CA1193602A - Pyrid-2-one derivatives, a process for their manufacture and pharmaceutical preparations containing them - Google Patents
Pyrid-2-one derivatives, a process for their manufacture and pharmaceutical preparations containing themInfo
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- CA1193602A CA1193602A CA000424485A CA424485A CA1193602A CA 1193602 A CA1193602 A CA 1193602A CA 000424485 A CA000424485 A CA 000424485A CA 424485 A CA424485 A CA 424485A CA 1193602 A CA1193602 A CA 1193602A
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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
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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
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- General Health & Medical Sciences (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Abstract of the disclosure:
New pyrid-2-one derivatives of the formula I
New pyrid-2-one derivatives of the formula I
Description
~36~
The invelltion r~lates to pyri~-2-one derivatives, a process for their manufacture, and pharmaceutical preparations ~hich con-tai~ Pyridone derivatives aild have an antiinfldrnm~o~y action.
Kno~1n antiinfla~natory agents especially those f~r treatin~ rheumatic diseases suEfer from the dis-advantage o-f consid~rable side effects which rnanifest tilem-selves, in a troublesome manner, in part;cular in the case of prolonged treatrnent. There ;s, therefore, a need for com-pounds having an ant1phlo~istic action which exhibit improved gastric acceptab;l;ty.
The invention relates to pyr;d 2-one der;vatives of the formula I, R ~ R1 (I) stereo;somers thereo-F and salts thereof with a phys;ologically acceptable acid or~ ;f R2 represents a carboxyl group~ with a base, ;n wllich formula ~ denotes hydrogen or alkyl having 1 to 6 carbon atoms, R2 denotes a ~CH-0, -COOR~ or ~C1l2~0-R5 group, R4 representing hydrogen~ alkyl havin~ 1 to 12 carhon atoms or ben~yl and R5 representin0 h)~drogen~ alkyl having 1 to 4 carbon atoms, alkanoyl ha~ g 1 to 9 carbon atoms, cyclo~
alkanoyl ha~.~ing 4 to 7 carbon 3~0ms~ alkoxycarbonyl ~,.
~3~
havintJ 2 to 5 carbon atomsr phenoxycarbonyl or a benzoyl ~roup which can carry one or two halogcl1, trifluoromethyl or all;yl or alkoxy substituents, each of which has 1 to 4 carbon atoms, and R3 represents 2-th;enyl~ 3-thienyl, tertO-butyl or a phenyl group which can carry one or two substituents denot;l1g halogen, trifluoromethyl or al~yl or alko~y, each of which has 1 ~o b, carbon atoms.
Pre-Ferred compounds of the formula I are those in which R1 represents methyi, ethyl or propyl and R2 denotes a -Cl-l=O, -COOCH3, ~COOC2H5~ ~COOH or -Cl~2~0-R5 group. In this connection R5 denotes hydroyen, a formyl, acetyl~ pro-panoyl, n-butanoyl, 2~2-d;methylpropanoyl, n-octanoyl, cyclo-propanoylr cyclobutanoyl, cyclopentanoyl or cyclohexanoyl group, or a rnethoxycarbonyl, ethoxycarbonyl or benzoyl group~
the latter bein~ either unsubstituted or being monosubsti-tuted by fluorine, chLorine, bromine, trifluoromethyl or methyl.
In addition to the 2-th;enyl, 3-thienyl and tert.-butyl groups, a suitable group for R3 ;s, in particular, thephenyl group which is either unsubst;tuted or carries one subst;tuent, fluorine, chlorine, brornine, trifluoromethyl', methyl and metho~y being preferred substituents~
Compounds of the formula I which should be singled out particularly are those in which R1 represents methyl or ethyl, in which R2 is ~CH=O, -COOCH3, ~COOC~Hs~ ~COOH or a -CH2-o-R5 ~roupr R5 denot;n~ hydrogen, acetyl, propanoyl, 2 rr,ethylpropanGyl or n-butanoyl, and ;n which R3 is 2~thienyl~
phenyl~ ~-fluorophenyl or tert~-butyl.
~3~
. ~, Compouncs of the formula I which are very particularly preferred are those in which R1 represents methyl and R2 represents a ~COOC~13, ~COOH or CH-~0~ yroup and R3 denotes
The invelltion r~lates to pyri~-2-one derivatives, a process for their manufacture, and pharmaceutical preparations ~hich con-tai~ Pyridone derivatives aild have an antiinfldrnm~o~y action.
Kno~1n antiinfla~natory agents especially those f~r treatin~ rheumatic diseases suEfer from the dis-advantage o-f consid~rable side effects which rnanifest tilem-selves, in a troublesome manner, in part;cular in the case of prolonged treatrnent. There ;s, therefore, a need for com-pounds having an ant1phlo~istic action which exhibit improved gastric acceptab;l;ty.
The invention relates to pyr;d 2-one der;vatives of the formula I, R ~ R1 (I) stereo;somers thereo-F and salts thereof with a phys;ologically acceptable acid or~ ;f R2 represents a carboxyl group~ with a base, ;n wllich formula ~ denotes hydrogen or alkyl having 1 to 6 carbon atoms, R2 denotes a ~CH-0, -COOR~ or ~C1l2~0-R5 group, R4 representing hydrogen~ alkyl havin~ 1 to 12 carhon atoms or ben~yl and R5 representin0 h)~drogen~ alkyl having 1 to 4 carbon atoms, alkanoyl ha~ g 1 to 9 carbon atoms, cyclo~
alkanoyl ha~.~ing 4 to 7 carbon 3~0ms~ alkoxycarbonyl ~,.
~3~
havintJ 2 to 5 carbon atomsr phenoxycarbonyl or a benzoyl ~roup which can carry one or two halogcl1, trifluoromethyl or all;yl or alkoxy substituents, each of which has 1 to 4 carbon atoms, and R3 represents 2-th;enyl~ 3-thienyl, tertO-butyl or a phenyl group which can carry one or two substituents denot;l1g halogen, trifluoromethyl or al~yl or alko~y, each of which has 1 ~o b, carbon atoms.
Pre-Ferred compounds of the formula I are those in which R1 represents methyi, ethyl or propyl and R2 denotes a -Cl-l=O, -COOCH3, ~COOC2H5~ ~COOH or -Cl~2~0-R5 group. In this connection R5 denotes hydroyen, a formyl, acetyl~ pro-panoyl, n-butanoyl, 2~2-d;methylpropanoyl, n-octanoyl, cyclo-propanoylr cyclobutanoyl, cyclopentanoyl or cyclohexanoyl group, or a rnethoxycarbonyl, ethoxycarbonyl or benzoyl group~
the latter bein~ either unsubstituted or being monosubsti-tuted by fluorine, chLorine, bromine, trifluoromethyl or methyl.
In addition to the 2-th;enyl, 3-thienyl and tert.-butyl groups, a suitable group for R3 ;s, in particular, thephenyl group which is either unsubst;tuted or carries one subst;tuent, fluorine, chlorine, brornine, trifluoromethyl', methyl and metho~y being preferred substituents~
Compounds of the formula I which should be singled out particularly are those in which R1 represents methyl or ethyl, in which R2 is ~CH=O, -COOCH3, ~COOC~Hs~ ~COOH or a -CH2-o-R5 ~roupr R5 denot;n~ hydrogen, acetyl, propanoyl, 2 rr,ethylpropanGyl or n-butanoyl, and ;n which R3 is 2~thienyl~
phenyl~ ~-fluorophenyl or tert~-butyl.
~3~
. ~, Compouncs of the formula I which are very particularly preferred are those in which R1 represents methyl and R2 represents a ~COOC~13, ~COOH or CH-~0~ yroup and R3 denotes
2~tl1ienyl~ above all phenyl or ~ fluorophenyl.
The compounds o~F the general ~formula (I) also display their essentia! propert;es in the form of the;r salts. Any physiologically acceptable acids are su;table -For the pre-paration o-f acîd addition salts~ These ac;ds ;ncludeO pre-ferentially~ the hydro~en hal;de ac;ds, such as, -for example, hydrochlor;c and hydrobromic acids, and also nitric acid and also phosphoric acid or sulfuric ac;d~ Preferred orgai1ic ac;ds are monoFunctional and biFunctional carboxylic ac;ds and hya'roxycarboxyl;c ac;ds~ such as, for example, acetic acia, maleic acid, oxalic acid, succinic acid~ fumaric acid, tartar;c acid, ci.ric aci~, sal;cylic ac;d, sorbic ac;d, lact;c ac;d and sulfonic acids, such as, for examplef p-toluenesulfon;c ac;d, methylsul-Fonic ac;d, phenylsulfon;c acid and 1,5 naphthalenedisulfon;c ac;d~ The salts of the compounds of the formula (I~ can be obta;ned ;n a simple manner by custornary methods of salt formation, for example by dissolvin~ a compound o-f the formula I ;n a su;table ;nert solvent and addin~ the acid, for example hydrochloric acid or n;tr;c acid, and can be ;solated in a kno~n manner, for exampie by filtration, and can, if appropriate~ be purified 2S by washing with~ or recrystall;zat;on frorn~ an inert or~anic solvent.
The salts of the compounds oF the formula I with physiolog;calLy acceptable bases are advantageously sod;urn~
potassium~ magnesium or calcium salts of those compounds ~3~
of the follnula I in which R2 denotes a carboxyl group~
The ;nvention also relates to a process -for the pre-paration of the compounds of- the formula I, which comprises reacting a compound o-f the formula II
~0 R3 (II) with a compound of the formula III
X -- ~ ~ R2 (III) h;ch forrnulae R1, R2 and R3 have the mean;ngs indicated above and X represents haLogen, alkylsulfonyloxy, substituted - 10 or unsubstituted phenylsulfonyloxy or the radical of a re~
active ester~ In particular, X denotes here chlorine, bro-mine, methylsulfonyloxy, phenylsulfonyloxyr 4-metl1ylphenyl-^
sulfonyloxy or 4~chlorophenylsulfonyloxy or the radical of a react;ve ester, such as trifluoroacetoxyr phenylcarbonyl-oxy or methoxycarbonyloxy.
The process accordir.g to the inven~iorl is carriedout between 30 and 150C, preferably between 40 and 1Z0C, in the presence of a base, in water or in an inert organic solvent, such as N~N dimetl1ylformamide, N,N-dimethyl acetamide~ d;rnetl1yl sulfoxide, aceton;trile~ N methyl ~--pyrrolidolle~ dioxaner tei:~al~ drorlJranf, ettlel~ /t Ill~?thyl~-2~
336~
pentanone, methanol, ethanol, isopropyl alcohol, propanol~
butanol~ pentanol, tert. butyl alcohol, methylglycol, d1-methylglycol, dimethyld;~lycol, methylbutyldt~lycol or poly~
ethylene glycols. In add;lion, it is also possible ~o use methylene chlor;de or an arornatic hydrocarbon~ such as benz-ene~ chlorobenzene, toluene or xylene and also mlxtures of t-he solvents mentioned aboveO
Examples of suitable bases are alkali metal or alkal;ne earth metal carbonates, bicarbonates, hydroxides~
alcoholates or hydrides, such as sodium carbonate, sodium b;carbonate, potass;um carbonate, sod;um hydrox;de, sodium methylate or sodium hydride~ It ;s also poss1ble to employ organic bases here, such as tr;ethylam;ne~ tr;butylamine, ethylmornholine pyridine~ dimethylalninopyridine or quinoline~
The reaction also takes place with good yields under conditions of a phase transfer reaction, by allo~ing the reactants to react with one another in one o~ the above sol-vents~ w;th vigorous stirring~ in the presence of a phase transfer catalyst and either a powdered alkal; metal hydrox-ide or a concentrated aqueous solution of an alkali metal hydrox;de, and within a temperature range between 20 and 150C.
Examples of sui~able phase transfer catalysts are tr;alkylbenzyiammon;uln or tetraalkylammonium halides~
hydroxides or bisul-fates, preferahly having up to 1? carbon atoms ;n the alkyl radical, or crown etl1ers~ such as 12 crown~
4, 15-crown-5, 18 crown-6 or diben~o-18~crowl1-6~
h compound of the formula I in whicl1 F~2 is a -Cl~2 o-R5 ~roup is advantageously prepared by reducing a compound o-f 36~
-- 7 ~
the formula T ;n which p~2 is a CoOR4 yroup, to give ~he ~CI-l20 group, which ;s then reacted with alkylating or acylating agents to g;ve the CH~-O-RS group. Examples of sui.able reduc;ng agents are lithium alum;num l1ydrider diisobutyl-aluminum hydride or sodiurn borohydride, whicli are employeclin an inert solvent at temperatures between O and ~0C~
The alkylation and acylation reactions are carried out in an inert solvent in the presence of a suil-able base and at temperatures between 10 and 1~0C.
