)-2,6-bis[(2-methylpropan-2-yl)oxycarbonylamino]hexanoate Chemical compound CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O IQVLXQGNLCPZCL-ZDUSSCGKSA-N 0.000 description 1
- CROCAQYJJNCZQH-UHFFFAOYSA-N (2,6-dihydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=C(O)C=CC=C1O CROCAQYJJNCZQH-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- BWBQXMAXLAHHTK-YFKPBYRVSA-N (2r)-2-(2-methylpropanoylamino)-3-sulfanylpropanoic acid Chemical compound CC(C)C(=O)N[C@@H](CS)C(O)=O BWBQXMAXLAHHTK-YFKPBYRVSA-N 0.000 description 1
- FDKWRPBBCBCIGA-REOHCLBHSA-N (2r)-2-azaniumyl-3-$l^{1}-selanylpropanoate Chemical compound [Se]C[C@H](N)C(O)=O FDKWRPBBCBCIGA-REOHCLBHSA-N 0.000 description 1
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- POGSZHUEECCEAP-ZETCQYMHSA-N (2s)-2-amino-3-(3-amino-4-hydroxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(N)=C1 POGSZHUEECCEAP-ZETCQYMHSA-N 0.000 description 1
- OXNUZCWFCJRJSU-VIFPVBQESA-N (2s)-2-amino-3-[4-(hydroxymethyl)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(CO)C=C1 OXNUZCWFCJRJSU-VIFPVBQESA-N 0.000 description 1
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 1
- OSCCDBFHNMXNME-WDCZJNDASA-N (2s,3s,4r)-2-amino-4-hydroxy-3-methylpentanoic acid Chemical compound C[C@@H](O)[C@@H](C)[C@H](N)C(O)=O OSCCDBFHNMXNME-WDCZJNDASA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- QBLFZIBJXUQVRF-UHFFFAOYSA-N (4-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Br)C=C1 QBLFZIBJXUQVRF-UHFFFAOYSA-N 0.000 description 1
- YUFFSWGQGVEMMI-JLNKQSITSA-N (7Z,10Z,13Z,16Z,19Z)-docosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCCC(O)=O YUFFSWGQGVEMMI-JLNKQSITSA-N 0.000 description 1
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 description 1
- YFXWTVLDSKSYLW-UHFFFAOYSA-N (E)-3,4-dihydroxy-5-methoxycinnamic acid Natural products COC1=CC(C=CC(O)=O)=CC(O)=C1O YFXWTVLDSKSYLW-UHFFFAOYSA-N 0.000 description 1
- YFXWTVLDSKSYLW-NSCUHMNNSA-N (E)-5-hydroxyferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC(O)=C1O YFXWTVLDSKSYLW-NSCUHMNNSA-N 0.000 description 1
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 description 1
- IADUEWIQBXOCDZ-VKHMYHEASA-N (S)-azetidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCN1 IADUEWIQBXOCDZ-VKHMYHEASA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- JACRWUWPXAESPB-MRVPVSSYSA-N (S)-tropic acid Chemical compound OC[C@@H](C(O)=O)C1=CC=CC=C1 JACRWUWPXAESPB-MRVPVSSYSA-N 0.000 description 1
- CQNPVMCASGWEHM-VMPITWQZSA-N (e)-3-[4-(dimethylamino)phenyl]prop-2-enoic acid Chemical compound CN(C)C1=CC=C(\C=C\C(O)=O)C=C1 CQNPVMCASGWEHM-VMPITWQZSA-N 0.000 description 1
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- ADUSGJRADQMJGN-UHFFFAOYSA-N 2,3,6-trihydroxybenzoic acid Chemical compound OC(=O)C1=C(O)C=CC(O)=C1O ADUSGJRADQMJGN-UHFFFAOYSA-N 0.000 description 1
- KKTUQAYCCLMNOA-UHFFFAOYSA-N 2,3-diaminobenzoic acid Chemical compound NC1=CC=CC(C(O)=O)=C1N KKTUQAYCCLMNOA-UHFFFAOYSA-N 0.000 description 1
- FODBVCSYJKNBLO-UHFFFAOYSA-N 2,3-dimethoxybenzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1OC FODBVCSYJKNBLO-UHFFFAOYSA-N 0.000 description 1
- OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical compound OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 description 1
- NYJBTJMNTNCTCP-UHFFFAOYSA-N 2,5-dimethoxybenzoic acid Chemical compound COC1=CC=C(OC)C(C(O)=O)=C1 NYJBTJMNTNCTCP-UHFFFAOYSA-N 0.000 description 1
- IGCZQNUHGOYVJI-UHFFFAOYSA-N 2,6-dihydroxynicotinic acid Chemical compound OC(=O)C1=CC=C(O)N=C1O IGCZQNUHGOYVJI-UHFFFAOYSA-N 0.000 description 1
- CCMSNQOGKCTUKR-UHFFFAOYSA-N 2-(2,3-dihydroxyphenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=CC(O)=C1O CCMSNQOGKCTUKR-UHFFFAOYSA-N 0.000 description 1
- RZWGTXHSYZGXKF-UHFFFAOYSA-N 2-(2-methylphenyl)acetic acid Chemical class CC1=CC=CC=C1CC(O)=O RZWGTXHSYZGXKF-UHFFFAOYSA-N 0.000 description 1
- BYRVXROVZBYNOZ-UHFFFAOYSA-N 2-(3-hydroxyphenyl)propionic acid Chemical compound OC(=O)C(C)C1=CC=CC(O)=C1 BYRVXROVZBYNOZ-UHFFFAOYSA-N 0.000 description 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- KUHAYJJXXGBYBW-UHFFFAOYSA-N 2-amino-3-fluorobenzoic acid Chemical compound NC1=C(F)C=CC=C1C(O)=O KUHAYJJXXGBYBW-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- LMIZLNPFTRQPSF-UHFFFAOYSA-N 2-azaniumyl-2-(2-chlorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=CC=C1Cl LMIZLNPFTRQPSF-UHFFFAOYSA-N 0.000 description 1
- IOABLDGLYOGEHY-UHFFFAOYSA-N 2-azaniumyl-3-[2-(trifluoromethyl)phenyl]propanoate Chemical compound OC(=O)C(N)CC1=CC=CC=C1C(F)(F)F IOABLDGLYOGEHY-UHFFFAOYSA-N 0.000 description 1
- ZAYJDMWJYCTABM-UHFFFAOYSA-N 2-azaniumyl-3-hydroxy-4-methylpentanoate Chemical compound CC(C)C(O)C(N)C(O)=O ZAYJDMWJYCTABM-UHFFFAOYSA-N 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- VFIVMIIQIYPVCM-UHFFFAOYSA-N 2-hydroxy-4,5-dimethylbenzoic acid Chemical compound CC1=CC(O)=C(C(O)=O)C=C1C VFIVMIIQIYPVCM-UHFFFAOYSA-N 0.000 description 1
- 239000001903 2-oxo-3-phenylpropanoic acid Substances 0.000 description 1
- ONPJWQSDZCGSQM-UHFFFAOYSA-N 2-phenylprop-2-enoic acid Chemical compound OC(=O)C(=C)C1=CC=CC=C1 ONPJWQSDZCGSQM-UHFFFAOYSA-N 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- QFRURJKLPJVRQY-UHFFFAOYSA-N 3-Aminopentanoic acid Chemical compound CCC(N)CC(O)=O QFRURJKLPJVRQY-UHFFFAOYSA-N 0.000 description 1
- LNTQBWYEEYBVAK-UHFFFAOYSA-N 3-amino-2-(3-methoxyphenyl)propanoic acid Chemical compound COC1=CC=CC(C(CN)C(O)=O)=C1 LNTQBWYEEYBVAK-UHFFFAOYSA-N 0.000 description 1
- OQEBBZSWEGYTPG-UHFFFAOYSA-N 3-aminobutanoic acid Chemical compound CC(N)CC(O)=O OQEBBZSWEGYTPG-UHFFFAOYSA-N 0.000 description 1
- QCHPKSFMDHPSNR-UHFFFAOYSA-N 3-aminoisobutyric acid Chemical compound NCC(C)C(O)=O QCHPKSFMDHPSNR-UHFFFAOYSA-N 0.000 description 1
- KMXXSJLYVJEBHI-UHFFFAOYSA-N 3-guanidinopropanoic acid Chemical compound NC(=[NH2+])NCCC([O-])=O KMXXSJLYVJEBHI-UHFFFAOYSA-N 0.000 description 1
- NPOAOTPXWNWTSH-UHFFFAOYSA-N 3-hydroxy-3-methylglutaric acid Chemical compound OC(=O)CC(O)(C)CC(O)=O NPOAOTPXWNWTSH-UHFFFAOYSA-N 0.000 description 1
- FVMDYYGIDFPZAX-UHFFFAOYSA-N 3-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=CC(O)=C1 FVMDYYGIDFPZAX-UHFFFAOYSA-N 0.000 description 1
- WHSXTWFYRGOBGO-UHFFFAOYSA-N 3-methylsalicylic acid Chemical compound CC1=CC=CC(C(O)=O)=C1O WHSXTWFYRGOBGO-UHFFFAOYSA-N 0.000 description 1
- UOFQNDPLYKPNRC-UHFFFAOYSA-N 4-(hydroxymethoxy)benzoic acid Chemical compound OCOC1=CC=C(C(O)=O)C=C1 UOFQNDPLYKPNRC-UHFFFAOYSA-N 0.000 description 1
- NGSWKAQJJWESNS-ZZXKWVIFSA-M 4-Hydroxycinnamate Natural products OC1=CC=C(\C=C\C([O-])=O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-M 0.000 description 1
- ZDWWCRQXNJGGFF-UHFFFAOYSA-N 4-[5]-ladderane-butanoic acid Chemical compound C12CCC2C(C23)C1C3C1C2CC1CCCC(=O)O ZDWWCRQXNJGGFF-UHFFFAOYSA-N 0.000 description 1
- CMUHFUGDYMFHEI-QMMMGPOBSA-N 4-amino-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N)C=C1 CMUHFUGDYMFHEI-QMMMGPOBSA-N 0.000 description 1
- FZGYCAHIHBHTNY-UHFFFAOYSA-N 4-hydroxy-2-methyl-5-propan-2-ylbenzoic acid Chemical compound CC(C)C1=CC(C(O)=O)=C(C)C=C1O FZGYCAHIHBHTNY-UHFFFAOYSA-N 0.000 description 1
- BXZSKDOPGDPDEG-UHFFFAOYSA-N 4-hydroxy-8-methoxyquinaldic acid Chemical compound N1C(C(O)=O)=CC(=O)C2=C1C(OC)=CC=C2 BXZSKDOPGDPDEG-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- KKADPXVIOXHVKN-UHFFFAOYSA-N 4-hydroxyphenylpyruvic acid Chemical compound OC(=O)C(=O)CC1=CC=C(O)C=C1 KKADPXVIOXHVKN-UHFFFAOYSA-N 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- AQSCHALQLXXKKC-UHFFFAOYSA-N 4-phenylmethoxybenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OCC1=CC=CC=C1 AQSCHALQLXXKKC-UHFFFAOYSA-N 0.000 description 1
- 229940117976 5-hydroxylysine Drugs 0.000 description 1
- HUNCSWANZMJLPM-UHFFFAOYSA-N 5-methyltryptophan Chemical compound CC1=CC=C2NC=C(CC(N)C(O)=O)C2=C1 HUNCSWANZMJLPM-UHFFFAOYSA-N 0.000 description 1
- AYMKDPCMEDAVJJ-UHFFFAOYSA-N 6-[3]-ladderane-hexanoic acid Chemical compound C1C(CCCCCC(=O)O)CCC2C3C4CCC4C3C12 AYMKDPCMEDAVJJ-UHFFFAOYSA-N 0.000 description 1
- FWADMOZVPHIBNO-UHFFFAOYSA-N 6-[5]-ladderane-hexanoic acid Chemical compound C12CCC2C(C23)C1C3C1C2CC1CCCCCC(=O)O FWADMOZVPHIBNO-UHFFFAOYSA-N 0.000 description 1
- BLHCMGRVFXRYRN-UHFFFAOYSA-N 6-hydroxynicotinic acid Chemical compound OC(=O)C1=CC=C(O)N=C1 BLHCMGRVFXRYRN-UHFFFAOYSA-N 0.000 description 1
- LLAWHKBFIBTIBH-UHFFFAOYSA-N 7,8-dihydro-7,8-dihydroxykynurenic acid Chemical compound C1=C(C(O)=O)N=C2C(O)C(O)C=CC2=C1O LLAWHKBFIBTIBH-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- DFYRUELUNQRZTB-UHFFFAOYSA-N Acetovanillone Natural products COC1=CC(C(C)=O)=CC=C1O DFYRUELUNQRZTB-UHFFFAOYSA-N 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 206010001497 Agitation Diseases 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
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 208000036640 Asperger disease Diseases 0.000 description 1
- 201000006062 Asperger syndrome Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- ZYFJDFORVMPWOP-UHFFFAOYSA-N CCCCCCCCCC(CCCCCCCCCCCCCCCC=CC(O)=O)=O Chemical class CCCCCCCCCC(CCCCCCCCCCCCCCCC=CC(O)=O)=O ZYFJDFORVMPWOP-UHFFFAOYSA-N 0.000 description 1
- QPASWNBVNXONKE-UHFFFAOYSA-N COC(C(C(CCCC1)N1C(O)=O)=O)C1=CC=CC=C1 Chemical compound COC(C(C(CCCC1)N1C(O)=O)=O)C1=CC=CC=C1 QPASWNBVNXONKE-UHFFFAOYSA-N 0.000 description 1
- RNXCQLGWOINOSC-UHFFFAOYSA-N COC(C(C(CCCC1)N1C(OCOC(C1=CC=NC=C1)=O)=O)=O)C1=CC=CC=C1 Chemical compound COC(C(C(CCCC1)N1C(OCOC(C1=CC=NC=C1)=O)=O)=O)C1=CC=CC=C1 RNXCQLGWOINOSC-UHFFFAOYSA-N 0.000 description 1
- GLIJIYHIGNJSEU-UHFFFAOYSA-N COC(C(C(CCCC1)N1C(OCOC(C1=CN=CC=C1)=O)=O)=O)C1=CC=CC=C1 Chemical compound COC(C(C(CCCC1)N1C(OCOC(C1=CN=CC=C1)=O)=O)=O)C1=CC=CC=C1 GLIJIYHIGNJSEU-UHFFFAOYSA-N 0.000 description 1
- IJVBHPNKHOXCKA-UHFFFAOYSA-N COC(C(C(CCCC1)N1C(OCOP(OCC1=CC=CC=C1)(OCC1=CC=CC=C1)=O)=O)=O)C1=CC=CC=C1 Chemical compound COC(C(C(CCCC1)N1C(OCOP(OCC1=CC=CC=C1)(OCC1=CC=CC=C1)=O)=O)=O)C1=CC=CC=C1 IJVBHPNKHOXCKA-UHFFFAOYSA-N 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- YPWSLBHSMIKTPR-UHFFFAOYSA-N Cystathionine Natural products OC(=O)C(N)CCSSCC(N)C(O)=O YPWSLBHSMIKTPR-UHFFFAOYSA-N 0.000 description 1
- 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 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
- FDKWRPBBCBCIGA-UWTATZPHSA-N D-Selenocysteine Natural products [Se]C[C@@H](N)C(O)=O FDKWRPBBCBCIGA-UWTATZPHSA-N 0.000 description 1
- ILRYLPWNYFXEMH-UHFFFAOYSA-N D-cystathionine Natural products OC(=O)C(N)CCSCC(N)C(O)=O ILRYLPWNYFXEMH-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- ODBLHEXUDAPZAU-ZAFYKAAXSA-N D-threo-isocitric acid Chemical compound OC(=O)[C@H](O)[C@@H](C(O)=O)CC(O)=O ODBLHEXUDAPZAU-ZAFYKAAXSA-N 0.000 description 1
- 208000024254 Delusional disease Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021294 Docosapentaenoic acid Nutrition 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 208000030814 Eating disease Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- QURCVMIEKCOAJU-HWKANZROSA-N Isoferulic acid Natural products COC1=CC=C(\C=C\C(O)=O)C=C1O QURCVMIEKCOAJU-HWKANZROSA-N 0.000 description 1
- CZCIKBSVHDNIDH-LLVKDONJSA-N L-Abrine Natural products C1=CC=C2C(C[C@@H](NC)C(O)=O)=CNC2=C1 CZCIKBSVHDNIDH-LLVKDONJSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- 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 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- QUOGESRFPZDMMT-UHFFFAOYSA-N L-Homoarginine Natural products OC(=O)C(N)CCCCNC(N)=N QUOGESRFPZDMMT-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-UHNVWZDZSA-N L-allo-Isoleucine Chemical compound CC[C@@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-UHNVWZDZSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- ILRYLPWNYFXEMH-WHFBIAKZSA-N L-cystathionine Chemical compound [O-]C(=O)[C@@H]([NH3+])CCSC[C@H]([NH3+])C([O-])=O ILRYLPWNYFXEMH-WHFBIAKZSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- QUOGESRFPZDMMT-YFKPBYRVSA-N L-homoarginine Chemical compound OC(=O)[C@@H](N)CCCCNC(N)=N QUOGESRFPZDMMT-YFKPBYRVSA-N 0.000 description 1
- XIGSAGMEBXLVJJ-YFKPBYRVSA-N L-homocitrulline Chemical compound NC(=O)NCCCC[C@H]([NH3+])C([O-])=O XIGSAGMEBXLVJJ-YFKPBYRVSA-N 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 1
- ZFOMKMMPBOQKMC-KXUCPTDWSA-N L-pyrrolysine Chemical compound C[C@@H]1CC=N[C@H]1C(=O)NCCCC[C@H]([NH3+])C([O-])=O ZFOMKMMPBOQKMC-KXUCPTDWSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 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 1
- 206010024264 Lethargy Diseases 0.000 description 1
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- CZCIKBSVHDNIDH-NSHDSACASA-N N(alpha)-methyl-L-tryptophan Chemical compound C1=CC=C2C(C[C@H]([NH2+]C)C([O-])=O)=CNC2=C1 CZCIKBSVHDNIDH-NSHDSACASA-N 0.000 description 1
- WRUZLCLJULHLEY-UHFFFAOYSA-N N-(p-hydroxyphenyl)glycine Chemical compound OC(=O)CNC1=CC=C(O)C=C1 WRUZLCLJULHLEY-UHFFFAOYSA-N 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- 108010079364 N-glycylalanine Proteins 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- CZCIKBSVHDNIDH-UHFFFAOYSA-N Nalpha-methyl-DL-tryptophan Natural products C1=CC=C2C(CC(NC)C(O)=O)=CNC2=C1 CZCIKBSVHDNIDH-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 206010029216 Nervousness Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- RGHMISIYKIHAJW-DRNAETIESA-N O(C=1C=C([C@@H](C(=O)O)O)C=CC=1O[2H])[2H] Chemical compound O(C=1C=C([C@@H](C(=O)O)O)C=CC=1O[2H])[2H] RGHMISIYKIHAJW-DRNAETIESA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 235000010676 Ocimum basilicum Nutrition 0.000 description 1
- 240000007926 Ocimum gratissimum Species 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010033864 Paranoia Diseases 0.000 description 1
- 208000027099 Paranoid disease Diseases 0.000 description 1
- 208000012202 Pervasive developmental disease Diseases 0.000 description 1
- QPFYXYFORQJZEC-FOCLMDBBSA-N Phenazopyridine Chemical compound NC1=NC(N)=CC=C1\N=N\C1=CC=CC=C1 QPFYXYFORQJZEC-FOCLMDBBSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 241000289690 Xenarthra Species 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 150000003869 acetamides Chemical class 0.000 description 1
- VJCZCTYNRNFPQY-UHFFFAOYSA-N acetic acid;2-phenylpropanoic acid Chemical compound CC(O)=O.OC(=O)C(C)C1=CC=CC=C1 VJCZCTYNRNFPQY-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 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
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- WNNNWFKQCKFSDK-UHFFFAOYSA-N allylglycine Chemical compound OC(=O)C(N)CC=C WNNNWFKQCKFSDK-UHFFFAOYSA-N 0.000 description 1
- YOFPFYYTUIARDI-UHFFFAOYSA-N alpha-aminosuberic acid Chemical compound OC(=O)C(N)CCCCCC(O)=O YOFPFYYTUIARDI-UHFFFAOYSA-N 0.000 description 1
- DEDGUGJNLNLJSR-UHFFFAOYSA-N alpha-hydroxycinnamic acid Natural products OC(=O)C(O)=CC1=CC=CC=C1 DEDGUGJNLNLJSR-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000014398 anacardic acid Nutrition 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- ZYTLPUIDJRKAAM-UHFFFAOYSA-N benzyl 2-hydroxypropanoate Chemical compound CC(O)C(=O)OCC1=CC=CC=C1 ZYTLPUIDJRKAAM-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000005621 boronate group Chemical class 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 235000004883 caffeic acid Nutrition 0.000 description 1
- 229940074360 caffeic acid Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 235000005473 carotenes Nutrition 0.000 description 1
- 150000001746 carotenes Chemical class 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000003943 catecholamines Chemical group 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229940099352 cholate Drugs 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 150000001851 cinnamic acid derivatives Chemical class 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 229940112502 concerta Drugs 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- PYRZPBDTPRQYKG-UHFFFAOYSA-N cyclopentene-1-carboxylic acid Chemical compound OC(=O)C1=CCCC1 PYRZPBDTPRQYKG-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- ARISNIBDHYEENQ-UHFFFAOYSA-N ditert-butyl 2-(pyridine-3-carbonylamino)butanedioate Chemical compound CC(C)(C)OC(=O)CC(C(=O)OC(C)(C)C)NC(=O)C1=CC=CN=C1 ARISNIBDHYEENQ-UHFFFAOYSA-N 0.000 description 1
- NAGJZTKCGNOGPW-UHFFFAOYSA-N dithiophosphoric acid Chemical class OP(O)(S)=S NAGJZTKCGNOGPW-UHFFFAOYSA-N 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- DVSZKTAMJJTWFG-UHFFFAOYSA-N docosa-2,4,6,8,10,12-hexaenoic acid Chemical class CCCCCCCCCC=CC=CC=CC=CC=CC=CC(O)=O DVSZKTAMJJTWFG-UHFFFAOYSA-N 0.000 description 1
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-MDZDMXLPSA-N elaidic acid Chemical compound CCCCCCCC\C=C\CCCCCCCC(O)=O ZQPPMHVWECSIRJ-MDZDMXLPSA-N 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229940064982 ethylnicotinate Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 description 1
- 235000001785 ferulic acid Nutrition 0.000 description 1
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 description 1
- 229940114124 ferulic acid Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- OSCCDBFHNMXNME-UHFFFAOYSA-N gamma-hydroxyisoleucine Natural products CC(O)C(C)C(N)C(O)=O OSCCDBFHNMXNME-UHFFFAOYSA-N 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- NNNVXFKZMRGJPM-UHFFFAOYSA-N hexadec-6-enoic acid Chemical compound CCCCCCCCCC=CCCCCC(O)=O NNNVXFKZMRGJPM-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000006445 hexyl cyclopropyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 229930005346 hydroxycinnamic acid Natural products 0.000 description 1
- 235000010359 hydroxycinnamic acids Nutrition 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- VVIUBCNYACGLLV-UHFFFAOYSA-N hypotaurine Chemical compound [NH3+]CCS([O-])=O VVIUBCNYACGLLV-UHFFFAOYSA-N 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229940060367 inert ingredients Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- KPJPHPFMCOKUMW-UHFFFAOYSA-N iodomethane Chemical compound I[CH2] KPJPHPFMCOKUMW-UHFFFAOYSA-N 0.000 description 1
- XLLBTSILSOJMTH-UHFFFAOYSA-N iodomethyl carbamate Chemical compound NC(=O)OCI XLLBTSILSOJMTH-UHFFFAOYSA-N 0.000 description 1
- BWXLCOBSWMQCGP-UHFFFAOYSA-N isohomovanillic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1O BWXLCOBSWMQCGP-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- GCHPUFAZSONQIV-UHFFFAOYSA-N isovaline Chemical compound CCC(C)(N)C(O)=O GCHPUFAZSONQIV-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-O lysinium(1+) Chemical compound [NH3+]CCCCC([NH3+])C([O-])=O KDXKERNSBIXSRK-UHFFFAOYSA-O 0.000 description 1
- 229920001427 mPEG Polymers 0.000 description 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001961 meglutol Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- HWDNZLIVCGDZFU-UHFFFAOYSA-N methyl 2-phenyl-2-piperidin-1-ylacetate Chemical compound C=1C=CC=CC=1C(C(=O)OC)N1CCCCC1 HWDNZLIVCGDZFU-UHFFFAOYSA-N 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 229940000455 methylphenidate chewable tablet Drugs 0.000 description 1
- JUMYIBMBTDDLNG-UHFFFAOYSA-N methylphenidate hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(C(=O)OC)C1CCCC[NH2+]1 JUMYIBMBTDDLNG-UHFFFAOYSA-N 0.000 description 1
- 229940000431 methylphenidate oral solution Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- SKEAGJWUKCNICJ-LSDHHAIUSA-N n-[(4-fluoro-3-methoxyphenyl)methyl]-6-[2-[[(2s,5r)-5-(hydroxymethyl)-1,4-dioxan-2-yl]methyl]tetrazol-5-yl]-2-methylpyrimidine-4-carboxamide Chemical compound C1=C(F)C(OC)=CC(CNC(=O)C=2N=C(C)N=C(C=2)C2=NN(C[C@@H]3OC[C@@H](CO)OC3)N=N2)=C1 SKEAGJWUKCNICJ-LSDHHAIUSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 1
- ANPWLBTUUNFQIO-UHFFFAOYSA-N n-bis(phenylmethoxy)phosphanyl-n-propan-2-ylpropan-2-amine Chemical compound C=1C=CC=CC=1COP(N(C(C)C)C(C)C)OCC1=CC=CC=C1 ANPWLBTUUNFQIO-UHFFFAOYSA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000003880 negative regulation of appetite Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 1
- BMQNWLUEXNQIGL-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O.CCCCCCCCC(O)=O BMQNWLUEXNQIGL-UHFFFAOYSA-N 0.000 description 1
- 230000002474 noradrenergic effect Effects 0.000 description 1
- 230000000966 norepinephrine reuptake Effects 0.000 description 1
- 230000012154 norepinephrine uptake Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- LDCYZAJDBXYCGN-UHFFFAOYSA-N oxitriptan Natural products C1=C(O)C=C2C(CC(N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-UHFFFAOYSA-N 0.000 description 1
- SECPZKHBENQXJG-BQYQJAHWSA-N palmitelaidic acid Chemical compound CCCCCC\C=C\CCCCCCCC(O)=O SECPZKHBENQXJG-BQYQJAHWSA-N 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 208000002851 paranoid schizophrenia Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000000863 peptide conjugate Substances 0.000 description 1
- CNVZJPUDSLNTQU-OUKQBFOZSA-N petroselaidic acid Chemical compound CCCCCCCCCCC\C=C\CCCCC(O)=O CNVZJPUDSLNTQU-OUKQBFOZSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WRAQQYDMVSCOTE-UHFFFAOYSA-N phenyl prop-2-enoate Chemical compound C=CC(=O)OC1=CC=CC=C1 WRAQQYDMVSCOTE-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 1
- 150000008298 phosphoramidates Chemical class 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 229940081066 picolinic acid Drugs 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 210000005215 presynaptic neuron Anatomy 0.000 description 1
- 230000003405 preventing effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000003368 psychostimulant agent Substances 0.000 description 1
