AP640A - A Pyrimidine of formula (1) - Google Patents

A Pyrimidine of formula (1) Download PDF

Info

Publication number: AP640A
Authority: AP; ARIPO
Prior art keywords: salt; pyrimidine; enantiomer; diamino; dichlorophenyl
Prior art date: 1995-09-05

Application number

APAP/P/1996/000857A

Other languages

English (en)

Other versions

AP9600857A0 (en

Inventor

Malcolm Stuart Nobbs

Sandra Jane Rodgers

Original Assignee

Glaxo Group Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1995-09-05

Filing date

1996-09-06

Publication date

1998-04-14

1996-09-06 Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd

1996-10-31 Publication of AP9600857A0 publication Critical patent/AP9600857A0/xx

1998-04-14 Application granted granted Critical

1998-04-14 Publication of AP640A publication Critical patent/AP640A/en

Links

CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title claims abstract description 22
150000003839 salts Chemical class 0.000 claims abstract description 112
239000002253 acid Substances 0.000 claims abstract description 58
239000001961 anticonvulsive agent Substances 0.000 claims abstract description 10
208000002551 irritable bowel syndrome Diseases 0.000 claims abstract description 9
208000020925 Bipolar disease Diseases 0.000 claims abstract description 8
239000012458 free base Substances 0.000 claims description 31
150000001875 compounds Chemical class 0.000 claims description 29
238000000034 method Methods 0.000 claims description 27
GKBLWFDYSYTVEA-UHFFFAOYSA-N 5-(2,3-dichlorophenyl)-6-(fluoromethyl)pyrimidine-2,4-diamine Chemical compound FCC1=NC(N)=NC(N)=C1C1=CC=CC(Cl)=C1Cl GKBLWFDYSYTVEA-UHFFFAOYSA-N 0.000 claims description 25
HBQWFGBUDSKBDG-UHFFFAOYSA-N [2,6-diamino-5-(2,3-dichlorophenyl)pyrimidin-4-yl]methanol Chemical compound OCC1=NC(N)=NC(N)=C1C1=CC=CC(Cl)=C1Cl HBQWFGBUDSKBDG-UHFFFAOYSA-N 0.000 claims description 20
239000004480 active ingredient Substances 0.000 claims description 20
238000002360 preparation method Methods 0.000 claims description 19
230000008569 process Effects 0.000 claims description 15
239000002585 base Substances 0.000 claims description 14
SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 13
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
230000001773 anti-convulsant effect Effects 0.000 claims description 7
229960003965 antiepileptics Drugs 0.000 claims description 7
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
229910019142 PO4 Inorganic materials 0.000 claims description 6
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 6
230000000202 analgesic effect Effects 0.000 claims description 6
208000035475 disorder Diseases 0.000 claims description 6
239000003814 drug Substances 0.000 claims description 6
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
239000010452 phosphate Substances 0.000 claims description 6
229910021653 sulphate ion Inorganic materials 0.000 claims description 6
239000003795 chemical substances by application Substances 0.000 claims description 4
239000008194 pharmaceutical composition Substances 0.000 claims description 4
239000003085 diluting agent Substances 0.000 claims description 3
230000001939 inductive effect Effects 0.000 claims description 3
238000004519 manufacturing process Methods 0.000 claims description 3
208000015122 neurodegenerative disease Diseases 0.000 claims description 2
238000002560 therapeutic procedure Methods 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims 1
229940035676 analgesics Drugs 0.000 abstract description 2
239000000730 antalgic agent Substances 0.000 abstract description 2
229940125681 anticonvulsant agent Drugs 0.000 abstract description 2
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 93
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
239000000243 solution Substances 0.000 description 49
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
239000000203 mixture Substances 0.000 description 45
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
239000007787 solid Substances 0.000 description 34
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
239000000725 suspension Substances 0.000 description 23
PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical group NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 21
241000700159 Rattus Species 0.000 description 20
238000009472 formulation Methods 0.000 description 20
229960001848 lamotrigine Drugs 0.000 description 20
230000000694 effects Effects 0.000 description 19
239000002904 solvent Substances 0.000 description 16
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
238000002347 injection Methods 0.000 description 14
239000007924 injection Substances 0.000 description 14
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
239000003826 tablet Substances 0.000 description 12
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
229940093499 ethyl acetate Drugs 0.000 description 11
235000019439 ethyl acetate Nutrition 0.000 description 11
CZLINJDTCHACEH-UHFFFAOYSA-N 2-(2,3-dichlorophenyl)acetonitrile Chemical compound ClC1=CC=CC(CC#N)=C1Cl CZLINJDTCHACEH-UHFFFAOYSA-N 0.000 description 10
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
241001465754 Metazoa Species 0.000 description 10
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
208000002193 Pain Diseases 0.000 description 9
238000012360 testing method Methods 0.000 description 9
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
241000699670 Mus sp. Species 0.000 description 8