The preparation of compounds of the form-lla I in which R2 is a CH-O group is advantageously effected by oxidizing cornpounds of the formula I in wl1ich R2 is a ~CH20H
group. Oxidizing agents which are suitable for this purpose are lead tetraacetate, chromium trioxide~ cl1rolnium~6 oxide bis-pyridine complex, manganese dioxide~ Ni203.3H20, dimethyl sulfoxide/tr;fluoroacetic anhydrider dimethyl sulfoxide/
oxalyl chloride, dirnethyl sulfoxide/cyclohexylcarbodiimide/
phosphoric ac;d, the pyridine/S03 complex or aluminum iso-propoxide in combination with a carbonyl compound, such as 4-methoxybenzaldehyde, 2-chlorobenzaldellyde, cinnamaldehyde or benzophenone. In addition to the solvents rnentioned abo~e for the reaction of the compound II w;th the compound IXI, glacial acetic acidr chloroform~ carbon tetrachloride and petroleum ether are also additionally used~ llowever, a cataly~ic oxidation with the aid of a catalyst containin~
a noble metal of the VIIIti- group, in particular platinum and/or palladiunlr is also possiblen The compounds of the formula II ~hich are reqlJired . --as intermediate products can be prepared ei~her in accordance
The compounds o~F the general ~formula (I) also display their essentia! propert;es in the form of the;r salts. Any physiologically acceptable acids are su;table -For the pre-paration o-f acîd addition salts~ These ac;ds ;ncludeO pre-ferentially~ the hydro~en hal;de ac;ds, such as, -for example, hydrochlor;c and hydrobromic acids, and also nitric acid and also phosphoric acid or sulfuric ac;d~ Preferred orgai1ic ac;ds are monoFunctional and biFunctional carboxylic ac;ds and hya'roxycarboxyl;c ac;ds~ such as, for example, acetic acia, maleic acid, oxalic acid, succinic acid~ fumaric acid, tartar;c acid, ci.ric aci~, sal;cylic ac;d, sorbic ac;d, lact;c ac;d and sulfonic acids, such as, for examplef p-toluenesulfon;c ac;d, methylsul-Fonic ac;d, phenylsulfon;c acid and 1,5 naphthalenedisulfon;c ac;d~ The salts of the compounds of the formula (I~ can be obta;ned ;n a simple manner by custornary methods of salt formation, for example by dissolvin~ a compound o-f the formula I ;n a su;table ;nert solvent and addin~ the acid, for example hydrochloric acid or n;tr;c acid, and can be ;solated in a kno~n manner, for exampie by filtration, and can, if appropriate~ be purified 2S by washing with~ or recrystall;zat;on frorn~ an inert or~anic solvent.
The salts of the compounds oF the formula I with physiolog;calLy acceptable bases are advantageously sod;urn~
potassium~ magnesium or calcium salts of those compounds ~3~
of the follnula I in which R2 denotes a carboxyl group~
The ;nvention also relates to a process -for the pre-paration of the compounds of- the formula I, which comprises reacting a compound o-f the formula II
~0 R3 (II) with a compound of the formula III
X -- ~ ~ R2 (III) h;ch forrnulae R1, R2 and R3 have the mean;ngs indicated above and X represents haLogen, alkylsulfonyloxy, substituted - 10 or unsubstituted phenylsulfonyloxy or the radical of a re~
active ester~ In particular, X denotes here chlorine, bro-mine, methylsulfonyloxy, phenylsulfonyloxyr 4-metl1ylphenyl-^
sulfonyloxy or 4~chlorophenylsulfonyloxy or the radical of a react;ve ester, such as trifluoroacetoxyr phenylcarbonyl-oxy or methoxycarbonyloxy.
The process accordir.g to the inven~iorl is carriedout between 30 and 150C, preferably between 40 and 1Z0C, in the presence of a base, in water or in an inert organic solvent, such as N~N dimetl1ylformamide, N,N-dimethyl acetamide~ d;rnetl1yl sulfoxide, aceton;trile~ N methyl ~--pyrrolidolle~ dioxaner tei:~al~ drorlJranf, ettlel~ /t Ill~?thyl~-2~
336~
pentanone, methanol, ethanol, isopropyl alcohol, propanol~
butanol~ pentanol, tert. butyl alcohol, methylglycol, d1-methylglycol, dimethyld;~lycol, methylbutyldt~lycol or poly~
ethylene glycols. In add;lion, it is also possible ~o use methylene chlor;de or an arornatic hydrocarbon~ such as benz-ene~ chlorobenzene, toluene or xylene and also mlxtures of t-he solvents mentioned aboveO
Examples of suitable bases are alkali metal or alkal;ne earth metal carbonates, bicarbonates, hydroxides~
alcoholates or hydrides, such as sodium carbonate, sodium b;carbonate, potass;um carbonate, sod;um hydrox;de, sodium methylate or sodium hydride~ It ;s also poss1ble to employ organic bases here, such as tr;ethylam;ne~ tr;butylamine, ethylmornholine pyridine~ dimethylalninopyridine or quinoline~
The reaction also takes place with good yields under conditions of a phase transfer reaction, by allo~ing the reactants to react with one another in one o~ the above sol-vents~ w;th vigorous stirring~ in the presence of a phase transfer catalyst and either a powdered alkal; metal hydrox-ide or a concentrated aqueous solution of an alkali metal hydrox;de, and within a temperature range between 20 and 150C.
Examples of sui~able phase transfer catalysts are tr;alkylbenzyiammon;uln or tetraalkylammonium halides~
hydroxides or bisul-fates, preferahly having up to 1? carbon atoms ;n the alkyl radical, or crown etl1ers~ such as 12 crown~
4, 15-crown-5, 18 crown-6 or diben~o-18~crowl1-6~
h compound of the formula I in whicl1 F~2 is a -Cl~2 o-R5 ~roup is advantageously prepared by reducing a compound o-f 36~
-- 7 ~
the formula T ;n which p~2 is a CoOR4 yroup, to give ~he ~CI-l20 group, which ;s then reacted with alkylating or acylating agents to g;ve the CH~-O-RS group. Examples of sui.able reduc;ng agents are lithium alum;num l1ydrider diisobutyl-aluminum hydride or sodiurn borohydride, whicli are employeclin an inert solvent at temperatures between O and ~0C~
The alkylation and acylation reactions are carried out in an inert solvent in the presence of a suil-able base and at temperatures between 10 and 1~0C.
The preparation of compounds of the form-lla I in which R2 is a CH-O group is advantageously effected by oxidizing cornpounds of the formula I in wl1ich R2 is a ~CH20H
group. Oxidizing agents which are suitable for this purpose are lead tetraacetate, chromium trioxide~ cl1rolnium~6 oxide bis-pyridine complex, manganese dioxide~ Ni203.3H20, dimethyl sulfoxide/tr;fluoroacetic anhydrider dimethyl sulfoxide/
oxalyl chloride, dirnethyl sulfoxide/cyclohexylcarbodiimide/
phosphoric ac;d, the pyridine/S03 complex or aluminum iso-propoxide in combination with a carbonyl compound, such as 4-methoxybenzaldehyde, 2-chlorobenzaldellyde, cinnamaldehyde or benzophenone. In addition to the solvents rnentioned abo~e for the reaction of the compound II w;th the compound IXI, glacial acetic acidr chloroform~ carbon tetrachloride and petroleum ether are also additionally used~ llowever, a cataly~ic oxidation with the aid of a catalyst containin~
a noble metal of the VIIIti- group, in particular platinum and/or palladiunlr is also possiblen The compounds of the formula II ~hich are reqlJired . --as intermediate products can be prepared ei~her in accordance
3~
~ith the process described by J. Thes;ng et al., Chem. Ber.
90, 7il (1957) or analo~ously to the instruct;ons giver, by F~ ~rohnke et al. in Chem. Ber. 103, 322 et sec1,. (1970).
However, it is particularly acivanta~eous to react a compound of the formula IV
R3 - C - Cl-13 (IV) o with an acrylic acid ester o-f the formula V
CHz - C~l - C - oR6 (V~
g to give a compound of the formula V
R3 - C - CH2 - Ci~2 - CH~ ~ C - oR6 (VI
g 11 wh;c1~ I,en cycli~ed by medns o~ arnmon;a to cj;ve a cori7pour,d of the formula VII
~ ' R3 1 (VII~
~ [
wh;ch is finally dehydrogenated to g;ve a compound of the 15 formula II. In the formulae ment;oned above, R3 has the mean;ngs ment;oned in cla;m 1 and R6 is an alkyl rad;cal having 1 to 6 carbon atolns.
The preparat;on of the compound VI froln the ketone IV and th~ acryl;c acid ester V is carriecl out at ternpera tures bet~Jeen 20 and 220C~ under alkaline cond;t;ons ;n an inert solvent~ It is also possible to dispense w1th the use oi solvents in this reaction and to carry out the reaction ~lithout a diluent. The base whicl1 is added to the react;on ~L~9~
_ 9 ~
mixture is preferably a pr;Mary amine, such as methylam;ne, ethylamine~ propylam;ne~ isopropylamine, butylam1ne, cyclo-hexylaln;ne or the ~ -N~alkylam;noprop;onate wl1;ch ;s formed ~rom the acryl;e ester and arn;ne usedO The rract;on 1s 5 earr;ed out ;n the presence of eatalyt;e amounts oF al1 aeid, sueh as benzo;c ac;d, phenylsulfon;c ac;d~ toluenesulfonie ae;d, salieylie ac;d~ acet;c ac;d or acryl;c ac;d~
The compound VI is then reac~ed with ammon1a in an inert solvent or w;thout a d;luent a1: a temperature between 10 100 and 250C, preFerably in an autoclave, to g;ve the eompound VII. The latter ;s then dehydrc)~enated usincJ a dehydrogena~;on eatalyst, such as pallad;um-on-charcoal~
to give the compound II.
The cenpoundc of the for!nula III which are used as 1S starting materials are known.
It can be seen from the formula I that the colnpounds aeeord;ng to the invention eonta1r at least one eenter of asymmetry in the ~-position in relat;on to the o~y~en atom, prov;ded that R1 does not denote hydrogen. The racema~es of the Formula I which can be obtained if raeemic eompounds of the formula III are used, can be resolved into the;r optieal ant;podes in a eustomary manner. Th~s compounds of the formula I in wh;ch R2 denotes COOH ean be trea~ed us;ng an optically active base. The optieal antipodes of 2~ compounds of the formula I are obtained in an advantageous manner if the startil1g mater;als of the formula IJX are already optically active.
~ y v;rtue of the phar!nacological tests wh;ch follow and the results obtait1ed tr,ere;n, the eompounds accordi~
1~33~
~ 10 -to the ;nvention can be c!esignated suhstances which have a pronounced ant;inflamnlatory action and, at the same time, a low toxicity. They can~ therefore, be used as drugs having an antiphlogistic action, in particular against rheumatic diseases.
1~ Adju\~ant arthritis _._ ___ The tests were carried out by Pearson's method (Arthr;t. Rheum~ 2~ 440 (1~5~ The test animaLs used were male rats of a l~is~ar Lewis strain having a body weight betueen l30 and 200 9. The compounds to be compared were administered orally every day from the 1st to the 5th day of the test~ The anirnals in a control group only received the solvent. Groups of 8 an;mals were used for each dosage and in the ~ontrol groupn The criterion of action used was the reductioll in the increase of pau volume compared w;th that of the untreated control ~roup~ The ED50 values were determined graphically from the dose activity curve.
2. Ga ~ on The tests were carried out on groups of 10 male Sprague-Dawley rats having a body weight of 200~300 9. The feed was taken away, while free access to dr;nkin~ water was permitted, from 48 hours before the aclministration of the compounds to be compared until the animals were sacri-ficed~ The rats were sacrificed 24 hours after the oral adm;nistration~ and the stomachs were taken out, cleaned under runiling water and ;nspected for lesions to tl-le illUCOUS
membranes~ r~ll les-iorls visible to the naked eye were coun~ed as ulcers. Ttle propoltion of ar,imals havin~ ulcers a. each dose ar~d the ub50 as specified by lichtfield and ~J;lcoxon 36~
(J. Ph~3rmacol. exp~ Ther. 96, 99 (1949)) were determ;ned~
3 . Acute t_x1 c~ty Acute toxici1y W2S deterrl7ined by standard methods using rats of the Sprac7lle-Dawley strain~ 6 anirnals were 5 used per dosaye. The LDSo values were determined by the method of LichtF;eld and ~Jilcoxon~
CEi - R2 Substance R Adj~Nant arthritis Gastric ulcers 7r~iex __ _ ~ . ~ _ _ Sulindac 13.0 rng/kg 26.0 mg/kg 2 _ _ _ _~ . ... ._ Naproxen 15.0 mg/kg 21~0 mg/kg 2 ~ . _ _ _~ .
Exar,ple 4 COOH 20.0 n~7/kg 175 nlg/kg 9 ~ __ .. .. _ Exarrple 7 CC~C2H5 15.0 mg/kg 125 rr~/kg 8 ~ ............... _ _ _. . . I
Exarriple 9 CHzOH 20.0 n~g/kg 220.0 rrg/kg 11 _ ._ ~
S~bstance50 TI D50/ED50) Acute toxicity in~7ex ___ . ~_~
Naproxen 3~5 n~7/kg 26 __ _____ _ _ Exarn~)le 9 1,C00 rr~7/kg 50 ~3f~
- 12 ~
The connpounds tested exhibited a clear advant&ge com-pared w;th the known comparison folmulations sulindac and naproxen on the basis of their excellent gastric tolerance by rats, which constitute a model animal of good effeccive~
ness as an indicator of the most imporcant s;de effect of this class of substances in humans. A therapeutic index which is at least 4 times that of the compar-ison formulations is derived from these tests. In add;tion~ the alcohol (Example 9) has an acute tox-icity tLD50 1J00~ mg~kg) which ;s unusually good For antiphlogistic agent~ and is more than twice the LD50 of naproxen (395 rng/kg)~
The drugs accordirlg to the invent-ion can be admini~
stered orally, rectally or parenterally.