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 1
- VXHVELPLHCCGQL-UHFFFAOYSA-N pyridine-3-carboxylic acid;silver Chemical compound [Ag].OC(=O)C1=CC=CN=C1 VXHVELPLHCCGQL-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229940070891 pyridium Drugs 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 229940055619 selenocysteine Drugs 0.000 description 1
- 235000016491 selenocysteine Nutrition 0.000 description 1
- ZKZBPNGNEQAJSX-UHFFFAOYSA-N selenocysteine Natural products [SeH]CC(N)C(O)=O ZKZBPNGNEQAJSX-UHFFFAOYSA-N 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- GWEHCLOUYRTZBW-UHFFFAOYSA-M silver;3,4,5-tris(phenylmethoxy)benzoate Chemical compound [Ag+].C=1C=CC=CC=1COC=1C(OCC=2C=CC=CC=2)=CC(C(=O)[O-])=CC=1OCC1=CC=CC=C1 GWEHCLOUYRTZBW-UHFFFAOYSA-M 0.000 description 1
- NQWOVPVQKPJSGY-UHFFFAOYSA-M silver;4-bis(phenylmethoxy)phosphoryloxybenzoate Chemical compound [Ag+].C1=CC(C(=O)[O-])=CC=C1OP(=O)(OCC=1C=CC=CC=1)OCC1=CC=CC=C1 NQWOVPVQKPJSGY-UHFFFAOYSA-M 0.000 description 1
- LTYHQUJGIQUHMS-UHFFFAOYSA-M silver;hexadecanoate Chemical compound [Ag+].CCCCCCCCCCCCCCCC([O-])=O LTYHQUJGIQUHMS-UHFFFAOYSA-M 0.000 description 1
- OOCBYRSQSSLQFR-UHFFFAOYSA-M silver;pyridine-4-carboxylate Chemical compound [Ag+].[O-]C(=O)C1=CC=NC=C1 OOCBYRSQSSLQFR-UHFFFAOYSA-M 0.000 description 1
- PCMORTLOPMLEFB-UHFFFAOYSA-N sinapinic acid Natural products COC1=CC(C=CC(O)=O)=CC(OC)=C1O PCMORTLOPMLEFB-UHFFFAOYSA-N 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008234 soft water Substances 0.000 description 1
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical compound CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical group C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YIBXWXOYFGZLRU-UHFFFAOYSA-N syringic aldehyde Natural products CC12CCC(C3(CCC(=O)C(C)(C)C3CC=3)C)C=3C1(C)CCC2C1COC(C)(C)C(O)C(O)C1 YIBXWXOYFGZLRU-UHFFFAOYSA-N 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILNOTKMMDBWGOK-UHFFFAOYSA-N tert-butyl n-[2-(4-hydroxyphenyl)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCC1=CC=C(O)C=C1 ILNOTKMMDBWGOK-UHFFFAOYSA-N 0.000 description 1
- JYEVUDXCQHLXNG-UHFFFAOYSA-N tert-butyl pyridine-3-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=CN=C1 JYEVUDXCQHLXNG-UHFFFAOYSA-N 0.000 description 1
- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940026510 theanine Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 150000004764 thiosulfuric acid derivatives Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- NGSWKAQJJWESNS-ZZXKWVIFSA-N trans-4-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-N 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- KQTIIICEAUMSDG-UHFFFAOYSA-N tricarballylic acid Chemical compound OC(=O)CC(C(O)=O)CC(O)=O KQTIIICEAUMSDG-UHFFFAOYSA-N 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 150000003668 tyrosines Chemical class 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 230000006441 vascular event Effects 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- FBZONXHGGPHHIY-UHFFFAOYSA-N xanthurenic acid Chemical compound C1=CC=C(O)C2=NC(C(=O)O)=CC(O)=C21 FBZONXHGGPHHIY-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- 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
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- 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
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
Abstract
Disclosed herein are methylphenidate prodrug compositions comprising the compound of the general formula shown. The compositions are intended for the treatment of various diseases and/or disorders including ADHD. Also disclosed is the synthesis of methylphenidate and the prodrug derivatives thereof. (...)
Description
METHYLPHENIDATE-PRODRUGS, PROCESSES OF MAKING AND USING THE
SAME
RELATED ATIONS
This application claims the benefit of the priority of US. Provisional
Application No. 61/512,658, entitled METHYLPHENIDATE-OXOACID CONJUGATES,
PROCESSES OF MAKING AND USING THE SAME, filed July 28, 2011, which is
incorporated herein by reference in its entirety.
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[Not Applicable]
BACKGROUND OF THE INVENTION
Methylphenidate is a psychostimulant which is a chain substituted
amphetamine tive. Similar to amphetamine and cocaine, phenidate targets
the central s system, ically the dopamine transporter (DAT) and
nephrine orter (NET). Methylphenidate is thought to act by increasing the
concentrations of dopamine and norepinephrine in the synaptic cleft, as
methylphenidate has both dopamine transporter (DAT) and norepinephrine transporter
(NET) binding capabilities. gh an amphetamine derivative, the pharmacology of
methylphenidate and amphetamine differ, as amphetamine is a dopamine transport
substrate whereas methylphenidate works as a dopamine transport blocker. As a
norepinephrine and dopamine re-uptake inhibitor, methylphenidate thus blocks re-
uptake of dopamine and norepinephrine (noradrenaline) into presynaptic neurons (and
possibly stimulates the release of dopamine from dopamine nerve terminals at high
doses), thereby increasing the levels of dopamine and norepinephrine in the synapse.
In some in vitro studies, methylphenidate has been shown to be more potent as an
inhibitor of norepinephrine uptake/re-uptake when compared to dopamine. However,
some in vivo studies have indicated that methylphenidate is more potent in potentiating
extracellular ne concentrations than norepinephrine trations. Unlike
amphetamine, it has been duggested in the scientific and/or al research comunity
that methylphenidate does not seem to significantly facilitate the release of these two
monoamine neurotransmitters at therapeutic doses.
Four isomers of methylphenidate are known to exist: d—erythromethylphenidate
, /-erythro-methylphenidate, d—threo-methylphenidate, and /-threo-
methylphenidate. Originally, methylphenidate was ed as a mixture of two
tes, d/l-erythro—methylphenidate and d/l-threo—methylphenidate. Subsequent
research showed that most of the pharmacological activity of the mixture is associated
with the threo—isomer resulting in the marketing of the isolated threo—methylphenidate
racemate. Later, the scientific community determined that the d—threo—isomer is mostly
responsible for the stimulant activity. Consequently, new products were ped
containing only d—threo—methylphenidate (also known as “d—threo—MPH”).
Stimulants, including methylphenidate (“MPH”), are believed to enhance the
ty of the sympathetic nervous system and/or l nervous system (CNS).
Stimulants such as MPH and the various forms and derivatives thereof are used for the
treatment of a range of conditions and disorders predominantly assing, for
example, attention deficit hyperactivity er (ADHD), attention deficit disorder
(ADD), obesity, narcolepsy, appetite suppression, depression, anxiety and/or
wakefulness.
Methylphenidate is currently approved by the United States Food and Drug
Administration (“FDA”) for the treatment of attention-deficit hyperactivity disorder and
narcolepsy. phenidate has also shown efficacy for some off-label indications that
include depression, y and lethargy. In some embodiments, the prodrugs of the
present technology may be administered for the ent of attention-deficit
hyperactivity disorder and narcolepsy, or any condition that requires the blocking of the
norepinephrine and/or dopamine orters.
Attention deficit hyperactivity disorder (ADHD) in en has been treated
with stimulants for many years. However, more recently, an increase in the number of
iptions for ADHD therapy in the adult population has, at times, formed the
growth of the pediatric market. Although there are various drugs currently in use for the
treatment of ADHD, including some stimulants and some non-stimulant drugs,
methylphenidate (commercially available from, for example, Novartis International AG
(located in Basel, Switzerland) under the trademark Ritalin®) is commonly prescribed.
Moreover, during classroom trials, non-stimulants have shown to be less effective in
improving behavior and attention of ADHD afflicted children than amphetamine
derivatives.
Behavioral deterioration nd or “crashing”) is ed in a significant
portion of children with ADHD as the medication wears off, typically in the afternoon or
early evening. Rebound symptoms include, for example, irritability, crankiness,
hyperactivity worse than in the unmedicated state, sadness, , and in rare cases
psychotic episodes. The symptoms may subside quickly or last several hours. Some
patients may experience rebound/crashing so severe that treatment must be
discontinued. Rebound/crashing effects can also give rise to addictive behavior by
enticing ts to administer additional doses of stimulant with the intent to prevent
anticipated rebound/crashing negative outcomes and side effects.
ants, such as methylphenidate and amphetamine, have been shown in
the conventional art to exhibit noradrenergic and dopaminergic effects that can lead to
vascular events comprising, for example, increased heart rate, hypertension,
palpitations, tachycardia and in isolated cases cardiomyopathy, , myocardial
infarction and/or sudden death. Consequently, currently available stimulants expose
patients with isting ural cardiac abnormalities or other severe cardiac
indications to even greater health risks and are frequently not used or used with caution
in this patient population.
Methylphenidate, like other stimulants and amphetamine derivatives, can
become addictive and is prone to substance abuse. Oral abuse has been reported, and
euphoria can be achieved through intranasal and intravenous stration.
Methylphenidate also has limited water lity ally in an
unconjugated form. The ties of limited bioavailability and limited water solubility
make ating methylphenidate for oral administration more difficult because the
dosage forms for administration are limited. There is a need in the art for more
bioavailable and water soluble forms of methylphenidate that maintain the
pharmacological benefit when administered, in particular via the oral route.
BRIEF SUMMARY OF THE INVENTION
The present technology utilizes, for example, covalent conjugation of
methylphenidate, various forms and derivatives thereof with certain alcohol, amine,
oxoacid, thiol, or derivatives thereof to provide, for example, improved bioavailability
and increased water solubility when compared to unconjugated phenidate. The
increased bioavailability and/or increased water solubility in some instances provides
the y of the prodrug or composition to be administered in forms that are not easily
utilized with the ugated methylphenidate. For example, the increased water
solubility of the ate compared to unconjugated methylphenidate provides the
ability of the conjugate or prodrug to be administered in an oral thin film or strip with
higher dose loading capacity as compared to unconjugated methylphenidate
In one aspect, the t technology provides a prodrug composition
comprising at least one conjugate, the conjugate comprising at least one
methylphenidate, and at least one alcohol, amine, d, thiol, or derivatives thereof.
In some aspects, the prodrug composition r ses a linker, n the linker
chemically bonds the at least one methylphenidate with the at least one alcohol, amine,
oxoacid, thiol, or derivatives thereof. In some aspects, the linker comprises at least one
(acyloxy)alkyloxy , derivatives thereof, or combinations thereof.
In further aspects, the present technology provides one or more conjugates of
methylphenidate comprising methylphenidate, a derivative thereof, or combinations
thereof and at least one alcohol, amine, oxoacid, thiol, or derivatives f, n
the at least one oxoacid is a carboxylic acid.
In another aspect, the present technology provides at least one g
composition comprising at least one conjugate of methylphenidate, derivatives thereof
or combinations thereof and at least one inorganic d, or derivatives thereof with a
free —OH group, an organic derivative thereof, an inorganic derivative thereof, or a
combination thereof.
In a further aspect, the present logy provides at least one prodrug
composition comprising at least one conjugate of methylphenidate, derivatives thereof
or combinations thereof and an alcohol, amine, oxoacid, thiol, or derivatives thereof and
a linker, wherein the linker ses an (acyloxy)alkyloxy group, a derivative thereof or
combination thereof with the l formula -C(O)O-X-O- , wherein, X is selected from
a representative group including optionally substituted alkyl, optionally substituted aryl,
optionally tuted ryl, ally substituted heteroalkyl, optionally substituted
heteroaryl, optionally substituted heterocycle, optionally substituted alkenyl, optionally
substituted alkynyl, ally tuted cycloalkyl, optionally substituted cycloalkenyl,
optionally tuted cycloalkynyl, or optionally substituted alkoxy.
[0016a] Specifically, the present invention provides a prodrug composition
comprising at least one conjugate of methylphenidate wherein the conjugate is of the
following structure:
wherein G2 is selected from the group ting of standard amino acids,
nonstandard amino acids and synthetic amino acids; and
wherein the amino acid is attached to the rest of the molecule by an amide linkage.
In another aspect, the present technology provides a prodrug composition
comprising at least one conjugate of methylphenidate having a structure of formula (I) or
formula (II):
O O X O O
N Y Gm N
(I) (II)
(Followed by page 5a)
-5a-
wherein X is selected from the group consisting of O, S, Se and NR1; wherein Y
is absent or selected from the group consisting of O, S, Se, NR2 and CR3R4; wherein R1
and R2 are selected independently from the group consisting of hydrogen, alkenyl,
alkenylaminocarbonyl, alkoxy, carbonyl, alkyl, alkylamino, alkylaminocarbonyl,
alkylammonium, alkylcarbonyl, arbonylamino, alkylcarbonyloxy, alkylsulfinyl,
ulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aminocarbonyl, aryl, substituted
aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl,
arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy,
arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,
arylsulfonylamino, arylthio, ioalkyl, cycloalkenyl, lkenylalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl,
cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl,
(Followed by page 6)
heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino,
heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio,
hydroxy, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and
polyethylene glycol; wherein R3 and R4 are selected independently from the group
consisting of hydrogen, l, alkenylaminocarbonyl, , alkoxycarbonyl, alkyl,
alkylamino, minocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino,
alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl,
amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy,
arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo,
arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl,
arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, lfonylamino, arylthio, arylthioalkyl, cyano,
cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, lkylalkyl, cycloalkylamino,
cycloalkyloxy, lkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy,
haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino,
heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy,
heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, nitro, oxo,
polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene
glycol and thiol; wherein L is absent or —[-A — Z-]-n; wherein A is ed ndently
for each repeating subunit from the group ting of CRSRG, aryl, substituted aryl,
arylene, carbocycle, cycloalkenyl, cycloalkyl, cycloalkynyl, heterocycle and heteroaryl;
wherein R5 and R6 are selected independently from each other and independently for
each repeating subunit from the group consisting of hydrogen, alkenyl,
laminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl,
alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl,
alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl,
um, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl,
arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, rbonylamino,
arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl,
arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl,
cycloalkenylalkyl, carboxyl, cycloalkyl, lkylalkyl, lkylamino, lkyloxy,
cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl,
heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl,
heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl,
arylsulfonyl, heteroarylthio, hydroxy, nitro, oxo, polycycloalkenyl,
polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol and thiol;
wherein Z is either absent or ed independently for each repeating subunit from the
group consisting of O, 8, Se and NH; wherein n is 0-50; wherein G is selected
independently for each ing subunit from the group consisting of alcohol, amine,
amino acid, ammonium, d, peptide, poly(ethylene glycols) (PEG), thiol,
derivatives thereof and combinations thereof; wherein E is an oxoacid; and wherein m is
0-5.
In another aspect, the present technology provides at least one prodrug
composition comprising at least one conjugate, wherein the at least one conjugate can
be, for e, nicotinate-CH20CO-methylphenidate, phosphate-CH20CO-
methylphenidate, phosphate-CH20CO-methylphenidate, gallate-CH20CO-
methylphenidate, gallate-CH20CO-methylphenidate, lactate-CH20CO-methylphenidate,
phenidate-C02CH2-nicotinoyl-Asp, phenidate-C02CH2-nicotinoyl-Val,
methylphenidate-C02CH2-nicotinoyl-Gly-Ala, Valaminohexanoate-CH20CO-
methylphenidate, methylphenidate-C02CH2-nicotinamide, 6-Aminohexanoate-CH20CO-
methylphenidate, methylphenidate-C02CH2-nicotinoyl-O‘Bu, methylphenidate-C02CH2-
nicotinate, methylphenidate-C02CH2-nicotinoyl-OEt, phenidate-C02CH2-pyridine,
otinate-CH20CO-methylphenidate, or phosphate-(p—salicylate)-CH20CO-
methylphenidate.
Moreover, the t technology provides at least one prodrug composition
comprising at least one oxyalkyl carbamate.
In yet another aspect, the present technology provides a method for
chemically synthesizing any of the methylphenidate conjugates of the present
technology by perforing the appropriate steps to conjugate methylphenidate to at least
one ligand.
In r aspects, prodrug compositions of the present technology are
believed to unexpectedly exhibit a rate of release equivalent to free or unmodified
methylphenidate. In other aspects, the one or more prodrug composition of the present
logy are believed to surprisingly exhibit a slower rate of release over time as
compared to fied methylphenidate.
In yet other aspects, conjugates or prodrugs of the present logy are
believed to unexpectedly exhibit an increased absorption when administered orally as
ed to unmodified methylphenidate. onally, ates or prodrugs of the
present technology are believed to surprisingly have increased bioavailability as
compared to unmodified methylphenidate.
In yet a further aspect, the conjugates or prodrugs of the present logy
are believed to surprisingly exhibit less interpatient variability in the oral
pharmacokinetic (PK) profile when compared to ugated methylphenidate.
In yet another aspect, the conjugates or prodrugs of the present technology
are provided in an amount sufficient to provide an increased AUC when compared to
unconjugated methylphenidate when administered orally at equimolar doses. In still
other aspects, the conjugates or gs are provided in an amount sufficient to
provide an unexpected increased Cmax as compared to unconjugated phenidate
when administered orally at equimolar doses.
In yet further aspects, the conjugates or prodrugs of the present technology
are provided in an amount sufficient to provide a surprisingly increased Cmax and an
increased AUC as compared to unconjugated methylphenidate when administered
orally at equimolar doses.
In yet an alternative aspect, the conjugates or prodrugs of the present
logy e reduced side effects as compared to unconjugated methylphenidate
when administered at lar doses, and are also contemplated in some alternative
aspects to provide reduced abuse potential as ed to unconjugated
methylphenidate.
In addition, the conjugates or prodrugs of the present technology are also
believed to unexpectedly provide an amount sufficient to provide an extended Tmax
when compared to unconjugated methylphenidate when administered at equimolar
doses, and/or provide an equivalent Tmax when compared to unconjugated
methylphenidate when administered at equimolar doses.
Moreover, the present technology provides at least one method of treating
one or more patients (human or animal) having at least one disease, disorder or
condition mediated by controlling, preventing, limiting, or inhibiting neurotransmitter
uptake/re-uptake or hormone uptake/re-uptake comprising orally administering to one or
more patients a pharmaceutically effective amount of at least one of the prodrug
compositions of the present technology.
In still yet a r aspect, the present technology provides at least one
method of treating a t (human or animal) having at least one disorder or condition
requiring stimulation of the l nervous system of the patient, comprising orally
administering a pharmaceutically effective amount of one or more prodrug compositions
of the present technology.
