IL97892A - 3-] 4-) 6-Fluoro-1,2-benziazoxazole-3-yl (piperidine-1-ilalkyl [-H4- pyrido] A-1,2 [pyrimidine-4-lobes 9-metamorphoses, their preparation and crude preparations - Google Patents

3-] 4-) 6-Fluoro-1,2-benziazoxazole-3-yl (piperidine-1-ilalkyl [-H4- pyrido] A-1,2 [pyrimidine-4-lobes 9-metamorphoses, their preparation and crude preparations

Info

Publication number: IL97892A
Authority: IL; Israel
Prior art keywords: formula; compound; compounds; methyl; alk
Prior art date: 1990-04-19

Application number

IL9789291A

Other languages

English (en)

Hebrew (he)

Other versions

IL97892A0 (en

Original Assignee

Janssen Pharmaceutica Nv

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.)

1990-04-19

Filing date

1991-04-17

Publication date

1995-03-30

1991-04-17 Application filed by Janssen Pharmaceutica Nv filed Critical Janssen Pharmaceutica Nv

1992-06-21 Publication of IL97892A0 publication Critical patent/IL97892A0/xx

1995-03-30 Publication of IL97892A publication Critical patent/IL97892A/en

Links

239000008194 pharmaceutical composition Substances 0.000 title claims description 8
238000002360 preparation method Methods 0.000 title description 12
150000001875 compounds Chemical class 0.000 claims abstract description 83
-1 5-methyl-2-furanyl Chemical group 0.000 claims abstract description 40
239000002253 acid Substances 0.000 claims abstract description 24
150000003839 salts Chemical class 0.000 claims abstract description 20
238000000034 method Methods 0.000 claims abstract description 18
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims abstract description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
239000004480 active ingredient Substances 0.000 claims abstract description 7
239000001257 hydrogen Substances 0.000 claims abstract description 5
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 4
DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 claims description 18
239000002585 base Substances 0.000 claims description 18
239000003153 chemical reaction reagent Substances 0.000 claims description 16
238000003756 stirring Methods 0.000 claims description 16
239000012442 inert solvent Substances 0.000 claims description 12
150000002923 oximes Chemical class 0.000 claims description 11
230000000561 anti-psychotic effect Effects 0.000 claims description 6
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
239000003513 alkali Substances 0.000 claims description 5
125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
230000002152 alkylating effect Effects 0.000 claims description 3
230000007062 hydrolysis Effects 0.000 claims description 3
238000006460 hydrolysis reaction Methods 0.000 claims description 3
150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
239000012458 free base Substances 0.000 claims description 2
238000007327 hydrogenolysis reaction Methods 0.000 claims description 2
231100000252 nontoxic Toxicity 0.000 claims description 2
230000003000 nontoxic effect Effects 0.000 claims description 2
239000007800 oxidant agent Substances 0.000 claims description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
230000001590 oxidative effect Effects 0.000 claims 2
239000003814 drug Substances 0.000 claims 1
125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
238000004519 manufacturing process Methods 0.000 claims 1
239000000203 mixture Substances 0.000 abstract description 36
VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 abstract description 10
208000028017 Psychotic disease Diseases 0.000 abstract description 6
230000001154 acute effect Effects 0.000 abstract description 5
229960003638 dopamine Drugs 0.000 abstract description 5
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
230000003389 potentiating effect Effects 0.000 abstract description 3
239000005557 antagonist Substances 0.000 abstract description 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 3
125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 abstract 1
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
239000000243 solution Substances 0.000 description 33
239000000543 intermediate Substances 0.000 description 30
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 20
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
239000011541 reaction mixture Substances 0.000 description 15
VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 13
229960004046 apomorphine Drugs 0.000 description 13
239000002904 solvent Substances 0.000 description 13
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
238000006243 chemical reaction Methods 0.000 description 12
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
230000008485 antagonism Effects 0.000 description 11
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
238000001816 cooling Methods 0.000 description 10
239000000047 product Substances 0.000 description 10
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 9
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
241000700159 Rattus Species 0.000 description 8
238000013019 agitation Methods 0.000 description 8
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
238000007363 ring formation reaction Methods 0.000 description 8
239000003826 tablet Substances 0.000 description 8
KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 7
241000282472 Canis lupus familiaris Species 0.000 description 7
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
229910052784 alkaline earth metal Inorganic materials 0.000 description 7
229940025084 amphetamine Drugs 0.000 description 7
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 7
238000010992 reflux Methods 0.000 description 7
239000000741 silica gel Substances 0.000 description 7
229910002027 silica gel Inorganic materials 0.000 description 7
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
239000000010 aprotic solvent Substances 0.000 description 6
150000004945 aromatic hydrocarbons Chemical class 0.000 description 6
229960001701 chloroform Drugs 0.000 description 6
238000004440 column chromatography Methods 0.000 description 6
239000003480 eluent Substances 0.000 description 6
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
239000002244 precipitate Substances 0.000 description 6
229910000029 sodium carbonate Inorganic materials 0.000 description 6
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 5
UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 5
125000003118 aryl group Chemical group 0.000 description 5
125000004432 carbon atom Chemical group C* 0.000 description 5
239000003210 dopamine receptor blocking agent Substances 0.000 description 5
