IE43907B1 - 3-(alpha-iminobenzyl)-4-hydroxy-2(1h)-pyridone derivatives - Google Patents
3-(alpha-iminobenzyl)-4-hydroxy-2(1h)-pyridone derivativesInfo
- Publication number
- IE43907B1 IE43907B1 IE528/76A IE52876A IE43907B1 IE 43907 B1 IE43907 B1 IE 43907B1 IE 528/76 A IE528/76 A IE 528/76A IE 52876 A IE52876 A IE 52876A IE 43907 B1 IE43907 B1 IE 43907B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- methyl
- formula
- hydrogen
- stated
- Prior art date
Links
- PPMDIMDNKWLLPX-UHFFFAOYSA-N 3-(benzenecarboximidoyl)-4-hydroxy-1H-pyridin-2-one Chemical class N=C(C1=CC=CC=C1)C=1C(NC=CC1O)=O PPMDIMDNKWLLPX-UHFFFAOYSA-N 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 69
- 239000001257 hydrogen Substances 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- -1 ach hydrogen Chemical class 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims 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 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 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 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000001117 sulphuric acid Substances 0.000 description 3
- 235000011149 sulphuric acid Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- GFLXTDJQSFMTKF-UHFFFAOYSA-N 5-(2-hydroxy-2-phenylethyl)-n-methyl-3-phenyl-1,2-oxazole-4-carboxamide Chemical compound O1N=C(C=2C=CC=CC=2)C(C(=O)NC)=C1CC(O)C1=CC=CC=C1 GFLXTDJQSFMTKF-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229940117975 chromium trioxide Drugs 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 230000028527 righting reflex Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WZKXUAOTZXJBRD-UHFFFAOYSA-N 3-(benzenecarboximidoyl)-4-hydroxy-1-methyl-6-phenylpyridin-2-one Chemical compound O=C1N(C)C(C=2C=CC=CC=2)=CC(O)=C1C(=N)C1=CC=CC=C1 WZKXUAOTZXJBRD-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 150000001342 alkaline earth metals Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- VEQAGSPCZANNDR-UHFFFAOYSA-N azepine-1-sulfonamide Chemical compound NS(=O)(=O)N1C=CC=CC=C1 VEQAGSPCZANNDR-UHFFFAOYSA-N 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 159000000007 calcium salts Chemical group 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- MAFGERLXTNIVPA-UHFFFAOYSA-N n-methyl-5-phenacyl-3-phenyl-1,2-oxazole-4-carboxamide Chemical compound O1N=C(C=2C=CC=CC=2)C(C(=O)NC)=C1CC(=O)C1=CC=CC=C1 MAFGERLXTNIVPA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical group [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS The invention provides novel 3-(.alpha.-iminobenzyl)-4-hydroxy-2(1H)-pyridone derivatives, useful as sleep inducers and minor tranquillisers, and processes for their production.
Description
This invention relates to 3-(alpha-iminobenzyl)-4-hydroxy-2(lH)pyridone derivatives.
More particularly, this.invention provides compounds of formula I, in which Rp Rg and R^, which may be the same or different, each signifies hydrogen, fluorine, chlorine, trifluoromethyl or alkyl or alkoxy of 1 to 4 carbon atoms, and .
R3 is alkyl of 1 to 4 carbon atoms, . provided that when Rp Rg and R^ are each hydrogen, then R3 is other than methyl.
The invention also provides a process for the production of compounds of formula I, comprising reducing a compound of formula II, in which R,, Rg, R, and R^ are as defined above, in an inert organic solvent.
The process may be effected in conventional manner, for example by catalytic hydrogenation. Suitable catalysts include palladium on carbon, platinum oxide and Raney nickel, preferably palladium on carbon. An inert organic solvent, such as a alkanol, e.g. methanol or, preferably ethanol, is suitably employed. The hydrogenation is conveniently effected at a temperature of from 10° to 50°C, preferably 20° to 30°C, and the reaction time may vary, for example from 1 to 10 hours, more usually 2 to 3 hours.
The resulting compounds of formula I may be isolated and purified using conventional techniques. Where required, free hydroxy forms of the compounds may be converted into base salt forms in conventional manner, and vice versa.
