CA1064935A - Production of 3-iminoalkyl-1(1h)-pyridines - Google Patents
Production of 3-iminoalkyl-1(1h)-pyridinesInfo
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- CA1064935A CA1064935A CA258,375A CA258375A CA1064935A CA 1064935 A CA1064935 A CA 1064935A CA 258375 A CA258375 A CA 258375A CA 1064935 A CA1064935 A CA 1064935A
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- 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
-
- 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
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- 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
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
3-IMINOALKYL-2-(1H)-PYRIDINES
Abstract of the Disclosure This invention relates to compounds of formula I, I
in which R1 is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 caxbon atoms, R2 is hydrogen, fluorine, chlorine, or alkyl or alkoxy of 1 to 4 carbon atoms, and R3 is straight chain alkyl of 1 to 4 car-bon atoms, which are obtained by reduction of compounds of formula II
II
in which R1, R2 and R3 are as defined above.
The compounds of formula I, and their acid and base addition salt forms, are useful as sleep inducers, minor tranquillisers and neuroleptic agents.
Abstract of the Disclosure This invention relates to compounds of formula I, I
in which R1 is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 caxbon atoms, R2 is hydrogen, fluorine, chlorine, or alkyl or alkoxy of 1 to 4 carbon atoms, and R3 is straight chain alkyl of 1 to 4 car-bon atoms, which are obtained by reduction of compounds of formula II
II
in which R1, R2 and R3 are as defined above.
The compounds of formula I, and their acid and base addition salt forms, are useful as sleep inducers, minor tranquillisers and neuroleptic agents.
Description
. Case 600-6714 10~4~3$ CAN~D~
IMP~O~7~M~NTS IN OR ~.ELATING TO ~RG~IC COMPOUNDS
This invention relates to 3-iminoalkyl-2(1 pyridines.
More particularlv, this invention provides compounds of formula I, HO ~
~r in which Rl is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atom.s, R2 i5 hydrogen, fluorine, chlorine, or alkyl or alkoxy of 1 to 4 carbon atoms, and R3 is straight chain alkyl of 1 to 4 car-bon atoms.
The compounds of formula I may exist in tautomeric forms of formulae Ia, Ib and Ic, ~ N~.-.R3 ~3R2 ~3R2 Ia Ib ,~ ~
,, - ~ .- , . . .
~t~ 3~ 6~0-6714 l ~H
H~l ~ N-~3 ~,~
~R2 Ic in which R~, R2 and R3 are as defined above.
While reference is made hereinafter only to the form of formula I, or the corresponding chemical name, it is : to be understood that the invention is not intended to S be limited to any particular form of the compounds.
The invention also provides a process for the production of compounds of formula I, characterlsed bY
reducing a compound of formula II, ~2 II
ln which Rl, R2 and R3 are as de~ined a~,ov~.
The reduction is suitably efected by cat:alytic hydrogenation and ln an inert organic solvent. Suitable catalysts include palladium on carbon, platinum oxide ~nd Raney ni.ckel and suitable golvents include lower alk~nols,
IMP~O~7~M~NTS IN OR ~.ELATING TO ~RG~IC COMPOUNDS
This invention relates to 3-iminoalkyl-2(1 pyridines.
More particularlv, this invention provides compounds of formula I, HO ~
~r in which Rl is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atom.s, R2 i5 hydrogen, fluorine, chlorine, or alkyl or alkoxy of 1 to 4 carbon atoms, and R3 is straight chain alkyl of 1 to 4 car-bon atoms.
The compounds of formula I may exist in tautomeric forms of formulae Ia, Ib and Ic, ~ N~.-.R3 ~3R2 ~3R2 Ia Ib ,~ ~
,, - ~ .- , . . .
~t~ 3~ 6~0-6714 l ~H
H~l ~ N-~3 ~,~
~R2 Ic in which R~, R2 and R3 are as defined above.
While reference is made hereinafter only to the form of formula I, or the corresponding chemical name, it is : to be understood that the invention is not intended to S be limited to any particular form of the compounds.