239000000706 filtrate Substances 0.000 description 5
125000005843 halogen group Chemical group 0.000 description 5
239000012044 organic layer Substances 0.000 description 5
125000006239 protecting group Chemical group 0.000 description 5
125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 5
239000011780 sodium chloride Substances 0.000 description 5
239000000725 suspension Substances 0.000 description 5
208000024891 symptom Diseases 0.000 description 5
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 4
HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 4
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
239000002202 Polyethylene glycol Substances 0.000 description 4
238000005804 alkylation reaction Methods 0.000 description 4
239000002775 capsule Substances 0.000 description 4
239000003054 catalyst Substances 0.000 description 4
239000003795 chemical substances by application Substances 0.000 description 4
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
201000010099 disease Diseases 0.000 description 4
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
150000002576 ketones Chemical class 0.000 description 4
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
239000002858 neurotransmitter agent Substances 0.000 description 4
239000003921 oil Substances 0.000 description 4
235000019198 oils Nutrition 0.000 description 4
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
230000036284 oxygen consumption Effects 0.000 description 4
230000000144 pharmacologic effect Effects 0.000 description 4
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
229920001223 polyethylene glycol Polymers 0.000 description 4
239000000376 reactant Substances 0.000 description 4
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-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
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
229920002472 Starch Polymers 0.000 description 3
150000007513 acids Chemical class 0.000 description 3
239000000654 additive Substances 0.000 description 3
150000004703 alkoxides Chemical class 0.000 description 3
230000037396 body weight Effects 0.000 description 3
229910052799 carbon Inorganic materials 0.000 description 3
238000004587 chromatography analysis Methods 0.000 description 3
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
239000002552 dosage form Substances 0.000 description 3
239000003937 drug carrier Substances 0.000 description 3
150000008282 halocarbons Chemical class 0.000 description 3
150000004678 hydrides Chemical class 0.000 description 3
239000007788 liquid Substances 0.000 description 3
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
238000007254 oxidation reaction Methods 0.000 description 3
229910000027 potassium carbonate Inorganic materials 0.000 description 3
239000000843 powder Substances 0.000 description 3
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
150000003254 radicals Chemical class 0.000 description 3
201000000980 schizophrenia Diseases 0.000 description 3
235000017557 sodium bicarbonate Nutrition 0.000 description 3
229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
239000012312 sodium hydride Substances 0.000 description 3
229910000104 sodium hydride Inorganic materials 0.000 description 3
239000012453 solvate Substances 0.000 description 3
235000019698 starch Nutrition 0.000 description 3
239000007858 starting material Substances 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
CUJPFPXNDSIBPG-UHFFFAOYSA-N 1,3-propanediyl Chemical group [CH2]C[CH2] CUJPFPXNDSIBPG-UHFFFAOYSA-N 0.000 description 2
OMIVCRYZSXDGAB-UHFFFAOYSA-N 1,4-butanediyl Chemical group [CH2]CC[CH2] OMIVCRYZSXDGAB-UHFFFAOYSA-N 0.000 description 2
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
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 2
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 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
241001465754 Metazoa Species 0.000 description 2
239000012359 Methanesulfonyl chloride Substances 0.000 description 2
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
206010047700 Vomiting Diseases 0.000 description 2
230000003213 activating effect Effects 0.000 description 2
150000001299 aldehydes Chemical class 0.000 description 2
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
150000001412 amines Chemical class 0.000 description 2
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
230000003042 antagnostic effect Effects 0.000 description 2
229940082988 antihypertensives serotonin antagonists Drugs 0.000 description 2
239000003420 antiserotonin agent Substances 0.000 description 2
239000012298 atmosphere Substances 0.000 description 2
HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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 2
238000009835 boiling Methods 0.000 description 2
BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
239000000969 carrier Substances 0.000 description 2
238000006482 condensation reaction Methods 0.000 description 2
150000002148 esters Chemical class 0.000 description 2
150000002170 ethers Chemical class 0.000 description 2
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
239000000284 extract Substances 0.000 description 2
229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 description 2
239000008103 glucose Substances 0.000 description 2
235000011187 glycerol Nutrition 0.000 description 2
230000002140 halogenating effect Effects 0.000 description 2
LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
150000004679 hydroxides Chemical class 0.000 description 2
230000005764 inhibitory process Effects 0.000 description 2
238000002347 injection Methods 0.000 description 2
239000007924 injection Substances 0.000 description 2
235000014655 lactic acid Nutrition 0.000 description 2
239000008101 lactose Substances 0.000 description 2
238000004811 liquid chromatography Methods 0.000 description 2
238000009115 maintenance therapy Methods 0.000 description 2
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
229940100688 oral solution Drugs 0.000 description 2
150000007530 organic bases Chemical class 0.000 description 2
230000003647 oxidation Effects 0.000 description 2
FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
239000006187 pill Substances 0.000 description 2
239000001267 polyvinylpyrrolidone Substances 0.000 description 2
229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
229960003415 propylparaben Drugs 0.000 description 2
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
- 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