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 8
239000004615 ingredient Substances 0.000 description 8
230000005764 inhibitory process Effects 0.000 description 8
239000012452 mother liquor Substances 0.000 description 8
239000012071 phase Substances 0.000 description 8
239000000047 product Substances 0.000 description 8
-1 pyrimidine compound Chemical class 0.000 description 8
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
239000007788 liquid Substances 0.000 description 7
239000000463 material Substances 0.000 description 7
239000012074 organic phase Substances 0.000 description 7
230000036407 pain Effects 0.000 description 7
238000010992 reflux Methods 0.000 description 7
229910000033 sodium borohydride Inorganic materials 0.000 description 7
239000012279 sodium borohydride Substances 0.000 description 7
STVBVTWXWZMRPZ-UHFFFAOYSA-N (2,3-dichlorophenyl)methanol Chemical compound OCC1=CC=CC(Cl)=C1Cl STVBVTWXWZMRPZ-UHFFFAOYSA-N 0.000 description 6
241000282414 Homo sapiens Species 0.000 description 6
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 6
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
108010022394 Threonine synthase Proteins 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
150000007513 acids Chemical class 0.000 description 6
239000002775 capsule Substances 0.000 description 6
102000004419 dihydrofolate reductase Human genes 0.000 description 6
239000008101 lactose Substances 0.000 description 6
239000000843 powder Substances 0.000 description 6
239000011541 reaction mixture Substances 0.000 description 6
238000010792 warming Methods 0.000 description 6
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 5
230000009471 action Effects 0.000 description 5
239000007963 capsule composition Substances 0.000 description 5
239000002178 crystalline material Substances 0.000 description 5
206010015037 epilepsy Diseases 0.000 description 5
239000008187 granular material Substances 0.000 description 5
235000019359 magnesium stearate Nutrition 0.000 description 5
238000002844 melting Methods 0.000 description 5
230000008018 melting Effects 0.000 description 5
229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
239000008213 purified water Substances 0.000 description 5
238000001953 recrystallisation Methods 0.000 description 5
239000002002 slurry Substances 0.000 description 5
239000011734 sodium Substances 0.000 description 5
YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 4
XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 4
206010003591 Ataxia Diseases 0.000 description 4
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 4
238000005481 NMR spectroscopy Methods 0.000 description 4
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
239000000969 carrier Substances 0.000 description 4
238000013270 controlled release Methods 0.000 description 4
230000001419 dependent effect Effects 0.000 description 4
XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 4
VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
238000003682 fluorination reaction Methods 0.000 description 4
229960000789 guanidine hydrochloride Drugs 0.000 description 4
PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 4
238000010438 heat treatment Methods 0.000 description 4
HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 4
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
210000003205 muscle Anatomy 0.000 description 4
230000003287 optical effect Effects 0.000 description 4
239000003208 petroleum Substances 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 4
239000002244 precipitate Substances 0.000 description 4
229910052708 sodium Inorganic materials 0.000 description 4
239000011780 sodium chloride Substances 0.000 description 4
239000000126 substance Substances 0.000 description 4
239000000829 suppository Substances 0.000 description 4
CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 description 3
PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 3
LLMLNAVBOAMOEE-UHFFFAOYSA-N 2,3-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1Cl LLMLNAVBOAMOEE-UHFFFAOYSA-N 0.000 description 3
XWDJXOXMYJHBFY-UHFFFAOYSA-N 2,6-diamino-5-(2,3-dichlorophenyl)pyrimidine-4-carbaldehyde Chemical compound O=CC1=NC(N)=NC(N)=C1C1=CC=CC(Cl)=C1Cl XWDJXOXMYJHBFY-UHFFFAOYSA-N 0.000 description 3
VJNOBGNYVNOXAC-UHFFFAOYSA-N 2-(2,3-dichlorophenyl)-3-ethoxy-4-fluorobut-2-enenitrile Chemical compound CCOC(CF)=C(C#N)C1=CC=CC(Cl)=C1Cl VJNOBGNYVNOXAC-UHFFFAOYSA-N 0.000 description 3
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
108091006146 Channels Proteins 0.000 description 3
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 3
208000004454 Hyperalgesia Diseases 0.000 description 3
208000035154 Hyperesthesia Diseases 0.000 description 3
229920000168 Microcrystalline cellulose Polymers 0.000 description 3
101001135571 Mus musculus Tyrosine-protein phosphatase non-receptor type 2 Proteins 0.000 description 3
WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
108010058846 Ovalbumin Proteins 0.000 description 3
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
230000029936 alkylation Effects 0.000 description 3
238000005804 alkylation reaction Methods 0.000 description 3
230000036592 analgesia Effects 0.000 description 3
238000003556 assay Methods 0.000 description 3
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
238000006243 chemical reaction Methods 0.000 description 3