Examples cf su;table scLid or l;quid ph3rmareutical forms for formulation are granules, powders, tablets, dragees, (micro~capsules, suppositoriesr syrups, emuls;ons, suspen~
sions, drops or injectable solutions and also form-llations having a protracted release of active compound, which are customarily prepared by using auxiliaries, such as excipients, disintegrators, binders, coating agents, swelling agents, slip agents, lubricants, flavoring substances, sweeteners or solubilizers~ Lactose~ mannitol and other sugars, talc~
lactalbumin, gelatine, starchr cellulose and derivatives thereof, vegetâble oils, polyethylene glycols and solvents~
such as, for instance, ster;le water~ may be ment;oned as examples of aux;liaries which are ~requently used~
The formulatiorls are preferably prepared and admilli stered in dosage un;ts, each unit conta1n;ng a specific dose o-f active substance accord;ng to formula I~ In the case ~19~
- 13 ~
of solid dosage un1ts, such as tablets, capsules or supposi-tor;es~ th;s dose can be up to 1,000 m9, but preferably 50 to 300 mg~ and in the case of injection solutions in the form of ampuls ;t can be up to 200 mg, bwt preferably 20 to 100 mg~
Depending on the effect;veness of the compounds according to formula I on hulnans~ the daily doses indicated for the treatment o-f an adult patient suffering from inflam-~ atory processes are 100 to 500 my of act;ve compound, pre-ferably 200 to 300 mg, in the case o-f oral admin;strat;on, and 20 to 150 m9, preferably ~0 to ~0 mg~ in the case of ;ntravenous admin;stration. Undrr certa;n circurnstances, however, it is also possible to administel higher or lower da;ly doces. The daily ~Jose can be administered either by a single administrat;on in the form of an individual dosage unit or several small dosage un;tsr or by the repeated admii-~i-stration of subdivided doses at speci-fic intervals~
- ~he ;nvention is illustrated by means of ~he follow-ing examples.
Example 1a _ Methyl Dl-2-(6 phel1ylpyridirl-2~oxy) propanoate 34.2 g of 6-phenylpyrid-2-one are dissolved in 200 ml of dimethylfrJrmamide~ 24~5 g of methyl Dl- ~-chloropro~ionate and 27.3 9 of K2C03 are added successively and the mixture is then stirred for ~ hours at 90C~ The reaction mixture is then filtered while hot and the f;lter cake is washed with a little acetone. The acetone and the ~olvent are removed by distillation under redured pressure (dowl1 to 13 mbar), and the residue is distillrd urlder a greatly redured pressure 1~3~
throuyh a 20 cm Viyreux column~ This g;ves 44.3 g (86% of theory) of a colorless oil of bo;ling point 177C at 3 mhar.
Dimethyl sulfoxide, d;methylacetamide~ N-methyl~2-pyrrolidone or ~irnethyldiglycol can also be used as the solvent, with sodium carbonate as the base~ in the same procedure as des-cribed above.
Example 1b The following compounds of the formula I, listed in Table 1, are prepared in accordance with Exa~ple 1a, but us;n~ equ;valent quantities of the corresponding compounds of the forrnulae II and III tDL-, D- or L~forrrl)~
.9;.3~
Ta~le 1:
~ O H ~ ~1 R H R
H
Comp~r~ X R3 R1 R2 . ... : ::
_ _ _ . . . _ . . . _ _ 1.1 Cl CGH5 H ,~ M p.: 62C
_ _ . _ . . . _ 3 D,L
1.2 Br C6H5 CH3 -C-O-C2H5 B P 2 5 = 1 7 5-1 7 7 C
. .. ___ . D,I.
1.3 Br C6H5 CH3 O Mp.: 74C
-C-C-GH(c~3)2 D,L
__ _ _ . .... __ _ ___ 1.4 Cl C6H5 G~3 ( 2)11 3 MP 39-LIOOC
~ ~ --~---- --- - - . - - ~---1.5 C1 C6.Y5 CH3 -C-O-CH2-C6ll Mp 67-68 C
.. . _ . . . _ _ ,.. _ 1.6 Br C6H5 C2H5 O
. .. _ ... _ . ___ . . ~
1~7 Br C6l~5 C2H5 -C-O-C2H5 Bp~ = 187C
. __ ~_ _ . .... ~
1.8 BrC6H5 ( 2)2~3 ~l . -C-o-C~13 __ _~ ~ ..... _ __ ~ _. .. ~
1.9 Br C6~35 -~G~2)2~ 3 O BP~2 _ 185C
_ . ~ - ~C--O-C2~5 D,L
. . . _ _ _~_ _ _ _ ~._ ~ 16 _ Tab l e 1 cont i n~led ___ _ _ Ccnpound X R3 R1 l R2 ~ - _ _ . . . .. _ __ 1 . 10 Br CG~5-CH (CE13 ) ~ ,~ . . . .
_ _ __ . _ 1.11 -I2 C6H5 H C~2{> (C~ 2) 3 3 ~3 _. __ _ , ~
1 . 12 _S02 t~6H5 H ~2~C 13 Bp O ~= 128-a~3 _____ ~ _ ~ L,L
.1 3 B- C~ O C~i O ~ ~P 1 -3 ~> -C~-C2H5 ~ 180~C
__ __ . __ __ ___ 1.1 4 13r ~3{~ ~ c~3 -C-~C2.~15 ~ _ _ 1.15 Br CH3~ CH3 -C~C2H5 E~p 0 6 - 14~C
1 . 16 Br a~3 C~13 -'-~C2~15 __ ~ _ . ___ ._ 1.17 Br (~ 3 ~{) CII
__AA_A_ .___ __ . _ _ . .. _ _ 1.18 B~ ~ ~ U.~3 -C (}C2'H5 O 1 = 125-___ ___ ,~
~336~
_ 17 _ Tab ~ ~ 1 cont i nued _~____ _ C~I~b. d X R~ R 1 R2 _ __ _ ~
1 .19 3r F ~C-~ CE13 -C~C2~5 __~ __ 1 . 20 Br Cl-(~ CT-I3 ~ (}C~5 Bpo 5 1 5 5 -1 6 0 C
__. _ __ _ __ 1. 21 3r Cl C ~3 C C2~5 ~___~_ __ 1. 22 Br ~ C l3 _~___ _ 1. 23 Br Gi3 ~ O
¢~ C-~C~3 . S .
__ . __ _ __ 1 . 24 Br 1 3 CH3 O
}~3C 1- -C-~C~15 _ ___ ~
1.25 Cl C,H~ Ct~ O Bp 0.8 150-154C
D ( + ) ~C~3 ~G] D = + 1 1 . 4 ~G~C' 3) ~__ _ ___ -- _ ~ _ _ _ ._. .
1. 26 Cl ~ a~3 O
__ _ --C-'~I
1 . 27 Cl 1 3 aI3 O
1~3C-C- -C~3 ~3 _ ~
.. .. __ _ _ ___ _.__... .. ____. , _ ___ ____._. .
_ 18 -Tab l e 1 cont i nued _~ ___ Comp~nd i ~ R3 . R1 R~
No. . ..... .. .. ..
1.23 ___ _ _____. ____.___ ___ . .... .
~1 -C-~-C1~3 1.2g Cl - - C~13 O_ _~
<~- ~-C~13 ~3 ___ ... _ _ _ __ __ .... __ _ ... _ ..... _ ._.___ 1.30 Cl Cl~ G13 " Bp o 6 ~ 150-155C
D ( ~) C-OC~3 la] ~5 = * 11,4 ~C'Cl3) _ ___~ __ ... ___ ... .. _ 1.31 Cl H3C~ C~3 ~ Mp . ~102C
D(+) -C-{~3 ~]D = +1~.3 (CHC13) .. . --_ . _ ~
1.32 Cl ~ C~ ~3 ~ Mp,: 125--l 26 D (~- ) -C-CX~I ~ ] D +14 - (CHC13 ~
1.33 C.l . __ . _ ___ ~ ___ _.______ D(+) F~ C~13 --C~ 3 Bpr 0 1 = 127-135 C
_ [a] 25 = + 11.2 (C~Cl3) . _ _ __.___ . .
1.34 Cl F~ G O Bp - O ? - 145-150&
D~+) \_~r~ ~3 - C-CC21l5 [o]~5 = ~11,4 (CrlC
1.35 Cl . . G~ _ ~ ~~ 0 6 = 1so-l 52 L (-) ~._ 3 -C-OC2H5 [~] 25 -12,1 (c~c13) 1.36 Cl _~.. _ __ _____ _~_ ___.~_ --CI~O~-' C - ~ --C-CC2H5 Mp : 70 _ ~_ ~ ._ _____ . __ .~936(~'~
~9 Example Z
____ Ethyl DL~2 C6~ dichlorophenyl)-pvrid;n~2~oxy~pro~arloate 24 g oF 6-(3,4~dichlorophenyl~-pyrid-2-one are added in port;Gns, and while st;rr;ng and cooling, co a suspension of 3 g of sodium hydride (an 80% strength d;spers;on ;n o;l) ;n 2DO ml of d;methylforrllaln;de at such a rate that the tem~
perature does not exceed 30Cr st;rr;ng ;s cont;nued at 40C unt;l ttle evolut;on of hydrogen is completer and 1~.1 9 of ethyl DL- ~ bromopropionate are then added dropwise and stirr;ng ;s cont1nued For 5 hours at 80C~ After cooling, the reaction mixture is poured into 500 rnl of ice water, the mixture is extracted with methylene chloride, the extract ;s worl~ed up in a customary manner and the residue ;s d;stitled under ~ greatly reduced pres~uren Th;s gives 25.5 g (75X of theory) of mat2rial of boil;ng point 1~0C at n.3 mbar, melt;ng po;n~: 70C.
Example 3 _ DL~2-~6~phenylpyridin~2~oxy)~ethanoic ac;d 0.3 g of tetrabutylammon;um hrom;de is added to a solution of 17u1 9 of 6-phenylpyrid-2-one in 1ûO ml cf dirnethylformamide~ and 1~3 g of very finely powdered KOH
are added while stirr;ng vigorously~ 12~2 9 of ethyl chloro-acetate are then added dropwi3e at 80C~ v;gorous stirring is continued for a further 4 hours. 10 ml of water are addedr stirr;ng îs continued for a further 30 m;nutes and the solvent is removcd under reduceo pressure~ The residue ;s taken up in 40 ml of waterr the solution is ac1di-Fied with 2 N H2S04 and the precipitated ac;cl ;5 filtered ofF wi-h suction~ dried at 500C ;n a dryirlg cabinet and .hen recrystall;zed from 33~il)'~
~ 2~ _ di;sopropyl ether/hexane. This gives 1~ g, melting point 125~126C.
Example 4 . .
DL-2-~6-phenylpyridin-2 oxy)~propanoic acid A mixture of 12.9 g of methyl DLw2-(6-phenylpyr;din-2-ox,~?-propanoate, 2~4 g of NaOH and 10 ml of methanol is heated at 80C for 30 minutes~ AFter cooling, the mixture ;s acidifed w;th 2 N H~SO~,~ and the precipitated acid is dried at 50C in a drying cabinet and is then recrystalw lized from di;sopropyl etlier/hexane. This gives 10.9 g (~0%
of theory) r melting point : 142-143C.
Example 5 Tlle following compounds of the formula I, listed in Tab-~ 2~ al~e prepared i,l accordance W jth Example 4,. but using corresponding quantities of compounds from Table 1 and NaOH.
~3~
Table 2 ~1 0 ~ ~0 - C - ~C - O - ~
Cornpour~ 1 R3 R1 Prepared -frcm M~p.: [ C] [a]D (CE~301i) - . ~ Cc~lpound No _~--2 . 1 C6H5 -C2H5 1 . 7 0 _._ .. _ . _ _ 2.2 ~ CH3 1.22 154 oo ._ _ _ _ 2 . 3 ~ CH3 1 . 21 ~ 0 . . _ . __, .~ a- l 0O
2 . S H3C- IC- GH3 1 . 24 Oo ~ _ 2 . 6 H C-~>-- CH3 1 .15 169 O
~ ~.. __. ~
_ ..
2. 7 F3C-~ Cli13 1 .19 0 _ ___ ~_~ ... .
D ( + ) Cl~>_ C 33 1 . 3 ~) 1 5 6 - 1 5 7 + 7 . 0 ~ ___ ____ ~93ti~
- 22 _ Tab l e 2 con t i nued _ Ccnpound 3 ~1 Prepared fran M.p: [ C] k~D (C~.3n~) No. Cony: ~uncl l\b.
