CA1198107A - 4h-thiopyrans, process for their preparation and their use in medicaments - Google Patents
4h-thiopyrans, process for their preparation and their use in medicamentsInfo
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- CA1198107A CA1198107A CA000425122A CA425122A CA1198107A CA 1198107 A CA1198107 A CA 1198107A CA 000425122 A CA000425122 A CA 000425122A CA 425122 A CA425122 A CA 425122A CA 1198107 A CA1198107 A CA 1198107A
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
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- General Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Dental Preparations (AREA)
- Materials For Medical Uses (AREA)
- Luminescent Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Paper (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
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Abstract
ASTRACT OF THE DISCLOSURE
Thiopyrans of the formula in which R is an optionally substituted aryl or heterocyclic radical, R1, R3 and R4 each independently is hydrogen, an achiral alkyl radical, an optionally substituted aryl or heterocyclic radical, or one of R1 and R4 is bridged via a ring with R, R2 is hydrogen, alkyl, aryl, carboxyalkyl or amino-alkyl, and X is O, S or NH, are produced by reacting a thione of the formula with an acetylene compound of the formula
Thiopyrans of the formula in which R is an optionally substituted aryl or heterocyclic radical, R1, R3 and R4 each independently is hydrogen, an achiral alkyl radical, an optionally substituted aryl or heterocyclic radical, or one of R1 and R4 is bridged via a ring with R, R2 is hydrogen, alkyl, aryl, carboxyalkyl or amino-alkyl, and X is O, S or NH, are produced by reacting a thione of the formula with an acetylene compound of the formula
Description
/
The present invention relates to a new and chemic-ally ori3inal process ~or the preparation of new thiopyr-ans and to their use in medicaments, in particular in agents affecting the circulation.
It has already been disclosed that ~unsaturated thiones are able to take part in ~iels-Alder reactions (con~pare Nishio et al~, J. Heterocycl. Chem. 17, 405 ~1980), Smuthy, Turner, Tetrahedron 23, 3785 ~1967), Smuthy, J. Am. Chem. Soc. 91, Z0~ ~1969), Kalish, Tetra-10 hedron Lett. 1971, 2241).
Diels-Alder reactions of ~ s~unSaturated thione esters have not hitherto been disclosed (preparation:
compare Scheithauer, Mayer, Chem. Ber. 100, 1413 ~1967), Barnikow, Strickmann, Chem. Ber. 100r 1428 ~1967) with 15 acetylenes, which would lead to 2-alkoxythiopyrans.
The present invention relates to new thiopyrans of the general formula ~I), R OOC ~ COOR ~ I
R2 S ~R
in which R represents aryl, furyl, pyrryl, pyrazolyl, imid-azolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, ind-olyl, benzimidazolyl, quinazolyl or quinoxalyl, the aryl radical and the heterocycles mentioned optionally contain 1, 2 or 3 identical or differ-ent substituents from the group comprising phenyl, alkyl, alkenyl, alkinyl, alkoxy, alkylene, dioxy-alkylene, halogen, trifluoromethyl" trifluoro-Le A 21 553 methoxy, alkylamino, nitro, cyano, azido or car-boxamido, R1, R3 and R4 are iden-t;cal or different and each represent hydrogen or an achiral straigh~-chain or branched alkyl radical, or each represent one of the radicals listed in the definition of R and are identical to or different from this, or wherein one of the rad;cals R1 or R4 can be br;dged via a r;ng with the radical R~
R2 represents hydrogen, alkyl, aryl, carboxy-alkyl or aminoalkyl and X represents 0, S or NH, and their pharmacologically acceptable acid addition sa~ts.
The invention also relates to a process for the preparation of comPounds of the general formula (I), which is characterised in that th;ones of the general formula (II) R
R OOC ~
20 ¦ (II) R3X ~ S
;n which R, R3~ R4 and X have the abovementioned meanings, are reacted, at temperatures between 0 and 200C~ opti-onally in the presence of inert organic solvents, w;th acetylene compounds of the general formula (III) Ic, 2 ( I I I
in which Le A 21 553 ~ 3 -R1 and R2 have the abovementioned meanings.
If methyl benzylideneth;onomalonate and methyl acetylenecarboxylate are used, the course of the reaction can be represented by the following equation:
EI3COOC ~ ~
CH 300C I ~COOCH 3 C l~,COOCH3 Q ~ ~
S OCH 3 1 0 0 C H 5~ OCH 3 The benzylidenethionomalonic esters of the gen-eral formula (II) used as starting materials are known or can be prepared by known methods (Scheithauer and Mayer, Chem. Ler. 100, 1413 (1967), Barnikow, Strickmann, Chem. Ber. 100, 1428 (1967)~.
The acetylenecarboxylic esters of the general formula (III) used as starting materials are also known or can be orepared by known processes.
The acetylenecarboxylic esters of the formula 15 (III), employed in excess, or inert organic solvents, such as toluene, ethanol~ dio~ane or ethylene glycol, can serve as the solvent.
In carrying out the process according to the invent;on, the temperature range preferably used is from 20 0 to 20ûC, in particular in a range from 50 to 150C.