238000007906 compression Methods 0.000 description 3
230000006835 compression Effects 0.000 description 3
239000000796 flavoring agent Substances 0.000 description 3
239000007903 gelatin capsule Substances 0.000 description 3
235000011187 glycerol Nutrition 0.000 description 3
229910052943 magnesium sulfate Inorganic materials 0.000 description 3
239000012528 membrane Substances 0.000 description 3
239000008108 microcrystalline cellulose Substances 0.000 description 3
229940016286 microcrystalline cellulose Drugs 0.000 description 3
235000019813 microcrystalline cellulose Nutrition 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
239000011591 potassium Substances 0.000 description 3
229910052700 potassium Inorganic materials 0.000 description 3
230000003389 potentiating effect Effects 0.000 description 3
229940069328 povidone Drugs 0.000 description 3
239000011369 resultant mixture Substances 0.000 description 3
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
238000007920 subcutaneous administration Methods 0.000 description 3
229940095064 tartrate Drugs 0.000 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 description 3
BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
ZDZHCHYQNPQSGG-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalene Chemical group C1=CC=C2C(C=3C4=CC=CC=C4C=CC=3)=CC=CC2=C1 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 2
UOFNNRVVBSSTPM-UHFFFAOYSA-N 2-(2,3-dichlorophenyl)-3,4,4-triethoxybut-2-enenitrile Chemical compound CCOC(OCC)C(OCC)=C(C#N)C1=CC=CC(Cl)=C1Cl UOFNNRVVBSSTPM-UHFFFAOYSA-N 0.000 description 2
OFUULLAOUJVTSP-UHFFFAOYSA-N 2-(2,3-dichlorophenyl)-4-fluoro-3-hydroxybut-2-enenitrile Chemical compound FCC(O)=C(C#N)C1=CC=CC(Cl)=C1Cl OFUULLAOUJVTSP-UHFFFAOYSA-N 0.000 description 2
TXBRTFNTEOEZPB-UHFFFAOYSA-N 2-(diethoxymethyl)pyrimidine Chemical compound CCOC(OCC)C1=NC=CC=N1 TXBRTFNTEOEZPB-UHFFFAOYSA-N 0.000 description 2
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
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 2
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
239000001856 Ethyl cellulose Substances 0.000 description 2
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
206010020751 Hypersensitivity Diseases 0.000 description 2
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
235000010643 Leucaena leucocephala Nutrition 0.000 description 2
240000007472 Leucaena leucocephala Species 0.000 description 2
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 2
208000004550 Postoperative Pain Diseases 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
229930006000 Sucrose Natural products 0.000 description 2
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 2
230000001154 acute effect Effects 0.000 description 2
239000012670 alkaline solution Substances 0.000 description 2
208000026935 allergic disease Diseases 0.000 description 2
BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
238000004458 analytical method Methods 0.000 description 2
239000008346 aqueous phase Substances 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
230000015572 biosynthetic process Effects 0.000 description 2
239000012267 brine Substances 0.000 description 2
210000003169 central nervous system Anatomy 0.000 description 2
238000004296 chiral HPLC Methods 0.000 description 2
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 2
238000009833 condensation Methods 0.000 description 2
230000005494 condensation Effects 0.000 description 2
230000008878 coupling Effects 0.000 description 2
238000010168 coupling process Methods 0.000 description 2
238000005859 coupling reaction Methods 0.000 description 2
239000006071 cream Substances 0.000 description 2
238000000354 decomposition reaction Methods 0.000 description 2
238000004821 distillation Methods 0.000 description 2
239000012153 distilled water Substances 0.000 description 2
229960003638 dopamine Drugs 0.000 description 2
229940079593 drug Drugs 0.000 description 2
238000001647 drug administration Methods 0.000 description 2
238000001035 drying Methods 0.000 description 2
239000000839 emulsion Substances 0.000 description 2
150000002084 enol ethers Chemical class 0.000 description 2
XCLBIKIQSCTANZ-UHFFFAOYSA-N ethyl 2,2-diethoxyacetate Chemical compound CCOC(OCC)C(=O)OCC XCLBIKIQSCTANZ-UHFFFAOYSA-N 0.000 description 2
VCYZVXRKYPKDQB-UHFFFAOYSA-N ethyl 2-fluoroacetate Chemical compound CCOC(=O)CF VCYZVXRKYPKDQB-UHFFFAOYSA-N 0.000 description 2
235000019325 ethyl cellulose Nutrition 0.000 description 2
229920001249 ethyl cellulose Polymers 0.000 description 2
238000002474 experimental method Methods 0.000 description 2
238000011049 filling Methods 0.000 description 2
239000000706 filtrate Substances 0.000 description 2
238000001914 filtration Methods 0.000 description 2
235000019634 flavors Nutrition 0.000 description 2
VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 2
229930195712 glutamate Natural products 0.000 description 2
229940116364 hard fat Drugs 0.000 description 2
210000004295 hippocampal neuron Anatomy 0.000 description 2
SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
239000001863 hydroxypropyl cellulose Substances 0.000 description 2
235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
230000009610 hypersensitivity Effects 0.000 description 2
238000001990 intravenous administration Methods 0.000 description 2
229940045996 isethionic acid Drugs 0.000 description 2
239000000314 lubricant Substances 0.000 description 2