__ .~ ._ ~_ ~ ._ D(+) ~I C-~ C~T3 1.31 169-170 ~ 7,2 . _ ~ . _ _ _ 2 . 1 0 ~3C~ CH3 1 . 3 2 1 6 0 ~ 1 1 . 0 _ __ . _. ~ _ . ___ _ . _ _ _ 2 . 1 1 ~ CE~3 1 . 33 13--1 19 t 9 . ~1 _ . __ _~___ ~._ . _ _ .
2 . 12 _ __ _ 3 1 . 3 5 1 25-1 2 6 -10, 0 _. ~_ ..
1~93~
Examp e_6 Dt~)-2~(6~- henyLpyridin 2-oxy)-propanoic acid 25.7 9 of methyl D(~-2~(6 phenylpyridin~2-oxy)-propanoate, 20 ml of methanol, 20 g of l-l20 and 4.8 9 of NaOt1 are stirred at 75C for 3 hours and, after cooling~ are acidified with 2 N H2S04. The precipi~ated ac;d is pressed out on a clay plate and dissolved in diisopropyl ether, and the solution is dried with Na~S04. A^Fter f-iltering~ hexane ;s added to the hot solution until cloudiness is formed. On cooling, 18.5 9 (76% o-F theory) of product crystallize out, melting point: 126C~ specific rotacion C ~25 - ~ 4 (CH30H).
Example 7 _ ~ 2~(6-phcnylpyr,d-r;-2~oxy)-prop3noate 12aZ 9 of P(~-2-(6-phenylpyridin~2-oxy) propanoic acid, in a mixture of 50 ml of toluene and 30 ml of ethanol, are bo;led under reflux for 5 hours, the mixture of solvents is removed by distillation and the residue is fractionated under a greatly reduced pressure~ This yives 11~ 2%
o-f theory) of product, boiling point 138-142C at 0~5 mbar, specific rotation ~320 = 1ODOO (CHCl3).
Example 8 6-Phenylpyridin-2--oxyethyl ethyl ether .
A suspension of 8.6 9 of 6-phenylpyrid~2-one. 0.5 9 of tetrabutylamrnonium bromide, 5.4 g oF Z-chlorodiethyl ether, 100 ml of toluene and 20 ml of 50% strength sod;um hydroxide solution is vigorously stirred -For 5 hours at 100~. After cooling, 30 ml of water are added~ the orgarlic phase 1s separated of~, r;nsed ~Jith 2 N NaOH and dried over Na 36~
- 2~ -the solvent ;s removed under reduced pressure and the residue ;s distilled under a greatly reduced pressure. This gives 7.9 9 t66% of theoryj of- a colorless oil.
Example 9 ___ DL-2 ~6-phenylp~r~__n-2-oxy~ _ nol A solution of 13.6 g of ethyl DL~2-(6-phenylpyrid;n 2-oxy)~propanoate in 30 ml of absolute diethyl ether is added dropwise, at room tempelature and !Jhile st;rring, to a sus pension of 2~05 g of L;thium alum;num hydride in 75 ml of absolute d;ethyl ether, and the m;xture is st;rred under re-flux for 1 hour. After cooling, the m;xture is hydrolyzed w;th water and acidified l~ith 10% strength sulfur;c acid, and the aqueous phase is saturated with NaCl and is separated off, the remainder is extracted with ether, the combirled organic phases are dried over Na2S0~ and the solvent is removed under reduced pressure. 1he residue is distilled as described in Example 1a. Th;s gives 10.9 g ~95% of theory) of product~
boiling point 181C at 6-7 mbar.
Example 10 D(~)-2 (6 ~ din-2 oxy _propano_l 11.0 g (96~ of theory) of product, boilin~ point 180C at 6 mbar, spec;fic rotation C~ ~20 ~ -~2.1 ~CHCl3), are obtained ;n accordance with Example 9, but-using 1209 g of metl1yl D(1-)~2 ~6~phenylpyr;din 2~oxy)-propanoate~
Example 11 -The follo~ g compounds of the formula I, listed ;n Table 3, are prepared ;n accordance w1th Example 9~ but us;ng corresponding quantities or compounds from Tablc 1 and lithium aluminum hydr;de:
i~L936~'~
-. 25 _ T a b l e 3 /~ C) - C - CH2 ~ C~E-I
R3 ~!
C~o~Jn,d I ~3 R Prepared frcrn No~ i 1 Con~nd No.
. . . ~ __ 3~1 C6~5 ____ 1.7 3 . 2 ~3\ C~3 1 . 22 . ___ _ . .. , ~
3.3 (~l3~ _ Cii3 1.16 ___ 3 . 4 ~C:L CH3 1 . 21 ~T
.. _ ~ --C~3 1. 2~ _~
3 . 5H3('~ 3 1 .15 M p ~ 55 C
~ __ ~ . . ~ D, L
3 . 7CF3-~ C~-13 1 .19 ~.____ ____ ___ ._ _ ~ _ . . __ 3 . 8Cl~ C~13 1 . 2 0 M p 61 C
__ .. __ _ . . _~__~_ __._ . D, L ____ 3, 9 H3C~C)~-- C~3 1 ~14 M p ' 53C
__ ~ _____ __ _ _ ._ ___._.__~ D, ~
~ 93~
_ 26 _ Tab l e 3 cont i nued .__ ____ .
Car~ nd~R3 1 I Prepared frcm No. I Canpound No.
. _ _ .,,. . ___ 3 .10Cl-- ~ C~ 1 . 30 2 D(~) ~ ~ ~ 5 = +1 / ( 3.11 CH 1.31 Mp.: 55 C
D ( + )ll C -~ 3 [cl ] D = + 2 . ~ 'C'13 ) _~_ .. ~ _~_................. __ __ _ 3.12 H C~ CH3 1.32 Mp.: 5~ C
D(+) 3 ~C~]D = + 2.~', (ClICl3) ___ _~ . . ~ . .~_____ 3.13 F~ CH3 1.18 Bpo 1 = 150C
. _~ . __ __ _ D, L _ ___ 3.14 ~ S~3 1.33 BP'0~1 ~ 150 C
D t ~ ) _ _ ~ D + 1 . 7 ( l~iCl 3 ) _ _ ___ _ _ _ _____ 3.15 ~ C~3 1.35 Bpo 6 = 165&
~~ . ~ 5 - -2.2 (C-:Cl ~L ~93~
~ 27 -_ample 12 DL-2-(6 phenylpyridin-2-oxy)~propyl acetate 2.3 ~ of acetic anhydride are aclded dropwise at room ternperature and while stirring to a solution oF 406 ~ of DL--2-(6-phenylpyr;d;n-2 oxy)-propanol (from Exarnple 9~ in 10 ml of pyridine, stirring is continued for 4 hours a~ 6nc and the m;xture is cooled and poured ;nto 50 ml of ;ce water~
which is extracted w;th CH2Cl2 and the extract is worked up ;n a custornary manner~ The residue is d;st;lled under a greatly reduced pressure~ Th;s gi~es 4.3 CJ t80~/~ 0~ theory~
of a colorless oil~ boiling point 153--155C at 0~3 rnb~r.
Example 13 ___._ The following compounds of the fornlula I5 listed ;n Table f-~, are prepared ;n accorc!~nce with Exampl.e 12r but us;ng corresponding quant;ties of compounds from Table 3 and acet;c anhydr;de.
3~
Table 4 J~--C - CH - O - C - C f l 3 , CaTpo~rcl . R3 Prepared fr~
No~ Cc~npourd No~
~ . __~__ _
~ith the process described by J. Thes;ng et al., Chem. Ber.
90, 7il (1957) or analo~ously to the instruct;ons giver, by F~ ~rohnke et al. in Chem. Ber. 103, 322 et sec1,. (1970).
However, it is particularly acivanta~eous to react a compound of the formula IV
R3 - C - Cl-13 (IV) o with an acrylic acid ester o-f the formula V
CHz - C~l - C - oR6 (V~
g to give a compound of the formula V
R3 - C - CH2 - Ci~2 - CH~ ~ C - oR6 (VI
g 11 wh;c1~ I,en cycli~ed by medns o~ arnmon;a to cj;ve a cori7pour,d of the formula VII
~ ' R3 1 (VII~
~ [
wh;ch is finally dehydrogenated to g;ve a compound of the 15 formula II. In the formulae ment;oned above, R3 has the mean;ngs ment;oned in cla;m 1 and R6 is an alkyl rad;cal having 1 to 6 carbon atolns.
The preparat;on of the compound VI froln the ketone IV and th~ acryl;c acid ester V is carriecl out at ternpera tures bet~Jeen 20 and 220C~ under alkaline cond;t;ons ;n an inert solvent~ It is also possible to dispense w1th the use oi solvents in this reaction and to carry out the reaction ~lithout a diluent. The base whicl1 is added to the react;on ~L~9~
_ 9 ~
mixture is preferably a pr;Mary amine, such as methylam;ne, ethylamine~ propylam;ne~ isopropylamine, butylam1ne, cyclo-hexylaln;ne or the ~ -N~alkylam;noprop;onate wl1;ch ;s formed ~rom the acryl;e ester and arn;ne usedO The rract;on 1s 5 earr;ed out ;n the presence of eatalyt;e amounts oF al1 aeid, sueh as benzo;c ac;d, phenylsulfon;c ac;d~ toluenesulfonie ae;d, salieylie ac;d~ acet;c ac;d or acryl;c ac;d~
The compound VI is then reac~ed with ammon1a in an inert solvent or w;thout a d;luent a1: a temperature between 10 100 and 250C, preFerably in an autoclave, to g;ve the eompound VII. The latter ;s then dehydrc)~enated usincJ a dehydrogena~;on eatalyst, such as pallad;um-on-charcoal~
to give the compound II.
The cenpoundc of the for!nula III which are used as 1S starting materials are known.
It can be seen from the formula I that the colnpounds aeeord;ng to the invention eonta1r at least one eenter of asymmetry in the ~-position in relat;on to the o~y~en atom, prov;ded that R1 does not denote hydrogen. The racema~es of the Formula I which can be obtained if raeemic eompounds of the formula III are used, can be resolved into the;r optieal ant;podes in a eustomary manner. Th~s compounds of the formula I in wh;ch R2 denotes COOH ean be trea~ed us;ng an optically active base. The optieal antipodes of 2~ compounds of the formula I are obtained in an advantageous manner if the startil1g mater;als of the formula IJX are already optically active.
~ y v;rtue of the phar!nacological tests wh;ch follow and the results obtait1ed tr,ere;n, the eompounds accordi~
1~33~
~ 10 -to the ;nvention can be c!esignated suhstances which have a pronounced ant;inflamnlatory action and, at the same time, a low toxicity. They can~ therefore, be used as drugs having an antiphlogistic action, in particular against rheumatic diseases.
1~ Adju\~ant arthritis _._ ___ The tests were carried out by Pearson's method (Arthr;t. Rheum~ 2~ 440 (1~5~ The test animaLs used were male rats of a l~is~ar Lewis strain having a body weight betueen l30 and 200 9. The compounds to be compared were administered orally every day from the 1st to the 5th day of the test~ The anirnals in a control group only received the solvent. Groups of 8 an;mals were used for each dosage and in the ~ontrol groupn The criterion of action used was the reductioll in the increase of pau volume compared w;th that of the untreated control ~roup~ The ED50 values were determined graphically from the dose activity curve.
2. Ga ~ on The tests were carried out on groups of 10 male Sprague-Dawley rats having a body weight of 200~300 9. The feed was taken away, while free access to dr;nkin~ water was permitted, from 48 hours before the aclministration of the compounds to be compared until the animals were sacri-ficed~ The rats were sacrificed 24 hours after the oral adm;nistration~ and the stomachs were taken out, cleaned under runiling water and ;nspected for lesions to tl-le illUCOUS
membranes~ r~ll les-iorls visible to the naked eye were coun~ed as ulcers. Ttle propoltion of ar,imals havin~ ulcers a. each dose ar~d the ub50 as specified by lichtfield and ~J;lcoxon 36~
(J. Ph~3rmacol. exp~ Ther. 96, 99 (1949)) were determ;ned~
3 . Acute t_x1 c~ty Acute toxici1y W2S deterrl7ined by standard methods using rats of the Sprac7lle-Dawley strain~ 6 anirnals were 5 used per dosaye. The LDSo values were determined by the method of LichtF;eld and ~Jilcoxon~
CEi - R2 Substance R Adj~Nant arthritis Gastric ulcers 7r~iex __ _ ~ . ~ _ _ Sulindac 13.0 rng/kg 26.0 mg/kg 2 _ _ _ _~ . ... ._ Naproxen 15.0 mg/kg 21~0 mg/kg 2 ~ . _ _ _~ .