The reaction is customarily carried out under normal pressure, but can also be carried out under ele-vated pressure.
The new thiopyrans of the general formula (I) according to the invention have valuable pharmacological properties. Qwing to their action affecting the circula-tion, they can be used as vasodiiators and as coronary therapeutic agents and are thus to be regarded as an Le A 21 553 enrichment of pharmacy.
Compounds of the general formula (I) are of par ticular interest, in ~hich R represents phenyl~ naphthyl, furyl, pyrryl or pyridyl, these rings optionally containing 1, 2 or 3 identical or different substituents from the group comprising phenyl, alkyl, alkenyl, alkinyl, alkoxy, alkylene, dioxyalkylene, alkylamino, each having up to 4 carbon atoms, halogen, trifluoro-methyl, trifluoromethoxy, nitro, cyano, azido or carboxamido, R1, R3 and R4 are ;clentical or different and each represent hydrogen or an alkyl radical hav-ing up to 6 carbon atoms, or represent one of the radicals mentioned under R, or ~Jherein the radi-cals R4 and R can be bridged together via a 6-or 7-membered ring, R2 represents hydrogen, an alkyl radical having up to 4 carbon atoms, phenyl, carboxyalkyl having up to 6 carbon atoms or aminoalkyl having up to 4 carbon atoms, and X represents 0, S or -NH-~
Compounds of the general formula ~I) are of very Z5 particular interest, in which R represents phenyl, naphthyl or pyridyl, these rings optionally containing 1 or 2 identical or different substituents from the group comprising phenyl., alkyl, alkoxy, alkylene, dioxyalkylene, alkylamino, each having up to 4 carbon atoms~
halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano, azido or carboxamido, R1, R3 and R4 are identical or different and each represent hydrogen or an alkyl radical having up to 4 carbon atoms or phenyl~ or wherein Le A 21 553 the radicals R4 and R can be bridged via a 6-membered ring, R~ represents hydrogen, an alkyl radical having up to 4 carbon atoms, phenyl, carboxyalkyl having up to 6 carbon atoms or aminoalkyl having up to 4 carbon atomsJ and X represents 0, S or -NH-.
The compounds of the general formula ~I) exhibit interest;ng biolog;cal effects. They possess a wide and diverse spectrum of pharmacological actionO In particu-lar, the following ma;n effects may be mentioned:
1. The compounds, on parenteral, oral and perlingual administration, bring about a marked and long-lasting d;latation of the coronary vessels. This effect on the coronary vessels is intensified by a concurrent relieving effect on the heart resembling nitrites.
They affect or change the cardiac metabolism in the sense of an energy saving.
The present invention relates to a new and chemic-ally ori3inal process ~or the preparation of new thiopyr-ans and to their use in medicaments, in particular in agents affecting the circulation.
It has already been disclosed that ~unsaturated thiones are able to take part in ~iels-Alder reactions (con~pare Nishio et al~, J. Heterocycl. Chem. 17, 405 ~1980), Smuthy, Turner, Tetrahedron 23, 3785 ~1967), Smuthy, J. Am. Chem. Soc. 91, Z0~ ~1969), Kalish, Tetra-10 hedron Lett. 1971, 2241).
Diels-Alder reactions of ~ s~unSaturated thione esters have not hitherto been disclosed (preparation:
compare Scheithauer, Mayer, Chem. Ber. 100, 1413 ~1967), Barnikow, Strickmann, Chem. Ber. 100r 1428 ~1967) with 15 acetylenes, which would lead to 2-alkoxythiopyrans.
The present invention relates to new thiopyrans of the general formula ~I), R OOC ~ COOR ~ I
R2 S ~R
in which R represents aryl, furyl, pyrryl, pyrazolyl, imid-azolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, ind-olyl, benzimidazolyl, quinazolyl or quinoxalyl, the aryl radical and the heterocycles mentioned optionally contain 1, 2 or 3 identical or differ-ent substituents from the group comprising phenyl, alkyl, alkenyl, alkinyl, alkoxy, alkylene, dioxy-alkylene, halogen, trifluoromethyl" trifluoro-Le A 21 553 methoxy, alkylamino, nitro, cyano, azido or car-boxamido, R1, R3 and R4 are iden-t;cal or different and each represent hydrogen or an achiral straigh~-chain or branched alkyl radical, or each represent one of the radicals listed in the definition of R and are identical to or different from this, or wherein one of the rad;cals R1 or R4 can be br;dged via a r;ng with the radical R~
R2 represents hydrogen, alkyl, aryl, carboxy-alkyl or aminoalkyl and X represents 0, S or NH, and their pharmacologically acceptable acid addition sa~ts.
The invention also relates to a process for the preparation of comPounds of the general formula (I), which is characterised in that th;ones of the general formula (II) R
R OOC ~
20 ¦ (II) R3X ~ S
;n which R, R3~ R4 and X have the abovementioned meanings, are reacted, at temperatures between 0 and 200C~ opti-onally in the presence of inert organic solvents, w;th acetylene compounds of the general formula (III) Ic, 2 ( I I I
in which Le A 21 553 ~ 3 -R1 and R2 have the abovementioned meanings.
