IE46679B1 - Pyranotriazines,processes for their production and their use as pharmaceuticals - Google Patents
Pyranotriazines,processes for their production and their use as pharmaceuticalsInfo
- Publication number
- IE46679B1 IE46679B1 IE540/78A IE54078A IE46679B1 IE 46679 B1 IE46679 B1 IE 46679B1 IE 540/78 A IE540/78 A IE 540/78A IE 54078 A IE54078 A IE 54078A IE 46679 B1 IE46679 B1 IE 46679B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- stated
- hydrogen
- nitro
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 17
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 239000003814 drug Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 239000001257 hydrogen Substances 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 239000000460 chlorine Substances 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 239000011737 fluorine Substances 0.000 claims abstract description 5
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 239000012298 atmosphere Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 229910000510 noble metal Inorganic materials 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 11
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 230000000802 nitrating effect Effects 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000411 inducer Substances 0.000 abstract description 2
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- 239000003204 tranquilizing agent Substances 0.000 abstract 1
- 230000002936 tranquilizing effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 241000282693 Cercopithecidae Species 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- -1 benzene or toluene Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000803 paradoxical effect Effects 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010062519 Poor quality sleep Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000028527 righting reflex Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- WEQFQARMFHPBTG-UHFFFAOYSA-N 1,9,9-trimethyl-10-oxa-3,4,6-triazatricyclo[6.2.2.02,7]dodeca-2(7),3,5-triene Chemical class CC1(C2C=3N=CN=NC=3C(O1)(CC2)C)C WEQFQARMFHPBTG-UHFFFAOYSA-N 0.000 description 1
- YEGYBYPKILSAES-UHFFFAOYSA-N 1,9,9-trimethyl-5-(3-nitrophenyl)-6-oxido-10-oxa-3,4-diaza-6-azoniatricyclo[6.2.2.02,7]dodeca-2(7),3,5-triene hydrate Chemical compound O.CC1(C)OC2(C)CCC1C([N+]=1[O-])=C2N=NC=1C1=CC=CC([N+]([O-])=O)=C1 YEGYBYPKILSAES-UHFFFAOYSA-N 0.000 description 1
- GGSQPXUIROUJER-UHFFFAOYSA-N 1,9,9-trimethyl-5-phenyl-10-oxa-3,4,6-triazatricyclo[6.2.2.02,7]dodeca-2(7),3,5-triene Chemical compound CC1(C)OC(C2=NN=3)(C)CCC1C2=NC=3C1=CC=CC=C1 GGSQPXUIROUJER-UHFFFAOYSA-N 0.000 description 1
- QUBMKXLXAFPRMG-UHFFFAOYSA-N 1,9,9-trimethyl-6-oxido-5-phenyl-10-oxa-3,4-diaza-6-azoniatricyclo[6.2.2.02,7]dodeca-2(7),3,5-triene Chemical compound CC1(C)OC2(C)CCC1C([N+]=1[O-])=C2N=NC=1C1=CC=CC=C1 QUBMKXLXAFPRMG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- MWVFXWACGIPVQI-UHFFFAOYSA-N 6-hydroxyimino-2,2,4-trimethyl-3-oxabicyclo[2.2.2]octan-5-one Chemical compound C1CC2C(C)(C)OC1(C)C(=O)C2=NO MWVFXWACGIPVQI-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000282668 Cebus Species 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 1
- 238000006172 aromatic nitration reaction Methods 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 1
- 229960002456 hexobarbital Drugs 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-O nitrosooxidanium Chemical compound [OH2+]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-O 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- IECKAVQTURBPON-UHFFFAOYSA-N trimethoxymethylbenzene Chemical compound COC(OC)(OC)C1=CC=CC=C1 IECKAVQTURBPON-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged 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
- A61P25/20—Hypnotics; Sedatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Anesthesiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (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)
- Saccharide Compounds (AREA)
Abstract
600-6781 CANADA IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS This disclosure describes novel compounds of the formula wherein R1 and R2 each independently represent hydrogen, fluorine, chlorine, alkyl of 1 to 4 carbon atoms, straight chain alkoxy of 1 to 4 carbon atoms, amino, nitro or trifluoromethyl, and X represents or , which are useful as minor tranquilizers and sleep inducers.
Description
IMPROVEMENTS' IN OR RELATING TO ORGANIC COMPOUNDS This invention relates to 5,8-dihydro-6,6,8-trimethyl5,8-ethano-6H-pyrano[4,3-e]-as-triazines and their 4-oxidas.