In yet another aspect, the present technology provides one or more methods
of administering at least one [methylphenidate] composition or prodrug of the present
technology wherein the administration decreases the number and/or amount of
lites produced when ed with unconjugated phenidate. In other
s, the one or more methods of administering the one or more [methylphenidate]
compositions or prodrugs of the present technology is believed to decrease the
exposure of the patient to ritalinic acid when compared with unconjugated
methylphenidate.
In yet a further embodiment, the one or more compositions or prodrugs of the
present technology are ed to provide an increased water solubility of the
methylphenidate-based conjugate or prodrug ed to unconjugated
methylphenidate. In r embodiment, the sed water solubility is believed to
allow for the prodrug to be formed into certain dosage forms at higher concentrations,
dosage strengths, or higher dose loading capacities than unconjugated
methylphenidate. In some embodiments, such dosage forms include, for example, oral
thin films or strips with.
In still yet a further embodiment, the administration of one or more
methylphenidate-based itions or prodrugs are believed to provide a reduced
interpatient variability of methylphenidate plasma concentrations, and are believed to
have an ed safety profile when compared to unconjugated methylphenidate.
In yet another alternative embodiment, the present technology provides at
least one method of treating attention-deficit hyperactivity er comprising
administering a pharmaceutically effective amount of one or more conjugates or g
itions of the present technology.
In another further embodiment, the present technology provides at least one
prodrug composition for treating at least one patient having a disorder or condition
requiring stimulation of the central nervous system of the patient, wherein the at least
one prodrug or ition has a reduced abuse potential when administered
compared to unconjugated methylphenidate.
In a further embodiment, the one or more methylphenidate-based prodrug or
ate compositions of the present technology are contemplated to exhibit reduced
or prevented pharmacological ty when administered by parenteral routes, or
reduced plasma or blood concentration of released methylphenidate when administered
intranasally, intravenously, intramuscularly, subcutaneously or rectally as compared to
free unconjugated methylphenidate when administered at equimolar amounts.
In yet another embodiment, the present technology provides at least one
phenidate-based ate prodrug composition having an extended or
controlled release profile as measured by plasma trations of released
methylphenidate when compared to unconjugated methylphenidate when administered
orally at equimolar doses. In some embodiments, the plasma concentration of
methylphenidate released from the g would increase more slowly and over a
longer period of time after oral administration, resulting in a delay in peak plasma
concentration of released methylphenidate and in a longer duration of action when
compared to unconjugated methylphenidate.
In another aspect, the present technology provides a pharmaceutical kit
comprising a specified amount of individual doses in a package containing a
pharmaceutically effective amount of at least one ate of methylphenidate.
BRIEF DESCRIPTION OF THE GS
Figure 1. Chemical structures of some hydroxybenzoates for use in the
making of the conjugates of the present technology.
Figure 2. al structures of some aryl carboxylic acids for use in
the making of the conjugates of the present technology.
Figure 3. Chemical structures of some phenylacetates for use in the making
of the conjugates of the present technology.
Figure 4. Chemical structures of some benzylacetates for use in the making
of the conjugates of the present technology.
Figure 5. Chemical structures of some cinnamates for use in the making of
the conjugates of the present technology.
Figure 6. Chemical structures of some oxylic acids for use in the
making of the conjugates of the present technology.
Figure 7. Chemical structures of some tricarboxylic acids for use in the
making of the conjugates of the present technology.
Figure 8. Chemical structures of some inorganic oxoacids for use in the
making of the ates of the present technology.
Figure 9. Chemical structures of some inorganic oxoacid derivatives for use in
the making of the conjugates of the t technology.
Figure 10. Chemical structures of some standard amino acids for use in the
making of the conjugates of the present technology.
Figure 11. Chemical ures of some non-standard amino acids for use in
the making of the conjugates of the present technology.
WO 16668
Figure 12. Chemical structures of some synthetic amino acids for use in the
making of the conjugates of the present technology.
Figure 13. Oral PK curves comparing the nicotinate-CHgOCO-MPH conjugate
with unconjugated methylphenidate in rats.
Figure 14. Oral PK curves comparing the phosphate-CHgOCO-MPH
conjugate (data combined from three studies) with unconjugated phenidate in
rats (data combined from six studies).
Figure 15. Oral PK curves comparing the phosphate-CHgOCO-MPH
ate with unconjugated methylphenidate in rats.
Figure 16. Oral PK curves comparing the gallate-CHgOCO-MPH conjugate
with unconjugated methylphenidate (data ed from six studies) in rats.
Figure 17. Oral PK curves comparing the gallate-CHgOCO-MPH conjugate
with unconjugated methylphenidate in rats.
Figure 18. Oral PK curves ing the lactate-CHgOCO-MPH conjugate
with unconjugated methylphenidate in rats.
Figure 19. Oral PK curves comparing the MPH-COchg-nicotinoyl-Asp and
chg-nicotinoyl-Val conjugates with unconjugated methylphenidate in rats.
Figure 20. Oral PK curves comparing the MPH-COgCHg-nicotinoyl-Gly-Ala
and Valaminohexanoate-CHgOCO-MPH conjugates with unconjugated
methylphenidate in rats.
Figure 21. Oral PK curves comparing the 6-aminohexanoate-CHgOCO-MPH
conjugate with unconjugated methylphenidate in rats.
Figure 22. Oral PK curves ing the MPH-COchg-nicotinoyl-O‘Bu and
MPH-COchg-nicotinate conjugates with unconjugated methylphenidate in rats.
Figure 23. lntranasal PK curves comparing the MPH-COgCHg-nicotinoyl-O‘Bu
conjugate with unconjugated methylphenidate in rats.
Figure 24. lntranasal PK curves comparing the MPH-COchg-nicotinate
conjugate with unconjugated methylphenidate in rats.
Figure 25. Oral PK curves comparing the gCHg-nicotinoyI-OEt, MPH-
COgCHg-nicotinamide and gCHg-pyridine conjugates with unconjugated
methylphenidate in rats.
Figure 26. asal PK curves comparing the MPH-C02CH2-nicotinamide
conjugate with unconjugated methylphenidate in rats.
Figure 27. Intranasal PK curves comparing the MPH-COZCHg-pyridine
conjugate with unconjugated methylphenidate in rats.
Figure 28. Intravenous PK curves comparing the MPH-C02CH2-nicotinamide
conjugate with unconjugated methylphenidate in rats.
Figure 29. Intravenous PK curves comparing the MPH-COgCHg-pyridine
conjugate with unconjugated methylphenidate in rats.
Figure 30. Oral PK curves ing the isonicotinate-CHgOCO-MPH and
phosphate-(p-salicylate)-CHgOCO-MPH conjugates with unconjugated methylphenidate
in rats.
DETAILED DESCRIPTION OF THE INVENTION
The present technology provides at least one methylphenidate or one or more
derivatives or combinations thereof (MPH, methyl phenyl(piperidinyl)acetate)
conjugated to at least one organic or nic oxoacid to form oxylalkyl carbamates,
which are novel prodrugs compositions and/or conjugates of methylphenidate. In some
embodiments, the at least one conjugate or g of the present logy was
singly discovered by conjugating methylphenidate to a series of organic or
inorganic oxoacids through various linker molecules. In some embodiments, the linkers
are (acyloxy)alkyloxy moieties or tives thereof. The linker chain is connected on
one end to methylphenidate via a secondary carbamate bond and on the other to the
oxoacid via an ester bond.
The use of the term “methylphenidate” herein is meant to include any of the
stereoisomer forms of methylphenidate, including the four stereoisomers: d—erythro—
methylphenidate, /-erythro— methylphenidate, d—threo— methylphenidate and o—
methylphenidate and the salts and derivatives thereof. Methylphenidate is
interchangeable with methyl phenyl(piperidin-2—yl)acetate. The term “methylphenidate”
includes all salt forms. Methylphenidate is also known by its trade name Ritalin®,
Ritalin® SR, Methylin®, Methylin® ER (all commercially available from Novartis
ational AG, of Basil, Switzerland). The methylphenidate used in the present
technology can be any stereoisomer of methylphenidate, including, but not limited to, d-
erythro— methylphenidate, /-erythro—methylphenidate, d—threo—methylphenidate and /-
threo— methylphenidate. In some embodiments, the methylphenidate can be a mixture
of two or more racemates, for example, but not limited to, d/l-erythro—methylphenidate
and d/l-threo—methylphenidate. In some preferred embodiments, the conjugates contain
racemic threo—methylphenidate. In other preferred embodiments, the alcohol, amine,
d, or thiol is linked to a single o—methylphenidate . Depending on the
chemical structure of the linkers and alcohols, amines, oxoacids, and thiols as well as
the chiral composition of the methylphenidate to which they are ed, the resulting
prodrug conjugates can be optically active mixtures of isomers, racemic mixtures, single
s or combinations thereof.
As used herein, the phrases such as “decreased, reduced,” ished” or
“lowered” are meant to include at least about a 10% change in pharmacological activity,
area under the curve (AUC) and/or peak plasma concentration (Cmax) with greater
percentage changes being red for reduction in abuse potential and overdose
potential of the conjugates of the present technology as compared to ugated
methylphenidate. For instance, the change may also be greater than about 10%, about
%, about 20%, about 25%, about 35%, about 45%, about 55%, about 65%, about
75%, about 85%, about 95%, about 96%, about 97%, about 98%, about 99%, or
increments therein.
As used herein, the term “prodrug” refers to a substance converted from an
inactive form of a drug to an active drug in the body by a al or biological reaction.
In the present technology, the prodrug is a conjugate of at least one drug,
methylphenidate, and at least one oxoacid, for example. Thus, the conjugates of the
present technology are prodrugs and the gs of the present technology are
conjugates.
Prodrugs are often useful e, in some ments, they may be
easier to administer or process than the parent drug. They may, for instance, be more
bioavailable by oral administration s the parent drug is not. The prodrug may
also have improved solubility in pharmaceutical compositions over the parent drug. An
embodiment of a prodrug would be a methylphenidate conjugate that is lized to
reveal the active moiety. In certain embodiments, upon in vivo administration, a g
is chemically converted to the biologically, pharmaceutically or therapeutically more
active form of the compound. In certain embodiments, a prodrug is enzymatically
metabolized by one or more steps or processes to the biologically, pharmaceutically or
therapeutically active form of the nd. To produce a prodrug, a pharmaceutically
active compound is modified such that the active compound will be regenerated upon in
vivo administration. The prodrug is designed to alter the metabolism or the transport
characteristics of a drug in certain embodiments, to mask side-effects or ty, to
improve bioavailability and/or water solubility, to e the flavor of a drug or to alter
other characteristics or properties of a drug in other discrete embodiments.
In some ments, the present technology provides at least one prodrug
composition comprising at least one conjugate. The at least one conjugate may
comprise at least one methylphenidate and at least one alcohol, amine, oxoacid, thiol,
or derivatives therof. In some embodiments, the conjugate r comprises at least
one linker. The linker chemically bonds the methylphenidate to the alcohol, amine,
oxoacid, or thiol via one or more covalent bonds.
Depending on the linker and the alcohol, amine, oxoacid, and thiol conjugated
to methylphenidate or derivative thereof, the at least one prodrug formed can be either a
l rged), a free acid, a free base or a pharmaceutically acceptable anionic
or cationic salt form or salt mixtures with any ratio between positive and negative
components. These anionic salt forms can include, but are not limited to, for example,
acetate, /-aspartate, besylate, bicarbonate, carbonate, d—camsylate, l-camsylate, citrate,
edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride,
d—lactate, /-|actate, d,/-lactate, d,/-malate, /-ma|ate, mesylate, pamoate, phosphate,
succinate, sulfate, bisulfate, d—tartrate, /-tartrate, d,/-tartrate, meso-tartrate, benzoate,
gluceptate, d—glucuronate, hybenzate, isethionate, malonate, sufate, 2—napsylate,
WO 16668
nicotinate, nitrate, orotate, stearate, te, anate, acefyllinate, aceturate,
alicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate,
decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate,
furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate,
glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate,
hippurate, phenylpropionate, iodide, xinafoate, ionate, laurate, maleate,
mandelate, methanesufonate, myristate, napadisilate, , oxalate, palmitate, picrate,
pivalate, propionate, pyrophosphate, late, salicylsulfate, sulfosalicylate, tannate,
terephthalate, licylate, tribrophenate, valerate, valproate, adipate, 4-
acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, or
undecylenate. The cationic salt forms can include, but are not limited to, for example,
sodium, potassium, calcium, magnesium, zinc, aluminium, lithium, cholinate, lysinium,
um, or tromethamine.
Without wishing to be limited to the ing theory, it is believed that the
prodrugs/conjugates of the t technology undergo enzyme hydrolysis of the ester
bond in vivo, which subsequently leads to a cascade reaction resulting in rapid
regeneration of methylphenidate and the respective oxoacid, metabolites thereof and/or
derivatives thereof. The alcohols, amines, oxoacids, thiols, or derivatives therof, of the
present technology are non-toxic or have very low ty at the given dose levels and
are preferably known drugs, natural products, metabolites, or GRAS (Generally
ized As Safe) compounds (e.g., preservatives, dyes, flavors, etc.) or non-toxic
cs or derivatives thereof.
General Structures and Definitions
iations for the components of conjugates of the present technology
include: MPH stands for methylphenidate; MPH-HCI stands for methylphenidate
hydrochloride; Asp stands for aspartate; Val stands for valine; tBu stands for tert—butyl;
Et stands for ethyl.
In some embodiments, the general structure of the prodrugs of
methylphenidate of the present technology can be represented either by formula (I) or
by formula (II):
©2511“O 0
(l) (H)
To simplify the drawings, formulas (I) and (II) can also be depicted as:
MPH Y Gm MPH—Gm
(l) (H)
wherein X is ed from O, 8, Se or NR1;
Y is absent or selected from O, 8, Se, NR2 or CR3R4;
Fi1 and R2 are selected independently from hydrogen, l,
alkenylaminocarbonyl, , alkoxycarbonyl, alkyl, alkylamino,
alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino,
alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl,
alkynylaminocarbonyl, aminocarbonyl, aryl, substituted aryl, arylalkenyl,
arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium,
arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy,
aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio,
ioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl,
cycloheteroalkylalkyl, haloalkoxy, kyl, heteroaryl, heteroarylalkenyl,
heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, arylcarbonylamino,
aryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio,
hydroxy, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl,
polycycloalkylalkyl, or polyethylene glycol;
R3 and R4 are selected independently from hydrogen, l,
alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino,
alkylaminocarbonyl, alkylammonium, alkylcarbonyl, arbonylamino,
alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl,
alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl,
substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino,
arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino,
rbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, lfinyl, arylsulfinylalkyl,
arylsulfonyl, arylsulfonylamino, arylthio, ioalkyl, cyano, cycloalkenyl,
cycloalkenylalkyl, carboxyl, cycloalkyl, lkylalkyl, cycloalkylamino,
cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo,
haloalkoxy, kyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl,
heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo,
heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, arylthio, hydroxy, nitro,
oxo, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl,
polyethylene glycol or thiol;
L is absent or +A‘Z‘lg.
A is selected independently for each repeating subunit from CR5R6 or
optionally substituted aryl, arylene, carbocycle, cycloalkenyl, cycloalkyl,
cycloalkynyl, heterocycle, heteroaryl;
R5 and R6 are selected ndently from each other and independently
for each repeating subunit from hydrogen, l, alkenylaminocarbonyl, alkoxy,
alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium,
arbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl,
alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl,
ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl,
arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl,
arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, y, yalkyl,
arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, ioalkyl,
cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl,
cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl,
cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl,
WO 16668
heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino,
heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio,
hydroxy, nitro, oxo, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl,
polycycloalkylalkyl, polyethylene glycol or thiol;
Z is either absent or selected independently for each repeating subunit
from O, 8, Se or NH;
n is 0-50;
G is selected independently for each repeating subunit from alcohol,
amine, amino acid, ammonium, oxoacid, peptide, poly(ethylene s) (PEG) or
thiol, or derivatives thereof or combinations thereof;
E is an oxoacid; and
m is 0-5.
In some embodiments of formula (I), one or more G entities are covalently
bound to L, Y (if L absent), or to r G (e.g., one or more than one additional G).
le ences of G can be all identical, all uniquely different or a mixture of both.
In some embodiments of formula (II), one or more E entities (up to m entities) are
covalently bound to the nitrogen in the piperidine ring of methylphenidate or to another
E. Multiple occurrences of E can be all identical, all uniquely different or a mixture of
both.
In some red embodiments of formula (I), X is O.
In some preferred embodiments of formula (I), Y is absent or selected from O
or N. In some additional prefered ments of formula (I), Y is N.
In other preferred embodiments of formula(l),LIS selected from:
flit flit:- lili- filofoil}
infiQ (i3 0— or ill](,3 0‘0—
R8 R10 R8
O p q
wherein R7, R8, R9, R10 are independently selected for each repeating
subunit from hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, tuted aryl,
alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, or
heterocycle. Preferably, R7 and R9 are independently selected for each
repeating subunit from hydrogen, alkyl, alkoxy, aryl or tuted aryl, and R8
and R10 are preferably hydrogen;
q is 1-10, preferably 1-5;
0 and p are 0-10, preferably 0-2; and
Q is NH or O.
In some additional preferred embodiments of formula (I), L is ed from:
-§-(CH2)q-NH-§-,whereinq: 1-6 ;
3‘1“o—§—(CH2)5—NH-§- , - ,
NH-E- A
\ , oz;
_§©_r \ ,
, 3910771: $10.2
or if
In other preferred embodiments of formula (I), G is selected from oxoacids,
ry amines or poly(ethylene glycol) derivatives.
In some embodiments of formula (I), G is a tertiary amine that is generally
defined by formulas (Ill) and (IV):
wherein R17 is independently selected for each repeating subunit from O,
8, Se, NR” or CR22R23;
R14, R15, R16, R20, R21 are selected independently from alkenyl,
alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino,
alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino,
alkylcarbonyloxy, ulfinyl, alkylsulfonyl, alkylthio, alkynyl,
alkynylaminocarbonyl, aminocarbonyl, aryl, substituted aryl, arylalkenyl,
koxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, monium,
arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy,
aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio,
ioalkyl, cycloalkenyl, lkenylalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkylamino, cycloalkyloxy, lkynyl, cycloheteroalkyl,
cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl,
heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino,
heteroaryloxo, heteroaryloxy, arylsulfinyl, heteroarylsulfonyl, heteroarylthio,
hydroxy, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl,
polycycloalkylalkyl, or polyethylene glycol;
R20 may also be absent;
R18, R19, R22, R23 are selected independently from each other and
independently for each ing subunit (of R”) from hydrogen, alkenyl,
alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino,
alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino,
alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, hio, alkynyl,
alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl,
substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino,
arylaminocarbonyl, arylammonium, arylazo, rbonyl, arylcarbonylamino,
arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl,
lfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl,
cycloalkenylalkyl, carboxyl, cycloalkyl, lkylalkyl, cycloalkylamino,
cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo,
haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl,
heteroarylamino, heteroarylcarbonyl, arylcarbonylamino, heteroaryloxo,
heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, nitro,
oxo, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl,
hylene glycol or thiol; and
i is 0-10.
In some ments, formula (IV) is a heterocycle with a ring size of 3-10
atoms, of which at least one is a nitrogen atom and at least one is a carbon atom, and
the ring may be aliphatic containing any chemically feasible number and combination of
single, double or triple bonds or the ring may be ic.
In other embodiments, G is covalently bound to L via its tertiary nitrogen (see
formulas (Ill) and (IV)) or via an amino, hydroxyl or carboxyl functional group of one of
its substituents.
In some preferred embodiments of formula (I), the tertiary amines are defined
by formula (V), a a sub-class of formula (IV) wherein:
fl\/\)—R22
G = RzéN
(V); and
R18, R22 and R23 are as defined for a (IV).
Some additional preferred ments of formula (V) are defined by
as (VI), (VII) and (VIII):
G >~OH q
= /O U/ , G2 ,
N N (3)6
(VI) (VII) (VIII)
In these embodiments of formula (V), G is a carboxypyridine derivative,
preferably nicotinic acid, optionally bound via an ester or amide bond to a second
moiety, G2. In some ments, (32 is preferably an alcohol or an oxoacid, more
preferably an amino acid.
In these embodiments of formula (VIII), R26 is selected from hydrogen,
alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino,
minocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino,
alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl,
arbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl,
arylamino, arylaminocarbonyl, arylammonium, o, arylcarbonyl, arylcarbonylamino,
arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, lfinyl, arylsulfinylalkyl,
lfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl,
cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl,
heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino,
aryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio,
hydroxy, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, or
polyethylene glycol.
In some ments of formula (VIII), R26 is preferably en or alkyl.
In other embodiments of formula (I), the poly(ethylene glycol) derivatives are
generally defined by formula (IX):
/ (C H2) 1+0“’}Q \(CH2)|/ R25
G: k
(IX)
wherein R24 is H or NH2;
R25 is H, NH2 or COzH;
Q is absent or 0;
j and I are 0-5; and
kis1-100.
In some preferred embodiments of formula (I), the poly(ethylene glycol)
derivatives are:
H OH H 0 OH Ho NH
G = fofl/ 3 fog
, , VOi/V 2, HfO/NOH’ k k k
H N2 4 /\]“o OH H c
H C 3
3 [oyodkow O fofiO\/\ or NH2
k Vi]?
wherein k is 1-100, preferably 1-50 or 1-10.
In some preferred embodiments of formula (II), E is an oxoacid, preferably an
amino acid.
Oxoacids
Oxoacids (i.e., oxyacids, oxo acids, oxy-acids, oxiacids, oxacids) of the
present technology are a class of compounds which contain oxygen, at least one other
element, and at least one hydrogen bound to oxygen, and which produce a ate
base by loss of positive hydrogen ion(s) ns). Oxoacids can be categorized into
organic acids or inorganic acids and their derivatives. Organic acids include carboxylic
acids. Carboxylic acids are widespread in nature (naturally occurring), but ylic
acids can also be non-natural (synthetic). Carboxylic acids can be categorized into
numerous s based on their molecular structure or a, and many of the
different classes may overlap.
Without wishing to limit the scope to one classification, the carboxylic acids of
the present logy can be grouped into the following ries: aliphatic carboxylic
acids, aryl carboxylic acids, dicarboxylic, polycarboxylic acids, and amino acids.
Suitable aliphatic carboxylic acids for use in the t technology include,
but are not limited to, for example, saturated, monounsaturated, polyunsaturated,
acetylenic, tuted (e.g., alkyl, hydroxyl, methoxy, halogenated, etc.), atom
containing or ring containing carboxylic acids. Suitable examples of saturated
carboxylic acids include, but are not limited to, for example, methanoic, ethanoic,
WO 16668
propanoic, butanoic, pentanoic, hexanoic, heptanoic, octanoic, 2—propylpentanoic acid,
nonanoic, decanoic, dodecanoic, tetradecanoic, canoic, heptadecanoic,
octadecanoic, or eicosanoic acid. Suitable monounsaturated carboxylic acids for
practice of the present technology include, but are not limited to, for example, 4-
decenoic, 9—decenoic, 5-lauroleic, 4-dodecenoic, adecenoic, 5-tetradecenoic, 4-
ecenoic, 9—hexadecenoic, 6-hexadecenoic, 6-octadecenoic, or 9—octadecenoic
acid.