As will be appreciated, the compounds of formula I may exist in tautomeric forms of formulae Ia, Ib and Ic, - 3 4 3 3 0 7 ι which R-|, Rg, Rg and R^ are as defined above, While reference is made above and hereinafter solely to the form of irmula I, or the corresponding chemical name, it is to be understood that the ivention is not intended to be limited to, or to the production or use of, any irticular form of the' compounds.
The compounds of formula II, may be produced by cyclising a compound ; formula III, which Rp Rg, Rg and R^ are as defined above, in the presence of an acid and a lvent. - 4 4 3 0 0 7 The cyclisation may he effected in conventional manner, for example by treatment of the compound of formula III with an acid, such as hydrochloric, P-toluenesulphonic, polyphosphoric or, preferably, sulphuric acid, and suitably in an inert solvent, such as an aromatic hydrocarbon, e.g. benzene or toluene.
Preferably, however, an excess of the acid may be employed to provide the reaction medium. The process is suitably effected at a temperature of from 80° to 150°C, preferably at the reflux temperature of the reaction mixture, and the reaction time may, for example, vary from 12 to 36, more usually 20 to 36 hours.
The resulting compounds of formula II may be isolated and purified using conventional techniques.
The compounds of formula III may be produced by oxidising a compound of formula IV, in which , R,,, Rg and R^. are as defined above.
The oxidation may be effected in conventional manner, for example with potassium permanganate or, preferably, chromium trioxide, and under aqueous acidic conditions. The preferred acids include mineral acids, such as sulphuric or hydrochloric acid and, preferably, organic acids, in particular acetic acid. The reaction temperature is conveniently from 10° to 50°C, preferably from 20° to °C, and the reaction time may, for example, vary from 1 to 5, more usually 1.5 to 2.5 hours.
The resulting compounds of formula III may be isolated and purified using conventional techniques. - 5 The compounds of formula IV may be produced by reacting a compound of ormula V, n which R and R, are as defined above, with a compound of formula VI, J HC •Z' II r4 . Οι which Rg and R^ are as defined above, in an inert organic solvent.
The reaction is suitably effected at a temperature of from -75° to 55°C, preferably -650 to -60°C and suitable solvents include aliphatic hydrocarbons, jch as pentane, hexane and heptane, and, preferably, ethers, such as diethyl ether r, in particular, tetrahydrofuran. The reaction time may, for example, vary from to 5, particularly 2.5 to 3.5 hours. The compounds of formula V are desirably oduced in situ in conventional manner from the corresponding 3-phenyl-N-alkyl-5ithyl-isoxazole-4-carboxamide by reaction with, for example, a alkyl lithium, irticularly n-butyllithium under the conditions, for example, of the subsequent ;ep for producing compounds IV.
The resulting compounds of formula IV may be isolated and purified ;ing conventional techniques. - 6 4390? The compounds of formula VI and the necessary starting materials for producing compounds of formula V are either known or may be produced in conventional manner from available materials.
The compounds of formulae III and IV are disclosed and claimed in our Patent Specification No. 43908 and 43909.
The compounds of formula I possess pharmacological activity. In particular, they possess sleep inducing and minor tranquillising activity as indicated 1) by tne hexobarbital reinduction method of Winter, J. Pharmacol, and Exp. Therap. 94 7-11, (1948); 2) 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 30-word adjective check sheet system basically as described by Irwin S. (Gordon Research Conference, Medicinal Chemistry, 1959) and Chen /"Symposium on Sedative and Hypnotic Drugs, Williams and Wilkins, (1954J7; 3) by their ability to antagonize chlonic convulsions and death in mice given about 35 mg/kg of the test compound followed immediately by 45 to 250 mg/kg, i.p., of N-sulfamoylazepine; and 4) by scoring for loss of righting reflex according to the method of Reed-Muench /."American Journal of Hygiene 27, 493-497, (1938J7. in which mice are administered 12.5 mg/kg, i.p., of Thoridazine, 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 of body weight. Sixty minutes after dosing, the mice are scored for loss of righting reflex; and 5) by their ability to reduce conflicts as defined in the Geller Conflict Test /"Irving Geller, Psychopharmacologia, I, 42-492 (1960)7· The compounds of formula I are therefore indicated for use as sleep inducers and minor tranquillisers. For the sleep-inducing indication, an indicated suitable daily dosage is from 35 to 1000 mg, which may be administered in divided doses of from about 3 to 500 mg, two to four times daily, but which is preferably administered as a single dose at bed-time. For the minor tranquillising activity, an indicated suitable daily dosage is from 30 to 1500 mg, suitably administered in divided dosages of from 7.5 to 750 mg, two to four times daily, or in retard form. - 7 4 3 9 Ο 7 The compounds may be administered in free hydroxy form or in the form if pharmacologically acceptable base salts, which salt forms have the same order of ictivity as the free forms. Suitable salt forms include alkali metal forms, in larticular lithium, sodium and potassium salt forms, and alkaline earth metal forms, n particular magnesium or calcium salt forms.