The invention also provides a process for the production of compounds of formula I, characterlsed bY
reducing a compound of formula II, ~2 II
ln which Rl, R2 and R3 are as de~ined a~,ov~.
The reduction is suitably efected by cat:alytic hydrogenation and ln an inert organic solvent. Suitable catalysts include palladium on carbon, platinum oxide ~nd Raney ni.ckel and suitable golvents include lower alk~nols,
- 2 -CANADA
60~-671 93~
- such as methanol or, preferably, ethanol. The reaction temperature is suitabl~ from 10 to 50C, preferably 20 to 30C, and the reaction time may vary, for example from 1 to lO, more usually 2 to 3 r hours.
The resulting compounds of formula I may be isolated and purified using conventional techniques.
Where requiredl non salt forms of the compounds may be converted into acid or base addition salt forms in con-ventional manner, and vice versa.
The compounds of formula II may be produced in accordance with the following reactlon scheme:-CANADA
169~g35 600-6714 .~C-NH-R
N ~11~ Step a)_ . . ~ II
CH -C~ cyclisation III
~xidation . . Step b~
Li~3 ~_~C-~H-R R~ ~1~3 CH2-CH Inert or: nnic ~LiG) 0~/~R2 OH~ R2 801vent IV V V~
Step d) Inext ox~anic Solvent R~C--~dH- R3 ` VII VIII
Rl, R2 and R3 being as defined above, and R4 signi~ying ~lkyl Or l to 4 carbon atoms.
C~N~Dp~
6~0-6714 ~;4~3S
~ The cyclisation in step a) i9 suitahly effected with an acid, e.y. hydrochloric, ~-toluenesulphonic, poly-phosphoric or, preerably sulphuric acid and in an inert organic solvent, such as an aromatic hydrocarbon, e.g.
benzene or toluene, or, alternatively and preferably, employing an excess of the acid to provide a reaction medium. The reaction temperature is suitably from 80 to 150C, preferably the reflux temperature of the reaction medium, and the reaction time may vary, for example from 12 to 36 hours, more usually 20 to 36 hours.
The oxidation in step b) ls suitably effected with pota.ssium permanganate or, preferably, chromlum trioxide,under ~cid conditions, provided for example by sulphuric, hyclr~chloric or, preferably, acetic acid, and in the pre~ence of ~ater. The reaction temperature is suitably from 10 to 50C, preerably 20 to 30C
and the reaction time may vary, for example from 1 to 5, more usually 1.5 to 2.5 hours.
Suitable solvents for use in s~ep c) include e~hers, ~uch a~ diethyl ~ther or tetxahydrouran, and aliphatic hydrocarbons, such as hexane, pentane or heptane, preferably tetrahydrofuran. The reaction temp-erature may, for example, be from 75 to -55C, prefer-CANADA
1~6~3~ 600-6714 - ably -65 to -60C, and the. reaction time may vary, for example from 1 to 5, more usuall~ 2.5 to 3.5 hours.
Step d) is suitably effected in the same sol-vents as described above for step c), hexane heing preferre~, however, and under the same conditions as for step c).
. The resulting compounds of formulae II, III, IV and V may be isolated and purified using conventional ~ techniques Where required, non salt forms of the : 10 compounds of formula II, III and IV may be converted into acid or base addition salt forms in conventlonal manner, or vice versa.