Suitable polyunsaturated carboxylic acids for use in the present technology
include, but are not limited to, for example, sorbic, octadecadienoic, octadecatrienoic,
octadecatetraenoic, eicosatrienoic, eicosatetraenoic, pentaenoic,
docosapentaenoic, or docosahexaenoic acids. le acetylenic carboxylic acids for
use in the present technology include, but are not limited to octadecynoic,
octadecenynoic, tadecenynoic, heptadecenynoic, tridecatetraenediynoic,
tridecadienetriynoic, octadecadienediynoic, heptadecadienediynoic,
octadecadienediynoic, octadecenediynoic, or octadecenetriynoic acids.
Suitable substituted carboxylic acids for practice of the present technology
include, but are not limited to, for example, methylpropanoic, isovaleric,
hexadecanoic, 8—methylnonenoic, methyloctadecanoic, trimethyloctacosanoic,
trimethyltetracosenoic, heptamethyltriacontanoic, tetramethylhexadecanoic,
tetramethylpentadecanoic, , ic, glycolic, threonic, oxypropionic,
hydroxyoctadecatrienoic, hydroxyoctadecenoic, hydroxytetracosanoic, 2—hydroxybutyric,
3-hydroxybutyric, 4-hydroxybutyric, 4-hydroxypentanoic, hydroxyoctadecadienediynoic,
hydroxyoctadecadienoic, 10-hydroxydecanoic, hydroxydecenoic, hydroxyeicosenoic,
hydroxyeicosadienoic, hydroxyhexadecanoic, dihydroxytetracosenoic,
dihydroxydocosanoic, ydocosanoic, trihydroxyoctadecanoic,
trihydroxyhexadecanoic, trihydroxyicosahexaenoic, trihydroxyicosapentaenoic, 2-
methoxyhexadecenoic, 2—methoxy hexadecanoic, 7-methoxytetradecenoic, 9-
methoxypentadecanoic, 1 1-methoxyheptadecanoic, 3-methoxydocosanoic,
diacetoxydocosanoic, 2—acetoxydocosanoic, 2—acetoxytetracosanoic, 2-
acetoxyhexacosanoic, onanoic, oxodecanoic, oxododecenoic,
hydroxyoxodecenoic, 10-oxodecenoic, fluorooctadecenoic, fluorodecanoic,
fluorotetradecanoic, hexadecanoic, fluorooctadecadienoic,
hydroxyhexadecanoic, chlorohydroxyoctadecanoic, dichlorooctadecanoic, 3-
bromononaenoic, 9,10-dibromooctadecanoic, 9,10,12,13-tetrabromooctadecanoic,
-nitro-9,12-octadecadienoic, 12-nitro-9,12-octadecadienoic, 9-nitrooctadecenoic, 9-
oxodecenoic, 9-oxooctadecenoic, oxooctadecatrienoic, 15-oxo-18—tetracosenoic,
17-oxohexacosenoic, or 19-oxooctacosenoic acids.
Suitable examples of heteroatom containing ylic acids include, but are
not d to, for example, 9-(1,3-nonadienoxy)nonenoic, 9-(1,3,6-nonatrienoxy)
nonenoic, 12-(1-hexenoxy)-9,11-dodecadienoic, 12-(1,3-hexadienoxy)-9,11-
dodecadienoic, 2-dodecylsulfanylacetic, 2-tetradecylsulfanylacetic, 3-
tetradecylsulfanylpropenoic, or adecylsulfanylpropanoic acid. Suitable
examples of ring containing carboxylic acids include, but are not d to, for example,
Hexylcyclopropyl)decanoic, 3-(2-[6-bromo-3,5-nondienylcyclopropyl)propanoic, 9-
(2-hexadecylcyclopropylidene)nonenoic, 8-(2-octylcyclopropenyl)octanoic, 7-(2-
octylcyclopropenyl)heptanoic, 9,10-epoxyoctadecanoic, 9,10-epoxy12-octadecenoic,
12,13-epoxyoctadecenoic, epoxyeicosenoic, 11-(2-cyclopenten
yl)undecanoic, 13-(2-cyclopentenyl)tridecanoic, 13-(2-cyclopentenyl)tridecenoic,
11-cyclohexylundecanoic, 13-cyclohexyltridecanoic, -dimethylpentylfuran
yl)heptanoic, 9-(4-methylpentylfuranyl)nonanoic, 4-[5]-ladderane-butanoic, 6-[5]-
ladderane-hexanoic, or 6-[3]-ladderane-hexanoic acid.
Suitable aryl carboxylic acids for use in the present technology to ate
methylphenidate, derivatives thereof or combinations thereof include, for example,
compounds that contain at least one carboxyl group attached to an aromatic ring.
Suitable aryl carboxylic acids of the present technology can include, but are not limited
to, for example:
(a) aryl carboxylic acids wherein the carboxylic acid group is directly attached
to the aryl moiety, which include, but are not limited to, benzoates or
aryl carboxylic acids;
(b) aryl carboxylic acids wherein the carboxylic acid group is separated by
one carbon from the aryl moiety, which include, but are not limited to,
branched phenylpropionic acids, or other derivatives of phenylacetate; or
(c) aryl carboxylic acids wherein the carboxylic acid group is separated by two
carbons from the aryl moiety, which include, but are not limited to,
benzylacetates, substituted derivatives thereof or analogs of cinnamic
acid.
Some embodiments of the present technology provide aryl carboxylic acids
of ry (a), (b), or (c) conjugated to methylphenidate, derivatives thereof, or
combinations thereof. Some embodiments of the present technology provide aryl
carboxylic acids of category (a) conjugated to methylphenidate, derivatives thereof or
combinations thereof, wherein the aryl ylic acid of ry (a) is benzoates,
heteroaryl carboxylic acids or derivatives thereof.
Some embodiments of the present technology provide at least one conjugate
of methylphenidate, derivatives thereof or combinations thereof, and at least one
benzoate. Suitable common benzoates include, but are not d to, for example,
benzoic acid, or hydroxybenzoates (e.g., salicylic acid analogs). The general structure
of benzoates for use in the present technology is shown in formula (X):
C02H
( R3 —Z)q fix
Y// (‘Riio
(F22)p
wherein X, Y and Z can be independently selected from a representative group
ing H, O, S or —(CH2)X—; R1, R2 and R3 can be, for example, independently
selected from any of the following: H, alkyl, alkoxy, aryl, substituted aryl, alkenyl,
alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl,
lkenyl or cycloalkynyl; o, p, q can be independently either 0 or 1; and x is an
integer between 1 and 10.
Benzoates are common in nature and can be found either in their free form,
as a salt, or as esters and . us benzoic acid analogs are also used in
the food and drug industry. Some of the more abundant benzoates are derivatives with
hydroxyl groups. The hydroxyl function may be present in its free form or capped with
another chemical moiety, ably, but not limited to, methyl or acetyl groups. The
phenyl ring may have additional substituents.
Suitable benzoates include, but are not limited to, for example, benzoic acid,
or hydroxybenzoates (e.g., salicylic acid analogs). Suitable examples of
hydroxybenzoates for use in the present technology e, but are not limited to, for
example, benzoic acid, lic acid, acetylsalicylic acid (aspirin), 3-hydroxybenzoic
acid, 4-hydroxybenzoic acid, 6-methylsalicylic acid, cresotinic acid, anacardic
acids, 4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflusinal, o,m,p-anisic acid, 2,3-
oxybenzoic acid HB), oc,B,y—resorcylic acid, protocatechuic acid, gentisic
acid, nylic acid, 3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-
methoxysalicylic acid, 6-methoxysalicylic acid, 3-hydroxymethoxybenzoic acid, 4-
hydroxymethoxybenzoic acid, 5-hydroxymethoxybenzoic acid, vanillic acid,
isovanillic acid, 5-hydroxymethoxybenzoic acid, 2,3-dimethoxybenzoic acid, 2,4-
dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric
acid (3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid, 2,3,4-
trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 3-O—
methylgallic acid (3-OMGA), 4-O—methylgallic acid (4-OMGA), dimethylgallic acid,
syringic acid, or 3,4,5-trimethoxybenzoic acid. Some structures of suitable
hydroxybenzoates for use in the practice of the present technology can be found in
Figure 1.
Heteroaryl Carboxylic Acids
In other ments, the present technology provides prodrug compositions
comprising at least one ate of phenidate, derivatives thereof or
combinations thereof, and one or more aryl or heteroaryl carboxylic acids. Suitably, the
heteroatom of common natural products and metabolites is nitrogen. The general
structures of heteroaryl carboxylic acids and derivatives thereof are illustrated in
formulas (XI), (Xll) and (Xlll):
COZH ZCOZH COZH
RBMPJX—z R3 2
//()OR1qYl/\:(R1)ONX [ 7X
N (R1)O
(Hi2) Y\
(F22)p (R2),
(XI) (XII) (XIII)
n X, Y and Z can be independently selected from the representative group
including H, O, S or —(CH2)X—; R1, R2 and R3 can be independently selected from any of
the following: H, alkyl, alkoxy, aryl, substituted aryl, alkenyl, alkynyl, halo, haloalkyl,
alkylaryl, arylalkyl, heterocycle, arylalkoxy, lkyl, cycloalkenyl or cycloalkynyl; o, p,
q can be independently selected from 0 or 1 ; and x is an integer between 1 and 10.
Nitrogen heterocyclic compounds are commonly found in nature and are
involved in several biological functions in plants and animals. Suitable examples of
heteroaryl carboxylic acids for use in the practice of the present technology e, but
are not limited to, for example, pyridine derivatives, some of which play an important
role in the nate and phan metabolism. In these compounds, one carbon of
the phenyl ring is replaced by a nitrogen atom. Besides the carboxyl group, this set of
nds can have additional substituents, preferably but not limited to, hydroxyl
groups.
Suitable examples of heteroaryl carboxylic acids for use in the present
technology include, but are not limited to, nicotinic acid (niacin), isonicotinic acid,
picolinic acid, 3-hydroxypicolinic acid, 6-hydroxynicotinic acid, inic acid, 2,6-
dihydroxynicotinic acid, kynurenic acid, xanthurenic acid, 6-hydroxykynurenic acid, 8-
methoxykynurenic acid, hydroxykynurenic acid, or 7,8—dihydro-7,8-
dihydroxykynurenic acid. Some structures of suitable heteroaryl carboxylic acids for
use in the practice of the t technology can be found in Figure 2.
Aryl Carboxylic Acids
Some embodiments of the present technology e aryl carboxylic acids of
category (b) conjugated to methylphenidate, derivatives thereof or combinations thereof,
where suitable carboxylic acids with a carboxyl group ted by one carbon from
the aryl moiety include, but are not limited to, for example, branched phenylpropionic
acids (i.e., 2-methylphenylacetates) or other tives of phenylacetate, for
example, compounds having the general formula as described in formula (XIV) below.
In some embodiments, the carboxylic acid is a phenylacetate, a branched
phenylpropionate, an unbranched phenylpropionate (benxylacetate), a phenyl
propenoate (cinnamate), salts thereof, derivatives thereof, or combinations thereof.
Suitable examples of these compounds, include, but are not limited to, certain types of
NSAIDs (Non-Steroidal nflammatory Drugs), such as profens, or tyrosine
metabolites (such as p—hydroxyphenyl pyruvate), among others. The general structure
of phenylpropionic acids or other tives of phenylacetate of the present technology
is shown in a (XIV):
wherein X, Y and Z can be independently selected from the representative group
including H, O, S or —(CH2)X—; R1, R2 and R3 can be independently selected from any of
the following: H, alkyl, alkoxy, aryl, substituted aryl, alkenyl, alkynyl, halo, haloalkyl,
alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; o, p,
q can be independently either 0 or 1; Alk is an alkyl chain —(CH2)n— with n being either 0
or 1; x is an r between 1 and 10; and R6 is selected from H, OH or carbonyl.
Phenylacetates
Phenylacetic acids encompass s subsets of natural products,
metabolites and pharmaceuticals. One such pharmaceutical subset are “profens”, a
type of NSAID and derivatives of certain phenylpropionic acids (i.e., 2-methyl-2—
phenylacetic acid s). Some other phenylacetates have central ons in the
phenylalanine and tyrosine lism. Suitable phenylacetates of the present
technology include, but are not limited to, acetic acid (hydratropic acid), 2-
hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid,
2012/048641
homoprotocatechuic acid, homogentisic acid, 2,6-dihydroxyphenylacetic acid,
homovanillic acid, homoisovanillic acid, homoveratric acid, atropic acid, d,l-tropic acid,
diclofenac, d,l-mandelic acid, 3,4-dihydroxy-d,l-mandelic acid, vanillyl-d,/-mandelic acid,
isovanillyl-d,/-mandelic acid, ibuprofen, ofen, fen, flurbiprofen, ketoprofen,
or naproxen. Some structures of le acetates for use in the practice of the
present technology can be found in Figure 3.
Benzylacetates and Cinnamates
In some embodiments of the present technology, aryl carboxylic acids of
category (c) are conjugated to methylphenidate, derivatives thereof or combinations
thereof, wherein the aryl carboxylic acids of category (c) e, but are not limited to,
for example, benzylacetates, substituted derivatives thereof or analogs of cinnamic acid,
for example nds with the general formulas (XV) and (XVI) below:
OVOH o OH
R4 R5
(R3) —Zq (R3) _Z
|\\—x q |\\_X
Y// (RUG Y// (Rtio
(R2)p (R2lp
(XV) (XVI)
wherein X, Y and Z can be independently selected from a representative group
including H, O, S or —(CH2)X—; R1, R2 and R3 can be independently selected from any of
the following: H, alkyl, alkoxy, aryl, substituted aryl, alkenyl, alkynyl, halo, haloalkyl,
alkylaryl, arylalkyl, heterocycle, arylalkoxy, lkyl, cycloalkenyl or cycloalkynyl; o, p,
q can be independently either 0 or 1; x is an integer from 1 to 10; R4 is H or OH; and R5
is H, OH or carbonyl. Both classes of nds are abundant in nature in the form of
natural products or metabolites (e.g., phenylalanine metabolism). The carboxyl group
can be attached directly to the aromatic ring or be ted by an alkyl or alkenyl
chain. The chain length of the alkyl or alkenyl group for use in this technology should
not preferably exceed two unbranched carbons, but is not limited in numbers of atoms
on potential side-chains or additional functional groups.
The present technology also includes both carbon only aryl and aryl groups
with heteroatoms (heteroaryl). The aryl or heteroaryl group which is connected directly
or through an alkyl or alkenyl chain to the carboxyl function, should preferably be a 6-
membered ring and should preferably n no or one heteroatom. It should be
appreciated by those skilled in the art additional substituted or unsubstituted aromatic or
tic rings may be fused to such a 6-membered aryl or heteroaryl moiety.
Benzylacetates are defined by an ethylene group between the yl
function and the phenyl ring. Both the alkyl chain and the aryl moiety can have, for
example, substituents, ably hydroxyl groups. Some compounds of this class can
be found in the phenylalanine metabolism. Suitable examples of benzylacetates for use
in the practice of the present technology e but are not limited to, for example,
benzylacetic acid, melilotic acid, 3-hydroxyphenylpropanoic acid, 4-
hydroxyphenylpropanoic acid, 2,3-dihydroxyphenylpropanoic acid, d,/-phenyllactic acid,
o,m,p-hydroxy-d,/-phenyllactic acid, or phenylpyruvic acid. Some structures of suitable
acetates for use in the practice of the present technology can be found in Figure
Cinnamic acids (3-phenylacrylic acids) are unsaturated analogs of
benzylacetic acids, which are found ubiquitously in plants and fruits. Cinnamates occur
in two isomeric forms: cis (Z) and trans (E). Use of cinnamates in the present
technology can be either isomer form, but are preferably in the trans configuration.
Similar to benzylacetates, derivatives of cinnamic acid can be substituted on the alkenyl
or aryl moiety of the molecule. Preferred tuents are hydroxyl and y
groups. Certain ates play a key role in the phenylalanine metabolism. Some
suitable cinnamates for use in the present technology include, but are not limited to, for
example, cinnamic acid, o,m,p-coumaric acid, hydroxycinnamic acid, 2,6-
dihydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid, 5-hydroxyferulic acid,
sinapic acid, or oxyphenylpropenoic acid. ures of suitable cinnamates
for use in the practice of the present technology can be found in Figure 5.
Dicarboxylic and Tricarboxylic Acids
In some ments, the methylphenidate, derivatives thereof or
combinations thereof, can be conjugated to one or more dicarboxylic or tricarboxylic
acids. Dicarboxylic acids are compounds with two carboxyl groups with a general
formula of -COOH, where R can be an alkyl, l, alkynyl or aryl group, or
derivatives thereof. Dicarboxylic acids can have ht carbon chains or ed
carbon chains. The carbon chain length may be short or long. Polycarboxylic acids are
ylic acids with three or more carboxyl groups. le examples of dicarboxylic
and tricarboxylic acids for the practice of the present technology include, but are not
limited to, for example, oxalic, malonic, succinic, glutaric, adipic, pimelic, suberic,
azelaic, sebacic, lic, thapsic, malic, ic, dihydroxymesoxalic, oc-hyroxyglutaric,
methylmalonic, meglutol, diaminopimelic, carbamoyl ic, fumaric, maleic,
mesaconic, 3-methylglutaconic, traumatic, phthalic acid, isophthalic, terephthalic,
dipicolinic, citric acid, isocitric, carballylic, or trimesic acid. Some ures of suitable
dicarboxylic acids for use in the practice of the present technology can be found in
Figure 6 and some ures of suitable tricarboxylic acids for use in the practice of the
present technology can be found in Figure 7.
Inorganic Oxoacids
In some embodiments of the present technology, at least one
methylphenidate, derivatives thereof or combinations thereof, is conjugated to at least
one inorganic oxoacid or an organic or inorganic derivative thereof. Inorganic oxoacids
of the present technology contain a —OH group (e.g., phosphoric acid) or they can be
organic or inorganic derivatives of the same (e.g., phosphonates, diphosphates). Some
suitable examples of inorganic oxoacids and their derivates include, but are not limited
to, phosphates, phosphonates, phosphinates, phosphoramidates, phosphoramidites,
diphosphates, triphosphates, biphosphonates, phosphorothioates, phosphorodithioates,
phosphites, sulfates, sulfonates, ates, sulfites, thiosulfates, thiosulfites, sulfinates,
nitrate, nitrite, borates, boronates, hypochlorite, carbonates, or carbamates. General
structures of some inorganic oxoacids for use in the practice of the present technology
can be found in Figure 8 and structures of some organic or inorganic derivatives of
inorganic oxoacids for use in the practice of the present technology can be found in
Figure 9.
Preferred embodiments of the present logy e one or more
inorganic oxoacids that are phosphate esters. More preferred ments include
nic oxoacids that are phosphate monoesters, even more preferably phosphoric
acid.
Additional preferred oxoacids of the present technology include fatty acids,
hydroxy carboxylic acids, amino acids, optionally esterified phosphoric acids and
optionally esterified dicarboxylic acids. More preferred ds of the present
technology are C224 carboxylic acids, aryl carboxylic acids, aminocaproic acid,
phosphoric acid, standard amino acids and non-standard amino acids.
Amino Acids
Amino acids are one of the most important ng blocks of life. They
tute the structural subunit of proteins, peptides, and many secondary metabolites.
In addition to the 22 standard (proteinogenic) amino acids that make up the backbone of
proteins, there are hundreds of other natural (non-standard) amino acids that have been
discovered either in free form or as components in l products. The amino acids
used in some embodiments of the prodrugs of this ion include natural amino
acids, synthetic (non-natural, unnatural) amino acids, and their derivatives.
Standard Amino Acids
There are currently 22 known standard or proteinogenic amino acids that
make up the monomeric units of proteins and are d in the genetic code. The
standard amino acids include alanine, arginine, asparagine, aspartic acid, cysteine,
glutamic acid, glutamine, glycine, histidine, isoleucine, e, lysine, methionine,
phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan,
tyrosine and valine. These standard amino acids have the general ure shown in
Figure 10, where R represents the side chain on the d-carbon.
Non-Standard Amino Acids
Non-standard amino acids can be found in proteins created by chemical
modifications of rd amino acids already incorporated in the proteins. This group
also includes amino acids that are not found in ns but are still present in living
organisms either in their free form or bound to other molecular entities. Non-standard
amino acids occur mostly as intermediates in metabolic pathways of standard amino
acids and are not encoded by the c code. Examples of non-standard amino acids
include but are not limited to ornithine, homoarginine, citrulline, homocitrulline,
homoserine, theanine, y—aminobutyric acid, 6-aminohexanoic acid, sarcosine, ine,
2—aminoadipic acid, pantothenic acid, taurine, hypotaurine, onine, steine,
cystathionine, homocysteine, B-amino acids such as B-alanine, B-aminoisobutyric acid,
B-leucine, B-lysine, B-arginine, B-tyrosine, B-phenylalanine, isoserine, B-glutamic acid, B-
tyrosine, B-dopa (3,4-dihydroxy-L-phenylalanine), oc,oc-disubstituted amino acids such as
2—aminoisobutyric acid, isovaline, di-n-ethylglycine, N-methyl acids such as yl-
alanine, L-abrine, hydroxy-amino acids such as 4-hydroxyproline, 5-hydroxylysine, 3-
hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, cyclic amino acids such
as ocyclopropylcarboxylic acid, azetidinecarboxylic acid and pipecolic acid.
Some structures of suitable non-standard amino acids that can be used in some
embodiments of the prodrugs of this invention are shown in Figure 11.
Synthetic Amino Acids
Synthetic amino acids do not occur in nature and are prepared synthetically.
Examples include but are not limited to allylglycine, cyclohexylglycine, N-(4-
hydroxyphenyl)glycine, N-(chloroacetyl)glycline ester, 2-(trifluoromethyl)-phenylalanine,
4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine, 2—chlorophenylglycine, 3-
guanidino propionic acid, 3,4-dehydro-proline, 2,3-diaminobenzoic acid, o
chlorobenzoic acid, 2—aminofluorobenzoic acid, allo-isoleucine, tert—leucine, 3-
serine, isoserine, 3-aminopentanoic acid, 2—amino-octanedioic acid, 4-chloro-B-
phenylalanine, B-homoproline, B-homoalanine, 3-amino(3-methoxyphenyl)propionic
acid, N-isobutyryl-cysteine, 3-amino-tyrosine, 5-methyl-tryptophan, 2,3-diaminopropionic
acid, ovaleric acid, and 4-(dimethylamino)cinnamic acid. Some structures of
2012/048641
suitable synthetic amino acids that can be used in some embodiments of the prodrugs
of this invention are shown in Figure 12.
Linkers
In some embodiments of the present technology, the methylphenidate,
derivatives f or combinations thereof, is conjugated to one or more organic or
inorganic ds via one or more linkers. Linker moieties of the present technology,
which connect the one or more organic or inorganic oxoacids to the methylphenidate,
derivatives thereof or combinations thereof, are preferably at least one xy)alkyloxy
group or a derivative thereof with the general formula:
—C(O)O—X—O—
wherein X is selected from a entative group including optionally substituted alkyl,
ally substituted aryl, optionally substituted alkylaryl, optionally substituted
heteroalkyl, optionally tuted heteroaryl, optionally substituted heterocycle,
optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted
cycloalkyl, optionally substituted cycloalkenyl, optionally substituted lkynyl, or
optionally substituted alkoxy substituents.