More particularly, this invention provides compounds of formula I, in which X signifies or and R^ provided that (i) and (ii) and R2, which may be the same or different, each signifies hydrogen, fluorine, chlorine, alkyl of 1 to 4 carbon atoms, straight chain alkoxy of 3. to 4 carbon atoms, amino, nitro or trifluoromethyl, when one of R^ and R^ is nitro, the other is other than nitro or trifluoromethyl, when one of R^ and R2 is t-butyl or trifluoromethyl, the other is other than trifluoromethyl on an adjacent carbon atom or t-butyl on - 2 46679 an adjacent carbon atom.
The invention also provides processes for the production of compounds of formula I, characterised by a) producing a compound of formula Ia, in which R and R2 are as defined above, by reacting the compound of formula II, II with a compound of formula III in which and R2 are as defined above, i and is methyl or ethyl, in an inert organic solvent and under an inert atmosphere , - 3 b) producing a compound of formula Iaa, in which- R| signifies hydrogen, fluorine, chlorine, alkyl of 1 to 4 carbon atoms, straight chain alkoxy of 1 to 4 carbon atoms, ia «hisk i§ as aWej is sr iassfe ©gfaa.is §©i.veR%f, @g p@aueipf ©f S@saula 46G79 in which R^ and R2 are as defined above, by reacting a compound of formula Ia, stated above, with cyclohexene in the presence of a noble metal catalyst, in an inert organic solvent and under an inert atmosphere. · Process a) is suitably effected at a temperature of from 70° to 200°C, preferably 130° to 150°C, and the reaction time may, for example, vary from 12 to 36 hours, more typically 15 to 20 hours. Suitable solvents include aromatic hydrocarbons, such as benzene or toluene, and lower alkanols, such as methanol or ethanol. Alternatively and preferably, an excess of the compound of formula III may be employed to provide a reaction medium. The inert atmosphere may, for example, be helium, argon or, preferably, nitrogen.
Process b) is a conventional aromatic nitration process which may be effected using conventional nitronium ion-forming reagents, including a mixture of sulphuric and nitric acid, a mixture of trifluoromethanesulphonic acid and fuming nitric acid, or a mixture of hydrogen fluoride and dinitrogen peroxide in nitromethane at -2Q°C saturated with boron trifluoride. The preferred reagent is a mixture of trifluoromethanesulphonic acid and fuming nitric acid, preferably in a molar ratio of 2:1, Suitable solvents include aromatic hydrocarbons, such as methylene chloride or chloroform, preferably methylene chloride. The reaction temperature is suitably from -80° to +70°C, preferably -35° to +35°C and the reaction time may, for example,;vary from 19 to 96 hours, more usually 60 to' 75 hours·. , tk In process c), the noble metal catalyst is suitably platinum, rhodium or, preferably, palladium, either neat or on a support, such conveniently effected !as charcoal. The process is then 'at a temperature of from 20° to 200°C, preferably 70° to 110°C and the reaction time may vary, for example from 5 to 72 hours, more ususally from 10 15 to 30 hours. Suitable solvents include lower alkanols, such as methanol or ethanol, preferably the latter.
Process c) is effected under an inert atmosphere such as helium, argon or,, preferably, nitrogen.
I The resulting compounds of formula I may be isolated 15 and purified using conventional techniques. Where required, free base forms thereof may be converted into acid addition salt forms ih conventional manner and vice versa.
The compound of formula II may be prepared by treating the compound of formula IV with hydrazine according to the following reaction scheme: + n2h4 fH3 IV (II) 6 6 7 9 The reaction is suitably effected at a temperature of from 0° to 150°C, preferably 75° to 85°C, in an inert organic solvent, for example a lower alkanol, preferably ethanol, and under an inert atmosphere. The reaction time may vary from 1 to 18 hours, more usually 2 to 8 hours.
The compounds of formulae III and IV are either known or may be produced in conventional manner from available materials.
The compounds of formula I possess pharmacological activity. In particular, they possess sleep-inducing and minor tranguillising activity, as indicated 1) by the hexobarbital reinduction method of Winter, J. Pharmacol, and Exp. Therap. 94, 7-11 (1948); 2) in the Cebus monkey using chronically implanted electrodes. Brain readings are obtained via a ten or sixteen channel electroencephalograph. For the recording sessions, the monkeys are restrained by neck and waist plates in chairs in full side observation cages, at the same time every night, for thirteen and one half hours, Monday through Thursday. Gross behavior is monitored via closed circuit television and video tape recordings.