The compounds of formula VI, VII and VIII are eithar known ox may be produced in conventional manner rom available materials The co~pounds of formula I possess pharmacol-~: ~ :; ogical aativity. In particular, they possess sleep-lnducing, minor tranquillising and neuroleptic activity, as indicated 1) by the hexobarbital reinduction methofl o Winter, J~ Pharmacol. and Exp Therap. 94, 7~ 1948), in which the re-inductlon o anaesthe~ia is used to determine sedative-hypnotic activity in ~ice given 70 mg/kg o~ animal hody weight i.p. o~ hexobarbital followed CANADA
immediately after the mice regain their righting reflexes by 4 to 200 mg/kg of animal hody weight i.p. of the test compound; 2) by their ability to ~roduce docility in behaviour tests in mice given 20 to 200 mg/kg of animal body weight, i.p. of the test compound, according to the 30~word adjective check sheet system baslcally a.s described by Irwin S. (Gordon Research Conference, Medicinal Chemistry, 1959) and Chen (Sympo~ium on Sedative and Hypnotic Drugs, l~illiams and Wilkins, 1954); 3) by their ability to antagonise chronic convulsions and death in m~ce given about 35 to 250 mg/kg of the test compound followed immediately by 50 mg!kg i.p. of N-sulfamoylazepine; 4).by the apomorphlne gnawing test basically as described by the meth~d of Ern~t ~Psychopharmacologica 10, 316 to 323 (1967)] in which male Wistar rats weighing 90 to 110 g are glven 17.3 mg/kg p.o. of the test compound followed 30 minutes latsr by 10 mg/kg i.p. of a~omorphine. It is well ~no~n that gnawing ls induced by apomor~h~ne and ~he test compound is said to have neuroleptic activity if it reduce~ the gnawing actlvity in rats; and 5) by the rat conditloned avoidance .response methodolog~ of L. Cook and C. Cantania, Effects of Drugs on Avoidance and Escape B~haviour, Federation Proceedings 23, 818-825, (1964) CAr~lADA
in which rats are administered orally 22.0 mg/kg o the test compound. After administration, if tlle com-pound blocks the avoidance response, said compound is said to be a neuroleptic agent.
The compounds are therefore indicated fox use as sleep-lnducers, minor tranquillisers and neurolep~ic agents. An indicated suitable daily dosage is, for sleep-inducing use, from 15 to 750 mg, suitably admini-stered as a single dose at bed-time, for minor tranquil-liser use from 10 to 1000 mg, conveniently administered in divided doses of from 2.5 to 500 mg, two to four times daily, or in retard form, and for neuroleptic use from 1 to looO mg, conveniently adm.inistered in divided doses of from 0.25 to 500 mg, t~ro to four tim~s ~ally, or in retard form.
The compounds may be admixed with conventional pharmaceutically accepta~le diluents or carriers, and, .
optionally, other excipients, and administered in such forms as tablets or capsules.
The compounds may be administered in non ~alt form or ln the orm ~ pharmaceutical].y acceptab~.e acid or base addition salts, ~hich salt ~orms possess the same order of activity as the non-salt form~. Suit-CA~JAD~
~ 00-6714 able salt forms include mineral acid, such as hydro-chloric, hydrobromic or sulphuric aci~, salt forms ~nd alkali metal, such as sodium or potassium s~lt forms.
- Preferred compounds of Formula I are those in which R3 ~s methyl, especially those in which R3 is methyl and R1 1s ethyl. Particularly preferred is the compound of Formula I in ~hich Rl is ethyl, R2 is hydrogen and R3 ls methyl, that is, 3~ iminopropyl)-4-hydroxy-6-phenyl~
~ 1-methyl-2(lH~-pyridone.
~ The ollowing Examples illustrate the in~ention.
_ 9 , CANADA
~ 3S 600-6714 EX~MPLE 1: 3~ Iminopropyl)-4~hydroxv-6-phenvl-1-ethyl-2(1l-1)-pyridone a) 3-Ethyl-5-1~-hvdroxy~henethyl)-M-meth~l-isoxazole-,__ _~__ ___ ____ ______ _________ ___________ 4-carboxamide ~compound of formula IV~
______________ ___ _______,__________ A suspension of 58.5 g (0.348 mole) of 3-ethyl-N,5-dlmethyl-isoxazole-4-carboxamide in 1 litre of tetra-hydrofuran is aooled to -65C and 478 ml of 1.6~
n-butyllithium in hexane (0.765 mole) ;is added, dropwise while maintainina the temperature between -6~ and -70C.