Exar,ple 4 COOH 20.0 n~7/kg 175 nlg/kg 9 ~ __ .. .. _ Exarrple 7 CC~C2H5 15.0 mg/kg 125 rr~/kg 8 ~ ............... _ _ _. . . I
Exarriple 9 CHzOH 20.0 n~g/kg 220.0 rrg/kg 11 _ ._ ~
S~bstance50 TI D50/ED50) Acute toxicity in~7ex ___ . ~_~
Naproxen 3~5 n~7/kg 26 __ _____ _ _ Exarn~)le 9 1,C00 rr~7/kg 50 ~3f~
- 12 ~
The connpounds tested exhibited a clear advant&ge com-pared w;th the known comparison folmulations sulindac and naproxen on the basis of their excellent gastric tolerance by rats, which constitute a model animal of good effeccive~
ness as an indicator of the most imporcant s;de effect of this class of substances in humans. A therapeutic index which is at least 4 times that of the compar-ison formulations is derived from these tests. In add;tion~ the alcohol (Example 9) has an acute tox-icity tLD50 1J00~ mg~kg) which ;s unusually good For antiphlogistic agent~ and is more than twice the LD50 of naproxen (395 rng/kg)~
The drugs accordirlg to the invent-ion can be admini~
stered orally, rectally or parenterally.
Examples cf su;table scLid or l;quid ph3rmareutical forms for formulation are granules, powders, tablets, dragees, (micro~capsules, suppositoriesr syrups, emuls;ons, suspen~
sions, drops or injectable solutions and also form-llations having a protracted release of active compound, which are customarily prepared by using auxiliaries, such as excipients, disintegrators, binders, coating agents, swelling agents, slip agents, lubricants, flavoring substances, sweeteners or solubilizers~ Lactose~ mannitol and other sugars, talc~
lactalbumin, gelatine, starchr cellulose and derivatives thereof, vegetâble oils, polyethylene glycols and solvents~
such as, for instance, ster;le water~ may be ment;oned as examples of aux;liaries which are ~requently used~
The formulatiorls are preferably prepared and admilli stered in dosage un;ts, each unit conta1n;ng a specific dose o-f active substance accord;ng to formula I~ In the case ~19~
- 13 ~
of solid dosage un1ts, such as tablets, capsules or supposi-tor;es~ th;s dose can be up to 1,000 m9, but preferably 50 to 300 mg~ and in the case of injection solutions in the form of ampuls ;t can be up to 200 mg, bwt preferably 20 to 100 mg~
Depending on the effect;veness of the compounds according to formula I on hulnans~ the daily doses indicated for the treatment o-f an adult patient suffering from inflam-~ atory processes are 100 to 500 my of act;ve compound, pre-ferably 200 to 300 mg, in the case o-f oral admin;strat;on, and 20 to 150 m9, preferably ~0 to ~0 mg~ in the case of ;ntravenous admin;stration. Undrr certa;n circurnstances, however, it is also possible to administel higher or lower da;ly doces. The daily ~Jose can be administered either by a single administrat;on in the form of an individual dosage unit or several small dosage un;tsr or by the repeated admii-~i-stration of subdivided doses at speci-fic intervals~
- ~he ;nvention is illustrated by means of ~he follow-ing examples.
Example 1a _ Methyl Dl-2-(6 phel1ylpyridirl-2~oxy) propanoate 34.2 g of 6-phenylpyrid-2-one are dissolved in 200 ml of dimethylfrJrmamide~ 24~5 g of methyl Dl- ~-chloropro~ionate and 27.3 9 of K2C03 are added successively and the mixture is then stirred for ~ hours at 90C~ The reaction mixture is then filtered while hot and the f;lter cake is washed with a little acetone. The acetone and the ~olvent are removed by distillation under redured pressure (dowl1 to 13 mbar), and the residue is distillrd urlder a greatly redured pressure 1~3~
throuyh a 20 cm Viyreux column~ This g;ves 44.3 g (86% of theory) of a colorless oil of bo;ling point 177C at 3 mhar.
Dimethyl sulfoxide, d;methylacetamide~ N-methyl~2-pyrrolidone or ~irnethyldiglycol can also be used as the solvent, with sodium carbonate as the base~ in the same procedure as des-cribed above.
Example 1b The following compounds of the formula I, listed in Table 1, are prepared in accordance with Exa~ple 1a, but us;n~ equ;valent quantities of the corresponding compounds of the forrnulae II and III tDL-, D- or L~forrrl)~
.9;.3~
Ta~le 1:
~ O H ~ ~1 R H R
H
Comp~r~ X R3 R1 R2 . ... : ::
_ _ _ . . . _ . . . _ _ 1.1 Cl CGH5 H ,~ M p.: 62C
_ _ . _ . . . _ 3 D,L
1.2 Br C6H5 CH3 -C-O-C2H5 B P 2 5 = 1 7 5-1 7 7 C
. .. ___ . D,I.
1.3 Br C6H5 CH3 O Mp.: 74C
-C-C-GH(c~3)2 D,L
__ _ _ . .... __ _ ___ 1.4 Cl C6H5 G~3 ( 2)11 3 MP 39-LIOOC
~ ~ --~---- --- - - . - - ~---1.5 C1 C6.Y5 CH3 -C-O-CH2-C6ll Mp 67-68 C
.. . _ . . . _ _ ,.. _ 1.6 Br C6H5 C2H5 O
. .. _ ... _ . ___ . . ~
1~7 Br C6l~5 C2H5 -C-O-C2H5 Bp~ = 187C
. __ ~_ _ . .... ~
1.8 BrC6H5 ( 2)2~3 ~l . -C-o-C~13 __ _~ ~ ..... _ __ ~ _. .. ~
1.9 Br C6~35 -~G~2)2~ 3 O BP~2 _ 185C
_ . ~ - ~C--O-C2~5 D,L
. . . _ _ _~_ _ _ _ ~._ ~ 16 _ Tab l e 1 cont i n~led ___ _ _ Ccnpound X R3 R1 l R2 ~ - _ _ . . . .. _ __ 1 . 10 Br CG~5-CH (CE13 ) ~ ,~ . . . .
_ _ __ . _ 1.11 -I2 C6H5 H C~2{> (C~ 2) 3 3 ~3 _. __ _ , ~
1 . 12 _S02 t~6H5 H ~2~C 13 Bp O ~= 128-a~3 _____ ~ _ ~ L,L
.1 3 B- C~ O C~i O ~ ~P 1 -3 ~> -C~-C2H5 ~ 180~C
__ __ . __ __ ___ 1.1 4 13r ~3{~ ~ c~3 -C-~C2.~15 ~ _ _ 1.15 Br CH3~ CH3 -C~C2H5 E~p 0 6 - 14~C
1 . 16 Br a~3 C~13 -'-~C2~15 __ ~ _ . ___ ._ 1.17 Br (~ 3 ~{) CII
__AA_A_ .___ __ . _ _ . .. _ _ 1.18 B~ ~ ~ U.~3 -C (}C2'H5 O 1 = 125-___ ___ ,~
~336~
_ 17 _ Tab ~ ~ 1 cont i nued _~____ _ C~I~b. d X R~ R 1 R2 _ __ _ ~
1 .19 3r F ~C-~ CE13 -C~C2~5 __~ __ 1 . 20 Br Cl-(~ CT-I3 ~ (}C~5 Bpo 5 1 5 5 -1 6 0 C
__. _ __ _ __ 1. 21 3r Cl C ~3 C C2~5 ~___~_ __ 1. 22 Br ~ C l3 _~___ _ 1. 23 Br Gi3 ~ O
¢~ C-~C~3 . S .
__ . __ _ __ 1 . 24 Br 1 3 CH3 O
}~3C 1- -C-~C~15 _ ___ ~
1.25 Cl C,H~ Ct~ O Bp 0.8 150-154C
D ( + ) ~C~3 ~G] D = + 1 1 . 4 ~G~C' 3) ~__ _ ___ -- _ ~ _ _ _ ._. .
1. 26 Cl ~ a~3 O
__ _ --C-'~I
1 . 27 Cl 1 3 aI3 O
1~3C-C- -C~3 ~3 _ ~
.. .. __ _ _ ___ _.__... .. ____. , _ ___ ____._. .
_ 18 -Tab l e 1 cont i nued _~ ___ Comp~nd i ~ R3 . R1 R~
No. . ..... .. .. ..
1.23 ___ _ _____. ____.___ ___ . .... .
~1 -C-~-C1~3 1.2g Cl - - C~13 O_ _~
<~- ~-C~13 ~3 ___ ... _ _ _ __ __ .... __ _ ... _ ..... _ ._.___ 1.30 Cl Cl~ G13 " Bp o 6 ~ 150-155C
D ( ~) C-OC~3 la] ~5 = * 11,4 ~C'Cl3) _ ___~ __ ... ___ ... .. _ 1.31 Cl H3C~ C~3 ~ Mp . ~102C
D(+) -C-{~3 ~]D = +1~.3 (CHC13) .. . --_ . _ ~
1.32 Cl ~ C~ ~3 ~ Mp,: 125--l 26 D (~- ) -C-CX~I ~ ] D +14 - (CHC13 ~
1.33 C.l . __ . _ ___ ~ ___ _.______ D(+) F~ C~13 --C~ 3 Bpr 0 1 = 127-135 C
_ [a] 25 = + 11.2 (C~Cl3) . _ _ __.___ . .
1.34 Cl F~ G O Bp - O ? - 145-150&
D~+) \_~r~ ~3 - C-CC21l5 [o]~5 = ~11,4 (CrlC
1.35 Cl . . G~ _ ~ ~~ 0 6 = 1so-l 52 L (-) ~._ 3 -C-OC2H5 [~] 25 -12,1 (c~c13) 1.36 Cl _~.. _ __ _____ _~_ ___.~_ --CI~O~-' C - ~ --C-CC2H5 Mp : 70 _ ~_ ~ ._ _____ . __ .~936(~'~
~9 Example Z
____ Ethyl DL~2 C6~ dichlorophenyl)-pvrid;n~2~oxy~pro~arloate 24 g oF 6-(3,4~dichlorophenyl~-pyrid-2-one are added in port;Gns, and while st;rr;ng and cooling, co a suspension of 3 g of sodium hydride (an 80% strength d;spers;on ;n o;l) ;n 2DO ml of d;methylforrllaln;de at such a rate that the tem~
perature does not exceed 30Cr st;rr;ng ;s cont;nued at 40C unt;l ttle evolut;on of hydrogen is completer and 1~.1 9 of ethyl DL- ~ bromopropionate are then added dropwise and stirr;ng ;s cont1nued For 5 hours at 80C~ After cooling, the reaction mixture is poured into 500 rnl of ice water, the mixture is extracted with methylene chloride, the extract ;s worl~ed up in a customary manner and the residue ;s d;stitled under ~ greatly reduced pres~uren Th;s gives 25.5 g (75X of theory) of mat2rial of boil;ng point 1~0C at n.3 mbar, melt;ng po;n~: 70C.
Example 3 _ DL~2-~6~phenylpyridin~2~oxy)~ethanoic ac;d 0.3 g of tetrabutylammon;um hrom;de is added to a solution of 17u1 9 of 6-phenylpyrid-2-one in 1ûO ml cf dirnethylformamide~ and 1~3 g of very finely powdered KOH
are added while stirr;ng vigorously~ 12~2 9 of ethyl chloro-acetate are then added dropwi3e at 80C~ v;gorous stirring is continued for a further 4 hours. 10 ml of water are addedr stirr;ng îs continued for a further 30 m;nutes and the solvent is removcd under reduceo pressure~ The residue ;s taken up in 40 ml of waterr the solution is ac1di-Fied with 2 N H2S04 and the precipitated ac;cl ;5 filtered ofF wi-h suction~ dried at 500C ;n a dryirlg cabinet and .hen recrystall;zed from 33~il)'~
~ 2~ _ di;sopropyl ether/hexane. This gives 1~ g, melting point 125~126C.
Example 4 . .
DL-2-~6-phenylpyridin-2 oxy)~propanoic acid A mixture of 12.9 g of methyl DLw2-(6-phenylpyr;din-2-ox,~?-propanoate, 2~4 g of NaOH and 10 ml of methanol is heated at 80C for 30 minutes~ AFter cooling, the mixture ;s acidifed w;th 2 N H~SO~,~ and the precipitated acid is dried at 50C in a drying cabinet and is then recrystalw lized from di;sopropyl etlier/hexane. This gives 10.9 g (~0%
of theory) r melting point : 142-143C.
Example 5 Tlle following compounds of the formula I, listed in Tab-~ 2~ al~e prepared i,l accordance W jth Example 4,. but using corresponding quantities of compounds from Table 1 and NaOH.
~3~
Table 2 ~1 0 ~ ~0 - C - ~C - O - ~
Cornpour~ 1 R3 R1 Prepared -frcm M~p.: [ C] [a]D (CE~301i) - . ~ Cc~lpound No _~--2 . 1 C6H5 -C2H5 1 . 7 0 _._ .. _ . _ _ 2.2 ~ CH3 1.22 154 oo ._ _ _ _ 2 . 3 ~ CH3 1 . 21 ~ 0 . . _ . __, .~ a- l 0O
2 . S H3C- IC- GH3 1 . 24 Oo ~ _ 2 . 6 H C-~>-- CH3 1 .15 169 O
~ ~.. __. ~
_ ..
2. 7 F3C-~ Cli13 1 .19 0 _ ___ ~_~ ... .