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
General Chemical & Material Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Chemical Kinetics & Catalysis (AREA)
Psychiatry (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Biomedical Technology (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Pyridine Compounds (AREA)
Electrochromic Elements, Electrophoresis, Or Variable Reflection Or Absorption Elements (AREA)

IL9789291A 1990-04-19 1991-04-17 3-] 4-) 6-Fluoro-1,2-benziazoxazole-3-yl (piperidine-1-ilalkyl [-H4- pyrido] A-1,2 [pyrimidine-4-lobes 9-metamorphoses, their preparation and crude preparations IL97892A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
GB909008850A GB9008850D0 (en)	1990-04-19	1990-04-19	Novel 2,9-disubstituted-4h-pyridol(1,2-a)pyrimidin-4-ones

Publications (2)

Publication Number	Publication Date
IL97892A0 IL97892A0 (en)	1992-06-21
IL97892A true IL97892A (en)	1995-03-30

Family

ID=10674694

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL9789291A IL97892A (en)	1990-04-19	1991-04-17	3-] 4-) 6-Fluoro-1,2-benziazoxazole-3-yl (piperidine-1-ilalkyl [-H4- pyrido] A-1,2 [pyrimidine-4-lobes 9-metamorphoses, their preparation and crude preparations

Country Status (26)

Country	Link
US (1)	US5482943A (de)
EP (1)	EP0453042B1 (de)
JP (1)	JP3216889B2 (de)
KR (1)	KR100190297B1 (de)
CN (1)	CN1027506C (de)
AT (1)	ATE186301T1 (de)
AU (1)	AU636969B2 (de)
BG (1)	BG60394B1 (de)
CA (1)	CA2040086C (de)
CZ (1)	CZ281135B6 (de)
DE (1)	DE69131759T2 (de)
DK (1)	DK0453042T3 (de)
ES (1)	ES2140381T3 (de)
FI (1)	FI96206C (de)
GB (1)	GB9008850D0 (de)
GR (1)	GR3032122T3 (de)
HU (1)	HUT57763A (de)
IE (1)	IE911301A1 (de)
IL (1)	IL97892A (de)
NO (1)	NO176840C (de)
NZ (1)	NZ237713A (de)
PL (2)	PL169740B1 (de)
PT (1)	PT97395B (de)
RU (1)	RU2037495C1 (de)
SK (1)	SK279005B6 (de)
ZA (1)	ZA912913B (de)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
ES2050069B1 (es) *	1992-07-10	1994-12-16	Vita Invest Sa	Procedimiento para la obtencion de 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-il)piperidino)etil)-2-metil-6,7,8,9-tetrahidro-4h-pirido(1,2-a) pirimidin-4-ona.
DE69330283T2 (de) *	1992-07-13	2002-01-10	Janssen Pharmaceutica Nv	Neue 4-(3-benzofuranyl) piperidinyl und 4-(3-benzothienyl) piperidinyl-derivate und diese enthaltende pharmazeutische zusammenstellungen