238000002156 mixing Methods 0.000 description 2
BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
238000000465 moulding Methods 0.000 description 2
208000004296 neuralgia Diseases 0.000 description 2
230000004770 neurodegeneration Effects 0.000 description 2
210000002569 neuron Anatomy 0.000 description 2
208000021722 neuropathic pain Diseases 0.000 description 2
238000006386 neutralization reaction Methods 0.000 description 2
229910001120 nichrome Inorganic materials 0.000 description 2
239000003921 oil Substances 0.000 description 2
239000004006 olive oil Substances 0.000 description 2
235000008390 olive oil Nutrition 0.000 description 2
VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
239000003444 phase transfer catalyst Substances 0.000 description 2
239000008363 phosphate buffer Substances 0.000 description 2
239000001267 polyvinylpyrrolidone Substances 0.000 description 2
229910000027 potassium carbonate Inorganic materials 0.000 description 2
230000035484 reaction time Effects 0.000 description 2
230000009467 reduction Effects 0.000 description 2
230000004044 response Effects 0.000 description 2
YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
229960001860 salicylate Drugs 0.000 description 2
238000000926 separation method Methods 0.000 description 2
WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
239000004299 sodium benzoate Substances 0.000 description 2
235000010234 sodium benzoate Nutrition 0.000 description 2
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
239000000600 sorbitol Substances 0.000 description 2
229910001220 stainless steel Inorganic materials 0.000 description 2
239000010935 stainless steel Substances 0.000 description 2
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
239000005720 sucrose Substances 0.000 description 2
208000024891 symptom Diseases 0.000 description 2
238000003786 synthesis reaction Methods 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
238000005406 washing Methods 0.000 description 2
SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
FOTRUJUPLHRVNU-QNBGGDODSA-N (2r,3r)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid;hydrate Chemical compound O.C1=CC(C)=CC=C1C(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 FOTRUJUPLHRVNU-QNBGGDODSA-N 0.000 description 1
DXDIHODZARUBLA-DTPOWOMPSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid;hydrate Chemical compound O.O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 DXDIHODZARUBLA-DTPOWOMPSA-N 0.000 description 1
NTOIKDYVJIWVSU-WOJBJXKFSA-N (2r,3r)-2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)[C@@](O)(C(O)=O)[C@](O)(C(O)=O)C(=O)C1=CC=C(C)C=C1 NTOIKDYVJIWVSU-WOJBJXKFSA-N 0.000 description 1
YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 1
DXDIHODZARUBLA-IODNYQNNSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid;hydrate Chemical compound O.O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 DXDIHODZARUBLA-IODNYQNNSA-N 0.000 description 1
AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-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
JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
KOWJANGMTAZWDT-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin-1-ium;chloride Chemical compound Cl.C1N(C)CCC(C=2C=CC=CC=2)=C1 KOWJANGMTAZWDT-UHFFFAOYSA-N 0.000 description 1
229940015297 1-octanesulfonic acid Drugs 0.000 description 1
238000005160 1H NMR spectroscopy Methods 0.000 description 1
VTSWSQGDJQFXHB-UHFFFAOYSA-N 2,4,6-trichloro-5-methylpyrimidine Chemical compound CC1=C(Cl)N=C(Cl)N=C1Cl VTSWSQGDJQFXHB-UHFFFAOYSA-N 0.000 description 1
YFMPSMITLLBENU-UHFFFAOYSA-N 3,4-dihydroxybenzylamine Chemical compound NCC1=CC=C(O)C(O)=C1 YFMPSMITLLBENU-UHFFFAOYSA-N 0.000 description 1
VUTBELPREDJDDH-UHFFFAOYSA-N 4-amino-5-hydroxymethyl-2-methylpyrimidine Chemical compound CC1=NC=C(CO)C(N)=N1 VUTBELPREDJDDH-UHFFFAOYSA-N 0.000 description 1
WOYVHBRLDIJCAD-UHFFFAOYSA-N 5-(2,3-dichlorophenyl)-6-(diethoxymethyl)pyrimidine-2,4-diamine Chemical compound CCOC(OCC)C1=NC(N)=NC(N)=C1C1=CC=CC(Cl)=C1Cl WOYVHBRLDIJCAD-UHFFFAOYSA-N 0.000 description 1
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
208000004998 Abdominal Pain 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
208000024827 Alzheimer disease Diseases 0.000 description 1
101100192215 Arabidopsis thaliana PTAC7 gene Proteins 0.000 description 1
241000416162 Astragalus gummifer Species 0.000 description 1
206010058019 Cancer Pain Diseases 0.000 description 1
208000000094 Chronic Pain Diseases 0.000 description 1
206010010904 Convulsion Diseases 0.000 description 1
AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
229920002261 Corn starch Polymers 0.000 description 1
241000699802 Cricetulus griseus Species 0.000 description 1
229920000858 Cyclodextrin Polymers 0.000 description 1
208000020401 Depressive disease Diseases 0.000 description 1
208000032131 Diabetic Neuropathies Diseases 0.000 description 1
ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
208000018522 Gastrointestinal disease Diseases 0.000 description 1
108010010803 Gelatin Proteins 0.000 description 1
208000034308 Grand mal convulsion Diseases 0.000 description 1
206010065681 HIV peripheral neuropathy Diseases 0.000 description 1
206010065390 Inflammatory pain Diseases 0.000 description 1
239000001358 L(+)-tartaric acid Substances 0.000 description 1
235000011002 L(+)-tartaric acid Nutrition 0.000 description 1
FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