The compounds may be admixed with conventional pharmaceutically icceptable diluents and carriers, and, optionally, other excipients, and administered n such forms as hard-filled capsules and tablets.
The preferred compounds of formula I are those in which R-| to R^ have he following significances:= hydrogen, chlorine, fluorine, trifluoromethyl, methyl or methoxy, particularly hydrogen or chlorine, more particularly hydrogen; :2 = hydrogen; = hydrogen, chlorine, fluorine, trifluoromethyl, methyl, or methoxy, particularly hydrogen, chlorine, trifluoromethyl, methyl or methoxy; 3 = methyl.
More preferred compounds are those having a combination of the above referred significances.
The following Example 2 illustrates the invention. Example 1 is ncluded as a description of the procedure employed in Example 2. The compound of xample 1 is disclosed and claimed in our Patent Specification No. 43908 and 43909.
EXAMPLE 1. 3-(alpha-Iminobenzyl)-4-hydroxy-6-phenyl-l-methyl-2(lH)-pyridone . ) .3-Phenyl-5-(beta-hydroxyphenethyl)-N-methylisoxazole-4-carboxamide /"compound IV7 A suspension of 75 g (0.348 mole) of 3-pheny1-5,N-dimethyT-1soxazole' -carboxamide and 1 liter of tetrahydrofuran is cooled to -65°C and 478 ml of 1.6M -butyllithium in hexane (0.755 mole) is added, dropwise, maintaining the temperature etween -60° and -70°C. After the addition is complete» the orange suspension is - 8 4 3 9 0 7 stirred for 1J hours at -50° to -70°C, and then 37.2 g (0.350 mole) of benzaldehyde in 375 ml of tetrahydrofuran is added, dropwise, maintaining the temperature between -60° and -70°C. After addition is complete, the mixture is stirred for 1| hours at -60° to -70°C and then warmed to -30°C and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo. The solid residue is triturated with a 50:50 mixture of ether/petroleum ether, filtered and washed with cold ether to give the heading compound, m.p. 183°-184°C. b) N-Methy1-5-phenacyl-3-phenylisoxazole-4-carbo'xamide Γcompound III? A suspension of 50 g (0,155 mole) of 3-phenyl-5-(beta-hydroxyphenethyl)N-methyl-isoxazole-4-carboxamide and 800 ml of acetic acid, at room temperature, is treated, dropwise, with 18.4 g (0.185 mole) of chromium trioxide in 185 ml of water. The resulting solution is stirred for 2 hours at room temperature and a portion of the acetic acid is removed in vacuo. The remainder is poured onto ice water and extracted with methylene chloride. The methylene chloride layer is washed with 2N sodium hydroxide, dried over anhydrous magnesium sulphate, filtered and eveporated in vacuo. The solid residue is triturated with hot ether, cooled to 0°C and filtered to give the heading compound, m.p. 125°-128°C. c) 5-Methyl-3,6-diphenyl-isoxazoloZ?4,5-c?pyridin-4(5H)-one /compound If? A mixture of 26.1 g (0.0815 mole) of N-methyl-5-phenacyl-3-phenylisoxazole-4-carboxamide and 261 ml of 2M sulphuric acid is refluxed for 24 hours.
