HRP960399A2 - Pharmacologically active compound - Google Patents

Pharmacologically active compound Download PDF

Info

Publication number: HRP960399A2
Authority: HR; Croatia
Prior art keywords: salt; pyrimidine; dichlorophenyl; enantiomer; diamino
Prior art date: 1995-09-05

Application number

HR9518027.9A

Other languages

English (en)

Croatian (hr)

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

1996-09-03

Publication date

1998-04-30

1996-09-03 Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd

1998-04-30 Publication of HRP960399A2 publication Critical patent/HRP960399A2/hr

Links

150000001875 compounds Chemical class 0.000 title claims description 29
150000003839 salts Chemical class 0.000 claims description 109
239000002253 acid Substances 0.000 claims description 48
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 32
239000012458 free base Substances 0.000 claims description 32
238000000034 method Methods 0.000 claims description 26
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
239000013543 active substance Substances 0.000 claims description 19
239000000126 substance Substances 0.000 claims description 18
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 12
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 10
239000001961 anticonvulsive agent Substances 0.000 claims description 9
230000008569 process Effects 0.000 claims description 9
230000002378 acidificating effect Effects 0.000 claims description 8
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
208000002551 irritable bowel syndrome Diseases 0.000 claims description 8
208000020925 Bipolar disease Diseases 0.000 claims description 7
208000035475 disorder Diseases 0.000 claims description 7
230000001773 anti-convulsant effect Effects 0.000 claims description 6
229960003965 antiepileptics Drugs 0.000 claims description 6
238000003682 fluorination reaction Methods 0.000 claims description 6
229910019142 PO4 Inorganic materials 0.000 claims description 5
239000003814 drug Substances 0.000 claims description 5
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
239000010452 phosphate Substances 0.000 claims description 5
230000006340 racemization Effects 0.000 claims description 5
QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 claims description 4
239000000825 pharmaceutical preparation Substances 0.000 claims description 4
230000000202 analgesic effect Effects 0.000 claims description 3
229940035676 analgesics Drugs 0.000 claims description 3
239000000730 antalgic agent Substances 0.000 claims description 3
239000003085 diluting agent Substances 0.000 claims description 3
238000004519 manufacturing process Methods 0.000 claims description 3
229940125681 anticonvulsant agent Drugs 0.000 claims description 2
208000015122 neurodegenerative disease Diseases 0.000 claims description 2
229940079593 drug Drugs 0.000 claims 2
206010012335 Dependence Diseases 0.000 claims 1
239000000654 additive Substances 0.000 claims 1
230000000996 additive effect Effects 0.000 claims 1
239000003937 drug carrier Substances 0.000 claims 1
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 91
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
239000000243 solution Substances 0.000 description 46
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
239000000203 mixture Substances 0.000 description 40
238000002360 preparation method Methods 0.000 description 37
229910001868 water Inorganic materials 0.000 description 37
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
241000700159 Rattus Species 0.000 description 20
PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical group NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 18
229960001848 lamotrigine Drugs 0.000 description 17
CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 16
239000002904 solvent Substances 0.000 description 16
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
239000002585 base Substances 0.000 description 14
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 12
230000000694 effects Effects 0.000 description 12
238000002347 injection Methods 0.000 description 12
239000007924 injection Substances 0.000 description 12
238000012360 testing method Methods 0.000 description 12
CZLINJDTCHACEH-UHFFFAOYSA-N 2-(2,3-dichlorophenyl)acetonitrile Chemical compound ClC1=CC=CC(CC#N)=C1Cl CZLINJDTCHACEH-UHFFFAOYSA-N 0.000 description 11
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
239000002775 capsule Substances 0.000 description 11
239000007788 liquid Substances 0.000 description 11
239000003826 tablet Substances 0.000 description 11
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
241001465754 Metazoa Species 0.000 description 9
241000699670 Mus sp. Species 0.000 description 9
208000002193 Pain Diseases 0.000 description 9
238000010438 heat treatment Methods 0.000 description 9
239000012452 mother liquor Substances 0.000 description 9
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
238000004090 dissolution Methods 0.000 description 8
VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
230000005764 inhibitory process Effects 0.000 description 8
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
239000012071 phase Substances 0.000 description 8
239000000047 product Substances 0.000 description 8
STVBVTWXWZMRPZ-UHFFFAOYSA-N (2,3-dichlorophenyl)methanol Chemical compound OCC1=CC=CC(Cl)=C1Cl STVBVTWXWZMRPZ-UHFFFAOYSA-N 0.000 description 7
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 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
-1 pyrimidine compound Chemical class 0.000 description 7
229910000033 sodium borohydride Inorganic materials 0.000 description 7
239000012279 sodium borohydride Substances 0.000 description 7
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
102000004419 dihydrofolate reductase Human genes 0.000 description 6
239000000843 powder Substances 0.000 description 6
239000011541 reaction mixture Substances 0.000 description 6
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 5
101001135571 Mus musculus Tyrosine-protein phosphatase non-receptor type 2 Proteins 0.000 description 5
239000002178 crystalline material Substances 0.000 description 5
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 5
229960002986 dinoprostone Drugs 0.000 description 5
206010015037 epilepsy Diseases 0.000 description 5
239000008187 granular material Substances 0.000 description 5
XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 5
238000001953 recrystallisation Methods 0.000 description 5
238000010992 reflux Methods 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
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 4
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 4
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 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
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
239000012359 Methanesulfonyl chloride Substances 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
229960003638 dopamine Drugs 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
SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 4
HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 4
239000008101 lactose Substances 0.000 description 4
235000019359 magnesium stearate Nutrition 0.000 description 4
238000002844 melting Methods 0.000 description 4
230000008018 melting Effects 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
210000001577 neostriatum 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
239000002244 precipitate Substances 0.000 description 4
239000008213 purified water Substances 0.000 description 4
239000011734 sodium Substances 0.000 description 4
229910052708 sodium Inorganic materials 0.000 description 4
239000000829 suppository Substances 0.000 description 4
LLMLNAVBOAMOEE-UHFFFAOYSA-N 2,3-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1Cl LLMLNAVBOAMOEE-UHFFFAOYSA-N 0.000 description 3
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 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
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
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 3
206010003591 Ataxia Diseases 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
OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 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
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 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
239000007864 aqueous solution Substances 0.000 description 3
210000004027 cell Anatomy 0.000 description 3
239000007903 gelatin capsule Substances 0.000 description 3
235000011187 glycerol Nutrition 0.000 description 3
238000001990 intravenous administration Methods 0.000 description 3
229910052943 magnesium sulfate Inorganic materials 0.000 description 3
235000019341 magnesium sulphate Nutrition 0.000 description 3
239000012528 membrane Substances 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
239000002245 particle Substances 0.000 description 3
229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
239000011591 potassium Substances 0.000 description 3
229910052700 potassium Inorganic materials 0.000 description 3
NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 3
230000003389 potentiating effect Effects 0.000 description 3
239000011780 sodium chloride Substances 0.000 description 3
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 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
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
OFQCQIGMURIECL-UHFFFAOYSA-N 2-[2-(diethylamino)ethyl]-2',6'-dimethylspiro[isoquinoline-4,4'-oxane]-1,3-dione;phosphoric acid Chemical compound OP(O)(O)=O.O=C1N(CCN(CC)CC)C(=O)C2=CC=CC=C2C21CC(C)OC(C)C2 OFQCQIGMURIECL-UHFFFAOYSA-N 0.000 description 2
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 2
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 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
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229920000168 Microcrystalline cellulose Polymers 0.000 description 2
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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
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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
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
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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
238000007906 compression Methods 0.000 description 2
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230000005494 condensation Effects 0.000 description 2
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238000000354 decomposition reaction Methods 0.000 description 2
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238000001035 drying Methods 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
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239000003981 vehicle Substances 0.000 description 1
239000007762 w/o emulsion Substances 0.000 description 1
238000010792 warming Methods 0.000 description 1
239000008215 water for injection Substances 0.000 description 1
238000005303 weighing Methods 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)