If methyl benzylideneth;onomalonate and methyl acetylenecarboxylate are used, the course of the reaction can be represented by the following equation:
EI3COOC ~ ~
CH 300C I ~COOCH 3 C l~,COOCH3 Q ~ ~
S OCH 3 1 0 0 C H 5~ OCH 3 The benzylidenethionomalonic esters of the gen-eral formula (II) used as starting materials are known or can be prepared by known methods (Scheithauer and Mayer, Chem. Ler. 100, 1413 (1967), Barnikow, Strickmann, Chem. Ber. 100, 1428 (1967)~.
The acetylenecarboxylic esters of the general formula (III) used as starting materials are also known or can be orepared by known processes.
The acetylenecarboxylic esters of the formula 15 (III), employed in excess, or inert organic solvents, such as toluene, ethanol~ dio~ane or ethylene glycol, can serve as the solvent.
In carrying out the process according to the invent;on, the temperature range preferably used is from 20 0 to 20ûC, in particular in a range from 50 to 150C.
The reaction is customarily carried out under normal pressure, but can also be carried out under ele-vated pressure.
The new thiopyrans of the general formula (I) according to the invention have valuable pharmacological properties. Qwing to their action affecting the circula-tion, they can be used as vasodiiators and as coronary therapeutic agents and are thus to be regarded as an Le A 21 553 enrichment of pharmacy.
Compounds of the general formula (I) are of par ticular interest, in ~hich R represents phenyl~ naphthyl, furyl, pyrryl or pyridyl, these rings optionally containing 1, 2 or 3 identical or different substituents from the group comprising phenyl, alkyl, alkenyl, alkinyl, alkoxy, alkylene, dioxyalkylene, alkylamino, each having up to 4 carbon atoms, halogen, trifluoro-methyl, trifluoromethoxy, nitro, cyano, azido or carboxamido, R1, R3 and R4 are ;clentical or different and each represent hydrogen or an alkyl radical hav-ing up to 6 carbon atoms, or represent one of the radicals mentioned under R, or ~Jherein the radi-cals R4 and R can be bridged together via a 6-or 7-membered ring, R2 represents hydrogen, an alkyl radical having up to 4 carbon atoms, phenyl, carboxyalkyl having up to 6 carbon atoms or aminoalkyl having up to 4 carbon atoms, and X represents 0, S or -NH-~
Compounds of the general formula ~I) are of very Z5 particular interest, in which R represents phenyl, naphthyl or pyridyl, these rings optionally containing 1 or 2 identical or different substituents from the group comprising phenyl., alkyl, alkoxy, alkylene, dioxyalkylene, alkylamino, each having up to 4 carbon atoms~
halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano, azido or carboxamido, R1, R3 and R4 are identical or different and each represent hydrogen or an alkyl radical having up to 4 carbon atoms or phenyl~ or wherein Le A 21 553 the radicals R4 and R can be bridged via a 6-membered ring, R~ represents hydrogen, an alkyl radical having up to 4 carbon atoms, phenyl, carboxyalkyl having up to 6 carbon atoms or aminoalkyl having up to 4 carbon atomsJ and X represents 0, S or -NH-.
The compounds of the general formula ~I) exhibit interest;ng biolog;cal effects. They possess a wide and diverse spectrum of pharmacological actionO In particu-lar, the following ma;n effects may be mentioned:
1. The compounds, on parenteral, oral and perlingual administration, bring about a marked and long-lasting d;latation of the coronary vessels. This effect on the coronary vessels is intensified by a concurrent relieving effect on the heart resembling nitrites.
They affect or change the cardiac metabolism in the sense of an energy saving.
2. The excitability of the impulse formation and conduction system within the heart is decreased so that an antifibrillation effect results which is detectable in therapeutic doses.
3. The tone of the smooth muscle of the vessels is greatly decreased under the action of the compounds. This vasospasmolytic effect can take place in the entire vascu-lar system~ or can manifest itself in more or less isola-ted restricted vascular areas (such as, for example, in the central nervous system).
4~ The compounds decrease the blood pressure of nor-motensive and hypertensive animals and can thus be usedas antihypertensive agents.
5. The compounds have positive inotropic effects and can thus be used as cardiotonic agents.
6. The compounds have strong muscular-spasmolytic effects, which are manifested on the smooth muscle of the stomach, intestinal tract~ the urogenital tract and the Le A 21 553 respirat;on system.
The new active compounds can be converted, in a known manner, into the customary formulations, such as tablets, capsules, coated tablets, pills, granules, aero-sols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic pharmaceutically stable vehicles or sol-vents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, that is to say in amounts which suffice to achieve the dosage range indicated.
The formulations are prepared~ for example, by extending the active compounds with solvents and/or veh;cles, optionally with the use of emulsifiers and/or dispersing agents, and, for example, when using water as a diluent, organic sol~ents can optionally be used as auxiliary solvents.