The compound of formula I is administered p.o. immediately on placing the monkey in the observation cages with at least seven days intervening between drug administration. Physiological saline is administered via a similar route and at the same time on all control - 7 466 78 runs. Control data are collected at, least three days per week and accumulated to give control data for fifteen sessions per monkey. Data from each session are statistically compared via computer analysis to the previous: 5-15 control sessions for'the particular animal, $i?tlr partidular emphasis being given to the following phases of the sleep-wakefulness cycle; resting awake, light sleep, deep sleep, paradoxical (REM) sleep, pseudo- paradoxical sleep, latency to onset of deep sleep, and latency to onset of first epoch of paradoxical sleep; · 3) by their ability to produce docility in behaviour tests in mice given 25 to 200 mg/kg of animal body weight, i.p., of the test compound according to the 30word adjective check sheet system basically as described by Irwin S. (Gordon Research Conference, Medicinal Chemistry, 1959) and Chen (Symposium on Sedative and Hypnotic drugs, Willians and Wilkins, 1954); j 4) by their ability to antagonize chronic convulsions anrf death in mce niyon 20-250 mn/kg i.n. of the test comnound 60 minutes nrior to administration of 50 mg/kg i.n. of ίΊ-sulfanoyl azepine. ) by scoring for loss of righting reflex according to the method of Reed-Muench [American Journal of Hygiene 27, 493-497, (1938)], in which mice are administered 12.5 mg/kg, i.p. of Thioridazine, immediately after which the test compound is administered at dosages of 5 to 100 mg/kg in a volume of 0.1 ml/10 g body weight.
Sixty minutes after dosing, the mice are scored for loss of righting reflex, and 6) by their ability to reduce conflicts as defined in the Geller Conflict Test [Irving Geller, Psychopharma- . cologia, I, 421-492, (I960)].
The compounds are therefore indicated for use as sleep inducers and minor tranquillisers. For sleep inducing usage, an indicated suitable daily dosage is from 1 to 300 mg, suitably given as a single dosage at bedtime. For minor tranquillising usage, ap-indicated suitable daily dosage is from 5 to 500 mg, suitably administered in divided dosages of from 1.25 to 250 mg, two to four times daily or in retard form.
The compounds may be admixed with conventional pharmaceutically acceptable diluents or carriers and, optionally, other excipients, and administered in such forms as tablets or capsules.
The compounds may be employed in free base form or in the form of pharmaceutically acceptable acid addition salts, which salt forms possess the same order of activity as the free base forms. Suitable acids for salt formation include mineral acids, such as hydrochloric, hydrobromic and sulphuric acid, and organic acids, such as succinic, benzoic and maleic acid.
The preferred compounds of formula I are those in which R^ is NOj or CF^, preferably in the m-position, and R2 is hydrogen.
The following Examples illustrate the invention: 6 6 7 9 - 9 EXAMPLE li 3-Phe'riyl-5,8-dihydro-6,6,8-trimethyl-5,8' ’ethano-SH-pyrano[4,3-e]-as-triazine-4-oxide. (process a)] (i) liJ^S-Trimethyl-^oxabicycloJ^j^^SESSEziixiiz^iEEEZ 5ζ25ί:2£ζέζίίΖ£22222£_ΐ£22ΪΕ222£_2£_£22ί?2ΐ2_ϊ£2.
. A mixture of 1.97 g (0.01 mole) 1,3,3-trimethyl2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime and 0.35 ml (0.011 mole) anhydrous hydrazine (98%) in 25 ml absolute ethanol is refluxed under nitrogen at a bath temperature of 80°C for 1 hour. After evaporation of the solvent, the residue is recrystallized from ether to give l,3,3-trimethyl-2-oxabicyclo[2,2,2]octan5,6-dione-5-oxime-6-hydrazone; m.p. 138 to 142°C. (ii) S^Phenyl-S.te-dihydro-fi^fj^B-trimethyl-S.jS^gthano15 £2zEX£S22lix5-eJ2Ss-triazine-42Oxide__(comgound_of fo£S2l£_i£l A solution of 2.11 g (0.01 mole) 1.3.3-trimethyl 2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone in 10 ml trimethylorthobenzoate is refluxed under nitrogen for 18 hours at a bath temperature of 140°C during which time all distillate is removed. The resulting mixture is cooled and evaporated to dryness ’ in Vacuo. After filtering the residue,dissolved in 2% methanol-chloroform,through silica gel, and 25 evaporation of the filtrate the resulting solid is - 10 triturated with ether,giving 3-phenyl-5,8-dihydro6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-astriazine-4-oxide; m.p. 186.5° to 189°C.
