GB2200117A - Tricyclic pyridine derivatives - Google Patents

Tricyclic pyridine derivatives Download PDF

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GB2200117A
GB2200117A GB08805796A GB8805796A GB2200117A GB 2200117 A GB2200117 A GB 2200117A GB 08805796 A GB08805796 A GB 08805796A GB 8805796 A GB8805796 A GB 8805796A GB 2200117 A GB2200117 A GB 2200117A
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optionally substituted
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lower alkyl
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Ulf Fischer
Fernand Schneider
Ulrich Widmer
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F Hoffmann La Roche AG
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • 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
    • C07D495/12—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 three hetero rings
    • C07D495/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Description

TRICYCLIC PYRIDINE DERIVATIVES -The present invention is concerned with compounds of the general formula
wherein Q1 and the nitrogen atom together signify a group of the formula > N-CH2CH2- (a), > N-CH2CH2CH2- (b) > N-CH=CH- (c), > N-CH2-CH=CH- (d). > N-CH2-S(O)p- (e).
> N-CH2CH2-S(O)p- (f) or > N-CH=CH-S9O)p- (g). p signifies the number 0,1 or 2, Ra signifies a phenyl, pyridyl or thienyl group which is optionally substituted by halogen, trifluoromethyl, nitro, lower alkyl or lower alkoxy, Rb and Rc together with the carbon atom denoted by a signify a group of the formula > Cα-S-CH=CH- (h), > Cα-CH=CH-S- (i) or > Cα-CH=CH-CH=CH- (j) which is optionally substitued by halogen. trifluoromethyl. lower alkyl lower alkoxy, nitro. amino or mono-or di (lower alkyl) amino. and the dotted line signifies an additional bond These compounds are intermediates for the manufacture of novel tricyclic pyridone derivatives of the general formula
wherein Ra, Rb, Rc, Q1 and the dotted line have the above significance and Rd signifies cyano, nitro or the group of the formula-CO- (Q A) q-R q signifies the number 0 or 1, A2 signifies lower alkylene or a direct bond, Q signifies an oxygen atom or the group-NR-, R1 signifies hydrogen, hydroxy, cyano. nitro, halogen, lower alkoxy, lower alkyl, lower alkoxycarobnyl, aryl. a group of the formula -NR3R4 or a 5-membered, saturated, partially unsaturated or aromatic heterocycle which is attached via a carbon atom and which is optionally substituted by one or two lower alkyl groups and optionally substituted by a (C3-6)-cycloalkyl. hydroxy, lower alkoxy, lower alkanoyloxy. lower hdyroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl. lower alkoxycar- bonyl, lower alkanoyl. carbamoyl, mono-or di (lower alkyl) carbamoyl, oxo or alkylenedioxy group, R2 signifies hydrogen, lower alkyl or aryl, R3 and R4 each signify hydrogen, lower alkyl, lower alkoxyalkyl. lower dialkoxyalkyl, lower alkylenedioxyalkyl, lower cyanoalkyl, lower haloalkyl, lower hydroxyalkyl, lower dihydroxyalkyl, lower alkanoyl, lower alkoxycarbonyl or a (C3~7)-cycloalkyl group which is optionally substituted by hydroxy, lower alkoxy, lower alkanoyl oxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, oxo, carbamoyl, mono-or di (lower alkyl) carbamoyl or by lower alkylenedioxy or together with the nitrogen atom signify a 3-to 7-membered. saturated N-heterocycle which is optionally substi tuted by one or two lower alkyl groups and optionally substituted by one or two hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl. lower alkoxycarbonyl, lower alkanoyl, carbamoyl, mono-or di (lower alkyl) car bamoyl, oxo or lower alkylenedioxy groups and which can contain as a ring member an oxygen or sulphur atom or the group > N-R5. and R signifies hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, lower alkanoyl, lower alkoxycarbonyl, carbamoyl or mono-or di (lower alkyl) carbamoyl, with the proviso that R1 has a significance different from hydroxy, cyano, nitro, halogen, lower alkoxycarbonyl, lower alkoxv and-NR3R4 when q signifies the number 1 and A2 signifies a direct bond, and of pharmaceutically acceptable acid addition salts of compounds of formula I which have one or more basic substituents.
These compounds of formula I have in turn valable pharmacological properties and can be used for the control or prevention of illnesses. In particular, they have muscle relaxant, sedative-hypnotic, anxiolytic and/or anticonvulsive activity and can accordingly be used in the control or prevention of muscle tensions, stress conditions, insomnia, anxiety states and/or convulsions.