Examples of auxiliaries whicn may be mentioned are:
Water, non-toxic organic solvents, such as paraf-fins (for example petroleum fractions), vegetable oils (for example groundnut oil/sesame oil), alcohols (for example ethyl alcohol and glycerol~, glycols (for example propylene glycol and polyethylene glycol), solid vehicles, such as, for example, natural roclc powders (for example kaolins, aluminas, talc and chalk), synth'etic rock pow-ders (for example highly disperse silica and silicates), sugars (for example sucrose, lactose and glucose), emul~
s;fiers (for example polyoxyethylene fatty acid esters, 3û polyoxyethylene fatty alcohol ethers~ alkyl sulphonates and aryl sulphonates)~ dispersing agen~s (for example l;gnin, sulph;te waste l;quors, methyLcelluLose, starch and polyvinylpyrrolidone) and lubricants (for example magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
Administration is effected in the customary manner, Le A 21 553 preferably orally or parenterally, in particular perlin gually or ;ntravenously. In the case of oral admin;stra-tion~ the tablets can, of course, also contain, in addi-tion to the vehicles mentioned, additives such as sodium citrate, calcium carbonate and dicalcium phosphate~ to-gether with various additional substances, such as starch, preferably potato starch, gelatin and the like. Further-more, lubricants such as magnesium stearate~ sodium lauryl sulphate and talc can be co-used when making tablets. In the case of aqueo~s suspensions and/or elixirs which are intended for oral use, the active compounds can be mixed with various flavour-improving agents or colorants in addition to the abovementioned auxiliaries.
In the case of parenteral administration, solu-tions of the active compounds, employing suitable liquidvehicles, can be used.
In general, it has proved advantageous, in ~he case of intravenous administration~ to administer amounts of about 0.0l to 10 mg/kg, preferably about 0O05 to 5 m~/kg of body weight daily to achieve effec~ive results, and in the case of oral administration, the dosage is about 0.05 to 20 m~/kg, preferably 0.5 to 5 mg/kg of body weight daily.
Nevertheless~ it can at times be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight of the experimen-tal animal or of the nature of the administration method, but also because of the species of animal and its ind;~
vidual behaviour towards the medicament, and the nature or the formulation of the medicament and ~he time or ;nterval over wh;ch the adm;nistration takes place. Thus it can suffice in some cases to manage with less than the abovementioned minimum amount, whilst in other cases the upper limit mentioned must be exceeded. Where relatively large amounts are administered, it can be advisable to divide these into several individual administrations over Le A 21 553 the course of the day. The same dosaye range is envisaged for administration in human medicine. In this connection, the above statements similarLy apply.
Example 1 Dimethyl 4-(2,4 dichlorophenyl)-2-methoxy-4H--thiopyran-3,5 dicarboxylate [ ~ Cl CH 300C / ~COOCH 3 301 9 (10 mmols) of dimethyl Z,4-dichlorobenzyl~
idenethionomalonate were heated to reflux with 6 ml of methyl propiolate for 3 hours. All volatiles were dis-tilled off in vacuo. 2.7 9 (70%~ were obtained as an oi l.
H-NMR (CDCl3):S3.6 Ss,6H), 3.9 (s,3H), 5.6 (s~1H),
The new active compounds can be converted, in a known manner, into the customary formulations, such as tablets, capsules, coated tablets, pills, granules, aero-sols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic pharmaceutically stable vehicles or sol-vents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, that is to say in amounts which suffice to achieve the dosage range indicated.
The formulations are prepared~ for example, by extending the active compounds with solvents and/or veh;cles, optionally with the use of emulsifiers and/or dispersing agents, and, for example, when using water as a diluent, organic sol~ents can optionally be used as auxiliary solvents.
Examples of auxiliaries whicn may be mentioned are:
Water, non-toxic organic solvents, such as paraf-fins (for example petroleum fractions), vegetable oils (for example groundnut oil/sesame oil), alcohols (for example ethyl alcohol and glycerol~, glycols (for example propylene glycol and polyethylene glycol), solid vehicles, such as, for example, natural roclc powders (for example kaolins, aluminas, talc and chalk), synth'etic rock pow-ders (for example highly disperse silica and silicates), sugars (for example sucrose, lactose and glucose), emul~
s;fiers (for example polyoxyethylene fatty acid esters, 3û polyoxyethylene fatty alcohol ethers~ alkyl sulphonates and aryl sulphonates)~ dispersing agen~s (for example l;gnin, sulph;te waste l;quors, methyLcelluLose, starch and polyvinylpyrrolidone) and lubricants (for example magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
Administration is effected in the customary manner, Le A 21 553 preferably orally or parenterally, in particular perlin gually or ;ntravenously. In the case of oral admin;stra-tion~ the tablets can, of course, also contain, in addi-tion to the vehicles mentioned, additives such as sodium citrate, calcium carbonate and dicalcium phosphate~ to-gether with various additional substances, such as starch, preferably potato starch, gelatin and the like. Further-more, lubricants such as magnesium stearate~ sodium lauryl sulphate and talc can be co-used when making tablets. In the case of aqueo~s suspensions and/or elixirs which are intended for oral use, the active compounds can be mixed with various flavour-improving agents or colorants in addition to the abovementioned auxiliaries.
