US3755367A - Substituted 1,4-benzodioxanes - Google Patents
Substituted 1,4-benzodioxanes Download PDFInfo
- Publication number
- US3755367A US3755367A US00183684A US3755367DA US3755367A US 3755367 A US3755367 A US 3755367A US 00183684 A US00183684 A US 00183684A US 3755367D A US3755367D A US 3755367DA US 3755367 A US3755367 A US 3755367A
- Authority
- US
- United States
- Prior art keywords
- benzodioxane
- mls
- benzodioxanes
- substituted
- aminomethyl
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Lifetime
Links
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical class C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 title description 17
- 150000001875 compounds Chemical class 0.000 abstract description 16
- 239000002253 acid Substances 0.000 abstract description 15
- 241000700159 Rattus Species 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 6
- 150000002367 halogens Chemical group 0.000 abstract description 2
- 229920006395 saturated elastomer Polymers 0.000 abstract description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 2
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical group [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- -1 2-substituted 1,4-benzodioxane Chemical class 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000002026 chloroform extract Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000001174 sulfone group Chemical group 0.000 description 4
- 206010001488 Aggression Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000003158 myorelaxant agent Substances 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- AECJTNPDMVQPNJ-UHFFFAOYSA-N (6-chloro-2,3-dihydro-1,4-benzodioxin-3-yl)methanamine Chemical compound C1=C(Cl)C=C2OC(CN)COC2=C1 AECJTNPDMVQPNJ-UHFFFAOYSA-N 0.000 description 2
- JHNURUNMNRSGRO-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-3-ylmethanamine Chemical compound C1=CC=C2OC(CN)COC2=C1 JHNURUNMNRSGRO-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000000962 organic group Chemical group 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- MCQGFLZGUXPQQQ-UHFFFAOYSA-N (5-methoxy-2,3-dihydro-1,4-benzodioxin-3-yl)methanamine Chemical compound O1CC(CN)OC2=C1C=CC=C2OC MCQGFLZGUXPQQQ-UHFFFAOYSA-N 0.000 description 1
- HLFWALLVQQOXDP-UHFFFAOYSA-N (5-methyl-2,3-dihydro-1,4-benzodioxin-3-yl)methanamine Chemical compound O1CC(CN)OC2=C1C=CC=C2C HLFWALLVQQOXDP-UHFFFAOYSA-N 0.000 description 1
- SKZVCDQMUMNCBY-UHFFFAOYSA-N 1-chloro-3-ethylsulfonylpropane Chemical compound CCS(=O)(=O)CCCCl SKZVCDQMUMNCBY-UHFFFAOYSA-N 0.000 description 1
- YDZXLBAMTMNQMM-UHFFFAOYSA-N 1-chloro-3-propan-2-ylsulfonylpropane Chemical compound CC(C)S(=O)(=O)CCCCl YDZXLBAMTMNQMM-UHFFFAOYSA-N 0.000 description 1
- BIDRHBDWACXXJK-UHFFFAOYSA-N 2-(2,3-dihydro-1,4-benzodioxin-3-yl)ethanamine Chemical compound C1=CC=C2OC(CCN)COC2=C1 BIDRHBDWACXXJK-UHFFFAOYSA-N 0.000 description 1
- UDOAUTTXEQXIMQ-UHFFFAOYSA-N 2-(3-chloropropylsulfonyl)-2-methylpropane Chemical compound CC(C)(C)S(=O)(=O)CCCCl UDOAUTTXEQXIMQ-UHFFFAOYSA-N 0.000 description 1
- JGEUTDFTBBIPKI-UHFFFAOYSA-N 3-(3-aminopropylsulfonyl)propan-1-amine Chemical compound NCCCS(=O)(=O)CCCN JGEUTDFTBBIPKI-UHFFFAOYSA-N 0.000 description 1
- QYLFKNVZIFTCIY-UHFFFAOYSA-N 3-(bromomethyl)-2,3-dihydro-1,4-benzodioxine Chemical compound C1=CC=C2OC(CBr)COC2=C1 QYLFKNVZIFTCIY-UHFFFAOYSA-N 0.000 description 1
- KNSAUQFVJMQGFP-UHFFFAOYSA-N 3-(chloromethyl)-5-methoxy-2,3-dihydro-1,4-benzodioxine Chemical compound ClCC1COC2=C(O1)C(=CC=C2)OC KNSAUQFVJMQGFP-UHFFFAOYSA-N 0.000 description 1
- QUYFSHOLLKVPGX-UHFFFAOYSA-N 3-methylsulfonylpropan-1-amine Chemical compound CS(=O)(=O)CCCN QUYFSHOLLKVPGX-UHFFFAOYSA-N 0.000 description 1
- FZBKHAJYDYCKMV-UHFFFAOYSA-N 6-(6-aminohexylsulfonyl)hexan-1-amine Chemical compound NCCCCCCS(=O)(=O)CCCCCCN FZBKHAJYDYCKMV-UHFFFAOYSA-N 0.000 description 1
