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IE43907B1 - 3-(alpha-iminobenzyl)-4-hydroxy-2(1h)-pyridone derivatives - Google Patents

3-(alpha-iminobenzyl)-4-hydroxy-2(1h)-pyridone derivatives

Info

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
Application number
IE528/76A
Other versions
IE43907L (en
Original Assignee
Sandoz Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sandoz Ltd filed Critical Sandoz Ltd
Priority to IE368/81A priority Critical patent/IE43908B1/en
Priority to IE369/81A priority patent/IE43909B1/en
Publication of IE43907L publication Critical patent/IE43907L/en
Publication of IE43907B1 publication Critical patent/IE43907B1/en

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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.
IE528/76A 1975-03-14 1976-03-12 3-(alpha-iminobenzyl)-4-hydroxy-2(1h)-pyridone derivatives IE43907B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
IE368/81A IE43908B1 (en) 1975-03-14 1976-03-12 3-(alpha-iminobenzyl)-4-hydroxy-6-phenyl-1 methyl-2(1h)-pyridone
IE369/81A IE43909B1 (en) 1975-03-14 1976-03-12 N-alkyl-3-phenylisoxazole-4-carboxamide derivatives

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

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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) FI760572A7 (en)
FR (2) FR2303545A1 (en)
GB (3) GB1545577A (en)
HK (2) HK46681A (en)
IE (1) IE43907B1 (en)
IL (1) IL49202A (en)
MY (2) MY8200142A (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)

* Cited by examiner, † Cited by third party
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

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Publication number Publication date
GB1545577A (en) 1979-05-10
ATA181576A (en) 1980-02-15
FI760572A7 (en) 1976-09-15
DE2609127A1 (en) 1976-09-23
FR2303545B1 (en) 1982-03-19
YU63676A (en) 1982-02-28
FR2303545A1 (en) 1976-10-08
IL49202A (en) 1979-09-30
JPS51113877A (en) 1976-10-07
AU505460B2 (en) 1979-11-22
DK98176A (en) 1976-09-15
GB1545576A (en) 1979-05-10
HK46681A (en) 1981-09-25
GB1545575A (en) 1979-05-10
IL49202A0 (en) 1976-05-31
PT64899B (en) 1977-08-18
AU1201276A (en) 1977-09-22
NZ180299A (en) 1978-07-28
FR2371435B1 (en) 1980-03-07
NO760764L (en) 1976-09-15
ES446035A1 (en) 1977-09-16
SE7602542L (en) 1976-09-15
CA1064038A (en) 1979-10-09
IE43907L (en) 1976-09-14
MY8200142A (en) 1982-12-31
AT358590B (en) 1980-09-25
FR2371435A1 (en) 1978-06-16
HK46581A (en) 1981-09-25
PT64899A (en) 1976-04-01
NL7602494A (en) 1976-09-16
MY8200141A (en) 1982-12-31
CH601241A5 (en) 1978-06-30

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