Preferred embodiments of the present logy include linkers where X is
at least one aliphatic group. More preferred embodiments include linkers where X is at
least one alkyl group. Even more preferred embodiments are (acyloxy)methyloxy,
(acyloxy)ethyloxy, or (acyloxy)methyl(methyl)oxy linkers.
Administration, Formulation and Advantages
The prodrugs or conjugate compositions of the present logy can be
stered orally and, upon administration, release the active methylphenidate,
derivatives f or combinations thereof, after being hydrolyzed in the body. Not
wishing to be bound by any particular theory, the oxoacids that are conjugated to the
methylphenidate, derivatives thereof or combinations thereof, of the present technology
are naturally occurring lites, pharmaceutically active compounds or mimetics
thereof or derivatives thereof. It is believed that the prodrugs or conjugates of the
present technology can be easily recognized by physiological systems resulting in
hydrolysis and release of phenidate.
The prodrugs of the present technology are believed to have no or limited
pharmacological activity themselves and uently may follow a metabolic pathway
that differs from the parent drug (i.e., methylphenidate). Without being bound by any
theory, it is believed that by choosing suitable linkers and oxoacids (“ligands”), the
release of methylphenidate into the systemic circulation can be controlled even when
the prodrug is administered via routes other than oral administration.
In one embodiment, the at least one conjugated methylphenidate, derivatives
thereof or combinations thereof, of the present technology are believed to surprisingly
e methylphenidate, derivatives thereof or combinations f, similar to free or
unmodified methylphenidate. In another alternative embodiment, the at least one
conjugated methylphenidate, derivatives thereof or combinations f, of the present
technology are believed to surprisingly be released in a controlled or sustained form.
It has been surprisingly found that in some ments of the present
technology, the prodrugs or conjugates of the present application provide an sed
bioavailability as compared with unconjugated methylphenidate. In some embodiments,
the prodrugs or conjugates of the present technology surprisingly provide increased
water lity as ed with unconjugated phenidate. In some
embodiments, the prodrugs or compositions of the present technology have at least
about 1.2x or at least about 1.5x the water solubility of unconjugated methylphenidate.
In some embodiments, the prodrugs or compositions of the present technology have at
least about 1.7x, at least about 2.0x, at least about 2.2x, at least about 2.5x, at least
about 3.0x, at least about 4.0x or at least about 5x the water lity of unconjugated
methylphenidate, and include any multiples in between or above that have water
solubility r than unconjugated methylphenidate. Not to be bound by any particular
theory, the increase in water solubility may allow for the ate to be formed into
certain dosage forms at higher concentrations, dosage strengths or higher dose g
capacities than unconjugated methylphenidate. In some embodiments, these dosage
forms e, but are not limited to, forms that require water solubility, including, but not
limited to, liquids and oral thin films or strips.
In a further embodiment, the at least one prodrug or conjugate of the present
technology is believed to unexpectedly have increased absorption over unmodified
phenidate. In yet another embodiment, the at least one prodrug or conjugate of
the present technology is believed to unexpectedly have increased bioavailability over
unconjugated methylphenidate. In some embodiments, the conjugate is capable of
being enzymatically or hydrolytically activated or converted into the active form. In one
embodiment, the composition or prodrug described herein would e
phenidate, its active metabolites and/or derivates and their combination ing
in increased peak plasma concentrations and/or exposure to methylphenidate, its active
metabolites and/or derivatives and their combination when compared to free or
ugated methylphenidate at lar doses. Not to be bound by any particular
theory, it is believed that this may allow for administration of a lower dose with equal or
improved therapeutic effect, but with fewer and/or less severe side effects when
compared to unmodified methylphenidate, thereby improving the safety profile of the
drug. Common side effects of methylphenidate are nervousness, agitation, anxiety, and
insomnia or drowsiness. Other common side effects are abdominal pain, weight loss,
ensitivity, nausea, dizziness, palpitation, headache, dyskinesia, blood pressure,
pulse changes, tachycardia, angina, and cardiac arrhythmia.
In a further embodiment, the increased absorption over fied
methylphenidate, or improved water solubility over free methylphenidate may provide
for a better bioavailability of phenidate referring to a higher area under the curve
(AUC) or having higher circulating plasma concentrations.
In one embodiment, the at least one prodrug or conjugate of the present
technology would alter the metabolic profile of methylphenidate, derivatives thereof or
combinations thereof, by, for example, changing the amounts and/or ratio of
methylphenidate and its metabolites, such as the inactive ritalinic acid within the body.
The at least one prodrug or conjugate, for example, would decrease the number and/or
amount of metabolites, including , ve, toxic or non-toxic metabolites,
produced by unmodified methylphenidate. Not wishing to be bound by any particular
theory, it is believed that this change in metabolism may potentially ate certain side
effects and improve upon the safety profile of methylphenidate.
In another ment, the prodrugs or conjugates of the present technology
would unexpectedly produce d interpatient variability of methylphenidate plasma
concentrations. Not to be bound by any particular theory, it can be assumed that the
reduction of interpatient ility of methylphenidate plasma concentrations may be
due to either increased bioavailability or a modified lic pathway or a combination
of both. In another embodiment, the prodrug of the present technology would alter the
metabolic pathway of the released methylphenidate when compared to unmodified
methylphenidate. It is believed that this new metabolism may decrease interpatient
variability and/or reduce side effects associated with unconjugated methylphenidate or
any of its metabolites.
] In a further embodiment, the at least one prodrug or ate of the present
technology can comprise racemic d— and /-methy|phenidate which is ably
hydrolyzed to d—methylphenidate in the body and thus delivers more of the
therapeutically active d—isomer. Wishing not to be bound by any particular theory, this
may reduce potential side effects caused by /-methy|phenidate and/or its metabolites.
In another embodiment, the at least one g or conjugate of the present
technology is believed to unexpectedly generate a Cmax value of released
methylphenidate, tives thereof or combinations thereof, that is higher than the
Cmax value produced by unconjugated methylphenidate, derivatives thereof or
combinations thereof, when administered orally at equimolar doses. In a r
embodiment, the at least one prodrug or conjugate are ed to surprisingly generate
an AUC value of released methylphenidate, derivatives thereof or combinations thereof,
that is higher than the AUC value produced by unconjugated methylphenidate when
administered orally at equimolar doses. In yet another ment, the at least one
prodrug or conjugate is believed to surprisingly generate both a Cmax and an AUC value
of released methylphenidate that is higher than the Cmax and AUC values produced by
ugated methylphenidate when administered orally at equimolar doses.
In some embodiments, the AUC is about 110% or greater of the AUC of
unconjugated methylphenidate, when administered orally at equimolar doses, for
example about 110% to about 260%, alternatively from about 120% to about 260%,
alternatively from about 110% to about 250%, ing, but not limited to, about 110%,
about 130%, about 150%, about 170%, about 190%, about 210%, about 230%, about
250% or any amounts in between, in ents of about 0.5%, about 1%, about 2%,
about 2.5%, about 5%, about 10%, or about 20%.
In some embodiments, the Cmax is about 110% or greater of the Cmax of
unconjugated methylphenidate, when administered orally at equimolar doses, for
example about 110% to about 260%, atively from about 120% to about 260%,
alternatively from about 110% to about 250%, including, but not limited to, about 110%,
about 130%, about 150%, about 170%, about 190%, about 210%, about 230%, about
250% or any amounts in between, in increments of about about 0.5%, about 1%, about
2%, about 2.5%, about 5%, about 10%, or about 20%.
In r embodiment, the at least one prodrug or conjugate is believed to
unexpectedly generate a Tmax value of released methylphenidate that is longer than the
Tmax value produced by unconjugated methylphenidate when administered at equimolar
doses. In another embodiment, the at least one prodrug or ate is believed to
surprisingly generate a Tmax value of released phenidate that is similar to the Tmax
value produced by unconjugated methylphenidate, when administered at equimolar
doses.
In some embodiments, the AUC is about 50% or smaller of the AUC of
unconjugated methylphenidate, when administered intranasally or intravenously at
equimolar doses, for example about 50% to about 0.1 %, alternatively from about 25% to
about 0.1%, alternatively from about 50% to about 1%, including, but not limited to,
about 50%, about 40%, about 30%, about 20%, about 10%, about 1% or any amounts
in between, in increments of about about 0.5%, about 1%, about 2%, about 2.5%, about
% or about 10%.
Methylphenidate is addictive and prone to substance abuse e of its
pharmacological similarity to e and amphetamine. Oral abuse has been reported
to lead to hallucinations, paranoia, euphoria, and delusional disorder. Oral abuse may
subsequently escalate to intravenous and intranasal abuse. Euphoria has been
reported after intravenous administration of methylphenidate. When administered
intranasally the effect is found to be r to intranasal use of amphetamines.
In some alternative embodiments of the present technology, the compounds,
prodrugs, compositions and/or methods of the present technology are believed to
provide reduced potential for overdose, reduced potential for abuse and/or improve the
characteristics of methylphenidate, derivatives thereof or combinations thereof with
regard to toxicities or suboptimal release profiles. In some alternative embodiments of
the present technology, some compositions of the present technology may ably
have no or a substantially decreased pharmacological activity when administered
through ion or intranasal routes of administration. However, they remain orally
bioavailable. t wishing to be limited to the below theory, it is believed that
overdose protection may occur due to the conjugates being exposed to ent
enzymes and/or metabolic pathways after oral administration whereby the conjugate of
the present technology is exposed to the gut and first-pass metabolism as opposed to
exposure to enzymes in the circulation or mucosal membranes in the nose which limits
the ability of the methylphenidate, derivatives thereof or combinations thereof, from
being ed from the conjugate. Therefore, in some alternative embodiments, abuse
resistance is provided by limiting the effectiveness of alternative routes of
stration. Again, not wishing to be bound by any particular theory, the
bioavailability can be a result of the hydrolysis of the chemical linkage (Le, a covalent
linkage) following oral administration. In at least one alternative embodiment, the
prodrugs of the present technology are envisioned to not yze or to hydrolyze at a
reduced rate or to a limited extent via non-oral routes. As a result, they are believed to
not te high plasma or blood concentrations of released phenidate when
injected or snorted compared to free phenidate administered through these
] In some alternative ments, it is contemplated that at least some
compositions of the present technology comprising the gs of one or more
methylphenidate, derivatives thereof or ations thereof, are resistant to abuse by
parenteral routes of administration, such as intravenous “shooting,” or intranasal
“snorting,” that are often employed during illicit use. In at least one contemplated
alternative embodiment, release of methylphenidate, derivatives thereof or
combinations f, is reduced when the composition of the present technology is
delivered by parenteral routes. In some other contemplated alternative embodiments,
the conjugates of the present technology, since they are ed to include covalently
bound phenidate, derivatives thereof or combinations thereof, are not able to be
ally manipulated to release the methylphenidate, derivatives thereof or
ations f, from the conjugated methylphenidate, derivatives thereof or
combinations thereof, by methods, for example, of grinding up or crushing of solid
forms. Further, some alternative conjugates of the present technology are
contemplated to exhibit resistance to chemical hydrolysis under conditions a potential
drug abuser may apply to “extract” the active portion of the molecule, for example, by
boiling, or acidic or basic solution treatment of the conjugate. In some ative
embodiments, some itions containing prodrugs or ates of the present
technology preferably have no or a substantially decreased pharmacological activity
when administered through injection or intranasal routes of administration. However,
they remain orally bioavailable.
For example, in one alternate embodiment, the at least one prodrug or
conjugate of the present technology is plated to surprisingly maintain its
effectiveness and abuse resistance following the crushing of the tablet, capsule or other
oral dosage form utilized to deliver the therapeutic component (i.e., active
ingredient/drug) which is believed to be due to the inherent release profile being a
property of the composition not formulation. In st, tional extended release
ations used to control the release of methylphenidate are subject to release of up
to the entire methylphenidate content immediately following crushing. When the content
of the d tablet is injected or snorted, the large dose of methylphenidate produces
the “rush” effect sought by addicts.
The present technology provides a stimulant based treatment modality and
dosage form for certain disorders ing the stimulation of the CNS such as,
attention-deficit hyperactivity er (ADHD), attention deficit disorder (ADD), autistic
spectrum disorder, autism, Asperger’s disorder, pervasive developmental disorder,
sleep disorder, obesity, depression, r disorder, eating disorder, chronic fatigue
me, schizophrenia, major depressive disorder narcolepsy, or autistic spectrum
disorder. Although not g to be bound by any particular theory, it is believed that
the treatment of such CNS conditions as noted above with compositions of the present
technology results in increased bioavailability as compared to existing stimulant
treatment modalities and dosage forms. In a preferred embodiment, the at least one
prodrug or ition of the present technology is used to treat attention-deficit
hyperactivity disorder (ADHD).
In some embodiments, the at least one composition or prodrug of the present
technology can be used in one or more methods of treating a patient having at least one
disease, disorder or condition requiring stimulation of the central nervous system of one
or more ts, comprising orally administering a pharmaceutically ive amount of
the at least one composition or prodrug.
In some ments, the at least one composition or prodrug of the present
technology can be used in one or more methods of treating one or more patients having
at least one disease, er or condition mediated by controlling, ting, limiting,
or inhibiting neurotransmitter uptake/re-uptake or hormone uptake/re-uptake comprising
administering to at least one patient a pharmaceutically effective amount of the at least
one prodrug or composition. In some embodiments, the neurotransmitter is serotonin,
dopamine or norepinephrine. In some embodiments, the hormone is catecholamine.
At least some compositions of the t technology comprising the
prodrugs of methylphenidate, derivatives thereof or combinations thereof, can also be
used for treating stimulant (cocaine, methamphetamine) abuse and addiction, for
ing battle field alertness, and/or for combating e.
] The at least one prodrug or conjugate of the present technology can be
formulated in to dosage forms to be administered orally. These dosage forms include
but are not limited to tablet, capsule, caplet, troche, lozenge, powder, suspension,
syrup, solution, oral thin film (OTF), oral strips, inhalation compounds or suppositories.
Preferred oral administration forms are capsule, tablet, ons and OTF. Suitable
dosing vehicles of the present technology include, but are not limited to, water,
phosphate buffered saline (PBS), 10% Tween in water, and 50% PEG-400 in water.
Solid dosage forms can optionally include the following types of excipients:
antiadherents, binders, coatings, disintegrants, fillers, flavors and colors, glidants,
lubricants, preservatives, sorbents and sweeteners.
Oral ations of the present technology can also be included in a solution
or a suspension in an s liquid or a non-aqueous liquid. The formulation can be
an emulsion, such as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
The oils can be stered by adding the purified and sterilized liquids to a prepared
enteral formula, which is then placed in the feeding tube of a t who is unable to
swallow.
Soft gel or soft gelatin capsules may be prepared, for example by dispersing
the formulation in an appropriate vehicle (vegetable oils are commonly used) to form a
high viscosity mixture. This mixture is then encapsulated with a gelatin based film using
technology and ery known to those in the soft gel industry. The individual units
so formed are then dried to constant weight.
Chewable tablets, for example, may be prepared by mixing the formulations
with excipients designed to form a relatively soft, flavored, tablet dosage form that is
intended to be chewed rather than swallowed. tional tablet machinery and
procedures, for example, direct compression and ation, i.e., or slugging, before
compression, can be utilized. Those duals ed in pharmaceutical solid
dosage form tion are versed in the processes and the machinery used, as the
chewable dosage form is a very common dosage form in the pharmaceutical industry.
Film coated tablets, for example may be prepared by coating tablets using
techniques such as rotating pan coating methods or air suspension methods to t
a contiguous film layer on a tablet.
Compressed tablets, for example may be prepared by mixing the formulation
with ents intended to add binding qualities to disintegration ies. The mixture
is either directly compressed or granulated and then compressed using methods and
machinery known to those in the ry. The resultant compressed tablet dosage
units are then packaged according to market need, for example, in unit dose, rolls, bulk
bottles, blister packs, etc.
The present technology also plates the use of biologically-acceptable
carriers which may be prepared from a wide range of materials. Without being limited
to, such als include diluents, binders and adhesives, lubricants, plasticizers,
disintegrants, colorants, bulking substances, flavorings, sweeteners and miscellaneous
materials such as buffers and adsorbents in order to prepare a particular medicated
composition.
] Binders may be selected from a wide range of als such as
hydroxypropylmethylcellulose, ethylcellulose, or other suitable cellulose derivatives,
ne, acrylic and methacrylic acid co-polymers, pharmaceutical glaze, gums, milk
derivatives, such as whey, starches, and derivatives, as well as other conventional
binders known to persons working in the art. Exemplary miting solvents are water,
ethanol, isopropyl alcohol, ene chloride or es and combinations thereof.
Exemplary non-limiting bulking substances include sugar, lactose, gelatin, starch, and
silicon dioxide.
] It should be understood that in addition to the ingredients particularly
mentioned above, the formulations of the present technology can include other suitable
agents such as flavoring agents, preservatives and antioxidants. Such antioxidants
would be food acceptable and could include vitamin E, carotene, BHT or other
antioxidants.
Other nds which may be included by admixture are, for example,
medically inert ingredients, e.g., solid and liquid diluents, such as lactose, dextrose,
saccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or
ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions;
lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate
and/or polyethylene glycols; gelling agents such as dal clays; thickening agents
such as gum anth or sodium alginate, binding agents such as starches, arabic
gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone;
disintegrating agents such as , alginic acid, a|ginates or sodium starch glycolate;
effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin,
polysorbates or |aury|su|fates; and other therapeutically acceptable accessory
ingredients, such as humectants, preservatives, buffers and antioxidants, which are
known additives for such formulations.
For oral administration, fine powders or es containing diluting,
dispersing and/or surface-active agents may be presented in a draught, in water or a
syrup, in capsules or sachets in the dry state, in a non-aqueous suspension wherein
suspending agents may be included, or in a suspension in water or a syrup. Where
ble, flavoring, preserving, ding, thickening or emulsifying agents can be
included.
Liquid dispersions for oral administration may be syrups, emulsions or
suspensions. The syrups may contain as r, for example, saccharose or
saccharose with glycerol and/or mannitol and/or sorbitol. In particular a syrup for
diabetic patients can contain as carriers only products, for example ol, which do
not metabolize to glucose or which metabolize only a very small amount to glucose.
The suspensions and the ons may contain a carrier, for example a natural gum,
agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl
alcohol.
Methylphenidate is being ed in numerous dosage forms and at various
dosage strengths either as racemic mixture of d— and l-threo-methylphenidate or as
single d—threo-isomer (Table 1). Recommended daily doses depend on the dosage
form, active ingredient (single isomer or racemic mixture) and individual patient titration.
Table 1. Examples of marketed methylphenidate dosage forms and dosage ths.
Active Dosage Dosage Proprietary
Ingredient Form Strength(s) Name s)
methylphenidate instant e 5, 10, 20 mg Ritalin
hydrochloride tablet
dexmethylphenidate instant release 2.5, 5, 10 mg Focalin®
h drochloride tablet
methylphenidate extended release 10, 20 mg Methylin ER,
h drochloride tablet te ER®
methylphenidate extended release 10, 18, 20, 27, Concerta
h drochloride tablet 36, 54 mo
methylphenidate chewable tablet 2.5, 5, 10 mg Methylin
h drochloride
methylphenidate extended release 10, 20, 30, 40 mg Ritalin LA
h drochloride caosules
methylphenidate ed e 10, 20, 30, 40, Metadate CD
hloride es 50, 60 mg
dexmethylphenidate extended release 5, 10, 15, 20, 30, Focalin XFi®
hydrochloride capsules 40 mg
methylphenidate transdermal patch 10, 15, 20, 30 na®
mg/9 h
methylphenidate oral solution 5, 10 mg/5 mL Methylin®
hydrochloride
Doses of the prodrug of the present technology can be higher or lower than
doses of unconjugated methylphenidate depending on their molecular weight, the
respective weight-percentage of phenidate as part of the whole conjugate or
conjugate salt and their bioavailability (with respect to released methylphenidate).
Therefore dosages may be higher or lower than the dosages of free methylphenidate.
Dosages can be calculated based on the strengths of dosages of methylphenidate
hydrochloride which range between, for example, but not limited to, about 2.5 mg and
about 54 mg per dose. Dose conversion from methylphenidate hydrochloride to
methylphenidate prodrug can be med using the following formula:
. MW(MPH prodrug)
dose(MPH prodrug): fBAXdose(MPH hydrochloride)><—
269.77 L
MPH = methylphenidate
MW = molecularweight
fBA = correction factor accounting for differences in bioavailability
between unmodified methylphenidate and gs of the present technology.
This correction factor is specific for each g.
Suitable dosages of the conjugated methylphenidate or prodrugs of the
present technology include, but are not limited to, formulations including an amount of
conjugated methylphenidate equimolar to an amount of unconjugated methylphenidate
from about 0.5 mg or higher, alternatively from about 2.5 mg or higher, alternatively
from about 5.0 mg or higher, alternatively from about 7.5 mg or higher, alternatively
from about 10 mg or higher, atively from about 20 mg or , alternatively from
about 30 mg or higher, alternatively from about 40 mg or higher, alternatively from about
50 mg or higher, atively from about 60 mg or higher, alternatively from about 70
mg or higher, alternatively from about 80 mg or higher, alternatively from about 90 mg
or higher, alternatively from about 100 mg or higher, and include any additional
increments thereof, for example, about 0.1, about 0.2, about 0.25, about 0.3, about 0.4,
about 0.5, about 0.6, about 0.7, about 0.75, about 0.8, about 0.9 or about 1.0 mg and
multiplied factors thereof, (e.g., about x1, about x2, about x2.5, about x5, about x10,
about x100, etc). The present technology also includes dosage formulations including
currently approved formulations of methylphenidate (See Table 1), where the dosage
can be calculated using the above-noted formula determined by the amount of
methylphenidate hydrochloride. The present technology provides for dosage forms
formulated as a single therapy or as a ation therapy.
In some ments, the ates of methylphenidate and oxoacids to
form prodrugs have one or more advantage, including, but not limited to, reduced or
improved side effect profile, formation of less potentially toxic metabolites, formation of
less inactive metabolites, improved water solubility, reduced drug abuse potential and/or
reduced atient variability in plasma concentrations as compared to ugated
methylphenidate.
tic Schemes
In some embodiments, one or more protecting groups may be attached to any
additional reactive functional groups that may interfere with the coupling to
methylphenidate. Any suitable ting group may be used depending on the type of
functional group and reaction conditions. Some protecting group suitable for use in the
present technology include, but are not limited to, acetyl (Ac), tert—butyoxycarbonyl
(Boc), benzyloxycarbonyl (Cbz), oxybenzylcarbonyl (M02), 9-
fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bn), oxybenzyl (PMB), 3,4
dimethoxybenzyl , p—methozyphenyl (PMP), tosyl (Ts), or amides (like
acetamides, pthalamides, and the like).