In the case of parenteral administration, solu-tions of the active compounds, employing suitable liquidvehicles, can be used.
In general, it has proved advantageous, in ~he case of intravenous administration~ to administer amounts of about 0.0l to 10 mg/kg, preferably about 0O05 to 5 m~/kg of body weight daily to achieve effec~ive results, and in the case of oral administration, the dosage is about 0.05 to 20 m~/kg, preferably 0.5 to 5 mg/kg of body weight daily.
Nevertheless~ it can at times be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight of the experimen-tal animal or of the nature of the administration method, but also because of the species of animal and its ind;~
vidual behaviour towards the medicament, and the nature or the formulation of the medicament and ~he time or ;nterval over wh;ch the adm;nistration takes place. Thus it can suffice in some cases to manage with less than the abovementioned minimum amount, whilst in other cases the upper limit mentioned must be exceeded. Where relatively large amounts are administered, it can be advisable to divide these into several individual administrations over Le A 21 553 the course of the day. The same dosaye range is envisaged for administration in human medicine. In this connection, the above statements similarLy apply.
Example 1 Dimethyl 4-(2,4 dichlorophenyl)-2-methoxy-4H--thiopyran-3,5 dicarboxylate [ ~ Cl CH 300C / ~COOCH 3 301 9 (10 mmols) of dimethyl Z,4-dichlorobenzyl~
idenethionomalonate were heated to reflux with 6 ml of methyl propiolate for 3 hours. All volatiles were dis-tilled off in vacuo. 2.7 9 (70%~ were obtained as an oi l.
H-NMR (CDCl3):S3.6 Ss,6H), 3.9 (s,3H), 5.6 (s~1H),
7.1-7.6 (m,4H~
The following were prepared in analogy to Example 1:
Example 2 Diethyl 4-(4-nitrophenyl)-2-ethoxy-4H-thiopyran-3,5-dicar-boxylate '~2 5 2 ~ 2 5 From diethyl 4-nitrobenzylidenethionomalona-te and ethyl propiolate dissolved in 5 ml of toluene.
Le A 21 553 H-NMR (CDCl3):~- 1.25 (t, J-7Hz, 6H), 1.4 (t, J=7H%, 3H), 4.2 (q, J-7Hz~ 6H), 5.5 (s, 1H), 7.6 (s, 1H), 7.6 (d, J=9Hz, ZH),
The following were prepared in analogy to Example 1:
Example 2 Diethyl 4-(4-nitrophenyl)-2-ethoxy-4H-thiopyran-3,5-dicar-boxylate '~2 5 2 ~ 2 5 From diethyl 4-nitrobenzylidenethionomalona-te and ethyl propiolate dissolved in 5 ml of toluene.
Le A 21 553 H-NMR (CDCl3):~- 1.25 (t, J-7Hz, 6H), 1.4 (t, J=7H%, 3H), 4.2 (q, J-7Hz~ 6H), 5.5 (s, 1H), 7.6 (s, 1H), 7.6 (d, J=9Hz, ZH),
8.1 (d, J=9Hz, 2H).
S MS: 407 (M+, 11%), 334 (100%), 211 (80%).
Yield: 90%
Example 3 Diethyl 4-(3-nitrophenyl)-2-ethoxy~4H-thiopyran-3,5-di-carboxylate ~--N02 H 5C 200C _~ COOC 2H 5 ~5c2o ~1 From diethyl 3-nitrobenzylidenethionomalonate and ethyl propiolate H-NMR (CDCl3) :~- 1 .3 (t~ J=8Hz, 6H), 1.45 (t, J=8Hz, 3H), 4.1-4.4 (m, 6H), 5.5 (s, 1H), 7.S
(t, J=7Hz, 1H), 7.65 (s, 1H~, 7.85 (d, J=7Hz, 1H), 8.1 (d, J=7Hz, 1H), 8.35 (s, 1H).
Yield: 40% (after chromatography with CHCl3 on s;lica gel).
Example 4 Diethyl 4 (2-trifluoromethylphenyl)-2-ethoxy-4H-thiopyran-3,5-dicarboxylate H 5C 200C ~, COOC 2H 5 Le A 21 553 H-NMR (CDCl3)~ 1.6 (m, 9H~, 3.9-4.5 (m, 6H)~
5.8 (s, 1H), 7.3-8.1 (m, 5H).
Yield: 75%
Example 5 Dimethyl 4 (2-chlorophenyl)~2-methoxy-4H-thiopyran 3,5-dicarboxylate ~1 CH 300C ~cC OOC H 3 H-NMR (CDCl3):~= 3.65 (s, 6H), 3.8 (s, 3H), 5.65 (s, 1H)~
7.0-7.6 (m, 4H), 7.55 (s, 1H).
MS: 354 (M~, 2~), 295 (7%), 235 (100%).