~.f~er addition is com~lete, ~he suspension is stlrred for 1 1~2 hours at -60 to -70C, and then 37.2 g (0.350 mole) of benzaldehyde in 37~ ml tetrahydrofuran is added, dropwise, ~hile maintaini.ng the temperature between -60Q and -70C. ~ter additlon is complete, the mixture ls stirred for 1 1/2 hours at -60 to -70C
and then warmed to -30C and quenched ~y the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the l.ayers are sep,arated. ~he tetrahydrofuran layer is washed twice wlth 50~ brine, and once with brine, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo.
The solid residue is triturated ~Jith ether and filtered to give the heading compound, m.p. 135 to 137C.
CANADA
~,~35 600~6714 b) 3~EthYl-N-methyl-s-E~henacyl-4-isoxyzole carboxamide ~coml2ound of formula III) A solution of 29.0 g (0.105 mole) of 3-ethyl-5-~B-hydroxyphenethyl)-M-methyl-isoxazole-4-carboxamide ana 500 ml of acetic acid, at room temperature, is treated, dropwise, rapidly with 12.5 g (0.125 mole) of chromium trioxide in 125 ml of water. The resulting solution is stirred for 2 hours at room temperature and a portion of the acetic ac'id is removed in vacuo. The remainder is poured onto ice/water and extracted with methylene chloride. The methylene chloride la~er is washed ~ith 2N sodium hydroxide, dried over anhydrous magnesium sulphate, iltered and e,vaporated in vacuo.
The solid residue is triturated with ether and recrystal-lised from eth~nol to give the he~ding compound, m.p.
lS 13~ to 136C.
c) 3-Ethyl-S-methyl-6-~henyl-isoxazolo~4L5-c]~yridin 4~5H)~one ~com~ound of _ormula. II) A mixture of 11.0 ~ (0.0405 mole) of 3-ethyl-N-methyl-5-phenacyl-4-i~oxazole carbox~ e and 120 ~,1 of 2M sulphuric acid is refluxed i~r 18 hours. The ~ixture is cooled and extraated with methylene chloride. The methylene chloride layer is washed with water and then brine, dried over anhydrous magnesium sulphate, filtered ~o~35 CA~`!ADA
and evaporated in vacuo. The residue is tritur~ted with ether and filtered to give the heading compound, m.p.
167 to 169C, d) 3~ Imino~ro~yll-4-h~droxy-6-~henyl-1-methyl-2(1H)-__________ __ ______ ____ ___ ___ ________ _______ ~yridone ~com~ound of formula I) A mixture of 7.2 g (0.0314 mole) of 3-ethyl-5-me~hyl-6-phenyl-isoxazolor4,5-c]pyridin-4(5H)-one, 160 ml of ethanol and 0.800 g of 10% palladium on carbon i5 hydro~enated at S0 psi and room temperature. The h~dro-genation is c~ased after 1 equivalent of hydrogen isabsorbed (ca. 4 hours). The mixture is filtered to remove the catalyst and the solvent i9 removed 1n vacuo.
The residue is crystallised from ether to ~ive the heading compound, m~p. 145 to 147C.
lS E~AMPLES 2-9:
In manner analogous to Example 1 and employln~
appropriate starting materials in appxoximatel~ equival-ent amounts, the compounds of formulae I, II, III, IV and V/ in which Rl, R2 and R3 have the ~ic!ni~icances indicated in the following Table, may be obtained.
~CA~IADA
.. . ..
_ . . _ .
Ex. . R R Meltin~ r~oint (C) - Compound No. 1 2 3 I II I:II IV
. . _ ,......... .... _ 2 cyclohexyl i~ C~l3
60~-671 93~
- such as methanol or, preferably, ethanol. The reaction temperature is suitabl~ from 10 to 50C, preferably 20 to 30C, and the reaction time may vary, for example from 1 to lO, more usually 2 to 3 r hours.
The resulting compounds of formula I may be isolated and purified using conventional techniques.
Where requiredl non salt forms of the compounds may be converted into acid or base addition salt forms in con-ventional manner, and vice versa.