EXAMPLE 2: 3-(m-nitropheny1)-5,8-dihydro-6,6,8-trimethy15,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide. [process b)] To a mixture of 0.2 ml [0.005 mole) fuming nitric acid and 1.5 g (0.01 mole) trifluoromethanesulfonic acid in 15 ml anhydrous methylene chloride maintained at a temperature of -30°C there is added dropwise a solution of 0.60 g (0.002 mole) 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano6H-pyrano[4,3-e]-as-triazine-4-oxide in 15 ml methylene chloride, maintaining the temperature at -30°C throughout the addition. The resulting mixture is stirred at ambient temperature for 72 hours, then poured onto ice and neutralized with solid sodium bicarbonate. The organic layer is removed, washed with saturated brine solution, dried over magnesium sulfate and evaporated. Trituration of the resulting residue with ether gives 3-(m-nitrophenyl)-5,8-dihydro6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4oxide-monohydrate; m.p. 150°C (decomposes).
EXAMPLE 3: 3-Phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano6H-pyrano[4,3-e]-as-triazine [process c)] To a solution of 1.80 g (0.006 mole) 3-pheny1-5,8dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as4 6 6 7 9 j'- 11 ( triazine-4-oxide and 1.50 g (0.018 mole) cyclohexene in 30 ml absolute ethanol there is added 60 mg 10% palladium on charcoal. The resulting mixture is refluxed under a nitrogen atmosphere for 18 hours. The catalyst is then . removed by filtration and the filtrate evaporated to give 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5, 8-ethano-6K-pyrano [4,3-e]-as-triazine; m.p. 180° to 189°C.
Further compounds of formula I, in which X, R^ and R2 have the significances indicated in the following table,may be prepared in manner analogous to the indicated Example(s) using appropriate starting materials in approximately equivalent amounts. - 12 10 46G79 Ex. No. Analogy to Ex. No. Process XR1R2 m.p. °C 4 1 a N->0 p-Cl H 5 1 a IJ p-F H 157-158° 6 1 a tl p-ch3 H 177-178° 7 1 a II P-OCH3 H 148-149° 8 1 a If m-CF3 H 157.5-158.5° 9 1 a II p-nh2 H 10 1 ‘ a II p-no2 H 11 1 a II m-N02 H 12 1 a II m-Cl H 180° 13 1 ' a tt m-0CH3 p-OCH3 14 2 b II ®-no2 p-ch3 15 2 b II a-N02 p-OCH3 133-135° 16 3 c N p-Cl H 17 3 c II p-F H 18 3 c II p-ch3 H 19 3 c II p-och3 H 20 3 c II m-CF3 H 235-250° (dec.) 21 3 c II p-nh2 H 22 3 c 11 p-no2 H 23 3 c II m-N02 H 300° (dec.) 24 3 c It m-Cl H 25 3 c II m-OCHj p-OCH3
Claims (32)
1. A process for the production of a compound in which X signifies or £ : and R^ and R 2 , which may be the same or different, each signifies hydrogen, fluorine, chlorine, alkyl of 1 to 4 _ carbon atoms, straight chain alkoxy of 1 to 4 carbon atoms, amino, nitro or trifluoromethyl, provided that (i) · when one of R^ and R 2 Is nitro, the other is Other than nitro or .trifluoromethyl, and (ii) when one of R^ and R^ is t-butyl or trifluoromethyl, the other is other than trifluoromethyl on an adjacent carbon atom or t-butyl on an adjacent carbon atom. characterised by a) producing a compound of formula la, I, I with a compound of formula III in which R. and '10 _ c(or 3 ) 3 III R^ are as defined above, and R 3 is methyl or ethyl, in an inert organic solvent and under an inert atmosphere , b) producing a compound of formula Iaa, t - 15 46679 ι ι ί I I in which R| signifies hydrogen, fluorine, chlorine, alkyl of 1 to 4 carbon atoms, straight chain alkoxy of 1 to 4 carbon atoms, or amino, by nitrating a compound of formula lab, i ' I I I I I in which R£ us as defined above, in an inert organic solvent, or c) producing a compound of formula Ib, in which R^ and Rj are as defined above, by reacting a compound of formula Ia, stated above, with cyclohexene in the presence of a noble metal catalyst, in an inert organic solvent and under an inert atmosphere. - 16
2. A process for the production of a compound of formula I, stated in Claim 1, substantially as described in any one of the Examples.