- FLYIUBWEPRSAPC-UHFFFAOYSA-N 6-chloro-3-(chloromethyl)-2,3-dihydro-1,4-benzodioxine Chemical compound C1=C(Cl)C=C2OC(CCl)COC2=C1 FLYIUBWEPRSAPC-UHFFFAOYSA-N 0.000 description 1
- 101150034533 ATIC gene Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001225883 Prosopis kuntzei Species 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 230000021824 exploration behavior Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000007788 liquid Substances 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
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical class CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000528 statistical test Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229940095064 tartrate 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
Definitions
- R is a hydrogen atom, a halogen atom having an atomic number not exceeding 35 or an alkyl or alkoxy group having from one to six carbon atoms,
- R is a saturated aliphatic group having one to eight carbon atoms
- n is an integer from 2 to 6 and acid addition salts of such benzodioxanes.
- the compounds exhibit an unusual combination of tranquilising, taming and aggression-building activity when administered 10 rats.
- This invention relates to the production of pharmacologically valuable 1,4-benzodioxanes.
- the present invention provides a basically 2-substituted 1,4-benzodioxane having the general formula:
- R is a hydrogen atom, a halogen atom having an atomic number not exceeding 35 or an alkyl or alkoxy group having one to six, preferably one or two, carbon atoms, R is a saturated aliphatic group having one to eight, preferably two to six, carbon atoms and n is an integer from Q, to 6, and acid addition salts of such benzodioxanes.
- the substituent R may be present in any of the four available positions in the benzene ring of the '1,4-benzodioxane nucleus, i.e., in the 5-, 6-, 7- or 8-position.
- the group R may be, for example, chlorine, bromine, methyl, ethyl, methoxy or ethoxy, but is most preferably hydrogen.
- the acid addition salt may be any pharmacologically acceptable salt, for example, the hydrochloride, hydrobromide, sulphate, phosphate, acid maleate, acid succinate, acid tartrate or lactate of the said 1,4-benzodioxanes.
- the substituent R may be an alkyl group having one to eight, preferably tWo to six, carbon atoms and may be a straight chain orbranched chain alkyl group. When it is a branched chain alkyl group it may be atertiary-alkyl group.
- alkyl groups are methyl ethyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tertiary-butyl, secondary-amyl, tertiary-amyl, n-hexyl, 2,2-dimethyl-nbutyl, 3,3-dimthyl-n-propy1, tertiary-heptyl and tertiaryoctyl.
- R may be a cycloalkyl group, for example a cyclohexyl group.
- the group (CH is a'polymethylene group containing not more than six carbon atoms: it is preferred that this group consist of two, threeor four methylene groups.
- the reaction may be between a Z-aminomethyl- 1,4-benz-odioxane and a straight chain omega-haloalkyl sulphone in which the second organic group attached to sulphur is a saturated aliph'atic group having 1 to 8 carbon atoms, or between a 2-halomethyl-1,4-benzodioxane and a straight chain omega-aminoalkyl sulphone in which the second organic group attached to sulphur is a saturated aliphatic group having 1 to 8 carbon atoms.
- Both of these reactions lead to the formation of a hydrohalide of the 2-substituted 1,4-benzodioxane.
- This hydrohalide may be subsequently decomposed by treating the crude product with an acid acceptor. It is preferred to use an inorganic acid acceptor and to carry out the reaction in the presence of a solvent for the base being liberated. After separation of the organic phase containing the free sulphone base, solvent and any low boiling volatile materials can be removed therefrom, the residue taken up in a volatile solvent and treated with a solution of an acid in order to form the corresponding salt.