235000019759 Maize starch Nutrition 0.000 description 1
FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
208000019695 Migraine disease Diseases 0.000 description 1
208000026072 Motor neurone disease Diseases 0.000 description 1
239000007832 Na2SO4 Substances 0.000 description 1
206010062501 Non-cardiac chest pain Diseases 0.000 description 1
238000013494 PH determination Methods 0.000 description 1
208000018737 Parkinson disease Diseases 0.000 description 1
206010056209 Partial seizures with secondary generalisation Diseases 0.000 description 1
239000002202 Polyethylene glycol Substances 0.000 description 1
206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
206010070834 Sensitisation Diseases 0.000 description 1
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
108010052164 Sodium Channels Proteins 0.000 description 1
102000018674 Sodium Channels Human genes 0.000 description 1
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
229920002472 Starch Polymers 0.000 description 1
229920001615 Tragacanth Polymers 0.000 description 1
208000030886 Traumatic Brain injury Diseases 0.000 description 1
FVECELJHCSPHKY-WTFKENEKSA-N Veratrine (amorphous) Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)O[C@@H]1[C@]2(O)O[C@@]34C[C@@]5(O)[C@H](CN6[C@@H](CC[C@H](C)C6)[C@@]6(C)O)[C@]6(O)[C@@H](O)C[C@@]5(O)[C@@H]4CC[C@H]2[C@]3(C)CC1 FVECELJHCSPHKY-WTFKENEKSA-N 0.000 description 1
102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 1
108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 1
RQZLIPHNDCFLPR-KUZQZCPWSA-N [(4s)-2-bromo-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid;hydrate Chemical compound O.C1C[C@@]2(CS(O)(=O)=O)C(=O)C(Br)C1C2(C)C RQZLIPHNDCFLPR-KUZQZCPWSA-N 0.000 description 1
MIOPJNTWMNEORI-OMNKOJBGSA-N [(4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-OMNKOJBGSA-N 0.000 description 1
210000003489 abdominal muscle Anatomy 0.000 description 1
229960000583 acetic acid Drugs 0.000 description 1
208000005298 acute pain Diseases 0.000 description 1
230000002411 adverse Effects 0.000 description 1
XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
229910052782 aluminium Inorganic materials 0.000 description 1
239000004411 aluminium Substances 0.000 description 1
WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
239000003963 antioxidant agent Substances 0.000 description 1
235000006708 antioxidants Nutrition 0.000 description 1
SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
239000011230 binding agent Substances 0.000 description 1
208000028683 bipolar I disease Diseases 0.000 description 1
239000008280 blood Substances 0.000 description 1
210000004369 blood Anatomy 0.000 description 1
230000037396 body weight Effects 0.000 description 1
210000004556 brain Anatomy 0.000 description 1
239000000872 buffer Substances 0.000 description 1
LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
210000004027 cell Anatomy 0.000 description 1
239000003874 central nervous system depressant Substances 0.000 description 1
208000015114 central nervous system disease Diseases 0.000 description 1
238000005119 centrifugation Methods 0.000 description 1
UWGBIKPRXRSRNM-UHFFFAOYSA-N cevadine Natural products CC=C(C)/C(=O)OC1CCC2(C)C3CCC4C5(O)CC(O)C6(O)C(CN7CC(C)CCC7C6(C)O)C5(O)CC24OCC13O UWGBIKPRXRSRNM-UHFFFAOYSA-N 0.000 description 1
239000003610 charcoal Substances 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
230000001684 chronic effect Effects 0.000 description 1
230000002566 clonic effect Effects 0.000 description 1
229960003920 cocaine Drugs 0.000 description 1
229940110456 cocoa butter Drugs 0.000 description 1
235000019868 cocoa butter Nutrition 0.000 description 1
239000007891 compressed tablet Substances 0.000 description 1
238000001816 cooling Methods 0.000 description 1
239000012043 crude product Substances 0.000 description 1
238000005520 cutting process Methods 0.000 description 1
238000013481 data capture Methods 0.000 description 1
239000008367 deionised water Substances 0.000 description 1
230000002939 deleterious effect Effects 0.000 description 1
238000001514 detection method Methods 0.000 description 1
238000011161 development Methods 0.000 description 1
SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Natural products CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 1
229960004698 dichlorobenzyl alcohol Drugs 0.000 description 1
208000010643 digestive system disease Diseases 0.000 description 1
201000010099 disease Diseases 0.000 description 1
239000002270 dispersing agent Substances 0.000 description 1
239000006185 dispersion Substances 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
201000006549 dyspepsia Diseases 0.000 description 1
230000002500 effect on skin Effects 0.000 description 1
238000000835 electrochemical detection Methods 0.000 description 1
201000003104 endogenous depression Diseases 0.000 description 1
150000002085 enols Chemical class 0.000 description 1
230000000763 evoking effect Effects 0.000 description 1
239000000284 extract Substances 0.000 description 1
238000000605 extraction Methods 0.000 description 1
235000013305 food Nutrition 0.000 description 1
235000013355 food flavoring agent Nutrition 0.000 description 1
208000018685 gastrointestinal system disease Diseases 0.000 description 1
229920000159 gelatin Polymers 0.000 description 1
239000008273 gelatin Substances 0.000 description 1
235000019322 gelatine Nutrition 0.000 description 1
235000011852 gelatine desserts Nutrition 0.000 description 1