3. A compound of formula I, stated in Claim 1, 5 whenever produced by a process as claimed in Claim 1 or 2.
4. A compound of formula I, stated in Claim 1.
5. A compound as claimed in Claims 3 or 4, in which R^ is a nitro or trifluoromethyl group, and R 2 is hydrogen. 10
6. A compound as claimed in Claim 5, in which the nitro or trifluoromethyl group is located in the meta position.
7. A compound of formula I, stated in Claim 1, in which X is N->0, R^ is hydrogen and R^ is hydrogen. 15
8. A compound of formula I, stated in Claim 1, in which X is N-»O, is £-chloro and R 2 is hydrogen.
9. A compound of formula I, stated in Claim 1, in which X is N->0, R^ is £-fluoro and R 2 is hydrogen.
10. A compound of formula I, stated in Claim 1, in 20 which X is N->0, R^ is £-methyl and R 2 is hydrogen.
11. A compound of formula I, stated in Claim 1, in which X is N->0, R^ is £-methoxy and R 2 is hydrogen.
12. A compound of formula I, stated in Claim 1, in which X is N->0, R 1 is m-trifluoromethyl and R 2 is hydrogen 25
13. A compound of formula I, stated in Claim 1, in which X is N->0, R^ is £-amino and R 2 is hydrogen. 4 6 6 7 8 - 17 which which which which which which which which which which which which which
14. A compound of formula I, stated in Claim 1, in X is N-»0, R^ is £-nitro and Rj is hydrogen.
15. A compound of formula I, stated in Claim 1, in X is N-»O, R^ is m-nitro and Rj is hydrogen.
16. A compound of formula I, stated in Claim 1, in i X is N-»O, R^ is m-chloro and Rj is hydrogen.
17. A compound of formula I, stated in Claim 1, in X is N->0, R^ is m-methoxy and Rj is £-methoxy.
18. A compound of formula I, stated in Claim 1, in X is N->0, R^ is m-nitro and Rj is ja-methyl,
19. A compound of formula I, stated in Claim 1, in X is N->0, R^ is m-nitro and Rj is £-methoxy.
20. A compound of formula I, stated in Claim 1, in X is H, is hydrogen and Rj is hydrogen.
21. A compound of formula I, stated in Claim 1, in X is N, R^ is £-chloro and Rj is hydrogen.
22. A compound of formula I, stated in Claim 1, in X is N, R^ is £-fluoro and Rj is hydrogen.
23. A compound of formula I, stated in Claim 1, in X is N, R^ is £-methyl and Rj is hydrogen.
24. A compound of formula I, stated in Claim 1, in X is N, R^ is £-methoxy and Rj is hydrogen.
25. ’5. A compound of formula I, stated in Claim 1, in X is N, R^ is m-trifluoromethyl and Rj is hydrogen.
26. A compound of formula I, stated in Claim 1, in X is N, R 1 is £-amino and Rj is hydrogen. - 18 46679
27. A compound of formula I, stated in Claim 1, in which X is N, R^ is £-nitro and R 2 is hydrogen.
28. A compound of formula I, stated in Claim 1, in which X is N, R^ is m-nitro and R 2 is hydrogen.
29. 5 29, A compound of formula I, stated in Claim 1, in which X is N, R^ is m-chloro and Rj is hydrogen.