The compounds of formula II may be produced in accordance with the following reactlon scheme:-CANADA
169~g35 600-6714 .~C-NH-R
N ~11~ Step a)_ . . ~ II
CH -C~ cyclisation III
~xidation . . Step b~
Li~3 ~_~C-~H-R R~ ~1~3 CH2-CH Inert or: nnic ~LiG) 0~/~R2 OH~ R2 801vent IV V V~
Step d) Inext ox~anic Solvent R~C--~dH- R3 ` VII VIII
Rl, R2 and R3 being as defined above, and R4 signi~ying ~lkyl Or l to 4 carbon atoms.
C~N~Dp~
6~0-6714 ~;4~3S
~ The cyclisation in step a) i9 suitahly effected with an acid, e.y. hydrochloric, ~-toluenesulphonic, poly-phosphoric or, preerably sulphuric acid and in an inert organic solvent, such as an aromatic hydrocarbon, e.g.
benzene or toluene, or, alternatively and preferably, employing an excess of the acid to provide a reaction medium. The reaction temperature is suitably from 80 to 150C, preferably the reflux temperature of the reaction medium, and the reaction time may vary, for example from 12 to 36 hours, more usually 20 to 36 hours.
The oxidation in step b) ls suitably effected with pota.ssium permanganate or, preferably, chromlum trioxide,under ~cid conditions, provided for example by sulphuric, hyclr~chloric or, preferably, acetic acid, and in the pre~ence of ~ater. The reaction temperature is suitably from 10 to 50C, preerably 20 to 30C
and the reaction time may vary, for example from 1 to 5, more usually 1.5 to 2.5 hours.
Suitable solvents for use in s~ep c) include e~hers, ~uch a~ diethyl ~ther or tetxahydrouran, and aliphatic hydrocarbons, such as hexane, pentane or heptane, preferably tetrahydrofuran. The reaction temp-erature may, for example, be from 75 to -55C, prefer-CANADA
1~6~3~ 600-6714 - ably -65 to -60C, and the. reaction time may vary, for example from 1 to 5, more usuall~ 2.5 to 3.5 hours.
Step d) is suitably effected in the same sol-vents as described above for step c), hexane heing preferre~, however, and under the same conditions as for step c).
. The resulting compounds of formulae II, III, IV and V may be isolated and purified using conventional ~ techniques Where required, non salt forms of the : 10 compounds of formula II, III and IV may be converted into acid or base addition salt forms in conventlonal manner, or vice versa.
The compounds of formula VI, VII and VIII are eithar known ox may be produced in conventional manner rom available materials The co~pounds of formula I possess pharmacol-~: ~ :; ogical aativity. In particular, they possess sleep-lnducing, minor tranquillising and neuroleptic activity, as indicated 1) by the hexobarbital reinduction methofl o Winter, J~ Pharmacol. and Exp Therap. 94, 7~ 1948), in which the re-inductlon o anaesthe~ia is used to determine sedative-hypnotic activity in ~ice given 70 mg/kg o~ animal hody weight i.p. o~ hexobarbital followed CANADA
immediately after the mice regain their righting reflexes by 4 to 200 mg/kg of animal hody weight i.p. of the test compound; 2) by their ability to ~roduce docility in behaviour tests in mice given 20 to 200 mg/kg of animal body weight, i.p. of the test compound, according to the 30~word adjective check sheet system baslcally a.s described by Irwin S. (Gordon Research Conference, Medicinal Chemistry, 1959) and Chen (Sympo~ium on Sedative and Hypnotic Drugs, l~illiams and Wilkins, 1954); 3) by their ability to antagonise chronic convulsions and death in m~ce given about 35 to 250 mg/kg of the test compound followed immediately by 50 mg!kg i.p. of N-sulfamoylazepine; 4).by the apomorphlne gnawing test basically as described by the meth~d of Ern~t ~Psychopharmacologica 10, 316 to 323 (1967)] in which male Wistar rats weighing 90 to 110 g are glven 17.3 mg/kg p.o. of the test compound followed 30 minutes latsr by 10 mg/kg i.p. of a~omorphine. It is well ~no~n that gnawing ls induced by apomor~h~ne and ~he test compound is said to have neuroleptic activity if it reduce~ the gnawing actlvity in rats; and 5) by the rat conditloned avoidance .response methodolog~ of L. Cook and C. Cantania, Effects of Drugs on Avoidance and Escape B~haviour, Federation Proceedings 23, 818-825, (1964) CAr~lADA
in which rats are administered orally 22.0 mg/kg o the test compound. After administration, if tlle com-pound blocks the avoidance response, said compound is said to be a neuroleptic agent.