- the Z-aminomethyl-l,4-benzodioxane from which the compounds of the present invention may be obtained include Z-aminomethyl-1,4-benzodioxane, 2-aminomethyl-7-chloro-1,4-benzodioxane, Z-aminomethyl-S-methyl-l,4-benzodioxane and 2-aminomethyl-8-methoxy-1,4-benzodioxane.
- compounds of the present invention may also be obtained include Z-chloromethyl-1,4-benzodioxane, 2-bromomethyl-1,4-benzodioxane, 2-chloromethyl-7-chloro-1,4-benzodioxane, Z-chloromethyl-S-methyl-1,4-benzodioxane and Z-chloromethyl-S-methoxy-1,4-benzodioxane.
- Examples of straight chain omega-aminoalkyl sulphones which may be reacted with the 2-halomethyl-1,4-benzodioxanes include tertiary-butyl-Z-aminoethyl sulphone, methyl 3-amino-n-propyl sulphone, ethyl 3-amino-n-propy1 sulphone, iso-propyl S-amino-n-propyl sulphone, tertiarybutyl 3-amino-n-propyl sulphone, tertiary-amyl 3-aminon-propyl sulphone, tertiary-butyl 4-amino-n-butyl sulphone, tertiary-butyl S-amino-n-pentyl sulphone, tertiarybutyl 6-amino-n-hexyl sulphone and cyclohexyl 3-amin
- 1,4-benzodioxanes having the first general formula given above may also be prepared by a process which comprises reacting a solution in an organic solvent of an acylated 2-substituted 1,4-benzodioxane having the general formula:
- R, R and n are as defined above with a miscible solution of hydrogen peroxide in an organic organic solvent, and thereafter hydrolysing the N-acyl group with a strong acid.
- acylated Z-substituted 1,4-benzodioxanes are in turn prepared by the acylation of basically 2-substituted 1,4-benzodioxanes having the general formula in which R, R and n are as above defined.
- Suitable acylating agents are the acid halides and anhydrides of aliphatic and aromatic monocarboxylic acids such as acetic and propionic anhydrides and benzoyl chloride.
- the basically substituted 1,4-benzodioxanes having the General Formula V may be prepared by the reaction of a Z-monosubstituted-methyl 1,4-benzodioxane having the General Formula II with a mono-substituted alkyl sulphide having the general formula in which R Z and n are as above defined.
- R is a hydrogen atom or an alkoxy group.
- Auslegeschrift No. 1,118,218 amongst the compounds disclosed therein are 2- w-methylmercapto-n-butylaminomethyl l ,4
- the oxidation of the acylated 2-substituted 1,4-benzodioxanes with hydrogen peroxide it is preferred to use the same organic solvent for both the acylated 1,4-benzodioxane and the hydrogen peroxide.
- the normally liquid alkane monocarboxylic acids, especially acetic acid, are suitable for this purpose.
- the oxidation is an exothermic reaction and it is therefore desirable to add the hydrogen peroxide solution over a period of time so as to prevent the temperature of the reaction mixture exceeding a predetermined maximum of, for example, 50 C.
- the resulting sulphone is conveniently isolated by taking advantage of its solubility in an organic solvent in which the organic solvent used to carry out the reaction is substantially insoluble, the solution freed from any residual hydrogen peroxide, and the produce then hydrolysed with a strong acid, conveniently after removal of the organic solvent.
- the compounds of the present invention have been tested upon mice and rats and have been found to exert muscle relaxant, sedative, tranquilising and taming properties thereon.
- An unusual feature of the compounds of the invention is their ability to induce agressive behaviour in male rats 12 to 24 hours after administration.
- the compounds of the invention appear able to induce in rats a characteristic combination of quietness or tameness and self-confidence in the face of aggression. This effect is however biphasic, and is superseded at higher dose levels by relaxant effects.
- R is a branched chain alkyl group and n is three have been found to exert muscle relaxant properties in rats for which ED is 0.1-1.0 mg. per kilogram bodyweight when administered subcutaneously and 10-100 mg./kg. when administered orally.