JP3553951B2 (ja) *	1993-11-23	2004-08-11	ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ	新規な９−ヒドロキシ−ピリド［１，２−ａ］ピリミジン−４−オンエーテル誘導体
ES2085234B1 (es) *	1994-02-24	1997-01-16	Vita Invest Sa	Agente activo sobre el sistema nervioso central, procedimiento para su preparacion y composiciones farmaceuticas que lo contienen.
JP3274579B2 (ja) *	1995-01-12	2002-04-15	住友製薬株式会社	脳血管障害に伴う精神症候治療剤
ES2141671B1 (es) *	1997-12-26	2001-01-01	Vita Invest Sa	Compuesto pirimidinico activo sobre el sistema nervioso central, procedimiento para su preparacion y composiciones farmaceuticas que lo contienen.
HU227118B1 (en) *	2001-11-13	2010-07-28	Egis Gyogyszergyar Nyilvanosan	Process for the preparation of 3-{2-[4-(6-fluoro-1,2-benzizoxazol-3-yl)-1-piperidinyl]-ethyl}-6,7,8,9-tetrahydro-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one
ES2197801B1 (es) *	2002-03-05	2005-03-16	Ferrer Internacional,S.A	Procedimiento de obtencion de la 3-(2-(4-(6-fluoro-benzo(d)isoxazol-3-il) piperidin-1-il)-etil)-2-metil-6,7,8,9-tetrahidro-4h-pirido-(1,2-a ) pirimidin-4-ona.
WO2004009591A1 (en) *	2002-07-22	2004-01-29	Aurobindo Pharma Ltd.	A process for the preparation of antipsychotic risperidone
BR0306204A (pt) *	2002-08-30	2004-09-08	Torrent Pharmaceuticals Ltd	Processo melhorado para a preparação de risperidona
KR20040025224A (ko) *	2002-09-18	2004-03-24	주식회사 대웅	2-(2-메틸-4-옥소-6,7,8,9-테트라하이드로-4Ｈ-피리도[1,2-ａ]피리미딘-3-일)아세트알데히드 및 그 제조방법
EP1560814A1 (de)	2002-11-13	2005-08-10	Synthon B.V.	Verfahren zur herstellung von risperidon und zwischenprodukte
WO2004094415A1 (en) *	2003-04-22	2004-11-04	Synthon B.V.	Risperidone monohydrochloride
HUP0401379A3 (en) *	2004-07-08	2006-04-28	Richter Gedeon Vegyeszet	Process for the preparation of risperidon
HUP0402163A2 (en) *	2004-10-25	2006-05-29	Richter Gedeon Vegyeszet	Process for the preparation of risperidone
EP1690540A1 (de) *	2005-02-15	2006-08-16	Neuro3D	Zusammensetzung enthaltend Ocaperidon
EP1695973A1 (de) *	2005-02-24	2006-08-30	Neuro3D	Ocaperidonsalz und dieser enthaltende pharmazeutische Zubereitung
JO2769B1 (en) *	2005-10-26	2014-03-15	جانسين فارماسوتيكا ان. في	Rapid decomposition of physiologically antagonistic agents of the 2-dopamine receptor
WO2009077551A1 (en) *	2007-12-18	2009-06-25	Janssen Pharmaceutica Nv	Process for preparing risperidone
WO2023135528A1 (en)	2022-01-11	2023-07-20	Suven Life Sciences Limited	Heteroalicyclic derivatives and their use in the treatment of cns disorders