In other embodiments, a base may be required at any step in the synthetic
scheme of prodrugs of methylphenidate of this invention. Suitable bases include, but
2012/048641
are not limited to, 4-methylmorpholine (NMM), ethylamino)pyridine , N,N-
diisopropylethylamine, lithium bis(trimethylsilyl)amide, lithium diisopropylamide (LDA),
any alkali metal tert.-butoxide (e.g., potassium utoxide), any alkali metal hydride
(e.g., sodium hydride), any alkali metal alkoxide (e.g., sodium methoxide), triethylamine
or any other tertiary amine.
le solvents that can be used for any reaction at any step in the
synthetic scheme of a prodrug of methylphenidate of this invention include, but are not
limited to, e, acetonitrile, l, chloroform, dichloromethane,
dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, ethanol, ethyl acetate,
diethyl ether, heptane, hexane, methanol, methyl tert-butyl ether (MTBE), isopropanol,
isopropyl acetate, diisopropyl ether, tetrahydrofuran, toluene, xylene or water.
In some embodiments, an acid may be used to remove certain protecting
groups. Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic
acid, hydrofluoric acid, hydriodic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid,
acetic acid, citric acid, methanesulfonic acid, p—toluenesulfonic acid and nitric acid. For
n other protecting groups, a catalytic hydrogenation may be used, e.g., palladium
on charcoal in the ce of hydrogen gas.
In one embodiment, the general synthesis of linking oxoacids to
methylphenidate include the following ons. To a solution of iodomethyl carbamate
of methylphenidate (1-1.5 mmol) in toluene (25-50 mL) was added the silver salt of the
respective oxoacid (3 eq.). The reaction was heated from 80 °C to reflux for 3 hours
depending on the oxoacid. uently, the solid was filtered off and the filtrate was
concentrated. The residue was purified by column chromatography to give the linked
oxoacid-methylphenidate ate.
Depending on the oxoacid the conjugate was either the final product or
required deprotection. For example, the benzyl groups protecting the phosphate
conjugate were removed by hydrogenation with 10% Pd/C in methanol using a
hydrogen balloon for 2 hours. The catalyst was filtered off and the filtrate was
concentrated and dried to give the final deprotected conjugate.
In some ments, the prodrug is hydrophilic and thus more water soluble
than the unconjugated methylphenidate.
In some embodiments, the general procedure for the synthesis of carbamate
derivatives of methylphenidate (MPH) with alkyl or aryl groups (3) is as follows:
O 2
02Me COZMe
R-o 0'
HN N
CHZCl2,TEA
1 OR
3a-b
3a:R= -CH2-Ph
3b: R: F-Ph
] To a solution of methylphenidate hydrochloride (MPH-HCI) (1 mmol) and
ylamine (TEA) (4 mmol) in dichloromethane (DCM) (8 mL) was added a solution of
chloroformate 2 (2 mmol) in DCM (2 mL) drop-wise at room temperature. After 4-6 h,
the reaction was quenched with water (1 mL) and stirred for 15 min. The solvent was
evaporated under reduced pressure. The residue was dissolved in cetate
(EtOAc) (50 mL) and washed with 5% aqueous sodium bicarbonate (NaHCOs) (2 x 40
mL) and brine (1 x 40 mL). The organic phase was dried under sodium sulfate
(Na2804) and concentrated in vacuum. The oily e was ed either by silica gel
chromatography or preparative HPLC.
In other embodiments, the sis of 4-fluorophenol-CO-MPH (3b) is as
follows:
To a solution of To a solution of MPH-HCI (0.25 g, 0.93 mmol) and TEA (0.52
mL, 3.7 mmol) in DCM (8 mL) was added a solution of rophenyl chloroformate
(0.33 g, 1.86 mmol) in DCM (3 mL) drop-wise at room temperature. The reaction
mixture was stirred for 6 h at room temperature and then quenched with water (1 mL).
The solvent was evaporated under reduced pressure. The residue was dissolved in
EtOAc (50 mL) and washed with 5% aqueous NaHCOs (2 x 40 mL) and brine (1 x 40
mL). The organic phase was dried under Na2804 and concentrated in vacuum. The
oily residue was purified by preparative HPLC to give 3b (0.35 g).
In some embodiments, the general procedure for the synthesis of carbamate
derivatives of MPH with hydroxy carboxylic acids (8) is as s:
R O o
TEA, CH 2 Cl 2
OBn + fix 00*/A OBn
HO O2N O 0'
02N T
4 5 ?\Ai MPH. HCI
DMF TEA
75°C
Pd-C/Hg/EtOH
N N
O\A O\A
Meogc Y 0%OH M6020 TI/
0 O O)'\OBn
aq. NaOH
8a: A = -CH2-
8b: A = -CH(CH3)-
8c: A = -CH(Ph)-
To a solution of protected hydroxyl acid 4 (1 mmol) in DCM (8 mL) was added
TEA (2.5 mmol) and the solution was cooled down to 0 °C. A solution of 4-nitrophenyl
chloroformate (5, 1 mmol) in DCM (2 mL) was added drop-wise at 0 °C. After the
addition the reaction e was slowly brought to room temperature and left overnight.
The solvent was evaporated and dried in vacuum to give the carbonate derivative 6.
Compound 6 was dissolved in dimethylformamide (DMF) and to the solution were
added TEA (3 mmol) and MPH-HCI (1.05 mmol). The mixture was heated for 8 h at 75
°C. Solvent was removed under reduced pressure. The residue was dissolved in
EtOAc (60 mL) and washed with 5% aq. NaHCOs (2 x 40 mL) and brine (1 x 40 mL).
The organic phase was dried over Na2804 and evaporated to s to give 8, which
was purified by preparative HPLC.
In other ments, the synthesis of MPH-CO-l—lactate (8b, A = -CH(CH3)-)
is as follows:
To a solution of benzyl lactate 4 (A = -CH(CH3)-; 0.39 g, 2 mmol) in DCM (8
mL) was added TEA (0.69 mL, 5 mmol) and the solution was cooled down to
0 °C. A solution of ophenyl chloroformate 5 (0.436 g, 2.1 mmol) in DCM (3 mL)
was added ise at 0 °C. Subsequently, the on mixture was slowly brought to
room temperature and left overnight. The solvent was evaporated in vacuum and dried
to give the carbonate derivative 6 (A = -CH(CH3)-). nd 6 was dissolved in DMF
(12 mL) and to the solution were added TEA (0.84 mL, 6 mmol) and MPH-HCI (0.604 g,
2.23 mmol). The mixture was heated for 20 h at 65 °C. Solvent was removed under
reduced pressure. The residue was dissolved in EtOAc (40 mL) and was washed with
% aq. NaHCOs (2 x 30 mL) and brine (1 x 30 mL). The organic phase was dried over
NagSO4, evaporated to dryness and purified by preparative HPLC to give 8b (0.62 g).
In other embodiments, the general procedure for the synthesis of aminoacid
derivatives of MPH with hydroxy carboxylic acid linkers (11) is as follows:
HCI o
N NHS, DCC N
0\A o\
Y A
+ H N2 #0 _,
MeOZC )‘on MeOZC Y
THF n )‘NH
9 R
O R = side chain of amino acid K
s‘AAO-E—= L 4N HCI/dioxane
8a: A = -CH2-
8b: A = -CH(CH3)-
8c: A = -CH(Ph)-
To a solution of 8 (1 mmol), H-AA-O‘Bu (AA = amino acid) (9, 1.1 mmol), N-
hydroxysuccinidimide (NHS) (1.1 mmol) in THF (8 mL) was added TEA (2 mmol) and
the mixture was stirred for 10 min. Subsequently, a solution of MN-
dicyclohexylcarbodiimide (DCC) (1 .1. mmol) in THF (2 mL) was added and the mixture
was stirred overnight at room ature. The reaction mixture was filtered and the
filtrate was evaporated to s to give the protected derivative 10, which was purified
by preparative HPLC.
Compound 10 was dissolved in 4N HCl/dioxane solution (8 mL) and the
solution was stirred for 6 h at room temperature. The solution was evaporated under
vacuum, co-evaporated with isopropyl acetate and dried to give 11.
] In some embodiments, the synthesis of MPH-CO-lactoyl-Lys (11a; A = -
CH(CH3)-, R = -(CH2)4NH2) is as follows:
To a solution of 8b (0.12 g, 0.34 mmol), H-Lys(Boc)-O‘Bu-HC| 9 (0.145 g,
0.37 mmol), NHS (0.044 g, 0.37 mmol) in THF (8 mL) was added TEA (0.15 mL, 1.02
mmol) and the mixture was stirred for 10 min. Subsequently, a solution of DCC
(0.076g, 0.37 mmol) in THF (2 mL) was added and the mixture was stirred overnight at
room temperature. The reaction mixture was filtered and the filtrate was ated to
dryness. The crude t was purified by preparative HPLC to give 10a (0.14 g).
] Compound 10a (A = -CH(CH3)-, = -(CH2)4NH2) (0.135g) was dissolved in
4N oxane (8 mL) and the solution was stirred for 6 h at room ature. The
solution was ated in vacuum, co-evaporated with isopropyl acetate (lPAc) and
dried to give 11a (0.12 g).
In other embodiments, the synthesis of MPH-CO-lactoyl-Ala (11b; A = -
CH(CH3)-, R = -CH3) is as follows:
To a solution of 8b (0.12g, 0.34 mmol), H-Ala-O‘Bu-HCI 9 (0.0.065g, 0.36
mmol), NHS (0.044 g, 0.37 mmol) in THF (8 mL) was added TEA (0.15 mL, 1.02 mmol)
and the mixture was stirred for 10 min. Subsequently, a solution of DCC (0.075g, 0.36
mmol) in THF (2 mL) was added and the reaction was stirred overnight at room
temperature. The suspension was filtered and the filtrate was ated to dryness.
The crude product was ed by ative HPLC to give 10b (A = -CH(CH3)-, = -
CH3) (0.095 g).
Compound 10b (A = -CH(CH3)-, R = -CH3) (0.09 g) was dissolved in 4N
HCl/dioxane (8 mL) and the solution was stirred for 4 h at room temperature. The
solution was evaporated in vacuum, co-evaporated with isopropyl acetate (lPAc) and
dried to give 11b (0.085 g).
] In other embodiments, the general procedure for the synthesis of carbamate
derivatives of MPH with amino alcohols (15) is as follows:
BocNH>_/OH i TEA, CH20I2 )k A]
+ _< >_ o NHB
CI 02N 0 CC
R O2N@O
12 5 —§- A—NH—E— = L
DMF, TEA
75 °c
N o\ ,NH 4N HCl/dioxane N 2
Meogc Y A HCI
‘— Meozc YO\A/NHBOC
153: A = -(CH2)2'
153-C 15bIA= -CH20H(CH3)-
15c = 19: A = -C4H4-(CH2)2'
To a solution of amino alcohol 12 (1 mmol) in DCM (8 mL) was added TEA
(2.5 mmol) and the solution was cooled down to 0 °C. A solution of 4-nitrophenyl
formate (5, 1 mmol) in DCM was added ise at 0 °C. uently, the
reaction mixture was slowly brought to room temperature and left overnight at rt. The
solvent was evaporated in vacuum and dried to give the carbonate derivative 13.
Compound 13 was dissolved in DMF and to the solution were added TEA (3 mmol) and
MPH-HCI (1.05 mmol). The mixture was heated for 15 h at 65 °C. Solvent was
removed under reduced pressure. The residue was dissolved in EtOAc (40 mL) and
washed with 5% aq. NaHCOs (2 x 30 mL) and brine (1 x 30 mL). The organic phase
was dried over NagSO4 and evaporated to s to give 14, which was purified by
preparative HPLC. Compound 14 was dissolved in 4N HCl/dioxane and the solution
was stirred under argon for 3-6 h depending on the amino acid derivative. The solvent
was evaporated, co-evaporated with lPAc and dried to give 15.
In other ments, the synthesis of tyramine-CO-MPH (19) is as follows:
To a solution of Boc-tyramine 16 (1 mmol) in DCM (8 mL) was added TEA
(2.5 mmol) and the solution was cooled down to 0 °C. A solution of 4-nitrophenyl
chloroformate (5, 1 mmol) in DCM was added drop-wise at 0 °C. Subsequently, the ice
bath was removed and the reaction mixture was d for 4 h at room temperature.
The solvent was evaporated under vacuum and dried to give the carbonate tive
17. nd 17 was dissolved in DMF and to the solution were added TEA (3 mmol)
and MPH-HCI (1.05 mmol). The mixture was heated for 15 h at 65 °C. Solvent was
removed under reduced pressure. The residue was dissolved in EtOAc (40 mL) and
was washed with 5% aq. NaHCOs (2 x 30 mL) and brine (1 x 30 mL). The organic
phase was dried over Na2804 and evaporated to dryness to give 18, which was purified
by preparative HPLC. Compound 18 was deprotected with 4N HCl/dioxane to produce
19 (0.38 g).
In some embodiments, the synthesis of succinate-tyramine-CO-MPH (20) is
as follows:
BocHN F< >’OH
TEA, CH2C|2 )J\ C c
)J\ 17
woo a MPH-HCI
DMF, TEA
75 0c
N o®fNHBoc
N OWN—I2
4N HCI/d'onane
Me02c ‘—
19 L 18
Succinic anhydride, TEA, THF
N o—< >—’
Me02c Y o o
WO 16668
To a solution of 19 (0.1 g, 0.23 mmol) and TEA (0.095 mL, 0.69 mmol) in THF
(8 mL) was added succinic anhydride (0.025g, 0.25 mmol) and the reaction mixture was
stirred for 3 h at room temperature. Solvent was evaporated under reduced pressure
and the residue was dissolved in EtOAc (50 mL). The EtOAc phase was washed with
1% aq. sodium bisulfate 4) (50 mL), brine (50 mL). The organic phase was
dried over Na2804 and evaporated to dryness to give 20 (0.11 g) as white solid.
In other embodiments, the general procedure for the synthesis of ylic
acid derivatives of MPH with amino l linkers (23 and 25) is as follows:
R2 = side chain of amino acid
—§—A-NH-§- = L BOCHNVkOSU
21 H
N o NH2 N
\ / HCI o /
M9020 \n/ A
TEA, THF M9020 \n/ \A Nm)\NHBOC
o —> o o
rt
\ CI
| 4N HCI/dioxane.
TEA, CHZCIZ, rt 24
Hogc/VCO H2 H
N o\ /N
M9020 Y A NHZ HCI
O O
N O\/\ fifiqz 23
MeOzC Y H
25a-b
25a: R2 = 3-pyridinyl
25b. R2 = '(CH2)2002H
To a solution of 15 (1 mmol) in THF were added TEA (2.5 mmol) and Boc-AA-
OSu (AA = amino acid) (21, 1.05 mmol) and the solution was stirred for 3 h at room
temperature. Solvent was ated in vacuum. The residue was dissolved in EtOAc
(50 mL) and washed with 5% aq. NaHCOs (2 x 30 mL) and brine (1 x 40 mL). The
organic phase was dried over NagSO4 and evaporated to dryness to give 22. After
purification, compound 21 was dissolved in 4N HCl/dioxane and d for 3-6 h at room
temperature. Solvent was evaporated, the residue was co-evaporated with lPAc and
dried to give 23.
In some embodiments, the synthesis of Lys-alaninol-CO-MPH (23; A = -
CH20H(CH3)-, R1 = -(CH2)4NH2) is as follows:
To a solution of 15b (0.09 g, 0.24 mmol) in THF were added TEA (2.5 mmol)
and Boc-Lys(Boc)-OSu 21 (0.113 g, 0.25 mmol) and the on was d for 3 h at
room temperature. t was ated in vacuum. The residue was dissolved in
EtOAc (50 mL) and was washed with 5% aq. NaHCOs (2 x 30 mL) and brine (1 x
40mL). The organic phase was dried over NagSO4 and evaporated to dryness to give
22 (A = -CH2CH(CH3)-, R1 = -(CH2)4NH2). After purification, compound 22 (0.135 g)
was dissolved in 4N oxane and stirred for 2 h at room temperature. t was
evaporated, the residue was co-evaporated with lPAc and dried to give 23 (0.13 g).
In other embodiments, the synthesis of nicotinate-ethanolamine-CO-MPH
(25a; R2 = 3-pyridinyl) is as follows:
To a solution of 15a (0.1 g, 0.28 mmol) and TEA (0.15 mL, 1.12 mmol) in
DCM (8 mL) was added nicotinoyl chloride (0.055 g, 0.31 mmol). After stirring for 2 h at
room temperature, the reaction was quenched with water (1 mL) and solvent was
evaporated to dryness. The residue was ved in EtOAc (60 mL) and washed with
% aq. NaHCOs (2 x 50 mL) and brine (1 x 50 mL). The organic phase was dried over
NagSO4 and evaporated to dryness to give nicotinic acid derivative 25a (0.13 g).
In some embodiments, the synthesis of succinate-ethanolamine-CO-MPH
(25b; R2 = -(CH2)2002H) is as follows:
To a solution of 15a (0.11 g, 0.31 mmol) and TEA (0.13 mL, 0.9 mmol) in THF
(8 mL) was added succinic anhydride (0.034 g, 0.34 mmol) and the reaction mixture
was stirred for 3 h at room temperature. The on was quenched with water and the
solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc
(50 mL) and washed with 1% aq. NaHSO4 (2 x 40 mL), brine (50 mL). The organic
phase was dried over NagSO4 and evaporated to s to give 25b (0.12 g) as solid.
In other embodiments, the synthesis of glycerol-CO-MPH (29) is as s:
4T\/>—/OHo 26 o
TEA, CHZCIZ )b
+ —> OgN®O O/\<’07L
)J\ 27
Moo 0. MPH- HCI
DMF, TEA
75 °c
N O N O
O O
OH O
A solution of 1,2-isopropylideneglycerol 26 (0.265 g, 2 mmol) and TEA (0.55
mL, 4 mmol) in DCM (8 mL) was cooled down to 0 °C. Subsequently, a solution of 4-
nitrophenyl chloroformate 5 (0.425 g, 2 mmol) in DCM was added drop-wise. The ice
bath was removed and the reaction mixture was stirred for 5 h at room temperature.
Solvents were evaporated in vacuum and dried to give the carbonate derivative 27.
Compound 27 was dissolved in DMF and to the solution were added TEA (0.69 mL, 5
mmol) and MPH-HCI (0.502 g, 1.85 mmol). The mixture was heated for 15 h at 70 °C.
Solvent was d under reduced pressure. The residue was dissolved in EtOAc
(70 mL) and washed with 5% aq. NaHCOs (2 x 50 mL) and brine (1 x 50mL). The
organic part was dried over NagSO4 and evaporated to s to give carbamate
derivative 28 (0.61 g) after purification by preparative HPLC.
lsopropylidene derivative 28 (0.6 g) was dissolved in methanol (MeOH) (20
mL) and to the solution was added esulfonic acid drate (TsOH-Hgo)
(0.035 g). After stirring for 3 h at room temperature, the reaction was quenched with 5%
aq. NaHCOs (1 mL) and solvent was evaporated to dryness. The residue was dissolved
in EtOAc (70 mL) and washed with 5% aq. NaHCOs (2 x 50 mL) and brine (1 x 50mL).
The organic phase was dried over Na2804 and evaporated to dryness to give glycerol
derivative 29 (0.46 g).
In other embodiments, the synthesis of ate conjugates of MPH with
poly(ethylene glycol) derivatives (32) is as follows.
H31Ar
TEA CHZCIZ
, —> .3.) “NowO
i n O
MPH-HCI, TEA
DMF
H3c+ /\4/oj cogue
In some embodiments, the synthesis of Me-PEG-CO-MPH (32a) is as follows:
To a solution of Me-PEG (poly(ethylene glycol) methyl ether) 30 (1 mmol) and
TEA (2 mmol) in DCM (8 mL) was added drop-wise a solution of 4-nitrophenyl
formate 5 (1.05 mmol) in DCM (3 mL) at room temperature. The solution was
stirred overnight at room temperature. The solvent was evaporated in vacuum and
dried to give the carbonate derivative 31. nd 31 was dissolved in DMF and to
the solution were added TEA (3 mmol) and MPH-HCI (1.05 mmol). The mixture was
heated for 15 h at 70 °C. Solvent was removed under d pressure. The oily
e was purified by preparative HPLC to give 32a as oil.
In other ments, the synthesis of Me-(OCH2CH2)3-OCO-MPH (32b; n =
3) is as follows:
To a solution of Me-PEG 30 (n :3; 0.165 g, 1 mmol) and TEA (0.3 mL, 2
mmol) in DCM (8 mL) was added drop-wise a on of 4-nitrophenyl chloroformate
(0.212 g, 1.05 mmol) in DCM (3 mL) at room temperature. The solution was stirred
overnight at room temperature. The solvent was evaporated in vacuum and dried to
give the carbonate derivative 31 (n :3). Compound 31 was dissolved in DMF and to the
solution were added TEA (0.42 mL, 3 mmol) and I (0.273 g, 1.05 mmol). The
mixture was heated for 6 h at 75 °C. Solvent was removed under reduced pressure.
The oily residue was purified by preparative HPLC to give 32b (n = 3) (0.24g) as oil.
In some embodiments, the synthesis of HgN-PEG-CO-MPH (34) is as follows:
EO\/\ /\/O\/\ Vko o OH
+ 002m
O/\/ \/\NH0 HN
GAO/é
1. D00, HOBt, TEA, DMF
rt, 2 d
2. 4N HCI/dioxane
%O/\/EN (30Me
O/\/O\/\NH2
To a solution of O—[2-(Boc-amino)ethyl]-O’-(2-carboxyethyl)polyethylene glycol
(Boc-NH-PEG-CogH) 33 (0.12 g, 0.26 mmol), MPH-HCI (0.93 g, 0.35 mmol), 1-
hydroxybenzotriazole (HOBt) (0.035 g, 0.26 mmol) and TEA (0.11 mL, 0.78 mmol) in
DMF (6 mL) was added a solution of DCC (0.056 g, 0.27 mmol) ise. The
reaction mixture was stirred for 2 days at room temperature. The suspension was
ed and the filtrate was evaporated to dryness in vacuum. The residue was purified
and ected with 4N HCI/dioxane to give the amide derivative 34 (0.13 g) as oil.
In other embodiments, the synthesis of Me-PEG-NH-succinoyl-alaninol-CO-
MPH (36) is as follows:
ifo /NH H30 o-N +
M9020 \A 2'“ “N
0 \lo n o
—§—A-NH-§- = L
H30 ArNNNI \ : N
To a solution of 15b (0.075 g, 0.2 mmol) and TEA (0.085 mL, 0.6 mmol) in
THF (8 mL) was added O—[(N-suooinimidyl)suooinyl-aminoethyl]-O’-methylpolyethylene
glycol (Me-PEG-Suo-OSu) 35 (average. Mp = 750, 0.15 g, 0.2 mmol) and the reaction
mixture was stirred for 2 days at room temperature. Solvent was evaporated under
reduced pressure and the e was purified by preparative HPLC to give 36 as oil.