Yield: 77%
Example 6 Dimethyl 4-(3-chlorophenyl)-2-methoxy-4H-thiopyran-3,5-dicarboxylate ~o~Cl CH 300C ~ COOCH 3 Melting point: 85 - 87 Yield: 43%
Example 7 Methyl 4-methoxy-9-nitro-5-oxo~5H,10bH thiopyrano~3,4-c]-Le A 21 553 1-benzopyr.~n-1-carboxylate CE~ 3o S H
Yield 2.Z 9 (60%), melting point: 230C (from ethyl acetate).
S Example 8 Ethyl 4-ethoxy-5-oxo-5H,10bH~thiopyranoC3,4~c]-1-benzo-pyran-1-carboxylate H~C20 ~COOC2H5 Melting point: 135 - 136C (from ace~one) Yield: 80%
Example 9 Ethyl 4-ethoxy-9-nitro-5-oxo-SH,10bH-thiopyranoC3,4~c]-1-benzopyran-1-carboxylate o~
~ COOC 2H5 Melting point: 131 - 133C (from ethanol) Yield: 67X
Le A 21 553 Exarnple 10 Ethyl 9-bromo-4-ethoxy-5-oxo-5H,10bH~thiopyranoC3,4-c]-1-benzopyran-1-carboxyLate $,Br O~C OOC 2 H 5 1H-NMR (CDCl3):~= 1.3 and 1.35 (2t, J=7Hz, each 3H~, 4.1 and 4.3 (2q, J=7Hz, each 2H), 5.1 (s, 1H)r 6.3 7.8 ~, 3H), 7.6 (s, 1H).
Yield: 74%
Example 11 Ethyl 7,9 dichloro-4-ethoxy-5-oxo-5H,10bH thiopyrano-[3,4-c]-1-benzopyran-1-carboxylate C.~,Cl ~ COOC 2H 5 Melting point: 148 - 149C
Yield: 86%
Example 12 Methyl 7,9-dichloro-4-methoxy-5~oxo 5H,10bH-thiopyrano-C3,4-c]-1-benzopyran-1-carboxylate Le A 21 553 C ,~
/~, C OOC H 3 "H3 S H
Melting po;nt: 202 - 203C (from ethyl acetate) Yield: 56%
Example 13 S Methyl 4-ethoxy-9-nitro-5-oxo-5H,10bH-thiopyranoC3,4-c]~
1-benzopyran-1-carboxylate NO
S ~
Melting point: 156C
Yield: 63%
Example 14 5-Ethyl-2,3 dimethyl 4-(4-nitrophenyl)-6-ethoxy-4H~thio-pyran-2~3,5-tricarboxylate ~2 ~O~ , H5C 200C ~ COOCH 3 4.7 9 of diethyl 4-nitrobenzylidenethionomalonateO
together with 8 ml of dimethyl acetylenedicarboxylate, in Le A 21 553 w 14 -50 ml of xylene were heated to ref~ux for 4 hours. All volatiles were distilled off in vacuo and the remaining oil was chromatographed on silica gel with ether.
1H-NMR (CDCl3~: - 1.3 (t, J=8Hz, 3H), 1.4 ~t, J=8Hz, 3H), 3.8 (s, 3H), 3.85 (s, 3H), 4.25 (q, J=8Hz, 4H), 5.5 (s, 1H), 7.~
(d, J=9Hz, ZH), 8.1 (d, J=9Hz, 2H).
Yield: 50% (after chromatography on silica gel with ether).
Le A 21 553
S MS: 407 (M+, 11%), 334 (100%), 211 (80%).
Yield: 90%
Example 3 Diethyl 4-(3-nitrophenyl)-2-ethoxy~4H-thiopyran-3,5-di-carboxylate ~--N02 H 5C 200C _~ COOC 2H 5 ~5c2o ~1 From diethyl 3-nitrobenzylidenethionomalonate and ethyl propiolate H-NMR (CDCl3) :~- 1 .3 (t~ J=8Hz, 6H), 1.45 (t, J=8Hz, 3H), 4.1-4.4 (m, 6H), 5.5 (s, 1H), 7.S
(t, J=7Hz, 1H), 7.65 (s, 1H~, 7.85 (d, J=7Hz, 1H), 8.1 (d, J=7Hz, 1H), 8.35 (s, 1H).
Yield: 40% (after chromatography with CHCl3 on s;lica gel).
Example 4 Diethyl 4 (2-trifluoromethylphenyl)-2-ethoxy-4H-thiopyran-3,5-dicarboxylate H 5C 200C ~, COOC 2H 5 Le A 21 553 H-NMR (CDCl3)~ 1.6 (m, 9H~, 3.9-4.5 (m, 6H)~
5.8 (s, 1H), 7.3-8.1 (m, 5H).
Yield: 75%
Example 5 Dimethyl 4 (2-chlorophenyl)~2-methoxy-4H-thiopyran 3,5-dicarboxylate ~1 CH 300C ~cC OOC H 3 H-NMR (CDCl3):~= 3.65 (s, 6H), 3.8 (s, 3H), 5.65 (s, 1H)~
7.0-7.6 (m, 4H), 7.55 (s, 1H).
MS: 354 (M~, 2~), 295 (7%), 235 (100%).