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4485107A (en) *	1982-11-01	1984-11-27	Janssen Pharmaceutica N.V.	[[Bis(aryl)methylene]-1-piperidinyl]alkyl-pyrimidinones
US4804663A (en) *	1985-03-27	1989-02-14	Janssen Pharmaceutica N.V.	3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
NZ223654A (en) *	1987-03-09	1990-03-27	Janssen Pharmaceutica Nv	1-alkyl-substituted-benzimidazole-4-piperidinamines and pharmaceutical compositions
US4777252A (en) *	1987-08-13	1988-10-11	E. R. Squibb & Sons, Inc.	2-oxo-1-[[(substituted sulfonyl)amino]-carbonyl]azetidines
CA2000786C (en) *	1988-11-07	1999-01-26	Cornelus G. M. Janssen	3-piperidinyl-1,2-benzisoxazoles
GB8900382D0 (en) *	1989-01-09	1989-03-08	Janssen Pharmaceutica Nv	2-aminopyrimidinone derivatives

1990
- 1990-04-19 GB GB909008850A patent/GB9008850D0/en active Pending
1991
- 1991-03-28 US US07/676,681 patent/US5482943A/en not_active Expired - Lifetime
- 1991-04-05 NZ NZ237713A patent/NZ237713A/en unknown
- 1991-04-09 CA CA002040086A patent/CA2040086C/en not_active Expired - Lifetime
- 1991-04-11 AU AU74366/91A patent/AU636969B2/en not_active Expired
- 1991-04-16 AT AT91200897T patent/ATE186301T1/de not_active IP Right Cessation
- 1991-04-16 ES ES91200897T patent/ES2140381T3/es not_active Expired - Lifetime
- 1991-04-16 DK DK91200897T patent/DK0453042T3/da active
- 1991-04-16 DE DE69131759T patent/DE69131759T2/de not_active Expired - Lifetime
- 1991-04-16 JP JP10968691A patent/JP3216889B2/ja not_active Expired - Lifetime
- 1991-04-16 EP EP91200897A patent/EP0453042B1/de not_active Expired - Lifetime
- 1991-04-17 IL IL9789291A patent/IL97892A/en not_active IP Right Cessation
- 1991-04-17 KR KR1019910006108A patent/KR100190297B1/ko not_active IP Right Cessation
- 1991-04-18 CZ CS911099A patent/CZ281135B6/cs not_active IP Right Cessation
- 1991-04-18 SK SK1099-91A patent/SK279005B6/sk not_active IP Right Cessation
- 1991-04-18 PL PL91289935A patent/PL169740B1/pl unknown
- 1991-04-18 PT PT97395A patent/PT97395B/pt not_active IP Right Cessation
- 1991-04-18 IE IE130191A patent/IE911301A1/en not_active IP Right Cessation
- 1991-04-18 RU SU914895183A patent/RU2037495C1/ru active
- 1991-04-18 FI FI911885A patent/FI96206C/fi active
- 1991-04-18 ZA ZA912913A patent/ZA912913B/xx unknown
- 1991-04-18 PL PL91312561A patent/PL169744B1/pl unknown
- 1991-04-18 NO NO911525A patent/NO176840C/no not_active IP Right Cessation
- 1991-04-18 BG BG94282A patent/BG60394B1/bg unknown
- 1991-04-19 HU HU911301A patent/HUT57763A/hu unknown
- 1991-04-19 CN CN91102516A patent/CN1027506C/zh not_active Expired - Lifetime
1999
- 1999-12-14 GR GR990403201T patent/GR3032122T3/el unknown