] In some embodiments, the synthesis of 6-aminohexanoate-CH20CO-MPH
(40) is as follows:
OMeCICOZCHZCI OMe OMe
Na I
NH DCM DMAP rt \n/OVCI Acetone rt N\n/O\/|
o o
1 37 38
. . . . OMe
Bocamtnohexanotc actd stlver salt
e, 80 90 °C_ N O O
\ll/ \/ \n/WNH-Boc
O 0
4N HCI in Dioxane
2 h, rt /O\n/\/\/\NH2 HCI
O O
A. Synthesis of Bocaminohexanoic acid silver salt:
Bocaminohexanoic acid (0.85 g, 3.68 mmol) was added to water (4 mL)
and cooled in ice bath. To this suspension 1N NaOH was added with constant stirring
until the pH of solution was about 7 and the mixture became a clear solution. To this
solution, silver e (0.63 g, 3.68 mmol) in water (2 mL) was added slowly. The
resulting precipitate was filtered and washed with water. The solid was dried in vacuum
over phosphorus pentoxide to yield a white solid (1.09 g) , 88%).
B. Synthesis of chloromethyl 2-(2-methoxyoxopheny|ethy|)piperidine
carboxylate (37):
Methylphenidate hydrochloride (1) (2.70 g, 10 mmol) was suspended in DCM
(75mL) and cooled in an ice bath. 4-Dimethylaminopyridine (DMAP) (4.887 g, 40 mmol)
was added and the resulting mixture was stirred for 10 min. Chloromethyl
chloroformate (3.224 g, 25 mmol) in DCM (10mL) was added slowly. The ice bath was
removed and the reaction was stirred for 5 h at room temperature. Ethyl acetate (250
mL) was added, followed by water (20 mL) to quench the reaction. The ethyl acetate
layer was separated and washed with 1N HCI (40mL) and brine (2 x 40 mL) and dried
over ous sodium sulfate. The solvent was evaporated and the residue was
purified by silica gel column chromatography (hexanes:EtOAc, 3:1) to give 37 as a
colorless oil (2.60 g) (yield, 80%).
C. Synthesis of iodomethyl ethoxyoxophenylethyl)piperidine
carboxylate (38):
] A mixture of 37 (0.28 g, 0.86 mmol) and sodium iodide (0.387 g, 2.58 mmol)
in acetone (6 mL) was stirred overnight. The acetone was evaporated. The residue
was dissolved in ethyl acetate (80 mL) and washed with saturated sodium ate (30
mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was
evaporated and the residue was dried in vacuum to give 38 as a syrup (0.263 g) (yield,
73%).
D. Synthesis of Bocaminohexanoate-CHgoco-MPH (39a):
A mixture of 38 (0.43 g, 1.03 mol) and Bocaminohexanoic acid silver salt
(1.05 g, 3.09 mmol) in toluene (30mL) was refluxed for 3 h. The solid was filtered off
and the filtrate was concentrated to dryness. The crude residue was ed by
preparative HPLC to give 39a as a hygroscopic solid (0.375 g) (yield, 70%).
E. Synthesis of 6-aminohexanoate-CHgoco-MPH (40):
nd 39a (0.21 g, 0.40 mmol) was stirred with 4N HCI/dioxane (5-6 mL)
for 2 h at room temperature. The solvent was concentrated to dryness to yield 40 as a
copic solid (0.166 g) (yield, 91%).
In other embodiments, the synthesis of lactate-CHgoco-MPH (39b) is as
follows:
0 O
OMe Silver lactate OMe
Toulene, 80 90 Co_
N\n/O\/' NYOVO
O O
38 39b
A mixture of compound 38 (0.428 g, 1.03 mmol) and silver lactate (0.61 g,
3.09 mmol) in 30 mL toluene was heated at 80-90 °C for 3 h. The solid was filtered off
and the filtrate was concentrated to dryness. The crude residue was purified by
preparative HPLC to give 39b as syrup (0.28 g) (yield, 64%).
In some embodiments, the l procedure for the synthesis of amino acid
and peptide derivatives of (6-aminohexanoyloxy)methyl methylphenidatecarboxylate
conjugates (42) is as follows:
-OSu
OMe o
NMM, THF, rt, 2-12hr
N o o
an/OVOWNH \n/ V \n/WNJkAA-NH-Boc
2- HCI o o H
o o
4N HCl/dioxane 0
—>23h N ovo JK
- n
, \n’ WIN AA-NH2 HCI
o o H
AA = Amino acid or a dipeptide
The hydrochloride salt of 40 (1 eq.) was treated with a otected amino
acid or a peptide succinimidyl ester (1.05 eq.) in the presence of N—methylmorpholine
(NMM) (3 eq.) in THF for 2-12 h at room temperature. The reaction mixture was
concentrated to dryness and the crude residue was taken in EtOAc and washed with
saturated bicarbonate, ammonium chloride solution and brine. The c layer was
dried over anhydrous sodium sulfate and concentrated to dryness to yield the Boc-
protected amino acid or the peptide tive 41. The Boc-protected tive 41 was
ected using 4N HCl/dioxane for 2-3 h at room temperature. The solvent was
evaporated to dryness to yield the hydrochloride salt of the amino acid or peptide
derivative 42.
In other embodiments, the synthesis of Valaminohexanoate-CH20CO-MPH
(42a) is as follows:
Boc-VaI-OSu
OMe 0
NMM, THF, rt, 3 h
N O O NH-BOC
\n/ \n/\/\/\NH2 H
O O
0 O HCI
4N HCI/dioxane
—> N
\n/OVO\n/W\ NH2 HC'
2 h, rt
O 0 Hj/Vk
A. Synthesis of Boc-Valaminohexanoate-CH20CO-MPH (41a):
Compound 40 (0.08 g, 0.175 mmol) was taken in anhydrous THF .
NMM (0.06 mL, 0.525 mmol) and Boc-protected succinimidyl ester (0.06 g, 0.184 mmol)
were added and the reaction e was d for 2 h at room temperature. Solvent
was concentrated to dryness and crude product was taken in ethyl acetate (100 mL),
washed once each with saturated bicarbonate (40 mL), ammonium chloride solution (40
mL) and brine (40 mL). The organic layer was dried over anhydrous sodium sulfate and
concentrated to dryness to yield 41a (0.084 g) (yield, 77%).
B. Synthesis of Valaminohexanoate-CH20CO-MPH (42a):
Compound 41a (0.084 g, 0.14 mmol) was dissolved in 4N HCl/dioxane (4-
5mL) and stirred at room temperature for 2 h. Dioxane was concentrated to dryness to
yield 42a (0.078 g) (yield, 100%).
In other embodiments, the l procedure for the synthesis of amino acid
and peptide conjugates of phenidate (44) is as follows:
800-AA-OH
DCC HOBt TEA in DMF N AA—Boc
rt, overnight \ii/
4N HCl/dioxane OMe 44
2-3 h H N\n,AA-NH2 HCI
AA = amino acid, dipeptide or tripeptide
Methylphenidate hydrochloride (1 eq.) was taken in anhydrous DMF. Boc-
protected amino acid or peptide (1.05 eq.), DCC (1.05 eq.), HOBt (1.1 eq.) and TEA
(2.5 eq.) were added. The mixture was stirred overnight at room temperature. DMF
was evaporated in vacuum and the e dissolved in ethyl acetate. The c
layer was washed with 1% sodium bisulfate and brine. The organic layer was
trated to dryness to yield the Boc-protected conjugate. The Boc group was
deprotected by treating with 4N HCl/dioxane for 2-3 h at room temperature. Dioxane
was evaporated to s to yield the amino acid or peptide derivative of
methylphenidate (44).
In some embodiments, the synthesis of Ala-MPH (44a) is as follows:
800-Ala-OH
DCC, HOBt, TEA in DMF
rt, overnight 'BOC
4N HCl/dioxane OMe
2 h, rt
NH2 HCI
A. Synthesis of Boc-Ala-MPH (43a):
Methylphenidate hydrochloride (0.274 g, 1.02 mmol) was taken in anhydrous
DMF (10 mL). Boc-Ala-OH (0.20 g, 1.07 mmol), TEA (0.35 mL, 2.54 mmol), HOBt (0.15
g, 1.11 mmol) and DCC (0.22 g, 1.07 mmol) were added. The reaction mixture was
stirred overnight at room temperature. DMF evaporated to dryness and the e was
taken in EtOAc (200 mL), and washed once each with 1% sodium bisulfate (60 mL) and
brine (60 mL). The organic layer was dried over anhydrous sodium sulfate and
concentrated to dryness to yield 43a (0.37 9) (yield, 90%).
B. Synthesis of Ala-MPH-HCI (44a):
Compound 43a (0.37 g) was taken in 4N HCl/dioxane (8 mL) and stirred for 2
h at room temperature. Dixoane was evaporated to dryness to yield 44a (0.31 9) ,
100%).
In other embodiments, the general ure for the synthesis of 1,3-
eride derivatives of methylphenidate with or without linker (chain length of
carboxylic acid preferably C14 or longer) is as follows:
0 it
OJL R1 p-nitrophenyl chloroformate 0 R1
HO< O
- O
TEAin DCM,0 oCtort,3 h \[f o R2
0 R2
\ii/ 0 \ii/
45 o 02N o
R1, R2 = fatty acid chain
MPH-HCI Mi
TEA in DMF, rt, overnight NYC—CORR2
0 1?
The yl group of 1,3-diglycerides (45) can be activated with p-
nitrophenyl chloroformate. The activated glyceride 46 can then be treated with
methylphenidate hydrochloride in the presence of TEA in DMF to yield the respective
carbamate derivative 47. es of 1,3-diglycerides include but are not limited to
glyceryl 1,3-dipalmitate, glyceryl 1,3-distearate or 1-palmitoylstearoyl-glycerol.
In some embodiments, the synthesis of 1,3-diglyceride derivatives of MPH
with hydroxycarboxylic acid linkers (48) is as follows:
OMe i fix OMe o
A 0_ _
0 ML
\ii/o\ A
A OH To )1o—CO
0 R3
0 if
8 1,3-diglyceride
DCC, DMAP in DCM, rt, ght R2 R3 = fatty acid chain
For example:
OMe O
OMe o )L
N o O R2
N o ‘n’ 0
\H/ OH 1 o R3
O R
0 Fl1 \n/
8a: R1: H 48a: Fl1 = H
8b:R1= CH. 48b:R1='CH3’
8c: Fl1 = P—h 48c: Fl1 = -Ph
A carbamate of methylphenidate and a linker with a free terminal carboxylic
acid group can also be attached to a glyceride derivative. Methylphenidate
carbamate conjugates of hydroxy carboxylic acids, for example, can be coupled to a
2012/048641
1,3-diglyceride using DCC and DMAP in DCM to give the respective fatty acid glycerol
derivatives 48. Examples of 1,3-diglycerides include but are not d to glyceryl 1,3-
dipalmitate, glyceryl 1,3-distearate or 1-palmitoylstearoyl-glycerol.
In other embodiments, the general procedure for the synthesis of conjugates
of phenidate with —(OC)OCHZO- linker'Is as follows.
GIL“)MeO O MeO
CICOZCHZCI Nal
—> OI:ID>—OCHZCI —>
MeO O O>_ MeO O
OCHZI O>_OCHZOR
N 1_ROAg N
2. Hg/Pd/C
or HCI
R = phosphoryl, acyl
To a solution of iodomethyl ate of methylphenidate 38 (1-1.5 mmol) in
toluene (25-50 mL) was added silver salt of acid (3 eq.). The mixture was heated from
80 °C to reflux for 3 h depending on the silver salt of the acid. After the reaction was
te, the solid was filter off and the filtrate was concentrated. The residue was
purified by column to give the conjugate. The conjugate was either the final product or
needed to be deprotected. All protecting groups in these procedures were benzyl
groups but others may be used. The conjugate in methanol was hydrogenated with
% Pd/C using a hydrogen balloon for 2 h. The catalyst was filtered off. The filtrate
was concentrated and dried to give the final conjugate 49.
In some embodiments, the synthesis of phosphate-CH20CO-MPH (49a), the
ure of which is shown below, is as follows in steps A, B and C:
M90 0
(316) we ROHo>_ 9,014
A. Synthesis of silver dibenzyl phosphate:
Dibenzyl phosphate (2.78 g, 10 mmol) in water (40 mL) was cooled in an ice
bath. Subsequently, 1N NaOH was added while shaking the flask until the pH of
solution was about 7. The solid dissolved almost completely. Then silver nitrate (1.89
g, 11 mmol) in water (20 mL) was added slowly. After , the resulting solid was
collected by filtration and washed with water. The solid was dried in vacuum over
phosphorus pentoxide to yield silver dibenzyl phosphate (3.18 g) (yield, 82.5%) as a
white solid.
B. Synthesis of (BnO)2-phosphate-CH20CO-MPH:
MeO O O g/OBn
yOCHZO—Px
N OBn
lodomethyl 2-(2-methoxyoxophenylethyl)piperidinecarboxylate 38
(0.260 g, 0.62 mmol) and silver dibenzyl phosphate (0.719 g, 1.87 mmol) in toluene (20
mL) were ed for 1.5 h. The solid was filtered off. The filtrate was concentrated
and the residue was purified by silica gel column chomatography (hexanes:EtOAc, 3:1
to 1 :1) to give a the protected ate (0.27 g) (yield, 76.3%) as colorless oil.
C. sis of phosphate-CH20CO-MPH (49a):
(Bis(benzyloxy)phosphoryloxy)methyl 2-(2-methoxyoxo
phenylethyl)piperidinecarboxylate (0.267 g, 0.47 mmol) in methanol (8 mL) was
enated under 10% Pd/C (dry, 90 mg) with a hydrogen n for 2 h. The
catalyst was filtered off through . The filtrate was evaporated to dryness to give
49a (0.136 g) (yield, was 74.6%) as a white amorphous solid.
In some embodiments, the synthesis of nicotinate-CH20CO-MPH-HC| (49b),
the structure of which is shown below, is as follows in steps A and B:
MeO O O
>—OCH2—o + _
\NHCI
N |
A. Synthesis of nicotinate-CH20CO-MPH, the structure of which is shown
below:
Iodomethyl 2- (2- methoxy---oxo 1-p-henylethyl)piperidine- 1--carboxylate 38
(0.457 g, 1.10 mmol) and silver nicotinate (0.755 g, 3.28 mmol) in toluene (20 mL) were
refluxed for 2 h. The solid was filtered off. The filtrate was concentrated and the
e was purified by silica gel column chomatography (hexanes:EtOAc, 2:1 to 1:1) to
give 49b in freebase form (0.256 g) , 56.7%) a colorless oil.
B. Synthesis of nicotinate-CH20CO-MPH-HC| (49b):
(2-(2-methoxyoxophenylethyl)piperidinecarbonyloxy)methyl nicotinate
(0.256 g, 0.62 mmol) in acetone (8 mL) was treated with 1.25N HCl/MeOH (0.75 mL,
0.93 mmol). The solvent was ated at room temperature. The resulting e
was coevaporated with acetone (2 x 3 mL) and then dissolved in acetone (0.8 mL) and
ether (20 mL) was added. Upon scratching with a spatula, solid formed gradually and
was collected by filtration to yield 49b (0.180 g) (yield, .
In other embodiments, the sis of isonicotinate-CH20CO-MPH-HC|
(49c), the structure of which is shown below, is as follows in steps A and B:
MeO O O
>—OCH2—o \
N |
/l>lH CI
A. Synthesis of isonicotinate-CH20CO-MPH, the structure of which is shown
below:
OCS\~ocug—o \
] Iodomethyl 2- (2- methoxy---oxo 1-p-henylethyl)piperidinecarboxylate 38
(0.555 g, 1.33 mmol) and silver isonicotinate (0.918 g, 3.99 mmol) in toluene (50 mL)
were heated for 1.5 h at 90 °C. The solid was filtered off through celite. The filtrate was
concentrated and the residue was ed by silica gel column ography
(hexanes:EtOAc, 1.2:1 to 1:1) to give 49c in freebase form (0.286 g) (yield, 52.1%) as a
syrup.
B. Synthesis of isonicotinate-CH20CO-MPH-HC| (49c):
(2-(2-methoxyoxophenylethyl)piperidinecarbonyloxy)methyl
isonicotinate (0.286 g, 0.62 mmol) in methanol (4 mL) was d with 1.25N
HCl/MeOH (1 mL, 1.25 mmol). The t was evaporated at room temperature. The
residue was coevaporated with methanol (2 x 5 mL) and acetone (4 mL) was added.
Solid formed gradually and acetone was evaporated. The solid was collected and
washed with ether (4 x 2 mL) to yield 49c (0.228 g) (yield, 73.2%) as an off-white solid.
In other embodiments, the synthesis of palmitate-CH20CO-MPH (49d), the
structure of which is shown below, is as follows:
MeO OOyOCHZO”(PC(CH))40H3
Iodomethyl 2-(2-methoxyoxophenylethyl)piperidinecarboxylate 38
(0.472 g, 1.13 mmol) and silver palmitate (1.233 g, 3.39 mmol) in toluene (50 mL) were
heated for 1 h at 95 °C. The solid was filtered off. The filtrate was concentrated and the
residue was purified by silica gel column chomatography (hexanes:EtOAc, 5:1) to give
49d (0.48 g) (yield, 77.8%) as a white solid.
In some embodiments, the synthesis of gallate-CH20CO-MPH (49e) the
structure of which is shown below, is as follows:
MeO O O
>—OCH2—O OH
Iodomethyl ethoxyoxophenylethyl)piperidinecarboxylate 38
(0.477 g, 1.14 mmol) and silver 3,4,5-tris(benzyloxy)benzoate (1.877 g, 3.43 mmol) in
toluene (50 mL) were heated for 1 h at 85 °C. The solid was filtered off through celite.
The filtrate was concentrated and the residue was purified by silica gel column
chomatography es:EtOAc, 3:1) to give 0.55 g of an amorphous solid, which was
hydrogenated under 10% Pd/C (dry, 150 mg) in methanol (25 mL) with a hydrogen
balloon for 2 h. The catalyst was filtered off through celite. The filtrate was evaporated
to dryness to give 49e (0.315 g) (yield, 60.1%) as an amorphous solid.
In other embodiments, the synthesis of phosphate-(p—salicylate)-CH20CO-
MPH (49f), the structure of which is shown below, is as follows:
MeO o O>—OCH2—OJ\©\
OP(O)(OH)2
Iodomethyl 2-(2-methoxyoxophenylethyl)piperidinecarboxylate 38
(0.47 g, 1.13 mmol) and silver 4-(bis(benzyloxy)phosphoryloxy)benzoate (1.01 g, 2
mmol) in toluene (50 mL) were heated for 1 h at 90 °C. The solid was filtered off
h celite. The filtrate was concentrated and the residue was purified by silica gel
column ography (hexanes:EtOAc, 3:1-2:1) to give 0.45 g of a colorless oil, which
was hydrogenated under 10% Pd/C (dry, 100 mg) in methanol (15 mL) with a hydrogen
balloon for 1 h. The catalyst was filtered off through . The filtrate was evaporated
to give 49f (0.326 g) (yield, 56.8%) as an amorphous solid.
In some embodiments, the general ure for the sis of pyridium-
type conjugates of methylphenidate is as follows:
cogMe cogMe R1
CICO CH Cl
#, I 50
HN N N/
O=f ,
OCHZCI
1 37
o=( m
HCI o=rN
OCPHz
_ ocH2
/N+| CI /N+| CI—
R1 \
51 52
R1 = H, -COZEt, -CONH2, cogtBu, -CO-Gly-Ala-OtBu, l-OtBu, -CO-Asp(OtBu)-OtBu
R2 = -CO-Gly-Ala, -CO-Val, p, -COZH
The chloromethyl carbamate of methylphenidate 37 (1-1.5 mmol) and pyridine
or pyridine tive 50 (1-7 mmol) in acetonitrile (6-10 mL) were heated for 3.5 h to 48
h at 70 °C. After the reaction was complete, the solvent was evaporated. The residue
was purified to give the conjugate. The conjugate was either the final product or
needed to be deprotected. All the protecting groups for these reactions were tert—butyl
groups, which were removed with 4N HCl/dioxane, but other protecting groups may be
used.
In other embodiments, the synthesis of MPH-COgCHg-pyridine chloride (51a),
the structure of which is shown below, is as follows:
COgMe
] The chloromethyl carbamate of methylphenidate 37 (0.326 g, 1 mmol) and
pyridine (0.566 mL, 7 mmol) in acetonitrile (6 mL) were heated for 3.5 h at 70 °C. The
solvent was evaporated and then coevaporated with e (2 x 5 mL). The resulting
residue was dissolved in DCM (1 mL) and tert—butyl methyl ether (TBME) (15 mL) was
added. The milky liquid was decanted. The e was dried in vacuum to give 51a
(0.404 g) (yield, 99.8%) as an amorphous solid.
In other embodiments, the sis of MPH-COgCHg-nicotinoyl-OEt chloride
(51 b), the structure of which is shown below, is as follows:
COZMe
o=( 51b
The chloromethyl carbamate of methylphenidate 37 (0.326 g, 1 mmol) and
ethyl nicotinate (0.453 g, 3 mmol) in acetonitrile (6 mL) were heated for 24 h at 70 °C.
The solvent was evaporated. The residue was dissolved in DCM (1.5 mL) and TBME
(40 mL) was added. Solid formed and liquid was decanted. The above procedure was
repeated twice. The resulting residue was dried in vacuum to give 51b (0.325 g) (yield,
68.1%) as an off-white solid.
In some embodiments, the sis of MPH-C02CH2-nicotinamide chloride
(51c), the structure of which is shown below, is as follows:
COZMe
0=l 51c
CONH2
The chloromethyl carbamate of methylphenidate 37 (0.326 g, 1 mmol) and
nicotinamide (0.122 g, 1 mmol) in itrile (6 mL) were heated for 26 h at 70 °C. The
t was evaporated and to the resulting residue was added EtOAc (40 mL). Upon
scratching with a spatula, solid formed gradually and was collected by filtration. The
solid was further washed with EtOAc (3 x 3 mL) and dried in vacuum to yield 51c (0.298
9) (yield, 66.5%) as an off-white solid.
In some embodiments, the synthesis of MPH-C02CH2-nicotinoyl-O‘Bu
chloride (51d), the structure of which is shown below, is as follows:
COZMe
0:] 51d
(1\‘
cogBu
The chloromethyl carbamate of methylphenidate 37 (0.489 g, 1.5 mmol) and
tert—butyl nicotinate (0.806 g, 4.5 mmol) in acetonitrile (10 mL) were heated for 7 h at 70
°C. The t was evaporated. To the e in DCM (1 mL) was added TBME (40
mL). The liquid was decanted and the residue was dissolved in DCM (1 mL) and then
TBME (30 mL) was added. The resulting solid was collected, washed with TBME (3 x 4
mL) and dried in vacuum to yield 51d (0.325 9) (yield, 47.4%) an ite solid.
In other embodiments, the synthesis of MPH-COgCHg-nicotinoyl-Gly-Ala
chloride (52a), the structure of which is shown below, is as follows in steps A, B and C:
COZMe
0=( 52a
CONHCHZCONHCIDHCOZH
A. Synthesis of tert—butyl 2-(2-(nicotinamido)acetamido)propanoate (50e), the
structure of which is shown below:
\ NU1
NHchogtBu
0 Me
] To H-Gly-Ala-O‘Bu (0.85 g, 4.2 mmol) in DCM (30 mL) was added Et3N (1.17
mL, 8.4 mmol). Nicotinoyl chloride hydrochloride (0.748 g, 4.2 mmol) was added in
portions (4 times, over 20 min.) in an ice-bath. After adding, the e was stirred for
1 h below 5 °C. Water (30 mL) was added to quench the reaction, ed by DCM (50
mL). The DCM layer was further washed with 5% NaHCOs and brine (30 mL each) and
dried over NagSO4. The solvent was evaporated and the residue was purified by silica
gel column ography (6% MeOH/DCM) to give 50e (0.881 g) (yield, 68.3%) as an
amorphous solid.