D ( + ) Cl~>_ C 33 1 . 3 ~) 1 5 6 - 1 5 7 + 7 . 0 ~ ___ ____ ~93ti~
- 22 _ Tab l e 2 con t i nued _ Ccnpound 3 ~1 Prepared fran M.p: [ C] k~D (C~.3n~) No. Cony: ~uncl l\b.
__ .~ ._ ~_ ~ ._ D(+) ~I C-~ C~T3 1.31 169-170 ~ 7,2 . _ ~ . _ _ _ 2 . 1 0 ~3C~ CH3 1 . 3 2 1 6 0 ~ 1 1 . 0 _ __ . _. ~ _ . ___ _ . _ _ _ 2 . 1 1 ~ CE~3 1 . 33 13--1 19 t 9 . ~1 _ . __ _~___ ~._ . _ _ .
2 . 12 _ __ _ 3 1 . 3 5 1 25-1 2 6 -10, 0 _. ~_ ..
1~93~
Examp e_6 Dt~)-2~(6~- henyLpyridin 2-oxy)-propanoic acid 25.7 9 of methyl D(~-2~(6 phenylpyridin~2-oxy)-propanoate, 20 ml of methanol, 20 g of l-l20 and 4.8 9 of NaOt1 are stirred at 75C for 3 hours and, after cooling~ are acidified with 2 N H2S04. The precipi~ated ac;d is pressed out on a clay plate and dissolved in diisopropyl ether, and the solution is dried with Na~S04. A^Fter f-iltering~ hexane ;s added to the hot solution until cloudiness is formed. On cooling, 18.5 9 (76% o-F theory) of product crystallize out, melting point: 126C~ specific rotacion C ~25 - ~ 4 (CH30H).
Example 7 _ ~ 2~(6-phcnylpyr,d-r;-2~oxy)-prop3noate 12aZ 9 of P(~-2-(6-phenylpyridin~2-oxy) propanoic acid, in a mixture of 50 ml of toluene and 30 ml of ethanol, are bo;led under reflux for 5 hours, the mixture of solvents is removed by distillation and the residue is fractionated under a greatly reduced pressure~ This yives 11~ 2%
o-f theory) of product, boiling point 138-142C at 0~5 mbar, specific rotation ~320 = 1ODOO (CHCl3).
Example 8 6-Phenylpyridin-2--oxyethyl ethyl ether .
A suspension of 8.6 9 of 6-phenylpyrid~2-one. 0.5 9 of tetrabutylamrnonium bromide, 5.4 g oF Z-chlorodiethyl ether, 100 ml of toluene and 20 ml of 50% strength sod;um hydroxide solution is vigorously stirred -For 5 hours at 100~. After cooling, 30 ml of water are added~ the orgarlic phase 1s separated of~, r;nsed ~Jith 2 N NaOH and dried over Na 36~
- 2~ -the solvent ;s removed under reduced pressure and the residue ;s distilled under a greatly reduced pressure. This gives 7.9 9 t66% of theoryj of- a colorless oil.
Example 9 ___ DL-2 ~6-phenylp~r~__n-2-oxy~ _ nol A solution of 13.6 g of ethyl DL~2-(6-phenylpyrid;n 2-oxy)~propanoate in 30 ml of absolute diethyl ether is added dropwise, at room tempelature and !Jhile st;rring, to a sus pension of 2~05 g of L;thium alum;num hydride in 75 ml of absolute d;ethyl ether, and the m;xture is st;rred under re-flux for 1 hour. After cooling, the m;xture is hydrolyzed w;th water and acidified l~ith 10% strength sulfur;c acid, and the aqueous phase is saturated with NaCl and is separated off, the remainder is extracted with ether, the combirled organic phases are dried over Na2S0~ and the solvent is removed under reduced pressure. 1he residue is distilled as described in Example 1a. Th;s gives 10.9 g ~95% of theory) of product~
boiling point 181C at 6-7 mbar.
Example 10 D(~)-2 (6 ~ din-2 oxy _propano_l 11.0 g (96~ of theory) of product, boilin~ point 180C at 6 mbar, spec;fic rotation C~ ~20 ~ -~2.1 ~CHCl3), are obtained ;n accordance with Example 9, but-using 1209 g of metl1yl D(1-)~2 ~6~phenylpyr;din 2~oxy)-propanoate~
Example 11 -The follo~ g compounds of the formula I, listed ;n Table 3, are prepared ;n accordance w1th Example 9~ but us;ng corresponding quantities or compounds from Tablc 1 and lithium aluminum hydr;de:
i~L936~'~
-. 25 _ T a b l e 3 /~ C) - C - CH2 ~ C~E-I
R3 ~!
C~o~Jn,d I ~3 R Prepared frcrn No~ i 1 Con~nd No.
. . . ~ __ 3~1 C6~5 ____ 1.7 3 . 2 ~3\ C~3 1 . 22 . ___ _ . .. , ~
3.3 (~l3~ _ Cii3 1.16 ___ 3 . 4 ~C:L CH3 1 . 21 ~T
.. _ ~ --C~3 1. 2~ _~
3 . 5H3('~ 3 1 .15 M p ~ 55 C
~ __ ~ . . ~ D, L
3 . 7CF3-~ C~-13 1 .19 ~.____ ____ ___ ._ _ ~ _ . . __ 3 . 8Cl~ C~13 1 . 2 0 M p 61 C
__ .. __ _ . . _~__~_ __._ . D, L ____ 3, 9 H3C~C)~-- C~3 1 ~14 M p ' 53C
__ ~ _____ __ _ _ ._ ___._.__~ D, ~
~ 93~
_ 26 _ Tab l e 3 cont i nued .__ ____ .
Car~ nd~R3 1 I Prepared frcm No. I Canpound No.
. _ _ .,,. . ___ 3 .10Cl-- ~ C~ 1 . 30 2 D(~) ~ ~ ~ 5 = +1 / ( 3.11 CH 1.31 Mp.: 55 C
D ( + )ll C -~ 3 [cl ] D = + 2 . ~ 'C'13 ) _~_ .. ~ _~_................. __ __ _ 3.12 H C~ CH3 1.32 Mp.: 5~ C
D(+) 3 ~C~]D = + 2.~', (ClICl3) ___ _~ . . ~ . .~_____ 3.13 F~ CH3 1.18 Bpo 1 = 150C
. _~ . __ __ _ D, L _ ___ 3.14 ~ S~3 1.33 BP'0~1 ~ 150 C
D t ~ ) _ _ ~ D + 1 . 7 ( l~iCl 3 ) _ _ ___ _ _ _ _____ 3.15 ~ C~3 1.35 Bpo 6 = 165&
~~ . ~ 5 - -2.2 (C-:Cl ~L ~93~
~ 27 -_ample 12 DL-2-(6 phenylpyridin-2-oxy)~propyl acetate 2.3 ~ of acetic anhydride are aclded dropwise at room ternperature and while stirring to a solution oF 406 ~ of DL--2-(6-phenylpyr;d;n-2 oxy)-propanol (from Exarnple 9~ in 10 ml of pyridine, stirring is continued for 4 hours a~ 6nc and the m;xture is cooled and poured ;nto 50 ml of ;ce water~
which is extracted w;th CH2Cl2 and the extract is worked up ;n a custornary manner~ The residue is d;st;lled under a greatly reduced pressure~ Th;s gi~es 4.3 CJ t80~/~ 0~ theory~
of a colorless oil~ boiling point 153--155C at 0~3 rnb~r.
Example 13 ___._ The following compounds of the fornlula I5 listed ;n Table f-~, are prepared ;n accorc!~nce with Exampl.e 12r but us;ng corresponding quant;ties of compounds from Table 3 and acet;c anhydr;de.
3~
Table 4 J~--C - CH - O - C - C f l 3 , CaTpo~rcl . R3 Prepared fr~
No~ Cc~npourd No~
~ . __~__ _
4.1 ~ 3.2 ~
._ , _ _ 4.2 ~13 3.3 ~ _.. ___ 4.3 (~Cl 3.4 ___~_ 4 . 4CH 3 3 . 5 H C - C -C~3 ~ . .
_ .
4 . 5H 3 C~>- 3 . 6 _._ ___ _ ___ 4 . 6F3 C-~ 3 . 7 ___ _ __ ~
4.7-- Cl-~ 3.8 .
_ ____~._ __ _ ._ 4 . 8 H3 C-O-(~ 3 . 9 __.__ _ _. ____~____ _~
D ( ~ ) L F~ 3 . 1 4 ~
336~'~
Example 1/~
DL-2-t6-phenylpyridii1-2-oxy)-propyl isobutyrate A solution of 201 g of isobutyryl chloride -in 5 ml of methylene chloride is added dropwise, while st;rring and cooling at 0C, to a solut;on of 4.6 g of DL~2-~6-phenyl~
pyridin-2-oxy)-propanol ~frorn Example 9) in Z0 rnl of methyl.
ene chloricle and 2.2 g of tr;ethylan1;ne, ancl the m;xture is allowecl to warm up to room temperature and stirring ;s then cont;nued under reflux for 2 hoursu After cool;ng, tl-e rn;x~
ture is extracted by shakiny ~lith water, tl1e extract is worked up in a customary manner and the residue is d;stilled under a greatly reduced pressure~ This gives ~ g (67% of theory) of product, boiling point: 155 158C at 0.2 mbar.
Example 15 The follow;ng compounds of the formul.a I, listed in TabLe 5, are prepared in accordance with Example 14, but using equivalent quantities of compounds frorn Examples 9 10 or Table 3 ancl a corresponding acyl chloride:
Table 5 _ , ~9360;~
_ 30 -Tab l e 5 c.ont i nuPd _._______ __ C~T~R2 R3 ¦f rorn No. . Compoun~l __ ______ , _.___ (1~.) __ ___._
._ , _ _ 4.2 ~13 3.3 ~ _.. ___ 4.3 (~Cl 3.4 ___~_ 4 . 4CH 3 3 . 5 H C - C -C~3 ~ . .
_ .
4 . 5H 3 C~>- 3 . 6 _._ ___ _ ___ 4 . 6F3 C-~ 3 . 7 ___ _ __ ~
4.7-- Cl-~ 3.8 .
_ ____~._ __ _ ._ 4 . 8 H3 C-O-(~ 3 . 9 __.__ _ _. ____~____ _~
D ( ~ ) L F~ 3 . 1 4 ~
336~'~
Example 1/~
DL-2-t6-phenylpyridii1-2-oxy)-propyl isobutyrate A solution of 201 g of isobutyryl chloride -in 5 ml of methylene chloride is added dropwise, while st;rring and cooling at 0C, to a solut;on of 4.6 g of DL~2-~6-phenyl~
pyridin-2-oxy)-propanol ~frorn Example 9) in Z0 rnl of methyl.
ene chloricle and 2.2 g of tr;ethylan1;ne, ancl the m;xture is allowecl to warm up to room temperature and stirring ;s then cont;nued under reflux for 2 hoursu After cool;ng, tl-e rn;x~
ture is extracted by shakiny ~lith water, tl1e extract is worked up in a customary manner and the residue is d;stilled under a greatly reduced pressure~ This gives ~ g (67% of theory) of product, boiling point: 155 158C at 0.2 mbar.
Example 15 The follow;ng compounds of the formul.a I, listed in TabLe 5, are prepared in accordance with Example 14, but using equivalent quantities of compounds frorn Examples 9 10 or Table 3 ancl a corresponding acyl chloride:
Table 5 _ , ~9360;~
_ 30 -Tab l e 5 c.ont i nuPd _._______ __ C~T~R2 R3 ¦f rorn No. . Compoun~l __ ______ , _.___ (1~.) __ ___._
5 .1 O <~>Examp le P 0 2=155-1 58C
-c~2~c- (c~2) 2-CH3 9 D,L
~ ~__ ---- _ __ _ __ 5.2 O Example B,oO 5= 160-165 C
-c~2~C--tcrl- -bU~ ~ 9 D, L
. ~ _ . _ _ ___ _ _ ____ 5 . 3 O . . - E xamp l e Bp 0 6=175-1 80C~C
- ---- C~2 ~C~CH2~G~3~~C~3 ~C(CH ) _ ___ D~L
5 . 4 O Exarnp le Bp .0 3=1 65-1 70 C
_CH;~_O-C--C2H5 ~ 9 D,L
5 . 5 _ _ _ E x amp i e; Bp = 17 0-1-7~ C`
-CL~2~ C~ ~ 9 . D ~ O ~ 5 _ _ . _ _ ___ _ _ _ 5.6 O Example {~2{~-C~ ~ 9 . _ . ___ _._ _ .___ . _ 5. 7 O Examp le Mp : 62--64 C
_CL~2~C_C~;3 ~ 9 D, L
5 . 8 O --- ~ _~ E xamp l e Mp : 68~70C
C.~2~}C~ ~ 9 D, I, 5 . 9 O - - ~ _ _ . E x a m p l e _ ~ . . - __ Cf~2--(}C~> <~ 9 D,L
_ _ _ , _ _ _ _ ~ _.__ . _ 5 . 10 O E xamp l e Mp ~ 6~3-69 C
2~ C- ~3 ~Cl ~ 9 D, L
~ _ ~._ _~ _.__ _ _ 5. 1 1 _ Example -C~2~C--~ 3 C~
_~_ ~ ~ _.. ... _ ~_ ____ .