Also Published As

Publication number	Publication date
IE911301A1 (en)	1991-10-23
NO176840B (no)	1995-02-27
IL97892A0 (en)	1992-06-21
CA2040086C (en)	2003-12-30
SK279005B6 (sk)	1998-05-06
FI96206C (fi)	1996-05-27
EP0453042A1 (de)	1991-10-23
HU911301D0 (en)	1991-10-28
PL169744B1 (pl)	1996-08-30
PL289935A1 (en)	1992-04-06
AU7436691A (en)	1991-10-24
PL169740B1 (pl)	1996-08-30
PT97395A (pt)	1992-01-31
US5482943A (en)	1996-01-09
ATE186301T1 (de)	1999-11-15
DE69131759T2 (de)	2000-06-21
ES2140381T3 (es)	2000-03-01
EP0453042B1 (de)	1999-11-03
CA2040086A1 (en)	1991-10-20
FI911885A (fi)	1991-10-20
KR100190297B1 (ko)	1999-06-01
KR910018380A (ko)	1991-11-30
FI911885A0 (fi)	1991-04-18
FI96206B (fi)	1996-02-15
ZA912913B (en)	1992-12-30
CZ281135B6 (cs)	1996-06-12
CN1055929A (zh)	1991-11-06
JP3216889B2 (ja)	2001-10-09
DK0453042T3 (da)	2000-04-25
DE69131759D1 (de)	1999-12-09
NO911525L (no)	1991-10-21
NZ237713A (en)	1992-09-25
AU636969B2 (en)	1993-05-13
RU2037495C1 (ru)	1995-06-19
BG60394B1 (bg)	1995-02-28
HUT57763A (en)	1991-12-30
NO911525D0 (no)	1991-04-18
JPH04234882A (ja)	1992-08-24
GB9008850D0 (en)	1990-06-13
PT97395B (pt)	1998-08-31
CS9101099A2 (en)	1991-11-12
CN1027506C (zh)	1995-01-25
GR3032122T3 (en)	2000-04-27
NO176840C (no)	1995-06-07

Legal Events

Date	Code	Title
1997-08-14	KB	Patent renewed
2001-07-24	KB	Patent renewed
2005-06-19	KB	Patent renewed
2009-09-15	KB	Patent renewed
2011-12-29	EXP	Patent expired

Publication	Publication Date	Title
US5482943A (en)	1996-01-09	(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl-alkyl-(2,9-disubstituted-4H-pyrido[1,2-a]pyrimidin-4-one) derivatives
JP2758045B2 (ja)	1998-05-25	新規な３―ピペリジニル―１，２―ベンズイソキサゾール
US6320048B1 (en)	2001-11-20	3-piperidinyl-1,2-benzisoxazoles
US5158952A (en)	1992-10-27	3-[2-[4-(6-fluoro-1,2-benzisoxozol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use
DK168537B1 (da)	1994-04-18	1,2-benzisoxazol-3-yl- og 1,2-benzisothiazol-3-yl-derivater, en fremgangsmåde til fremstilling deraf og farmaceutiske præparater indeholdende sådanne derivater
HU186952B (en)	1985-10-28	Process for preparing condensed pyrimidin-one derivatives
JPH0759578B2 (ja)	1995-06-28	ベンズオキサゾール‐及びベンゾチアゾールアミン誘導体
IL91194A (en)	1994-04-12	History of 3-pyrazinylbenzazole, their preparation and the pharmaceutical preparations containing them
US6348457B1 (en)	2002-02-19	4-[3-benzofuranyl]piperidinyl and 4-[3-benzothienyl]piperidinyl derivatives
HU223466B1 (hu)	2004-07-28	Allergia elleni imidazo[1,2a]tieno[2,3-d]azepin-származékok, eljárás előállításukra és az ezeket tartalmazó gyógyszerkészítmények
HU195793B (en)	1988-07-28	Process for the production of new derivatives of 1,2-benziazol -3-il and medical compositions containing thereof as active substance
SI9500345A (sl)	1997-06-30	1,2-benzizoksazol-3-il derivati
NO301329B1 (no)	1997-10-13	Nye 4-(3-benzofuranyl)piperidinyl- og 4-(3-benzotienyl)piperidinylderivater og farmasöytiske sammensetninger inneholdende dem
CZ280767B6 (cs)	1996-04-17	1,2-benzisoxazol-3-ylové a 1,2-benzisothiazol-3-ylové deriváty, způsob jejich výroby a farmaceutické přípravky na jejich bázi