The compounds are therefore indicated fox use as sleep-lnducers, minor tranquillisers and neurolep~ic agents. An indicated suitable daily dosage is, for sleep-inducing use, from 15 to 750 mg, suitably admini-stered as a single dose at bed-time, for minor tranquil-liser use from 10 to 1000 mg, conveniently administered in divided doses of from 2.5 to 500 mg, two to four times daily, or in retard form, and for neuroleptic use from 1 to looO mg, conveniently adm.inistered in divided doses of from 0.25 to 500 mg, t~ro to four tim~s ~ally, or in retard form.
The compounds may be admixed with conventional pharmaceutically accepta~le diluents or carriers, and, .
optionally, other excipients, and administered in such forms as tablets or capsules.
The compounds may be administered in non ~alt form or ln the orm ~ pharmaceutical].y acceptab~.e acid or base addition salts, ~hich salt ~orms possess the same order of activity as the non-salt form~. Suit-CA~JAD~
~ 00-6714 able salt forms include mineral acid, such as hydro-chloric, hydrobromic or sulphuric aci~, salt forms ~nd alkali metal, such as sodium or potassium s~lt forms.
- Preferred compounds of Formula I are those in which R3 ~s methyl, especially those in which R3 is methyl and R1 1s ethyl. Particularly preferred is the compound of Formula I in ~hich Rl is ethyl, R2 is hydrogen and R3 ls methyl, that is, 3~ iminopropyl)-4-hydroxy-6-phenyl~
~ 1-methyl-2(lH~-pyridone.
~ The ollowing Examples illustrate the in~ention.
_ 9 , CANADA
~ 3S 600-6714 EX~MPLE 1: 3~ Iminopropyl)-4~hydroxv-6-phenvl-1-ethyl-2(1l-1)-pyridone a) 3-Ethyl-5-1~-hvdroxy~henethyl)-M-meth~l-isoxazole-,__ _~__ ___ ____ ______ _________ ___________ 4-carboxamide ~compound of formula IV~
______________ ___ _______,__________ A suspension of 58.5 g (0.348 mole) of 3-ethyl-N,5-dlmethyl-isoxazole-4-carboxamide in 1 litre of tetra-hydrofuran is aooled to -65C and 478 ml of 1.6~
n-butyllithium in hexane (0.765 mole) ;is added, dropwise while maintainina the temperature between -6~ and -70C.
~.f~er addition is com~lete, ~he suspension is stlrred for 1 1~2 hours at -60 to -70C, and then 37.2 g (0.350 mole) of benzaldehyde in 37~ ml tetrahydrofuran is added, dropwise, ~hile maintaini.ng the temperature between -60Q and -70C. ~ter additlon is complete, the mixture ls stirred for 1 1/2 hours at -60 to -70C
and then warmed to -30C and quenched ~y the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the l.ayers are sep,arated. ~he tetrahydrofuran layer is washed twice wlth 50~ brine, and once with brine, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo.
The solid residue is triturated ~Jith ether and filtered to give the heading compound, m.p. 135 to 137C.
CANADA
~,~35 600~6714 b) 3~EthYl-N-methyl-s-E~henacyl-4-isoxyzole carboxamide ~coml2ound of formula III) A solution of 29.0 g (0.105 mole) of 3-ethyl-5-~B-hydroxyphenethyl)-M-methyl-isoxazole-4-carboxamide ana 500 ml of acetic acid, at room temperature, is treated, dropwise, rapidly with 12.5 g (0.125 mole) of chromium trioxide in 125 ml of water. The resulting solution is stirred for 2 hours at room temperature and a portion of the acetic ac'id is removed in vacuo. The remainder is poured onto ice/water and extracted with methylene chloride. The methylene chloride la~er is washed ~ith 2N sodium hydroxide, dried over anhydrous magnesium sulphate, iltered and e,vaporated in vacuo.