.
1~936~
_ 31 -Tab l e 5 c_nt i n ued C0,7~a ncl R2 R3 Prepared Nb~ f roin Co~ound ~ _ __ __ , , _ _ _~10 ) _ .. __ _ _.__ 5.12 0 Example -C~2~C4~ 0~-I3 (~ 9 . _ .. .. _ _ _, _............... ._ _.
5 . 13 -C~ -0 C- ~ CF ~ E x amp l e . _ ... . ------ ' ' ___ _____ _ 5.1'1 O C~l Example -CH2-0-C ~> ~ 9 . _ . . ~ _ _ .. _ ~
5. 15 ., _ Example Bp 0 3=153-155 C
D~+) CE~2~C-CH3 ~ 10[~)25 = ~3,4 ((:E-IC13) _ _ . _ _ .. __. . .......... ____ S.16 0 Example Bp 165-168C
D(+) -C~H2{~C-C2H5 ~ 10 0~25 0 _ _~ ~ (C~,C13) 5 . 17 = ~ _~ E x a mp l e o 2= 155-1 5bC
D(~-) -~I2-~C-C3~7 ~ 10 [C~J~5 = +3.2 (G'IC13 ) . _ . _ . . __ _ ______ 5.18 O Example E3p 0 2=155-158 C
D(+) -c~I2~~c-G~(G'I ) ~ 10 [Q]25 = + 3 3 _ __ _ _ ~ _ _ - _ 3 ___ 5.19 0 3.1 D ( +; CH2C) -C-C'H ~ _ _ __ _ . __~ _ _____ ~
5.20 0 3.14 V ( ~ ) "
5.21 _ ~___ ~___ D (+) -C~2~C-C~ (C7~3 ) 2 - F'-~>- 3 .14 . ~ __ __. ~ ~
~93~
~ 32-Tab l e S cont i nued Prepared Ccrrpound R2 R3 f rom No. Ccmpo~md 5 . 22 . ~___ _ __ _ ___(No. ) D (+) -CH2~C-C3~i7 ~) 3 . 14 . __ ___... __ __ ~_ 5 . 23 O M p: 75-76C
D(l) " 0~ Cl~- 3.10 [~)D = + 6.0 . ~_~ . __ ~ (~ICl3 ) 5. 2~ O Bp = 173-17~1 C
D (+) ~, Cl-~ 3 .10 ~5 . C~ICl3) _ ____ . . .. ____ 36V,'~
Exann~le 16 DL~2-(6-phenylpyr;din 2-oxy) propyl methyl ether A solution of ~.6 9 of DL-2-(6-phenylpyrid;n-2-oxy)-propanol (from Example ~) in 5 ml of absolute telra-hydrofuran (THF) is added dropwise, while stirr;ng at 20C~to a suspension oF 0.6 9 of YaH (~0% strength dispersion in oil~ în 30 ml of absolute THF, stirr;ng is continued until the evolut;on of hydrogen is complete, the mixture is cooled to ûC, a solution of 2.8 g of methyl iodide is added drop-wise, and the mixture is allol~ed to ~Jarrn up to room tempera~ture and is then boiled under reflux for 2 hours. After cooling, the solvent is removed under reduced pressure, work-ing up ;s carried out in a customary manner with water/methyl-ene chlor;de ~nd the residue is d;stilled under a ~reatly reducec! pressure. This gives 3.9 9 (8bx of theory) of pro-duct, boil;n~ po;nt 128-131C at 0.5 mbar.
Example 17 ~L-2~(6-phe _lpyrid;n-2 oxy)-propyl butyl ether 4.3 9 t75% of theory) of this product are obtained ;n accordance with Example 16, bu~ us;ng 4.~ 9 of DL-2-t6-phenylpyr;clirl-?-oxy)~propanol ~from Exanlple 5) and ?..7 g of n butyl bromidei Example 1 8 3L~2-(6~phenylpyridin 2~oxy~-propanal ?5 The exper;lment is carr;ed out under nitrogen as an ;nert gas. A solut;on of ~.78 ml of dirnethyl sulfox;de in 10 ml of ai~solute methylene chlor1de ;s added dropwise, wllile stirr;ng at -hOCo to a solution of 2.32 ml of oxaLyl chloride ;n 25 ml of absolute methylene chlor;der stirring is contirl-led 36~
~ 34 -for a further 5 m;nutes and a solu~;on of 3.7 g of DL-2-(6 phenylpyridin-2-oxy~ propanol (from Example 9) in 20 ml of absolute methylene chloride ;s then added all at oncen Stir ring is then continued at -60C for Z0 minutes, 1~4 ~l of triethylamine are added, the mixture is allowed to ~Jarm up slo~lly to room teMperature and 50 rnl of water are then added and the product is worked up in a customary manner. The residue is taken up in 40 rnl of ether, the sol~ltion is fil-tered through Celite and the solvent is removed under reclllced pressure. This gives ~ g (S6'~ of theory~ of a colorless oi l.
Examples of the preparation of compounds of the fornlula XI
Example 19
-c~2~c- (c~2) 2-CH3 9 D,L
~ ~__ ---- _ __ _ __ 5.2 O Example B,oO 5= 160-165 C
-c~2~C--tcrl- -bU~ ~ 9 D, L
. ~ _ . _ _ ___ _ _ ____ 5 . 3 O . . - E xamp l e Bp 0 6=175-1 80C~C
- ---- C~2 ~C~CH2~G~3~~C~3 ~C(CH ) _ ___ D~L
5 . 4 O Exarnp le Bp .0 3=1 65-1 70 C
_CH;~_O-C--C2H5 ~ 9 D,L
5 . 5 _ _ _ E x amp i e; Bp = 17 0-1-7~ C`
-CL~2~ C~ ~ 9 . D ~ O ~ 5 _ _ . _ _ ___ _ _ _ 5.6 O Example {~2{~-C~ ~ 9 . _ . ___ _._ _ .___ . _ 5. 7 O Examp le Mp : 62--64 C
_CL~2~C_C~;3 ~ 9 D, L
5 . 8 O --- ~ _~ E xamp l e Mp : 68~70C
C.~2~}C~ ~ 9 D, I, 5 . 9 O - - ~ _ _ . E x a m p l e _ ~ . . - __ Cf~2--(}C~> <~ 9 D,L
_ _ _ , _ _ _ _ ~ _.__ . _ 5 . 10 O E xamp l e Mp ~ 6~3-69 C
2~ C- ~3 ~Cl ~ 9 D, L
~ _ ~._ _~ _.__ _ _ 5. 1 1 _ Example -C~2~C--~ 3 C~
_~_ ~ ~ _.. ... _ ~_ ____ .
.
1~936~
_ 31 -Tab l e 5 c_nt i n ued C0,7~a ncl R2 R3 Prepared Nb~ f roin Co~ound ~ _ __ __ , , _ _ _~10 ) _ .. __ _ _.__ 5.12 0 Example -C~2~C4~ 0~-I3 (~ 9 . _ .. .. _ _ _, _............... ._ _.
5 . 13 -C~ -0 C- ~ CF ~ E x amp l e . _ ... . ------ ' ' ___ _____ _ 5.1'1 O C~l Example -CH2-0-C ~> ~ 9 . _ . . ~ _ _ .. _ ~
5. 15 ., _ Example Bp 0 3=153-155 C
D~+) CE~2~C-CH3 ~ 10[~)25 = ~3,4 ((:E-IC13) _ _ . _ _ .. __. . .......... ____ S.16 0 Example Bp 165-168C
D(+) -C~H2{~C-C2H5 ~ 10 0~25 0 _ _~ ~ (C~,C13) 5 . 17 = ~ _~ E x a mp l e o 2= 155-1 5bC
D(~-) -~I2-~C-C3~7 ~ 10 [C~J~5 = +3.2 (G'IC13 ) . _ . _ . . __ _ ______ 5.18 O Example E3p 0 2=155-158 C
D(+) -c~I2~~c-G~(G'I ) ~ 10 [Q]25 = + 3 3 _ __ _ _ ~ _ _ - _ 3 ___ 5.19 0 3.1 D ( +; CH2C) -C-C'H ~ _ _ __ _ . __~ _ _____ ~
5.20 0 3.14 V ( ~ ) "
5.21 _ ~___ ~___ D (+) -C~2~C-C~ (C7~3 ) 2 - F'-~>- 3 .14 . ~ __ __. ~ ~
~93~
~ 32-Tab l e S cont i nued Prepared Ccrrpound R2 R3 f rom No. Ccmpo~md 5 . 22 . ~___ _ __ _ ___(No. ) D (+) -CH2~C-C3~i7 ~) 3 . 14 . __ ___... __ __ ~_ 5 . 23 O M p: 75-76C
D(l) " 0~ Cl~- 3.10 [~)D = + 6.0 . ~_~ . __ ~ (~ICl3 ) 5. 2~ O Bp = 173-17~1 C
D (+) ~, Cl-~ 3 .10 ~5 . C~ICl3) _ ____ . . .. ____ 36V,'~
Exann~le 16 DL~2-(6-phenylpyr;din 2-oxy) propyl methyl ether A solution of ~.6 9 of DL-2-(6-phenylpyrid;n-2-oxy)-propanol (from Example ~) in 5 ml of absolute telra-hydrofuran (THF) is added dropwise, while stirr;ng at 20C~to a suspension oF 0.6 9 of YaH (~0% strength dispersion in oil~ în 30 ml of absolute THF, stirr;ng is continued until the evolut;on of hydrogen is complete, the mixture is cooled to ûC, a solution of 2.8 g of methyl iodide is added drop-wise, and the mixture is allol~ed to ~Jarrn up to room tempera~ture and is then boiled under reflux for 2 hours. After cooling, the solvent is removed under reduced pressure, work-ing up ;s carried out in a customary manner with water/methyl-ene chlor;de ~nd the residue is d;stilled under a ~reatly reducec! pressure. This gives 3.9 9 (8bx of theory) of pro-duct, boil;n~ po;nt 128-131C at 0.5 mbar.
Example 17 ~L-2~(6-phe _lpyrid;n-2 oxy)-propyl butyl ether 4.3 9 t75% of theory) of this product are obtained ;n accordance with Example 16, bu~ us;ng 4.~ 9 of DL-2-t6-phenylpyr;clirl-?-oxy)~propanol ~from Exanlple 5) and ?..7 g of n butyl bromidei Example 1 8 3L~2-(6~phenylpyridin 2~oxy~-propanal ?5 The exper;lment is carr;ed out under nitrogen as an ;nert gas. A solut;on of ~.78 ml of dirnethyl sulfox;de in 10 ml of ai~solute methylene chlor1de ;s added dropwise, wllile stirr;ng at -hOCo to a solution of 2.32 ml of oxaLyl chloride ;n 25 ml of absolute methylene chlor;der stirring is contirl-led 36~
~ 34 -for a further 5 m;nutes and a solu~;on of 3.7 g of DL-2-(6 phenylpyridin-2-oxy~ propanol (from Example 9) in 20 ml of absolute methylene chloride ;s then added all at oncen Stir ring is then continued at -60C for Z0 minutes, 1~4 ~l of triethylamine are added, the mixture is allowed to ~Jarm up slo~lly to room teMperature and 50 rnl of water are then added and the product is worked up in a customary manner. The residue is taken up in 40 rnl of ether, the sol~ltion is fil-tered through Celite and the solvent is removed under reclllced pressure. This gives ~ g (S6'~ of theory~ of a colorless oi l.
Examples of the preparation of compounds of the fornlula XI
Example 19
6-Phenylpyrid~2-one __ 1~ a) Methyl 5-phenyl-5-oY~opentanoate 3,220 g of acetophenone, 484 g of rnethyl acrylate, 80 g of isopropylamine and 2.7 g of benzoic acid are h~ated at 200C for 3 hours in a 5 liter autoclave. In addition to unreacted methyl acrylate and acetophenone, the subsequent distillation under reduced pressure gave 640 g of product, boiling point 175C at 7~5 mbar (55~5% of theory relative to methyl acrylate).
b) 6-Phenyl-3,4 dihydropylid-2-one 300 g of methyl 5 phenyl-5-oxopentanoate are heated to 180C in a 500 ml flask equipped with a descending con~
denser. Ammonia is then passed in for 3 hours. In the course oF this the \~ater and methanol formed d1stil c,Ff through the descending condenser~ After cooling~ the reactiol1 m1xture solidifies to give a mash of crystals. The mixt-lre is fil~ered ~93~13'h with suction and 130 g (53% of theory3 of product, melt;ng point 158C, are obtained. The mother liquor contains mainly unreacted starting material.
c) 6 Phenylpyrid-2-one 250 ml of methylbutyld;glycol and 5 9 of catalyst (2% strength Pd-on~charcoal) were added to 30 g o-f 6-phenyl-3,4~d;hydropyrid~2-one in a 500 ml glass flask equ;pped with a stirrer, a thermometer, a descending condenser and a gas meter. The apparatus ~las flushed w1th nitrogen and the methylbutyldiglycol was then heated to reflux temperature In the course of ~h;s ~.3 liters of exit gasr composed of 90% oF hydrogen, were formed dur;ng 5 hours. The apparatus was aga;n flushed ~;th N2; ~he solution was freed from the caLal,st by filtration ~!hi!e hot~ ~n coolln~; 25r3 9 (82X of theory) of product, melting poin'c 198C, crystallized out from the mother liquor.