238000007429 general method Methods 0.000 description 1
239000012362 glacial acetic acid Substances 0.000 description 1
239000011521 glass Substances 0.000 description 1
238000005469 granulation Methods 0.000 description 1
230000003179 granulation Effects 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
239000003701 inert diluent Substances 0.000 description 1
239000007972 injectable composition Substances 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
238000007913 intrathecal administration Methods 0.000 description 1
238000010253 intravenous injection Methods 0.000 description 1
239000003456 ion exchange resin Substances 0.000 description 1
229920003303 ion-exchange polymer Polymers 0.000 description 1
239000004816 latex Substances 0.000 description 1
229920000126 latex Polymers 0.000 description 1
210000004185 liver Anatomy 0.000 description 1
210000003141 lower extremity Anatomy 0.000 description 1
239000007937 lozenge Substances 0.000 description 1
230000001050 lubricating effect Effects 0.000 description 1
208000024714 major depressive disease Diseases 0.000 description 1
238000005259 measurement Methods 0.000 description 1
239000000155 melt Substances 0.000 description 1
229920000609 methyl cellulose Polymers 0.000 description 1
239000001923 methylcellulose Substances 0.000 description 1
206010027599 migraine Diseases 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
150000004682 monohydrates Chemical class 0.000 description 1
229960005181 morphine Drugs 0.000 description 1
208000005264 motor neuron disease Diseases 0.000 description 1
PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
WUOSYUHCXLQPQJ-UHFFFAOYSA-N n-(3-chlorophenyl)-n-methylacetamide Chemical compound CC(=O)N(C)C1=CC=CC(Cl)=C1 WUOSYUHCXLQPQJ-UHFFFAOYSA-N 0.000 description 1
231100000189 neurotoxic Toxicity 0.000 description 1
230000002887 neurotoxic effect Effects 0.000 description 1
229960002715 nicotine Drugs 0.000 description 1
SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
235000019198 oils Nutrition 0.000 description 1
229940005483 opioid analgesics Drugs 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
210000001672 ovary Anatomy 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
239000002245 particle Substances 0.000 description 1
235000010603 pastilles Nutrition 0.000 description 1
238000012402 patch clamp technique Methods 0.000 description 1
239000008188 pellet Substances 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
229960005235 piperonyl butoxide Drugs 0.000 description 1
239000004033 plastic Substances 0.000 description 1
229920003023 plastic Polymers 0.000 description 1
229920001223 polyethylene glycol Polymers 0.000 description 1
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
230000002265 prevention Effects 0.000 description 1
239000003368 psychostimulant agent Substances 0.000 description 1
238000000746 purification Methods 0.000 description 1
150000003230 pyrimidines Chemical class 0.000 description 1
238000011084 recovery Methods 0.000 description 1
238000011160 research Methods 0.000 description 1
230000002441 reversible effect Effects 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
238000007493 shaping process Methods 0.000 description 1
239000003579 shift reagent Substances 0.000 description 1
229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
229940045998 sodium isethionate Drugs 0.000 description 1
229910000162 sodium phosphate Inorganic materials 0.000 description 1
229940080313 sodium starch Drugs 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
LADXKQRVAFSPTR-UHFFFAOYSA-M sodium;2-hydroxyethanesulfonate Chemical compound [Na+].OCCS([O-])(=O)=O LADXKQRVAFSPTR-UHFFFAOYSA-M 0.000 description 1
229940032147 starch Drugs 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008227 sterile water for injection Substances 0.000 description 1
238000003756 stirring Methods 0.000 description 1
238000010254 subcutaneous injection Methods 0.000 description 1
229940086735 succinate Drugs 0.000 description 1
239000006228 supernatant Substances 0.000 description 1
239000004094 surface-active agent Substances 0.000 description 1
239000000375 suspending agent Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000007916 tablet composition Substances 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
239000002562 thickening agent Substances 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
230000001256 tonic effect Effects 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
239000000196 tragacanth Substances 0.000 description 1
235000010487 tragacanth Nutrition 0.000 description 1
229940116362 tragacanth Drugs 0.000 description 1
230000009529 traumatic brain injury Effects 0.000 description 1
206010044652 trigeminal neuralgia Diseases 0.000 description 1
238000001665 trituration Methods 0.000 description 1
229960005486 vaccine Drugs 0.000 description 1
238000005292 vacuum distillation Methods 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
239000008215 water for injection Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Medicinal Chemistry (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Engineering & Computer Science (AREA)
General Chemical & Material Sciences (AREA)
Biomedical Technology (AREA)
Pain & Pain Management (AREA)
Bioinformatics & Cheminformatics (AREA)
Neurosurgery (AREA)
Neurology (AREA)
Epidemiology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