The solid residue is triturated with ether and recrystal-lised from eth~nol to give the he~ding compound, m.p.
lS 13~ to 136C.
c) 3-Ethyl-S-methyl-6-~henyl-isoxazolo~4L5-c]~yridin 4~5H)~one ~com~ound of _ormula. II) A mixture of 11.0 ~ (0.0405 mole) of 3-ethyl-N-methyl-5-phenacyl-4-i~oxazole carbox~ e and 120 ~,1 of 2M sulphuric acid is refluxed i~r 18 hours. The ~ixture is cooled and extraated with methylene chloride. The methylene chloride layer is washed with water and then brine, dried over anhydrous magnesium sulphate, filtered ~o~35 CA~`!ADA
and evaporated in vacuo. The residue is tritur~ted with ether and filtered to give the heading compound, m.p.
167 to 169C, d) 3~ Imino~ro~yll-4-h~droxy-6-~henyl-1-methyl-2(1H)-__________ __ ______ ____ ___ ___ ________ _______ ~yridone ~com~ound of formula I) A mixture of 7.2 g (0.0314 mole) of 3-ethyl-5-me~hyl-6-phenyl-isoxazolor4,5-c]pyridin-4(5H)-one, 160 ml of ethanol and 0.800 g of 10% palladium on carbon i5 hydro~enated at S0 psi and room temperature. The h~dro-genation is c~ased after 1 equivalent of hydrogen isabsorbed (ca. 4 hours). The mixture is filtered to remove the catalyst and the solvent i9 removed 1n vacuo.
The residue is crystallised from ether to ~ive the heading compound, m~p. 145 to 147C.
lS E~AMPLES 2-9:
In manner analogous to Example 1 and employln~
appropriate starting materials in appxoximatel~ equival-ent amounts, the compounds of formulae I, II, III, IV and V/ in which Rl, R2 and R3 have the ~ic!ni~icances indicated in the following Table, may be obtained.
~CA~IADA
.. . ..
_ . . _ .
Ex. . R R Meltin~ r~oint (C) - Compound No. 1 2 3 I II I:II IV
. . _ ,......... .... _ 2 cyclohexyl i~ C~l3
- 3 C2H5 E~-Cl CH3
4 2 5 ~-F CH3188-189 2H5 ~-CH 3 - CH 3 6 C2H5 E~-CH30 CH3 7 C2H5 m-P OE13 ;
8 C2H5 o-F CH3121. 5-124 . . . . C2H5 O-CH 3 CH 3 . _
8 C2H5 o-F CH3121. 5-124 . . . . C2H5 O-CH 3 CH 3 . _
Claims (4)
1. A process for the Production of a compound of formula I, I
in which R1 is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R2 is hydrogen, fluorine, chlorine, or alkyl or alkoxy of 1 to 4 carbon atoms, and R3 is straight chain alkyl of 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof;
characterised by reducing a compound of formula II, II
in which R1, R2 and R3 are as defined above, and, where required, converting the resulting compound of formula I
into a pharmaceutically acceptable salt thereof.
in which R1 is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R2 is hydrogen, fluorine, chlorine, or alkyl or alkoxy of 1 to 4 carbon atoms, and R3 is straight chain alkyl of 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof;
characterised by reducing a compound of formula II, II
in which R1, R2 and R3 are as defined above, and, where required, converting the resulting compound of formula I
into a pharmaceutically acceptable salt thereof.
2. A process according to claim 1, in which the reduction is effected by catalytic hydrogenation at a temperature of from 10° to 50°C.
3. A process according to claim 1 or 2, in which, in the starting material of formula II, R1 is ethyl, R3 is methyl, and R2 is hydrogen.