The mixture is cooled and extracted with methylene chloride. The methylene chloride layer is washed with water and then brine, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The residue is triturated with ether and then recrystallised from ethanol to give the heading compound, m.p. 149-151.5°C. d) 3-(alpha-Iminobenzyl)-4-hydroxy-6-phenyl-l-methyl-2(lH)-pyri done /compound I? A mixture of 16.5 g (0.0545 mole) of N-methyl-3,6-diphenyl-isoxazolo- 9 43907 ~4,5-c7pyridin-4(5H)-one, 330 ml of ethanol and 1,65 g of 10# palladium on arbon is hydrogenated at 50 p.s.i, and room temperature,. The hydrogenation is aased after 1 equivalent of hydrogen is absorbed (ca. 2.5 hours). The mixture is reated with methylene chloride and the catalyst is removed by filtration. The olvents are removed in vacuo to a volume of ca. 50 ml and then ether is added to recipitate solids which are removed by filtration to give the heading compound, .ρ. 238°-240°C. The above compound is dissolved in methanol and treated with odium hydroxide solution-to yield after evaporation the sodium salt of 3-(alphaninoben2yl)-4-hydroxy-6-phenyl-l-methyl-2(lH)-pyridone.
EXAMPLE 2. in nanner analogous-to Example 1, and employing appropriate starting aterials in approximately equivalent amounts, the compounds of formula IV, III, I and Ij in which Rp Rg, Rg and R4 have the significances indicated in the allowing Table,, may be obtained. omber Rl r2 r3 r4 Melting Point °C IV III II I a) JO-CI HCH3- H b) jo-F H ch3 H 177-178 153-158 162-164 . -196.5-198.5 c) £-CH3 . H . ch3 H 182-183. E 154.5-155.5 236-237.5 d) p-CH3O H ch3 H e) m-CF3. H- . ch3 . H H .. H - .ch3 jo-Cl 167-170 151-161 167-173 221-223 3) H H ch3_ 2-F h) H H ch3 jo-CH3 148-150 155-156 238-240 i) H H ch3 2-CH30 143-145 119-131 149-150 222-225 j) H H ch3 m-CF3 149-151 132-143. 122-126 177-178,5 k) H H ch3 0-CH3 176-177 150-151.5 115.5-117 221.5-223 1) H 3C1 ch3 . 4-C1 m) £-Cl H ch3 £-Cl
Claims (9)
1. A process for the production of a compound of formula in which Rp Rg and Rp which may be the same or different, each signifies hydrogen, fluorine, chlorine, tri fluoromethyl or alkyl or alkoxy of 1 to 4 carbon atoms, and R 3 is alkyl of 1 to 4 carbon atoms, provided that when Rp Rg, and R^ are each hydrogen, then Rg is other than methyl characterised by reducing a compound of formula II, in which Rp Rg, Rg and R^ are as defined above, in an inert organic solvent.
2. A process as claimed in Claim 1, substantially as herein described with reference to Example 2. 15. 3A compound of formula I, stated in Claim 1, whenever produced by a process according to Claim 1 or 2. - 11 43807 A compound of formula I, stated in Claim 1. . A compound according to Claim 3, in which Rg is hydrogen. . A compound according to Claim 4, in which Rg is hydrogen. . A compound according to any one of Claims 3 to 6, in which R-j is ydrogen, fluorine, chlorine, trifluoromethyl, methyl or methoxy. A compound'according to Claim 7, in which R 1 is hydrogen or chlorine. A compound according to Claim 8, in which R-j is hydrogen. 0A compound according to any one of Claims 3 to 9, in which Rg is methyl, 1A compound according to any one of Claims 3 to 10, in which R^ is ydrogen, fluorine, chlorine, trifluoromethyl, jnethyl or methoxy. 2A compound according to Claim 11, in which R^ is hydrogen, chlorine, rifluoromethyl, methyl or methoxy.
3. A compound of formula I, stated in Claim 1, in which Rg and R^ are ach hydrogen, Rg is methyl and R^ is p-chloro.
4. A compound of formula I, stated in Claim 1, in which Rg and R^ are ach hydrogen, Rg is methyl and R-j is jj-fluoro.
5. A compound of formula I, stated in Claim 1, in which Rg and R^ are ach hydrogen, Rg is methyl and R^ is £-methyl.
6. A compound of formula I, stated in Claim 1, in which Rg and R^ are ach hydrogen, Rg is methyl and R 1 is p.-methoxy.
7. A.compound of formula I, stated in Claim 1, in which Rg and R^ are ach hydrogen, Rg is methyl and R^ is m-trifluoromethyl.