30. A compound of formula I, stated in Claim 1, in which X is N, R^ is m-methoxy and R 2 is £>-me thoxy.
31. A compound as claimed in any one of Claims 310 30, in the form of an acid addition salt.
32. A pharmaceutical composition comprising a compound as claimed in any one of Claims 3-30, in free base or pharmacologically acceptable acid addition salt form, in association with a p'harmacologically acceptable 15 diluent o’r carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US77907177A | 1977-03-18 | 1977-03-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE780540L IE780540L (en) | 1978-09-18 |
| IE46679B1 true IE46679B1 (en) | 1983-08-24 |
Family
ID=25115233
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE540/78A IE46679B1 (en) | 1977-03-18 | 1978-03-16 | Pyranotriazines,processes for their production and their use as pharmaceuticals |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS53116400A (en) |
| AT (1) | AT366688B (en) |
| AU (1) | AU519623B2 (en) |
| BE (1) | BE864987A (en) |
| CA (1) | CA1095518A (en) |
| DE (1) | DE2810224A1 (en) |
| DK (1) | DK104978A (en) |
| ES (1) | ES467999A1 (en) |
| FI (1) | FI62837C (en) |
| FR (1) | FR2383947A1 (en) |
| GB (1) | GB1597924A (en) |
| IE (1) | IE46679B1 (en) |
| IL (1) | IL54295A (en) |
| IT (1) | IT7848478A0 (en) |
| NL (1) | NL7802746A (en) |
| NZ (1) | NZ186713A (en) |
| PT (1) | PT67791A (en) |
| SE (1) | SE7802773L (en) |
| ZA (1) | ZA781587B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4233469A (en) * | 1979-02-13 | 1980-11-11 | Steppe Theodore W | Conduit bushing |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH617435A5 (en) * | 1974-05-01 | 1980-05-30 | Sandoz Ag | Process for the preparation of novel 5,5,7,7-tetramethylfuro-[3,4e]as-triazine-4-oxides and their use |
-
1978
- 1978-03-09 DK DK104978A patent/DK104978A/en not_active Application Discontinuation
- 1978-03-09 FI FI780758A patent/FI62837C/en not_active IP Right Cessation
- 1978-03-09 DE DE19782810224 patent/DE2810224A1/en not_active Withdrawn
- 1978-03-10 SE SE7802773A patent/SE7802773L/en unknown
- 1978-03-14 NL NL7802746A patent/NL7802746A/en not_active Application Discontinuation
- 1978-03-15 GB GB10254/78A patent/GB1597924A/en not_active Expired
- 1978-03-16 IL IL54295A patent/IL54295A/en unknown
- 1978-03-16 JP JP2936378A patent/JPS53116400A/en active Pending
- 1978-03-16 AU AU34224/78A patent/AU519623B2/en not_active Expired
- 1978-03-16 IE IE540/78A patent/IE46679B1/en unknown
- 1978-03-16 CA CA299,081A patent/CA1095518A/en not_active Expired
- 1978-03-16 NZ NZ186713A patent/NZ186713A/en unknown
- 1978-03-16 BE BE186013A patent/BE864987A/en not_active IP Right Cessation
- 1978-03-17 PT PT67791A patent/PT67791A/en unknown
- 1978-03-17 ES ES467999A patent/ES467999A1/en not_active Expired
- 1978-03-17 FR FR7807768A patent/FR2383947A1/en active Granted
- 1978-03-17 IT IT7848478A patent/IT7848478A0/en unknown
- 1978-03-17 AT AT0189678A patent/AT366688B/en not_active IP Right Cessation
- 1978-03-17 ZA ZA00781587A patent/ZA781587B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE2810224A1 (en) | 1978-09-28 |
| FI62837B (en) | 1982-11-30 |
| FI780758A (en) | 1978-09-19 |
| AU519623B2 (en) | 1981-12-17 |
| PT67791A (en) | 1978-04-01 |
| BE864987A (en) | 1978-09-18 |
| FI62837C (en) | 1983-03-10 |
| IL54295A (en) | 1981-02-27 |
| JPS53116400A (en) | 1978-10-11 |
| AU3422478A (en) | 1979-09-20 |
| ZA781587B (en) | 1979-10-31 |
| SE7802773L (en) | 1978-09-19 |
| NL7802746A (en) | 1978-09-20 |
| FR2383947B1 (en) | 1981-07-03 |
| DK104978A (en) | 1978-09-19 |
| ATA189678A (en) | 1981-09-15 |
| FR2383947A1 (en) | 1978-10-13 |
| GB1597924A (en) | 1981-09-16 |
| IL54295A0 (en) | 1978-06-15 |
| ES467999A1 (en) | 1979-09-01 |
| IT7848478A0 (en) | 1978-03-17 |
| NZ186713A (en) | 1980-09-12 |
| IE780540L (en) | 1978-09-18 |
| CA1095518A (en) | 1981-02-10 |
| AT366688B (en) | 1982-04-26 |
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