APAP/P/1996/000857A 1995-09-05 1996-09-06 A Pyrimidine of formula (1) AP640A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
GBGB9518027.9A GB9518027D0 (en)	1995-09-05	1995-09-05	Pharmacologically active compound

Publications (2)

Publication Number	Publication Date
AP9600857A0 AP9600857A0 (en)	1996-10-31
AP640A true AP640A (en)	1998-04-14

Family

ID=10780172

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
APAP/P/1996/000857A AP640A (en)	1995-09-05	1996-09-06	A Pyrimidine of formula (1)

Country Status (32)

Country	Link
US (1)	US6124308A (no)
EP (1)	EP0879230B1 (no)
JP (1)	JPH11512108A (no)
KR (1)	KR19990044397A (no)
CN (1)	CN1200729A (no)
AP (1)	AP640A (no)
AR (1)	AR004192A1 (no)
AT (1)	ATE203523T1 (no)
AU (1)	AU710091B2 (no)
BG (1)	BG65102B1 (no)
BR (1)	BR9610388A (no)
CA (1)	CA2230362A1 (no)
CO (1)	CO4750651A1 (no)
CZ (1)	CZ65598A3 (no)
DE (1)	DE69614150T2 (no)
EA (1)	EA000695B1 (no)
ES (1)	ES2160834T3 (no)
GB (1)	GB9518027D0 (no)
HR (1)	HRP960399A2 (no)
HU (1)	HUP9901260A3 (no)
ID (1)	ID17274A (no)
IL (1)	IL123414A0 (no)
IS (1)	IS4673A (no)
NO (1)	NO980923L (no)
NZ (1)	NZ318390A (no)
PL (1)	PL325329A1 (no)
SK (1)	SK28598A3 (no)
TR (1)	TR199800386T1 (no)
TW (1)	TW367326B (no)
WO (1)	WO1997009317A2 (no)
YU (1)	YU49796A (no)
ZA (1)	ZA967466B (no)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
AR016212A1 (es) *	1998-04-28	2001-06-20	Astra Ab	Uso de compuestos farmaceuticos que tienen una actividad antagonista de nmda para preparar un medicamento para el tratamiento del sindrome de intestino irritable (ibs), y composiciones farmaceuticas
EP1085890A1 (en) *	1998-06-08	2001-03-28	Advanced Medicine, Inc.	Novel sodium channel drugs and uses
US6420354B1 (en)	1998-06-08	2002-07-16	Advanced Medicine, Inc.	Sodium channel drugs and uses
GB9907965D0 (en) *	1999-04-09	1999-06-02	Glaxo Group Ltd	Medical use
US6479498B1 (en)	1999-06-04	2002-11-12	Theravance, Inc.	Sodium channel drugs and uses
PL365701A1 (en) *	2000-07-21	2005-01-10	Ortho-Mcneil Pharmaceutical, Inc.	Carbamate compounds for use in preventing or treating neuropathic pain and cluster and migraine headache-associated pain
CA2439468A1 (en)	2001-02-27	2002-09-06	Teva Pharmaceutical Industries Ltd.	New crystal forms of lamotrigine and processes for their preparations
EP2316468A1 (en)	2002-02-22	2011-05-04	Shire LLC	Delivery system and methods for protecting and administering dextroamphetamine
WO2003090693A2 (en) *	2002-04-23	2003-11-06	Teva Pharmaceutical Industries Ltd.	Pharmaceutical composition containing lamotrigine particles of defined morphology
CA2514574A1 (en) *	2003-01-30	2004-08-12	Dynogen Pharmaceuticals, Inc.	Use of sodium channel modulators for treating gastrointestinal tract disorders
GB0603087D0 (en) *	2006-02-15	2006-03-29	Glaxo Group Ltd	Novel use
US8093268B2 (en)	2007-01-24	2012-01-10	Glaxo Group Limited	Pharmaceutical compositions comprising 2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl-benzyl)-(2S-phenylpiperidin-3S-yl-)
GB201111712D0 (en)	2011-07-08	2011-08-24	Gosforth Ct Holdings Pty Ltd	Pharmaceutical compositions

Citations (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0372934A2 (en) *	1988-12-07	1990-06-13	The Wellcome Foundation Limited	Pharmacologically active CNS compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
PL124029B1 (en) *	1979-06-01	1982-12-31	Wellcome Found	Process for preparing novel derivatives of 1,2,4-triazine

1995
- 1995-09-05 GB GBGB9518027.9A patent/GB9518027D0/en active Pending
1996
- 1996-09-03 KR KR1019980701641A patent/KR19990044397A/ko not_active Withdrawn
- 1996-09-03 IL IL12341496A patent/IL123414A0/xx unknown
- 1996-09-03 EP EP96931006A patent/EP0879230B1/en not_active Expired - Lifetime
- 1996-09-03 WO PCT/EP1996/003856 patent/WO1997009317A2/en not_active Ceased
- 1996-09-03 AU AU69865/96A patent/AU710091B2/en not_active Ceased
- 1996-09-03 HR HR9518027.9A patent/HRP960399A2/hr not_active Application Discontinuation
- 1996-09-03 EA EA199800189A patent/EA000695B1/ru not_active IP Right Cessation
- 1996-09-03 DE DE69614150T patent/DE69614150T2/de not_active Expired - Lifetime
- 1996-09-03 CN CN96197823A patent/CN1200729A/zh active Pending
- 1996-09-03 TR TR1998/00386T patent/TR199800386T1/xx unknown
- 1996-09-03 AT AT96931006T patent/ATE203523T1/de not_active IP Right Cessation
- 1996-09-03 BR BR9610388A patent/BR9610388A/pt not_active Application Discontinuation
- 1996-09-03 SK SK285-98A patent/SK28598A3/sk unknown
- 1996-09-03 JP JP9510854A patent/JPH11512108A/ja not_active Ceased
- 1996-09-03 US US09/029,162 patent/US6124308A/en not_active Expired - Fee Related
- 1996-09-03 HU HU9901260A patent/HUP9901260A3/hu unknown
- 1996-09-03 NZ NZ318390A patent/NZ318390A/xx unknown
- 1996-09-03 CZ CZ98655A patent/CZ65598A3/cs unknown
- 1996-09-03 CO CO96046885A patent/CO4750651A1/es unknown
- 1996-09-03 CA CA002230362A patent/CA2230362A1/en not_active Abandoned
- 1996-09-03 PL PL96325329A patent/PL325329A1/xx unknown
- 1996-09-03 ES ES96931006T patent/ES2160834T3/es not_active Expired - Lifetime
- 1996-09-03 ID IDP962513A patent/ID17274A/id unknown
- 1996-09-04 YU YU49796A patent/YU49796A/sh unknown
- 1996-09-04 ZA ZA9607466A patent/ZA967466B/xx unknown
- 1996-09-04 AR ARP960104220A patent/AR004192A1/es unknown
- 1996-09-05 TW TW085110879A patent/TW367326B/zh active
- 1996-09-06 AP APAP/P/1996/000857A patent/AP640A/en active
1998
- 1998-02-23 IS IS4673A patent/IS4673A/is unknown
- 1998-03-04 NO NO980923A patent/NO980923L/no not_active Application Discontinuation
- 1998-03-23 BG BG102342A patent/BG65102B1/bg unknown