8. A compound of formula I» stated inClaim.1, in which R^ and Rg are ach hydrogen, Rg is methyl and R^ is £-chloro.
9. A compound of formula I, stated in Claim 1, in which R^ and Rg are ach hydrogen, Rg is methyl and R^ is p-fluoro, 0A compound of formula I, stated in Claim 1, in which R-j and Rg are ach hydrogen, Rg is methyl and R^ is £-methyl. 1A compound of formula I, stated in Claim 1, in which R-| and Rg are ach hydrogen, Rg is methyl and R^ is £-methoxy. - 12 4 S S 0 7 22. A compound of formula I, stated in Claim 1, in which R-j and Rg are each hydrogen, Rg is methyl and R^ is m-trifluoromethyl. 23. A compound of formula I, stated in Claim 1, in which R-j and Rg are each hydrogen, Rg is methyl and R^ is o-methyl. 24. A compound of formula I, stated in Claim 1, in which R-j is hydrogen, Rg is methyl, Rg is 3-chloro and Ris 4-chloro. 25. A compound of formula I, stated in Claim 1, in which R-j is p-chloro, k 0 is hydrogen, R, is methyl and % is p-chloro. 26. A compound according to any one of Claims 3 to 25, in free hydroxy form. 27. A compound according to any one of Claims 3 to 25, in the form of a base salt. 28. A compound according to Claim 27, in the form of an alkali or alkaline earth metal salt. 29. A pharmaceutical composition comprising a compound according to any one of Claims 3 to 25, in free hydroxy form, or in the form of a pharmaceutically acceptable base salt, in association with a pharmaceutically acceptable diluent or carrier.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE369/81A IE43909B1 (en) | 1975-03-14 | 1976-03-12 | N-alkyl-3-phenylisoxazole-4-carboxamide derivatives |
IE368/81A IE43908B1 (en) | 1975-03-14 | 1976-03-12 | 3-(alpha-iminobenzyl)-4-hydroxy-6-phenyl-1 methyl-2(1h)-pyridone |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US55841975A | 1975-03-14 | 1975-03-14 | |
US58476475A | 1975-06-09 | 1975-06-09 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE43907L IE43907L (en) | 1976-09-14 |
IE43907B1 true IE43907B1 (en) | 1981-07-01 |
Family
ID=27071738
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE528/76A IE43907B1 (en) | 1975-03-14 | 1976-03-12 | 3-(alpha-iminobenzyl)-4-hydroxy-2(1h)-pyridone derivatives |
Country Status (21)
Country | Link |
---|---|
JP (1) | JPS51113877A (en) |
AT (1) | AT358590B (en) |
AU (1) | AU505460B2 (en) |
CA (1) | CA1064038A (en) |
CH (1) | CH601241A5 (en) |
DE (1) | DE2609127A1 (en) |
DK (1) | DK98176A (en) |
ES (1) | ES446035A1 (en) |
FI (1) | FI760572A (en) |
FR (2) | FR2303545A1 (en) |
GB (3) | GB1545577A (en) |
HK (2) | HK46581A (en) |
IE (1) | IE43907B1 (en) |
IL (1) | IL49202A (en) |
MY (2) | MY8200141A (en) |
NL (1) | NL7602494A (en) |
NO (1) | NO760764L (en) |
NZ (1) | NZ180299A (en) |
PT (1) | PT64899B (en) |
SE (1) | SE7602542L (en) |
YU (1) | YU63676A (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4179566A (en) * | 1975-08-06 | 1979-12-18 | Sandoz, Inc. | Substituted hydroxy pyridones |
US4238616A (en) * | 1977-01-19 | 1980-12-09 | Sandoz, Inc. | 3-(Substituted)phenyl-5-(β-hydroxyphenethyl)-N-(alkyl)-isoxazole-4-carboxamides |