- the approximate LD values were 400 mg. per kilogram bodyweight when administered subcutaneously and greater'than 400 mg. per kilogram when administered orally.
- the approximate acute oral LD is 400 mg./kg.: subcutaneously it is 250 rug/kg.
- An unusual feature of the compounds of the invention is their ability to induce aggressive behaviour in male rats 12 to 24 hours after administration.
- EXAMPLE 1 2- (3 '-tertiary-amylsulphonyl-n-propyl) aminomethyl1- 1,4-benzodioxane Z-aminomethyl-l,4-benzodioxane (26.1 g.) and 3-tertiary-amylsulphonyl-n-propylchloride 16.7 g.) were heated at C. for two hours prior to mixing with 2 N caustic soda (40 mls.) and extracted with chloroform (once with 20 mls. and twice with 10 mls.). The chloroform extracts were combined and the combined extracts distilled to a final residue temperature of 220 C; at 0.05 mm. of mercury.
- Recrystallisation from isopropyl alcohol have the product as white crystals, melting point 157 to 160 C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4567170 | 1970-09-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3755367A true US3755367A (en) | 1973-08-28 |
Family
ID=10438121
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00183684A Expired - Lifetime US3755367A (en) | 1970-09-24 | 1971-09-24 | Substituted 1,4-benzodioxanes |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US3755367A (enrdf_load_stackoverflow) |
| AU (1) | AU454605B2 (enrdf_load_stackoverflow) |
| CA (1) | CA962277A (enrdf_load_stackoverflow) |
| CH (2) | CH559204A5 (enrdf_load_stackoverflow) |
| DE (1) | DE2147836A1 (enrdf_load_stackoverflow) |
| FR (1) | FR2107950B1 (enrdf_load_stackoverflow) |
| GB (1) | GB1307390A (enrdf_load_stackoverflow) |
| IL (1) | IL37771A (enrdf_load_stackoverflow) |
| NL (1) | NL7113213A (enrdf_load_stackoverflow) |
| ZA (1) | ZA716431B (enrdf_load_stackoverflow) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4168318A (en) * | 1974-06-14 | 1979-09-18 | Dr. Madaus & Co. | 1-(2,4,6-Trihydroxyphenyl)-propanedione-(1,2)-compounds and therapeutic compositions |
-
1970
- 1970-09-24 GB GB4567170A patent/GB1307390A/en not_active Expired
-
1971
- 1971-09-22 AU AU33807/71A patent/AU454605B2/en not_active Expired
- 1971-09-23 IL IL7137771A patent/IL37771A/xx unknown
- 1971-09-24 ZA ZA716431A patent/ZA716431B/xx unknown
- 1971-09-24 CH CH1166274A patent/CH559204A5/xx not_active IP Right Cessation
- 1971-09-24 NL NL7113213A patent/NL7113213A/xx unknown
- 1971-09-24 US US00183684A patent/US3755367A/en not_active Expired - Lifetime
- 1971-09-24 FR FR7134364A patent/FR2107950B1/fr not_active Expired
- 1971-09-24 CH CH1393871A patent/CH555330A/xx not_active IP Right Cessation
- 1971-09-24 DE DE19712147836 patent/DE2147836A1/de active Pending
- 1971-09-24 CA CA123,621A patent/CA962277A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4168318A (en) * | 1974-06-14 | 1979-09-18 | Dr. Madaus & Co. | 1-(2,4,6-Trihydroxyphenyl)-propanedione-(1,2)-compounds and therapeutic compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2107950A1 (enrdf_load_stackoverflow) | 1972-05-12 |
| AU454605B2 (en) | 1974-10-31 |
| FR2107950B1 (enrdf_load_stackoverflow) | 1975-04-18 |
| GB1307390A (en) | 1973-02-21 |
| IL37771A0 (en) | 1971-11-29 |
| IL37771A (en) | 1974-12-31 |
| DE2147836A1 (de) | 1972-05-10 |
| NL7113213A (enrdf_load_stackoverflow) | 1972-03-28 |
| ZA716431B (en) | 1972-07-26 |
| CA962277A (en) | 1975-02-04 |
| CH555330A (de) | 1974-10-31 |
| AU3380771A (en) | 1973-03-29 |
| CH559204A5 (enrdf_load_stackoverflow) | 1975-02-28 |
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