Yield: 77%
Example 6 Dimethyl 4-(3-chlorophenyl)-2-methoxy-4H-thiopyran-3,5-dicarboxylate ~o~Cl CH 300C ~ COOCH 3 Melting point: 85 - 87 Yield: 43%
Example 7 Methyl 4-methoxy-9-nitro-5-oxo~5H,10bH thiopyrano~3,4-c]-Le A 21 553 1-benzopyr.~n-1-carboxylate CE~ 3o S H
Yield 2.Z 9 (60%), melting point: 230C (from ethyl acetate).
S Example 8 Ethyl 4-ethoxy-5-oxo-5H,10bH~thiopyranoC3,4~c]-1-benzo-pyran-1-carboxylate H~C20 ~COOC2H5 Melting point: 135 - 136C (from ace~one) Yield: 80%
Example 9 Ethyl 4-ethoxy-9-nitro-5-oxo-SH,10bH-thiopyranoC3,4~c]-1-benzopyran-1-carboxylate o~
~ COOC 2H5 Melting point: 131 - 133C (from ethanol) Yield: 67X
Le A 21 553 Exarnple 10 Ethyl 9-bromo-4-ethoxy-5-oxo-5H,10bH~thiopyranoC3,4-c]-1-benzopyran-1-carboxyLate $,Br O~C OOC 2 H 5 1H-NMR (CDCl3):~= 1.3 and 1.35 (2t, J=7Hz, each 3H~, 4.1 and 4.3 (2q, J=7Hz, each 2H), 5.1 (s, 1H)r 6.3 7.8 ~, 3H), 7.6 (s, 1H).
Yield: 74%
Example 11 Ethyl 7,9 dichloro-4-ethoxy-5-oxo-5H,10bH thiopyrano-[3,4-c]-1-benzopyran-1-carboxylate C.~,Cl ~ COOC 2H 5 Melting point: 148 - 149C
Yield: 86%
Example 12 Methyl 7,9-dichloro-4-methoxy-5~oxo 5H,10bH-thiopyrano-C3,4-c]-1-benzopyran-1-carboxylate Le A 21 553 C ,~
/~, C OOC H 3 "H3 S H
Melting po;nt: 202 - 203C (from ethyl acetate) Yield: 56%
Example 13 S Methyl 4-ethoxy-9-nitro-5-oxo-5H,10bH-thiopyranoC3,4-c]~
1-benzopyran-1-carboxylate NO
S ~
Melting point: 156C
Yield: 63%
Example 14 5-Ethyl-2,3 dimethyl 4-(4-nitrophenyl)-6-ethoxy-4H~thio-pyran-2~3,5-tricarboxylate ~2 ~O~ , H5C 200C ~ COOCH 3 4.7 9 of diethyl 4-nitrobenzylidenethionomalonateO
together with 8 ml of dimethyl acetylenedicarboxylate, in Le A 21 553 w 14 -50 ml of xylene were heated to ref~ux for 4 hours. All volatiles were distilled off in vacuo and the remaining oil was chromatographed on silica gel with ether.
1H-NMR (CDCl3~: - 1.3 (t, J=8Hz, 3H), 1.4 ~t, J=8Hz, 3H), 3.8 (s, 3H), 3.85 (s, 3H), 4.25 (q, J=8Hz, 4H), 5.5 (s, 1H), 7.~
(d, J=9Hz, ZH), 8.1 (d, J=9Hz, 2H).
Yield: 50% (after chromatography on silica gel with ether).
Le A 21 553
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a thiopyran of the general formula (I) (I) in which R represents aryl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, quinazolyl or quinoxalyl, the aryl radical and the heterocycles mentioned optionally contain 1, 2 or 3 identical or different substituents from the group comprising phenyl, alkyl, alkenyl, alkynyl, alkoxy, alkylene, dioxyalkylene, halogen, trifluoromethyl, trifluoromethoxy, alkylamino, nitro, cyano, azido or carboxamido, R1, R3 and R4 are identical or different and each represent hydrogen or an achiral straight-chain or branched alkyl radical, or each represent one of the radicals listed in the definition of R and are identical to or different from this, or wherein one of the radicals R1 or R4 can be bridged via a ring with the radical R, R2 represents hydrogen, alkyl, aryl, carboxyalkyl or aminoalkyl and X represents O, S or NH, or a pharmacologically acceptable acid addition salt, which process comprises reacting a thione of the general formula (II) (II) in which R, R3, R4 and X have the abovementioned meanings, at a temperature between 0°C and 200°C with an acetylene compound of the general formula (III) (III) in which R1 and R2 have the abovementioned meanings and, if required; converting the product into a pharmaceutically acceptable acid addition salt thereof.
2. A process according to claim 1 wherein the reaction is carried out at a temperature between 50 and 150°C.
3. A process according to claim 1 wherein the reaction is carried out in an excess of the acetylenecarboxylic ester used or in an inert organic solvent.
4. A process according to claim 1 wherein the reaction is carried out in toluene, ethanol, dioxane or ethylene glycol as solvent.