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0372934A2 (en) *	1988-12-07	1990-06-13	The Wellcome Foundation Limited	Pharmacologically active CNS compounds

Also Published As

Publication number	Publication date
DE69614150D1 (de)	2001-08-30
PL325329A1 (en)	1998-07-20
ATE203523T1 (de)	2001-08-15
WO1997009317A3 (en)	1997-04-03
KR19990044397A (ko)	1999-06-25
WO1997009317A2 (en)	1997-03-13
ID17274A (id)	1997-12-18
TR199800386T1 (xx)	1998-05-21
ZA967466B (en)	1998-04-06
BG102342A (en)	1998-09-30
EP0879230A2 (en)	1998-11-25
JPH11512108A (ja)	1999-10-19
NO980923D0 (no)	1998-03-04
TW367326B (en)	1999-08-21
IL123414A0 (en)	1998-09-24
CA2230362A1 (en)	1997-03-13
NZ318390A (en)	1999-02-25
EA199800189A1 (ru)	1998-10-29
AU6986596A (en)	1997-03-27
HUP9901260A2 (hu)	1999-09-28
DE69614150T2 (de)	2001-11-22
CZ65598A3 (cs)	1998-07-15
ES2160834T3 (es)	2001-11-16
BG65102B1 (bg)	2007-02-28
US6124308A (en)	2000-09-26
HUP9901260A3 (en)	2001-04-28
IS4673A (is)	1998-02-23
NO980923L (no)	1998-05-04
CO4750651A1 (es)	1999-03-31
EA000695B1 (ru)	2000-02-28
AR004192A1 (es)	1998-11-04
HRP960399A2 (en)	1998-04-30
YU49796A (sh)	1999-07-28
EP0879230B1 (en)	2001-07-25
MX9801680A (es)	1998-05-31
AP9600857A0 (en)	1996-10-31
AU710091B2 (en)	1999-09-16
GB9518027D0 (en)	1995-11-08
SK28598A3 (en)	1998-09-09
BR9610388A (pt)	1999-07-06
CN1200729A (zh)	1998-12-02

Publication	Publication Date	Title
US7705148B2 (en)	2010-04-27	Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile
EP0879230B1 (en)	2001-07-25	Optically active phenyl pyrimidine derivative as analgesic agent
US7888345B2 (en)	2011-02-15	Benzaepinones as sodium channel blockers
EP1870405A1 (en)	2007-12-26	Carbonylated (Aza)cyclohexanes as dopamine D3 receptor ligands
JPWO1998047505A1 (ja)	2000-10-17	神経ペプチドｙ受容体拮抗剤
JPH11503167A (ja)	1999-03-23	タキキニン受容体拮抗物質としての２−アシルアミノプロパンアミド類
US20240425496A1 (en)	2024-12-26	Azetidinyl pyrimidines and uses thereof
US20080058535A1 (en)	2008-03-06	Methods and compositions for production, formulation and use of 1 aryl-3-azabicyclo[3.1.0]hexanes
US6465461B1 (en)	2002-10-15	Triazine compounds for treatment of CNS disorders
WO1992017440A1 (en)	1992-10-15	Tricyclic compound
WO2006115244A1 (ja)	2006-11-02	４－ブロモイソキノリン誘導体及びこれを含有する医薬
KR20010042904A (ko)	2001-05-25	광학 활성 테트라하이드로벤즈인돌 유도체
US12459956B2 (en)	2025-11-04	Heterobicyclic carboxamides and uses thereof
US20080214542A1 (en)	2008-09-04	Arylpiperazine Derivatives and their Use as Selective Dopamine D3 Receptor Ligands
KR20020082470A (ko)	2002-10-31	심리학적 장애의 치료를 위한 게피론의 생활성 대사물질의용도
US20120088809A1 (en)	2012-04-12	1-(2-alkyl-2,3-dihydro-benzofuran-4-yl)-pyrrolidin-3-ylamine acyl compounds
US20070185168A1 (en)	2007-08-09	Piperidine derivatives
EP2277882A1 (fr)	2011-01-26	Composés pipéridiniques, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
JP3999861B2 (ja)	2007-10-31	新規ピリダジン誘導体及びこれを有効成分とする医薬
JPH11180979A (ja)	1999-07-06	環状アミン誘導体
MXPA98001680A (en)	1998-10-23	Derivative of phenyl pyrimidine optically active as analges agent
JP2004525985A (ja)	2004-08-26	Ｎ−（２，３−ジメチル−５，６，７，８−テトラヒドロフロ［２，３−ｂ］キノリン−４−イル）−２−（２−オキソプロリジン−１−イル）アセトアミドの結晶多形
JPWO2006132192A1 (ja)	2009-01-08	新規２−キノロン誘導体
JPH07173161A (ja)	1995-07-11	ピリドピリミジン誘導体、その製造方法および用途
MXPA00006223A (en)	2001-06-26	Triazine compounds for treatment of cns disorders