The compound of formula I and their preparation starting from compounds of formula II are described in the British Patent Application No. 8527196 published as UK Patent Application No. 2.169.288.
The term"lower"denotes residues and compounds having a maximum of seven, preferably a maximum of four, carbon atoms. The term"alkyl". alone or in combinations such as alkanoyl, alkanoyloxy and alkoxyalkyl, denotes straight -chain or branche, saturated hydrocarbon residues such as methyl, ethyl, isopropyl and t-butyl. The term"cyclo- alkyl'l-denotes cyclic, saturated hydrocarbon residues such as cyclohexyl. The term"alkoxy"denotes alkyl groups attached via an oxygen atom, such as methoxy and ethoxy.
The term"hydroxyalkyl"denotes alkyl group6 substituted by hydroxy, such as 2-hydroxyethyl. The terms"alkanoyl" and"alkanoyloxy"denote fatty acid residues such as acetyl and acetoxy. The term"alkylene"denotes straight -chain or branche, saturated hydrocarbon residues having two free valencies, such as methylene. 1. 2-ethylene and 1,3-propylene. The term"halogen"denotes the four forms fluorine, chlorine, bromine and iodine.
The term"aryl"preferably denotes phenyl groups which are optionally substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitco, amino or mono-or di (lower alkyl) amino.
The 5-membered, saturated, partially unsaturated or aromatic heterocycles which are attached via a carbon atom preferably contain as the hetero ring member (s) an oxygen or sulphur atom or an imino or-lower alkylimino group and optionally one or two nitrogen atoms, with the carbon atom via which the heterocycle is attached being preferably situated adjacent to one hetero atom or between two hetero atoms. Examples of such heterocycles, which can be substituted as indicated earlier, are: 2-oxazolin-2-yl, 3-methyl-1, 2, 4-oxadiazol-5-yl. 2-thiazolin-2-yl, 2-tetrahydrofuryl and 2-thiazolyl.
The term"3-to 7-membered, saturated N-heterocycle which can contain as a ring member an oxygen or sulphur atom or the group > N-R5"as a possible value for -NR3R4 denotes on the one hand heterocycles having only one hetero atom, namely the nitrogen atom via which they are attached, and on the other hand heterocycles having two hetero atoms, namely the aforementioned nitrogen atom and an oxygen or sulphur atom or a second nitrogen atom. Examples of such heterocycles, which can be substituted as indicated earlier, are: 2- (lower alkoxy alkyl)-l-azetidinyl, 3- (lower alkoxy)-l-azetidinyl, 3 -hydroxy-l-azetidinyl, 2- (lower hydroxyalkyl)-l-azeti- dinyl. 2- (lower alkanoyloxyalkyl)-l-pyrrolidinyl. 3-oxo -1-pyrrolidinyl, 2-(lower alkoxycarobnyl)-1-pyrrolidinyl.
3-(lower alkoxy)-1-pyrrolidinyl. 3-hdyroxy-1-pyrrolidinyl, 2- (lower alkoxyalkyl)-l-pyrrolidinyl, 2- (lower hydroxy alkyl)-l-pyrrolidinyl, 2-(lower hydroxyalkyl)-4-hydroxy-1 -pyrrolidinyl, 2- (lower alkoxyalkyl)-4- (lower alkoxy)-l- -pyrrolidinyl, 4-morpholinyl, 2, 6-di (lower alkyl)-4 -morpholinyl, 4-thiomorpholinyl, 1-piperazinyl, 1- (lower alkyl)-4-piperazinyl. 1- (lower alkoxylalkyl)-4-piperazinyl, 1-(lower alkanoyl)-4-piperazinyl, 4-(lower hydroxyalkyl)-1-piperidinyl. 4-oxo-l-piperidinyl, 4- (lower alkoxy)-l-piperidinyl, 4- (lower alkoxycarbonyl)-1- -piperidinyl, 4-hydroxy-l-piperidinyl, 4- (lower alkylcar bamoyl)-l-piperidinyl, 4- (lower alkanoyloxy)-l-piperi- dinyl. 2- (lower alkoxyalkyl)-l-piperidinyl, 2- (lower hydroxyalkyl)-1-piperidinyl, 3- (lower alkoxy)-l-piperi- dinyl, 4, 4-(lower alkylendioxy)-1-piperidinyl and 3-hydroxy-1-piperidinyl.