B. Synthesis of MPH-C02CH2-nicotinoyl-Gly-Ala-O‘Bu chloride (51e), the
structure of which is shown below:
COZMe
O=f 51e
OCH2
Kl/N+ Cl
CONHCHZCONHSHCOZtBu
The chloromethyl carbamate of methylphenidate 37 (0.489 g, 1.5 mmol) and
tert—butyl 2-(2-(nicotinamido) acetamido)propanoate 50e (0.461 g, 1.5 mmol) in
acetonitrile (10 mL) were heated for 24 h at 70 °C. The solvent was evaporated. The
residue was dissolved in DCM (1.5 mL) and TBME (25 mL) was added. Solid formed
and the liquid was decanted. The above procedure was repeated four times. The solid
was collected, washed with TBME (3 x 2 mL) and dried in vacuum to give 51e (0.576 g)
(yield, 60.7%) as an off-white solid.
] C. Synthesis of MPH-C02CH2-nicotinoyl-Gly-Ala chloride (52a):
To 51e (0.367 g, 0.58 mmol)in DCM (1 mL) was added 4 M HCl/dioxane (5
mL). The mixture was stirred for 2 h. The solvent was evaporated. The residue was
dissolved in DCM (2 mL) and TBME (25 mL) was added. The resulting solid was
collected, washed with TBME (2 x 1 mL) and dried in vacuum to yield 52e (0.322 g)
(yield, 96.1%) as a solid.
In other embodiments, the sis of MPH-COgCHg-nicotinoyl-Val chloride
(52b), the structure of which is shown below, is as follows in steps A, B and C:
COZMe
O=l’ 52b
CONHCIDHCOZH
A. Synthesis of tert-butyl 3-methyl(nicotinamido)butanoate (50f), the
structure of which is shown below:
| NHCIDHCOZtBu
N/ CH(CH3)2
501 was prepared by the same procedure as 50e and was ed by silica
gel column chomatography (3% MeOH/DCM) to give 501 (0.882 g, 3 mmol scale) (yield,
98.4%) as a syrup.
B. Synthesis of MPH-C02CH2-nicotinoyl-Val-O‘Bu chloride (51f) ,the
ure of which is shown below:
COgMe
CONHCIDHcogtBu
CH(CH3)2
The chloromethyl carbamate of methylphenidate 37 (0.489 g, 1.5 mmol) and
tert—butyl 3-methyl(nicotinamido)butanoate 501 (0.278 g, 1 mmol) in acetonitrile (10
mL) were heated for 40 h at 70 °C. The solvent was evaporated. To the residue in
TBME (5 mL) was added hexanes (10 mL). The resulting solid was collected, washed
WO 16668 2012/048641
with TBME/hexanes (1 :1, 6 x 3 mL) and dried in vacuum to give 51f (0.464 g) (yield,
76.8%).
C. Synthesis of MPH-Cochg-nicotinoyl-Val chloride (52b):
To 51f (0.302 g, 0.5 mmol) in DCM (1 mL) was added 4N HCl/dioxane (5 mL).
The mixture was stirred for 5 h. The solvent was evaporated. The residue was
dissolved in DCM (1.5 mL) and TBME (25 mL) was added. The resulting solid was
collected, washed with TBME (4 x 2 mL) and dried in vacuum to give 52b (0.329 g)
(yield, 100%) as a solid.
In other embodiments, the synthesis of MPH-COgCHg-nicotinoyl-Gly-Asp
chloride (52c), the structure of which is shown below, is as followsin steps A, B and C:
cogMe
o=l 52c
OCH2
/N+| CI
CONHchogt
CH2C02H
A. Synthesis of di-tert—butyl 2-(nicotinamido)succinate (509), the ure of
which is shown below:
\ NHCIDHCOZtBu
N/ CHZCOZtBU
509 was prepared by the same procedure as 50e.
B. Synthesis of MPH-Cochg-nicotinoyl-Asp(O‘Bu)-O‘Bu chloride (519), the
structure of which is shown below:
COgMe
O=( 51g
ocH2
CONHCIDHCOZtBu
CchogtBu
The chloromethyl carbamate of methylphenidate 37 (0.489 g, 1.5 mmol) and
t—Butyl 2-(nicotinamido)succinate 509 (0.35 g, 1 mmol) in acetonitrile (10 mL) were
heated for 24 h at 70 °C. The solvent was evaporated. The residue was purified by
silica gel column chomatography (7% MeOH/DCM, then 11% MeOH/DCM) to give 519
(0.452 g) (yield, 66.8%) as an amorphous solid.
C. Synthesis of MPH-COgCHg-nicotinoyl-Asp chloride (52c):
519 (0.45 g, 0.67 mmol) in 4N HCl/dioxane (5 mL) was stirred for 3 h. The
t was evaporated. The residue was coevaporated with DCM (4 x 5 mL), then
ved in DCM (4 mL) and TBME (25 mL) was added. The resulting solid was
collected, washed with TBME (4 x 2 mL) and dried in vacuum to yield 52c (0.357 g)
, 95.1%) as a solid.
In other embodiments, the sis of MPH-C02CH2-nicotinate chloride
(52d), the structure of which is shown below, is as follows:
COZMe
o=( 52d
3-(tert-Butoxycarbonyl)((2-(2-methoxyoxophenylethyl)piperidine
carbonyloxy)methyl)pyridium chloride 51d (0.202 g, 0.4 mmol) in 4N HCl/dioxane (5 mL)
was stirred for 24 h. The solvent was evaporated. The residue was dissolved in DCM
(1 mL) and TBME (20 mL) was added. The resulting solid was collected, washed with
TBME (3 x 1 mL) and dried in vacuum to give 52d (0.172 g) (yield, 95.8%) as a solid.
In some embodiments, the synthesis of phosphate-(p—salicylate)-MPH (56),
the structure of which is shown below, is as followsin steps A, B, C and D:
MeO O
N HOC2
+ EDCl/HOBt w>—©’%n
Et3N/THF
Hg/Pd/C < >OH 2PN(CHMe2)2 tBuOOH
EtAc/MeOH 1H -tetrazole/DCM
MeO o O (P. MeO o o 9
OP(OBn)2 OP(OH)2
N Hg/Pd/C N
MeOH
55 56
A. Synthesis of BnO-p—salicylate-MPH (53), the structure of which is shown
below,:
MeO o
phenidate hydrochloride (2.698 g, 10 mmol), 4-benzyloxybenzoic acid
(2.282 g, 10 mmol) and HOBt-H20 (1.532 g, 10 mmol) in THF (60 mL) were added to
Et3N (3.07 mL, 22 mmol), followed by l(3-dimethylaminopropyl) carbodiimide)
hydrochloride (EDCI) (2.109 g, 11 mmol). The mixture was stirred for 4 days. EtOAc
(200 mL) was added and the e was washed with water (30 mL), 5% HOAc (50
mL) and brine (40 mL). The EtOAc layer was dried over Na2804. The solvent was
evaporated and the residue was crystallized from EtOAc (12 mL). The solid was
collected by filtration and washed with cold EtOAc (3 x 4 mL) to give 53 (3.48 g) ,
78.5%) as a white solid.
B. Synthesis of cylate-MPH (54), the structure of which is shown
below,:
MeO o
53 (3.48 g, 7.85 mmol) was hydrogenated under 10% Pd/C (wet, 700 mg) in
MeOH (10 mL) and EtOAc (100 mL) with a hydrogen balloon for 15 h. The catalyst was
filtered off through celite. The filtrate was evaporated to give 54 (2.94 g) as an
amorphous solid.
C. Synthesis of (BnO)2-phosphate-(p—salicylate)-MPH (55), the structure of
which is shown below,:
MeO o 9
OP(OBn)2
] To 54 (0.7 g, 1.98 mmol) in DCM (20 mL) was added dibenzyl
diisopropylphosphoramidite (0.752 g, 2.178 mmol), ed by 1N-tetrazole solution in
acetonitrile (0.45 M, 4.84 mL, 2.178 mmol). The mixture was stirred for 3 h.
Subsequently, 0.6 mL of 70% tert-BuOOH/water was added and stirred for 20 min. The
solvent was evaporated. The residue in EtOAc (100 mL) was washed with water and
brine (30 mL each) and dried over NagSO4. The solvent was ated and the
residue was purified by silica gel column chomatography (EtOAc:hexanes, 1.2:1) to give
55 (0.99 g) (yield, 81.5%) as a syrup.
D. Synthesis of phosphate-(p—salicylate)-MPH (56), the structure of which is
shown below,:
MeO o 9
or>(on)2
55 (0.99 g, 1.61 mmol) was hydrogenated under 10% Pd/C (wet, 300 mg) in
methanol (20 mL) with a hydrogen balloon for 3 h. The catalyst was filtered off through
celite. The te was evaporated to give 56 (0.675 g) (yield, 96.5%) as an amorphous
solid.
In some embodiments, the synthesis of Gly-(p—salicylate)-MPH (58) is as
follows in steps A and B:
MeO o O
N EDCI/HOBt
+ BocNHCHCOZH —>
033 COT/S MeO 00,} C o
N HC
NHBoc NH2
A. sis of Boc-Gly-(p—salicylate)-MPH (57), the structure of which is
shown below,:
CHEW?NHBoc
To 54 (0.353 g, 1 mmol), Boc-Gly-O-l-l (0.175 g, 1 mmol) and 20
(0.153 g, 1 mmol) in THF (10 mL) were added Et3N (0.15 mL, 1.1 mmol), followed by
EDCI (0.211 g, 11 mmol). The mixture was stirred for 15 h. Then another 0.4 mmol of
Boc—Gly-OH and EDCI were added and the mixture was again stirred for 3 h. EtOAc
(100 mL) was added and the mixture was washed with water (2 x 30 mL) and brine (30
mL). The EtOAc layer was dried over Na2804. The solvent was evaporated and the
residue was purified by silica gel column chomatography (2% MeOH/DCM) to give 57
(0.452 g) , 88.5%) as an amorphous solid.
B. Synthesis of Glyp(-salicylate))-lV|PH 5(8).
lVlOe @«
To 57 (0.45 g, 0.88 mmol ) in DCM (1 mL) was added 4 M HCI/dioxane (5
mL). The mixture was stirred for 1 h. The solvent was evaporated. The residue was
coevaporated with DCM (3 x 5 mL) and then dissolved in DCM (2 mL). EtOAc (10 mL)
and TBME (10 mL) were added. The resulting solid was collected, washed with
EtOAc/TBME (1 :1, 3 x 2 mL) and dried in vacuum to give 58 (0.329 g) (yield, 83.5%) as
an white solid.
Pharmaceutical Kits
In some embodiments, the present technology provides pharmaceutical kits
comprising a prodrug or composition of the t technology that has increased water
solubility than compared to the unconjugated methylphenidate. In some embodiments,
a specific amount of individual doses in a package contain a pharmaceutically effective
amount of the prodrugs or conjugate of the present technology. In some other
embodiments, the kit comprises oral thin films or strips comprising prodrugs or
conjugates of the present technology. The present technology es pharmaceutical
kits for the treatment or prevention of ADHD, ADD or drug withdrawal symptoms in a
patient. The patient may be a human or animal patient. le human patients
e pediatric patients, geriatric (elderly) patients, and normative patients. The kit
comprises a ic amount of the individual doses in a package containing a
pharmaceutically effective amount of at least one conjugate of methylphenidate of the
present logy. The kit can further include instructions for use of the kit. The
specified amount of dual doses may contain from about 1 to about 100 individual
s, alternatively from about 1 to about 60 individual dosages, alternatively from
about 10 to about 30 individual dosages, including, about 1, about 2, about 5, about 10,
about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about
55, about 60, about 70, about 80, about 100, and include any additional increments
f, for example, about 1, about 2, about 5, about 10 and multiplied factors thereof,
(e.g., about x1, about x2, about x2.5, about x5, about x10, about x100, etc).
The presently described technology and its advantages will be better
understood by reference to the ing examples. These examples are provided to
describe specific embodiments of the t logy. By providing these specific
examples, it is not intended limit the scope and spirit of the present technology. It will
be understood by those skilled in the art that the full scope of the presently described
technology encompasses the subject matter defined by the claims appending this
specification, and any alterations, modifications, or equivalents of those claims.
EXAMPLES
Example 1: Comparison of oral pharmacokinetic (PK) profiles of ates of
methylphenidate and oxoacids.
Exemplary g conjugates of the present logy were synthesized as
described above. The oral plasma concentrations of methylphenidate ed from
nicotinate-CH20CO-MPH, phosphate-CH20CO-MPH, gallate-CH20CO-MPH, lactate-
-MPH, MPH-C02CH2-nicotinoyl-Asp, MPH-C02CH2-nicotinoyl-Val, MPH-
C02CH2-nicotinoyl-Gly-Ala, Valaminohexanoate-CH20CO-MPH, MPH-C02CH2-
nicotinamide, 6-aminohexanoate-CH20CO-MPH, MPH-COgCHg-nicotinoyl-O‘Bu, MPH-
COgCHg-nicotinate, MPH-COgCHg-nicotinoyl-OEt, MPH-COgCHg-pyridine, isonicotinate-
CHgOCO-MPH and phosphate-(p—salicylate)-CH20CO-MPH were compared with
unconjugated methylphenidate after oral administration in rats. Rats were dosed with
oral solutions of the conjugated prodrugs in an amount equivalent to 2 mg/kg of
methylphenidate free base and compared to an equimolar solution of unconjugated
methylphenidate hydrochloride.
] The plasma concentrations of methylphenidate were measured by MS
over time. Figures 13 - 30 demonstrate the different PK curves achieved by the
different methylphenidate conjugates as compared with unconjugated forms and all of
the specific pharmacokinetic parameter data is presented in Tables 2 - 4. The release
of methylphenidate from the prodrugs varied depending on the linker and ds
attached to methylphenidate. Changes in the amount of methylphenidate released from
the prodrugs as measured by the area under the curve ranged from 0-185 %-AUC
compared to unconjugated methylphenidate hloride.
The dosing vehicles for the PK experiments are as follows: Figure 13 - 10%
Tween in water. s 14 and 15 — water. Figure 16 - conjugate in 50% PEG-400 in
water; control: water. Figure 17 - 50% PEG-400 in water. Figure 18 - 10% Tween in
water. Figures 19 - 27 — water. Figures 28 and 29 — phosphate buffered saline (PBS).
Figure 30 - 10% Tween in water.
Table 2. PK parameters for prodrugs of methylphenidate dosed via oral gavage in rats.
Methylphenidate
AUC'O-4h Cmax Tmax 4h Cmax Tmax Cmax'
Conjugate [ng/mLxh][ng/mL] [h] [ng/mLxh][ng/mL] [h] AUC-% % Tmax-%
Nicotinate-CH20CO-MPH
(P0) 64.3 83.8 0.300 93.0 110.1 0.250 69% 76% 120%
Phosphate-CH20CO-MPH
(PO)a 154.5 158.9 0.250 106.1 113.8 0.283 146% 140% 88%
Phosphate-CH20CO-MPH
(PO) 110.8 110.8 0.250 59.8 77.0 0.250 185% 144% 100%
Gallate-CHZOCO-MPH
(PO)b 85.6 77.3 0.600 106.1 113.8 0.283 81% 68% 212%
Gallate-CH20CO-MPH(PO) 85.6 77.3 0.600 187.2 176.8 0.450 46% 44% 133%
Lactate-CH20CO-MPH
(PO) 132.3 122.5 0.300 182.3 162.8 0.250 73% 75% 120%
MPH-C02CH2-nicotinoyl-
Asp (PO) 125.6 97.3 0.300 116.3 111.1 0.250 108% 88% 120%
MPH-COZCHg-nicotinoyl-Val
(P0) 91.4 75.2 0.350 121.6 111.1 0.250 75% 68% 140%
MPH-C02CH2-nicotinoyl-
Gly-Ala (P0) 71.0 71.8 0.250 76.9 89.6 0.300 92% 80% 83%
Valaminohexanoate-
CH20CO-MPH (P0) 44.9 52.7 0.250 76.9 89.6 0.300 58% 59% 83%
MPH-C02CH2-nicotinamide
(P0) 63.4 78.6 0.300 49.5 86.8 0.250 128% 91% 120%
ohexanoate-
CH20CO-MPH (PO) 145.6 173.5 0.350 177.9 159.1 0.400 82% 109% 88%
MPH-C02CH2-nicotinoyl-
OtBu (P0) 71.4 54.9 0.400 78.1 73.9 0.300 91% 74% 133%
ZCHg-nicotinate
(P0) 75.5 52.6 0.450 78.1 73.9 0.300 97% 71% 150%
MPH-C02CH2-nicotinoyl-
OEt (P0) 62.7 36.9 0.450 49.5 86.8 0.250 127% 43% 180%
MPH-COZCHg-pyridinePO) 72.0 87.1 0.250 49.5 86.8 0.250 145% 100% 100%
WO 16668
Isonicotinate-CH20CO-
MPH (P0) 51.9 69.8 0.250 42.1 79.9 0.250 123% 87% 100%
Phosphate-(p-salicylate)-
-MPH P0 35.3 57.1 0.250 42.1 79.9 0.250 84% 72% 100%
aPK parameters for phosphate-CHZOCO-MPH calculated from combined data of three studies and
for methylphenidate hydrochloride from combined data of six studies.
bPK parameters for gallate-CHZOCO-MPH calculated from data of one study and for
methylphenidate hydrochloride from combined data of six studies.
Table 3. PK parameters for prodrugs of phenidate dosed intranasally in rats.
Methylphenidate
AUC'O-4h Cmax Tmax 4h Cmax Tmax Cmax'
Conjugate [ng/mLxh][ng/mL] [h] [ng/mLxh][ng/mL] [h] AUC-% % Tmax-%
MPH-C02CH2-nicotinamide
(IN) 121.4 213.4 0.083 957.5 2137.0 0.083 13% 10% 100%
2CH2-nicotinoyl-
OtBu (IN) 51.6 156.3 0.083 824.0 2373.5 0.083 6% 7% 100%
MPH-COZCHg-nicotinate
(IN) 38.8 122.0 0.083 1045.3 2210.4 0.116 4% 6% 71%
MPH-C02CH2-pyridine(lN) 29.2 59.9 0.187 879.2 2128.4 0.083 3% 3% 226%
Table 4. PK parameters for prodrugs of methylphenidate dosed intravenously in rats.
Methylphenidate
AUC'O-4h c“'max Tmax AUCo.4h Cmax Tmax Cmax'
Con'u ate [n /mLxh] [n /mL] [h] [n /mLxh] [n /mL] [h] AUC-% % Tmax'%
MPH-COZCHZ-nicotinamide
(IV) 62.5 67.3 0.633 320.2 295.8 0.517 20% 23% 1 23%
MPH-C02CH2-pyridine (IV) 13.2 10.6 0.417 414.9 439.4 0.266 3% 2% 1 56%
Example 2: Water solubility of methylphenidate conjugates of the present
logy.
The water solubility of phosphate-CH20CO-methylphenidate and
unconjugated methylphenidate was determined at ambient temperature and the results
are found in Table 5.
Table 5. Water solubility of methylphenidate conjugates of oxoacids
nd Solubility in Water
phosphate-CH20CO-methylphenidate 432 mg/mL
methylphenidate hydrochloride 169 mg/mL
The results for unconjugated methylphenidate hydrochloride are consistent
with the solubility data found in the literature (191 mg/mL at 32 °C). The water solubility
of the phosphate-CH20CO-methylphenidate conjugate is about 2.5 times higher than
the unconjugated form.
In the t specification, use of the singular includes the plural except
where specifically indicated.
The presently described technology is now described in such full, clear,
concise and exact terms as to enable any person skilled in the art to which it pertains, to
practice the same. It is to be understood that the foregoing describes preferred
embodiments of the technology and that modifications may be made therein without
departing from the spirit or scope of the ion as set forth in the appended claims.
Claims (10)
1. A prodrug composition sing at least one conjugate of methylphenidate wherein the conjugate is of the ing structure: wherein G2 is selected from the group consisting of standard amino acids, nonstandard amino acids and synthetic amino acids; and wherein the amino acid is attached to the rest of the molecule by an amide linkage.
2. The prodrug composition of claim 1, n the amino acid is threonine.
3. The prodrug composition of claim 1, wherein the amino acid is serine.
4. The prodrug composition of claim 1, wherein the prodrug of methylphenidate has one of the following structures: O O O O O O N O CH N+ 2 N O CH N+ NH O NH O O O OH OH OH OH
5. The prodrug composition of claim 1, wherein the conjugate is a pharmaceutically acceptable anionic, amphoteric, zwitterionic or cationic salt form or salt mixtures thereof.
6. The prodrug composition of claim 5, wherein the anionic salt form is selected from the group consisting of acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, ylate, citrate, edisylate, formate, fumarate, ate, hydrobromide/bromide, hloride/chloride, d-lactate, l-lactate, d,l-lactate, d,lmalate , l-malate, te, pamoate, ate, succinate, sulfate, bisulfate, dtartrate , l-tartrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsufate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, e, cypionate, dichloroacetate, te, ethyl sulfate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutamate, ate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, ate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesufonate, myristate, napadisilate, oleate, oxalate, ate, e, te, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4- acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, and undecylenate.
7. The prodrug composition of claim 5, wherein the cationic salt form is selected from the group ting of sodium, potassium, calcium, magnesium, zinc, aluminium, lithium, cholinate, um, ammonium and tromethamine.
8. The prodrug composition of any one of claims 1 to 7, wherein the composition is in the form comprising a tablet, a capsule, a caplet, a troche, a e, an oral powder, a solution, a thin strip, an oral thin film (OTF), an oral strip, a rectal film, a transdermal patch, a syrup, a suspension, an inhalation compound or a suppository.
9. The prodrug composition of claim 1, wherein the conjugate is of the following structure: wherein G2 is selected from the group consisting of standard amino acids, nonstandard amino acids and synthetic amino acids; and n the amino acid is attached to the rest of the molecule by an amide
10. The prodrug composition according to claim 1, substantially as herein described with reference to any one of the anying examples and/or figures.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161512658P | 2011-07-28 | 2011-07-28 | |
US61/512,658 | 2011-07-28 | ||
PCT/US2012/048641 WO2013016668A2 (en) | 2011-07-28 | 2012-07-27 | Methylphenidate-prodrugs, processes of making and using the same |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ618113A NZ618113A (en) | 2015-06-26 |
NZ618113B2 true NZ618113B2 (en) | 2015-09-29 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6731090B2 (en) | Methylphenidate-prodrugs, methods of making and using the same | |
AU2012286683A1 (en) | Methylphenidate-prodrugs, processes of making and using the same | |
NZ618113B2 (en) | Methylphenidate-prodrugs, processes of making and using the same | |
WO2018191472A1 (en) | Levorphanol prodrugs and processes for making and using them | |
WO2018191477A1 (en) | Dextrorphan prodrugs and processes for making and using them |