4. A compound of formula I, I
in which R1 is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R2 is hydrogen, fluorine, chlorine or alkyl or alkoxy of 1 to 4 carbon atoms, and R3 is straight chain alkyl of 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof whenever produced by the process of claim 1 or an obvious chemical equivalent.
in which R1 is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R2 is hydrogen, fluorine, chlorine or alkyl or alkoxy of 1 to 4 carbon atoms, and R3 is straight chain alkyl of 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof whenever produced by the process of claim 1 or an obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60232475A | 1975-08-06 | 1975-08-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1064935A true CA1064935A (en) | 1979-10-23 |
Family
ID=24410893
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA258,375A Expired CA1064935A (en) | 1975-08-06 | 1976-08-04 | Production of 3-iminoalkyl-1(1h)-pyridines |
Country Status (16)
| Country | Link |
|---|---|
| AT (1) | ATA579476A (en) |
| AU (1) | AU507216B2 (en) |
| BE (1) | BE844882A (en) |
| CA (1) | CA1064935A (en) |
| CH (1) | CH626077A5 (en) |
| DE (1) | DE2633819A1 (en) |
| DK (1) | DK342876A (en) |
| ES (1) | ES450507A1 (en) |
| FI (1) | FI762152A (en) |
| FR (2) | FR2361886A1 (en) |
| GB (1) | GB1563336A (en) |
| IE (1) | IE43698B1 (en) |
| NO (1) | NO762643L (en) |
| NZ (1) | NZ181683A (en) |
| PH (1) | PH11844A (en) |
| ZA (1) | ZA764732B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2801190A1 (en) * | 1977-01-19 | 1978-07-20 | Sandoz Ag | 3- (ALPHA-IMINOBENZYL) -4-HYDROXY-2 (1H) - PYRIDONE DERIVATIVE |
-
1976
- 1976-07-26 CH CH952376A patent/CH626077A5/en not_active IP Right Cessation
- 1976-07-28 DE DE19762633819 patent/DE2633819A1/en not_active Withdrawn
- 1976-07-28 FI FI762152A patent/FI762152A/fi not_active Application Discontinuation
- 1976-07-29 DK DK342876A patent/DK342876A/en unknown
- 1976-07-29 NO NO762643A patent/NO762643L/no unknown
- 1976-08-04 PH PH18753A patent/PH11844A/en unknown
- 1976-08-04 CA CA258,375A patent/CA1064935A/en not_active Expired
- 1976-08-04 BE BE169559A patent/BE844882A/en unknown
- 1976-08-04 IE IE1724/76A patent/IE43698B1/en unknown
- 1976-08-04 GB GB32459/76A patent/GB1563336A/en not_active Expired
- 1976-08-04 NZ NZ181683A patent/NZ181683A/en unknown
- 1976-08-05 ES ES450507A patent/ES450507A1/en not_active Expired
- 1976-08-05 AT AT0579476A patent/ATA579476A/en not_active Application Discontinuation
- 1976-08-05 AU AU16612/76A patent/AU507216B2/en not_active Ceased
- 1976-08-06 ZA ZA00764732A patent/ZA764732B/en unknown
- 1976-08-06 FR FR7624026A patent/FR2361886A1/en not_active Withdrawn
-
1977
- 1977-02-01 FR FR7702710A patent/FR2360585A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| BE844882A (en) | 1977-02-04 |
| IE43698B1 (en) | 1981-05-06 |
| FI762152A (en) | 1977-02-07 |
| NZ181683A (en) | 1979-01-11 |
| ES450507A1 (en) | 1977-12-16 |
| FR2360585A1 (en) | 1978-03-03 |
| AU1661276A (en) | 1978-02-09 |
| GB1563336A (en) | 1980-03-26 |
| DK342876A (en) | 1977-02-07 |
| ZA764732B (en) | 1978-03-29 |
| NO762643L (en) | 1977-02-08 |
| PH11844A (en) | 1978-07-21 |
| FR2361886A1 (en) | 1978-03-17 |
| ATA579476A (en) | 1981-06-15 |
| DE2633819A1 (en) | 1977-02-24 |
| CH626077A5 (en) | 1981-10-30 |
| AU507216B2 (en) | 1980-02-07 |
| IE43698L (en) | 1977-02-06 |
| FR2360585B1 (en) | 1980-02-15 |
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