HR9518027.9A 1995-09-05 1996-09-03 Pharmacologically active compound HRP960399A2 (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 (1)

Publication Number	Publication Date
HRP960399A2 true HRP960399A2 (en)	1998-04-30

Family

ID=10780172

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
HR9518027.9A HRP960399A2 (en)	1995-09-05	1996-09-03	Pharmacologically active compound

Country Status (32)

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

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

Family Cites Families (2)

* 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
FI895821A7 (fi) *	1988-12-07	1990-06-08	The Wellcome Foundation Ltd	Farmaseuttisesti aktivisia CNS-yhdisteitä

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

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
AP640A (en)	1998-04-14
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
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

Legal Events

Date	Code	Title	Description
1998-04-29	AIPI	Request for the grant of a patent on the basis of a substantive examination of a patent application
1998-04-30	A1OB	Publication of a patent application
2000-09-03	ODRP	Renewal fee for the maintenance of a patent	Payment date: 20000903 Year of fee payment: 5
2002-10-22	ODBC	Application rejected

Publication	Publication Date	Title
DE69425662T2 (de)	2001-04-12	Als heilmittel nutzbare piperazin verbindungen
FI78691C (fi)	1989-09-11	Foerfarande foer framstaellning av i position 3-substituerade pyridazinderivat, vilka inverkar pao det centrala nervsystemet.
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JPH1171380A (ja)	1999-03-16	５Ｈ−チアゾロ（３，２−ａ）ピリミジン誘導体
JPH05320142A (ja)	1993-12-03	中枢神経系に薬理活性をもつ化合物
WO2007017092A1 (en)	2007-02-15	Substituted 4-benzyloxy-benzoic acid amide derivatives
US6124308A (en)	2000-09-26	Optically active phenyl pyrimidine derivatives as analgesic agent
DE60128587T2 (de)	2008-01-31	Lactamverbindungen
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US11365194B2 (en)	2022-06-21	Analgesic drug using PAC1 receptor antagonistic drug
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JP2003160480A (ja)	2003-06-03	Ｎｋ１受容体拮抗薬