CA2451057A1 (en) | 2001-06-14 | 2002-12-27 | Banyu Pharmaceutical Co., Ltd. | Novel isoxazolopyridone derivatives and use thereof |
GB0119911D0 (en) * | 2001-08-15 | 2001-10-10 | Novartis Ag | Organic Compounds |
-
1976
- 1976-02-26 SE SE7602542A patent/SE7602542L/en not_active Application Discontinuation
- 1976-03-02 CH CH255876A patent/CH601241A5/xx not_active IP Right Cessation
- 1976-03-05 FI FI760572A patent/FI760572A/fi not_active Application Discontinuation
- 1976-03-05 NO NO760764A patent/NO760764L/no unknown
- 1976-03-05 DE DE19762609127 patent/DE2609127A1/en not_active Withdrawn
- 1976-03-05 DK DK98176*#A patent/DK98176A/en unknown
- 1976-03-09 GB GB38668/78A patent/GB1545577A/en not_active Expired
- 1976-03-09 GB GB9317/76A patent/GB1545575A/en not_active Expired
- 1976-03-09 GB GB38667/78A patent/GB1545576A/en not_active Expired
- 1976-03-10 NL NL7602494A patent/NL7602494A/en not_active Application Discontinuation
- 1976-03-10 FR FR7606827A patent/FR2303545A1/en active Granted
- 1976-03-11 YU YU00636/76A patent/YU63676A/en unknown
- 1976-03-12 AT AT181576A patent/AT358590B/en not_active IP Right Cessation
- 1976-03-12 JP JP51026228A patent/JPS51113877A/en active Pending
- 1976-03-12 ES ES446035A patent/ES446035A1/en not_active Expired
- 1976-03-12 IE IE528/76A patent/IE43907B1/en unknown
- 1976-03-12 PT PT64899A patent/PT64899B/en unknown
- 1976-03-12 NZ NZ180299A patent/NZ180299A/en unknown
- 1976-03-12 IL IL49202A patent/IL49202A/en unknown
- 1976-03-12 CA CA247,763A patent/CA1064038A/en not_active Expired
- 1976-03-15 AU AU12012/76A patent/AU505460B2/en not_active Ceased
- 1976-11-30 FR FR7636022A patent/FR2371435A1/en active Granted
-
1981
- 1981-09-17 HK HK465/81A patent/HK46581A/en unknown
- 1981-09-17 HK HK466/81A patent/HK46681A/en unknown
-
1982
- 1982-12-30 MY MY141/82A patent/MY8200141A/en unknown
- 1982-12-30 MY MY142/82A patent/MY8200142A/en unknown
Also Published As
Publication number | Publication date |
---|---|
PT64899A (en) | 1976-04-01 |
HK46681A (en) | 1981-09-25 |
FR2371435A1 (en) | 1978-06-16 |
HK46581A (en) | 1981-09-25 |
FR2303545A1 (en) | 1976-10-08 |
SE7602542L (en) | 1976-09-15 |
YU63676A (en) | 1982-02-28 |
DK98176A (en) | 1976-09-15 |
NL7602494A (en) | 1976-09-16 |
CA1064038A (en) | 1979-10-09 |
GB1545575A (en) | 1979-05-10 |
JPS51113877A (en) | 1976-10-07 |
NZ180299A (en) | 1978-07-28 |
AT358590B (en) | 1980-09-25 |
MY8200141A (en) | 1982-12-31 |
AU1201276A (en) | 1977-09-22 |
GB1545577A (en) | 1979-05-10 |
PT64899B (en) | 1977-08-18 |
FR2371435B1 (en) | 1980-03-07 |
NO760764L (en) | 1976-09-15 |
IL49202A0 (en) | 1976-05-31 |
FI760572A (en) | 1976-09-15 |
IL49202A (en) | 1979-09-30 |
ES446035A1 (en) | 1977-09-16 |
ATA181576A (en) | 1980-02-15 |
FR2303545B1 (en) | 1982-03-19 |
DE2609127A1 (en) | 1976-09-23 |
CH601241A5 (en) | 1978-06-30 |
GB1545576A (en) | 1979-05-10 |
IE43907L (en) | 1976-09-14 |
AU505460B2 (en) | 1979-11-22 |
MY8200142A (en) | 1982-12-31 |
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