The catalyst can be used againO Even a-Fter being employed ten times, the yield of 6-phenylpyrid~2~one is approxilnately 80%~
Z0 Example Z0 -The following compounds of 'he forlnula II, listed in Table 6, are prepared in accordance with Example 1~, but using corresponding quantit;es of a kecone of the -formula O
R3-C-CH-~ and of an acryl;c acid ester of the formula Cll .
Cl12=Cr~~C~O~C~l~5:
i~93Ei~
36 _ Table 6 ___ Il L
N~O
H
Con~nd R
No. 3 . Melt ing poi n-t; ~ (3 ~ .__ ___.__ 6. ~ M3C;~_ , _______, _ . _ ______ 6 . 2 C~13O~ 172-176 a~
6 . 3 _ . .. . . _ 1 7 0 - 1 7 5 a ) ~'3C-~
__ _ __. _ _ 6.4 ~CT~3 . . C 1 _ _._ ._ 6.S Cl~
~ _ _ ___ ~
6.6 F~- . 178-183 a~
. ~ _ ~ ~
6 .7 ____ ~_____ __ ~
6 . 8 . 2G3-204 _ Cl~-_~ __ . _ .~_ _ _ _ .
a) Melting point not sharp because of slight impllrities in the cc>rresponding 3,l~,.5,6-tetrahydropyridin-2-ones.
. , , 37 _ Table 6 contin~led _ _ C onpamd; R3 ....
No. . Melting point: Lc]
_ _. ~ .~
6.9 ~-Cl 6. 10 CH3 6.11 ¦
__
b) 6-Phenyl-3,4 dihydropylid-2-one 300 g of methyl 5 phenyl-5-oxopentanoate are heated to 180C in a 500 ml flask equipped with a descending con~
denser. Ammonia is then passed in for 3 hours. In the course oF this the \~ater and methanol formed d1stil c,Ff through the descending condenser~ After cooling~ the reactiol1 m1xture solidifies to give a mash of crystals. The mixt-lre is fil~ered ~93~13'h with suction and 130 g (53% of theory3 of product, melt;ng point 158C, are obtained. The mother liquor contains mainly unreacted starting material.
c) 6 Phenylpyrid-2-one 250 ml of methylbutyld;glycol and 5 9 of catalyst (2% strength Pd-on~charcoal) were added to 30 g o-f 6-phenyl-3,4~d;hydropyrid~2-one in a 500 ml glass flask equ;pped with a stirrer, a thermometer, a descending condenser and a gas meter. The apparatus ~las flushed w1th nitrogen and the methylbutyldiglycol was then heated to reflux temperature In the course of ~h;s ~.3 liters of exit gasr composed of 90% oF hydrogen, were formed dur;ng 5 hours. The apparatus was aga;n flushed ~;th N2; ~he solution was freed from the caLal,st by filtration ~!hi!e hot~ ~n coolln~; 25r3 9 (82X of theory) of product, melting poin'c 198C, crystallized out from the mother liquor.
The catalyst can be used againO Even a-Fter being employed ten times, the yield of 6-phenylpyrid~2~one is approxilnately 80%~
Z0 Example Z0 -The following compounds of 'he forlnula II, listed in Table 6, are prepared in accordance with Example 1~, but using corresponding quantit;es of a kecone of the -formula O
R3-C-CH-~ and of an acryl;c acid ester of the formula Cll .
Cl12=Cr~~C~O~C~l~5:
i~93Ei~
36 _ Table 6 ___ Il L
N~O
H
Con~nd R
No. 3 . Melt ing poi n-t; ~ (3 ~ .__ ___.__ 6. ~ M3C;~_ , _______, _ . _ ______ 6 . 2 C~13O~ 172-176 a~
6 . 3 _ . .. . . _ 1 7 0 - 1 7 5 a ) ~'3C-~
__ _ __. _ _ 6.4 ~CT~3 . . C 1 _ _._ ._ 6.S Cl~
~ _ _ ___ ~
6.6 F~- . 178-183 a~
. ~ _ ~ ~
6 .7 ____ ~_____ __ ~
6 . 8 . 2G3-204 _ Cl~-_~ __ . _ .~_ _ _ _ .
a) Melting point not sharp because of slight impllrities in the cc>rresponding 3,l~,.5,6-tetrahydropyridin-2-ones.
. , , 37 _ Table 6 contin~led _ _ C onpamd; R3 ....
No. . Melting point: Lc]
_ _. ~ .~
6.9 ~-Cl 6. 10 CH3 6.11 ¦
__
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a pyrid-2-one derivative of the formula I
I
stereoisomers thereof and salts thereof with physiologically acceptable acids or bases, wherein R1 denotes hydrogen or alkyl having 1 to 6 carbon atoms, R2 denotes a -CH=O, -COOR4 or -CH2-O-R5 group, R4 represents hydrogen, alkyl having 1 to 12 carbon atoms or benzyl, and R5 represents hydrogen, alkyl having 1 to 4 carbon atoms, alkanoyl having 1 to 9 carbon atoms, cycloalkanoyl having 4 to 7 carbon atoms, alkoxycarbonyl having 2 to 5 carbon atoms, phenoxycarbonyl or a benzoyl group which can carry one or two halogen, trifluoromethyl or alkyl or alkoxy substituents, each of which has 1 to 4 carbon atoms, and R3 represents 2-thienyl, 3-thienyl, tert.-butyl or a phenyl group which can carry one or two substituents denoting halogen, trifluoromethyl or alkyl or alkoxy, each of which has 1 to 4 carbon atoms, in which a compound of the formula II
II
wherein R3 is as defined above is reacted with a compound of the formula III
(IMAGE) III
wherein R1 and R2 are as defined above and X represents halogen, alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy or the radical of a reactive ester.
I
stereoisomers thereof and salts thereof with physiologically acceptable acids or bases, wherein R1 denotes hydrogen or alkyl having 1 to 6 carbon atoms, R2 denotes a -CH=O, -COOR4 or -CH2-O-R5 group, R4 represents hydrogen, alkyl having 1 to 12 carbon atoms or benzyl, and R5 represents hydrogen, alkyl having 1 to 4 carbon atoms, alkanoyl having 1 to 9 carbon atoms, cycloalkanoyl having 4 to 7 carbon atoms, alkoxycarbonyl having 2 to 5 carbon atoms, phenoxycarbonyl or a benzoyl group which can carry one or two halogen, trifluoromethyl or alkyl or alkoxy substituents, each of which has 1 to 4 carbon atoms, and R3 represents 2-thienyl, 3-thienyl, tert.-butyl or a phenyl group which can carry one or two substituents denoting halogen, trifluoromethyl or alkyl or alkoxy, each of which has 1 to 4 carbon atoms, in which a compound of the formula II
II
wherein R3 is as defined above is reacted with a compound of the formula III
(IMAGE) III
wherein R1 and R2 are as defined above and X represents halogen, alkylsulfonyloxy, substituted or unsubstituted arylsulfonyloxy or the radical of a reactive ester.
2. A process as claimed in claim 1 in which the compound of the formula II is prepared by a process in which a compound of the formula IV
IV
is reacted with an acrylic acid ester of the formula V
V
to give a compound of the formula VI
VI
this compound is then cyclized by means of ammonia to give a compound of the formula VII
VII
and the latter is finally dehydrogenated to give a compound of the formula II, R3 in the above formula having the meaning mentioned in claim 1 and R6 being an alkyl radical having 1 to 6 carbon atoms.
IV
is reacted with an acrylic acid ester of the formula V
V
to give a compound of the formula VI
VI
this compound is then cyclized by means of ammonia to give a compound of the formula VII
VII
and the latter is finally dehydrogenated to give a compound of the formula II, R3 in the above formula having the meaning mentioned in claim 1 and R6 being an alkyl radical having 1 to 6 carbon atoms.
3. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or claim 2 or by an obvious chemical equivalent thereof.
4. A process as claimed in claim 1 wherein a compound of the formula I in which R2 is -CH=O or a -CH2-O-R5 group is prepared by reducing a compound of the formula I in which R2 is a -COOR4 group, to give the -CH2OH group, then oxidizing this group to give the -CH=O
group or reacting this group with an alkylating or acylating agent to give the -CH2-O-R5 group.
group or reacting this group with an alkylating or acylating agent to give the -CH2-O-R5 group.
5. A pyrid-2-one derivative of the formula I as set forth in claim 1 wherein R1, R3, R4, and R5 are as defined in claim 1 and R2 is as defined in claim 4, whenever obtained according to a process as claimed in claim 4 or by an obvious chemical equivalent thereof.
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3211395.1 | 1982-03-27 | ||
| DE19823211395 DE3211395A1 (en) | 1982-03-27 | 1982-03-27 | PYRIDON-2 DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1193602A true CA1193602A (en) | 1985-09-17 |
Family
ID=6159523
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000424485A Expired CA1193602A (en) | 1982-03-27 | 1983-03-25 | Pyrid-2-one derivatives, a process for their manufacture and pharmaceutical preparations containing them |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0090353A1 (en) |
| JP (1) | JPS58174365A (en) |
| KR (1) | KR840004075A (en) |
| AU (1) | AU1287083A (en) |
| CA (1) | CA1193602A (en) |
| DE (1) | DE3211395A1 (en) |
| DK (1) | DK138383A (en) |
| ES (1) | ES520986A0 (en) |
| FI (1) | FI831008L (en) |
| GR (1) | GR78498B (en) |
| IL (1) | IL68240A0 (en) |
| NO (1) | NO831094L (en) |
| PH (1) | PH19639A (en) |
| PT (1) | PT76449B (en) |
| ZA (1) | ZA832138B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5366982A (en) * | 1990-07-24 | 1994-11-22 | Rhone-Poulenc Rorer S.A. | Substituted bicyclic bis-aryl compounds exhibiting selective leukotriene B4 antagonist activity, their preparation and use in pharmaceutical compositions |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3346175A1 (en) * | 1983-12-21 | 1985-07-11 | Merck Patent Gmbh, 6100 Darmstadt | PYRIDYLTHIOPHENE |
| DE4227748A1 (en) * | 1992-08-21 | 1994-02-24 | Bayer Ag | Pyridyloxy-acrylic acid ester |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3655897A (en) * | 1971-01-25 | 1972-04-11 | Merck & Co Inc | Anti-inflammatory agents |
-
1982
- 1982-03-27 DE DE19823211395 patent/DE3211395A1/en not_active Withdrawn
-
1983
- 1983-03-23 GR GR70886A patent/GR78498B/el unknown
- 1983-03-24 EP EP83102926A patent/EP0090353A1/en not_active Withdrawn
- 1983-03-24 FI FI831008A patent/FI831008L/en not_active Application Discontinuation
- 1983-03-25 ES ES520986A patent/ES520986A0/en active Granted
- 1983-03-25 NO NO831094A patent/NO831094L/en unknown
- 1983-03-25 CA CA000424485A patent/CA1193602A/en not_active Expired
- 1983-03-25 KR KR1019830001216A patent/KR840004075A/en not_active Application Discontinuation
- 1983-03-25 JP JP58049106A patent/JPS58174365A/en active Pending
- 1983-03-25 DK DK138383A patent/DK138383A/en not_active IP Right Cessation
- 1983-03-25 ZA ZA832138A patent/ZA832138B/en unknown
- 1983-03-25 IL IL68240A patent/IL68240A0/en unknown
- 1983-03-25 PT PT76449A patent/PT76449B/en unknown
- 1983-03-25 PH PH28693A patent/PH19639A/en unknown
- 1983-03-25 AU AU12870/83A patent/AU1287083A/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5366982A (en) * | 1990-07-24 | 1994-11-22 | Rhone-Poulenc Rorer S.A. | Substituted bicyclic bis-aryl compounds exhibiting selective leukotriene B4 antagonist activity, their preparation and use in pharmaceutical compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| DK138383A (en) | 1983-09-28 |
| FI831008A0 (en) | 1983-03-24 |
| PT76449B (en) | 1986-01-27 |
| PT76449A (en) | 1983-04-01 |
| PH19639A (en) | 1986-06-04 |
| ES8401943A1 (en) | 1984-01-01 |
| GR78498B (en) | 1984-09-27 |
| DK138383D0 (en) | 1983-03-25 |
| KR840004075A (en) | 1984-10-06 |
| EP0090353A1 (en) | 1983-10-05 |
| NO831094L (en) | 1983-09-28 |
| JPS58174365A (en) | 1983-10-13 |
| ZA832138B (en) | 1983-12-28 |
| FI831008L (en) | 1983-09-28 |
| IL68240A0 (en) | 1983-06-15 |
| DE3211395A1 (en) | 1983-09-29 |
| ES520986A0 (en) | 1984-01-01 |
| AU1287083A (en) | 1983-09-29 |
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