5. A process according to claim 1, in which R represents phenyl, naphthyl, furyl, pyrryl or pyridyl, these rings optionally containing 1, 2 or 3 identical or different substituents from the group comprising phenyl, alkyl, alkenyl, alkynyl, alkoxy, alkylene, dioxy-alkylene, alkylamino, each having up to 4 carbon atoms, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano, azido or carboxamido, R1, R3 and R4 are identical or different and each represent hydrogen or an alkyl radical having up to 6 carbon atoms, or represent one of the radicals mentioned under R, or wherein the radicals R4 and R can be bridged together via a 6- or 7-membered ring, R2 represents hydrogen, an alkyl radical having up to 4 carbon atoms, phenyl, carboxyalkyl having up to 6 carbon atoms or aminoalkyl having up to 4 carbon atoms, and X represents O, S or -NH-.
6. A process according to claim 1, in which R represents phenyl, naphthyl or pyridyl, these rings optionally con-taining 1 or 2 identical or different substituents from the group comprising phenyl, alkyl, alkoxy, alkylene, dioxyalkylene, alkylamino, each having up to 4 carbon atoms, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano, azido or carboxamido, R1, R3 and R4 are identical or different, and each represent hydrogen or an alkyl radical having up to 4 carbon atoms or phenyl, or wherein the radicals R4 and R can be bridged via a 6-membered ring, R2 represents hydrogen, an alkyl radical having up to 4 carbon atoms, phenyl, carboxyalkyl having up to 6 carbon atoms or aminoalkyl having up to 4 carbon atoms, and X represents O, S or -N-
7. A compound of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.
8. A process for preparing dimethyl 4-(2,4-dichlorophenyl)-2-methoxy-4H-thiopyran-3,5-dicarboxylate which comprises refluxing dimethyl 2,4-dichloro-benzylidenethiomalonate with methyl propiolate.
9. The compound dimethyl 4-(2,4-dichlorophenyl)-2-methoxy-4H-thiopyran-3,5-dicarboxylate when prepared by a process according to claim 8 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3212737.5 | 1982-04-06 | ||
| DE19823212737 DE3212737A1 (en) | 1982-04-06 | 1982-04-06 | 4H-THIOPYRANS, METHOD FOR THEIR PRODUCTION AND THEIR USE IN MEDICINAL PRODUCTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1198107A true CA1198107A (en) | 1985-12-17 |
Family
ID=6160333
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000425122A Expired CA1198107A (en) | 1982-04-06 | 1983-03-31 | 4h-thiopyrans, process for their preparation and their use in medicaments |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0091051B1 (en) |
| JP (1) | JPS58183685A (en) |
| KR (1) | KR840004423A (en) |
| AT (1) | ATE24003T1 (en) |
| CA (1) | CA1198107A (en) |
| DE (2) | DE3212737A1 (en) |
| DK (1) | DK151883A (en) |
| ES (1) | ES521233A0 (en) |
| IL (1) | IL68283A0 (en) |
| ZA (1) | ZA832389B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2310128A2 (en) * | 1975-05-06 | 1976-12-03 | Little Inc A | Thieno-and thio-pyrano-benzopyran CNS active derivs - used as anti-anxiety agents and tranquillizers |
| US4198426A (en) * | 1977-11-28 | 1980-04-15 | Ayerst Mckenna & Harrison Ltd. | 2-Substituted-3-methyl-γ-pyrone tricyclic derivatives |
-
1982
- 1982-04-06 DE DE19823212737 patent/DE3212737A1/en not_active Withdrawn
-
1983
- 1983-03-28 EP EP83103043A patent/EP0091051B1/en not_active Expired
- 1983-03-28 DE DE8383103043T patent/DE3368058D1/en not_active Expired
- 1983-03-28 AT AT83103043T patent/ATE24003T1/en not_active IP Right Cessation
- 1983-03-31 CA CA000425122A patent/CA1198107A/en not_active Expired
- 1983-03-31 JP JP58054076A patent/JPS58183685A/en active Pending
- 1983-04-01 IL IL68283A patent/IL68283A0/en unknown
- 1983-04-04 KR KR1019830001396A patent/KR840004423A/en not_active Application Discontinuation
- 1983-04-05 DK DK151883A patent/DK151883A/en not_active IP Right Cessation
- 1983-04-05 ZA ZA832389A patent/ZA832389B/en unknown
- 1983-04-05 ES ES521233A patent/ES521233A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| ES8401975A1 (en) | 1984-01-01 |
| DK151883A (en) | 1983-10-07 |
| KR840004423A (en) | 1984-10-15 |
| ES521233A0 (en) | 1984-01-01 |
| IL68283A0 (en) | 1983-07-31 |
| EP0091051A3 (en) | 1984-07-25 |
| DE3368058D1 (en) | 1987-01-15 |
| EP0091051A2 (en) | 1983-10-12 |
| JPS58183685A (en) | 1983-10-26 |
| ATE24003T1 (en) | 1986-12-15 |
| DE3212737A1 (en) | 1983-10-06 |
| EP0091051B1 (en) | 1986-12-03 |
| DK151883D0 (en) | 1983-04-05 |
| ZA832389B (en) | 1983-12-28 |
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