The symbol Q1 and the nitrogen atom together preferably signify the group of the formula > N-CHzCH2- (a) or > N-CH=CH- (c). The symbol Ra preferably signifies a phenyl group which is optionally substituted by m-halogen or m-trifluoromethyl, with the value phenyl being especially preferred. The symbols Rb and Rc together with the carbon atom denoted by a preferably signify a group of the formula > C-S-CH=CH- (h) or > CQ-CH=CH-CH=CH- (j) which is optionally substituted by halogen, especially the group of the formula > Ca-S-CH=CH-or > C-CH=CCl-CH=CH-, whereby the dotted line signifies an additional bond.
The compounds of formula II can be prepared, for example, be reacting a compound of the general formula
wherein Q. Rb, Rc and the dotted line have the above significance, with a compound of the general formula Ra-CHXZ-COX1 RXII or
wherein X and X each signify halogen and Ra has the above significance.
The reaction of a compound of formula XXI with a compound of formula XXII in which X1 preferably signifies chlorine and X2 preferably signifies bromine is preferably carried out at room temperature in a halogenated hydrocarbon such as chloroform, whereupon treatment is carried out with a basic amine such as triethylamine. s reaction of a compound of formula XXI with a compound of formula XXIII is preferably carried out in an inert solvent such as acetone, N. N-dimethylformamide, dimethyl sulphoxide and the like at room temperature.
The following Examples serve to illustrate the present invention in more detail. However, they are not intended to limit its extent in any manner. All temperatures given in degrees Celsius.
Example 1 aa) Method A: 29. 4 g of a-bromophenylacetyl chloride are added dropwise while stirring to a solution of 23.3 g of 4, 5-dihydrothieno [2, 3-c] pyridine-7 (6H)-thione in 630 ml of chloroform, whereby care is taken that the temperature does not exceed 25 . After 30 minutes the mixture is treated with 25.45 g of triethylamine and stirred for a further 3 hours. The mixture is diluted with water, the organic phase is separated, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, evaporated and the residue is chromatographed on silica gel (elution agent toluene/ethanol 95: 5). There is obtained 5, 6-dihydro-3-hydroxy-2-phenylthiazolo [3, 2-a] thieno [2, 3-c] pyridinium hydroxide (internal salt) of m. p.
, 225 (dec.) (from dioxan/acetonitrile).
Method B : 28.6 g of 1-phenyl-2, 2-dicyano-oxirane are added while stirring to a solution of 26.35 g of 4, 5-dihydrothieno [2, 3-cjpyridine-7- (6H)-thione in 140 ml of dimethylformamide, whereby the solution immediately becomes deep red in colour. After 16 hours the crystalline precipitate is filtered off under suction and washed with ethyl acetate. There is obtained 5, 6-dihydro-3-hydroxy-2 -phenylthiazolo [3, 2-a] thieno [2, 3-c] pyridinium hydroxide (internal salt) of m. p. 208-209 .
In an analogous manner, ab) from 4, 5-dihydrothieno[2,3-c]pyridine-7 (6H)-thione and 1- (o-chlorophenyl)-2. 2-dicyano-oxirane there is obtained 5, 6-dihydro-3-hydroxy-2- (o-chlorophenyl)-thiazolo- [3, 2-a] thieno [2. 3-c] pyridinium hydroxide (internal salt) of m. p. 174-175 (from dioxan/acetonitrile) ; ac) from 4, 5-dihydrothieno [2, 3-c]pyridine-7 (6H)-thione and 1- (m-chlorophenyl)-2. 2-dicyano-oxirane there is obtained 5, 6-dihydro -3-hydroxy-2-(m-chlorophenyl)-thiazolo [3, 2-a] thieno [2. 3-cjpycidinium hydroxide (internal salt) of m. p. 179-181 : ad) from 4, 5-dihydrothieno [2, 3-c] pycidine-7 (6H)-thione-and 1-(p-chlorophenyl)-2. 2-dicyano-oxirane there is obtained 5, 6-dihydro-3-hydroxy-2- (p-chlorophenyl)-thiazolo- [3. 2-a] thieno [2, 3-c] pyridinium hydroxide (internal salt) of m. p. 215 (dec.) ; ae) from 4, 5-dihydrothieno [2, 3-c] pyridine-7 (6H)-thione and 1-(m-fluorophenyl)-2. 2-dicyano-oxirane there is obtained 5, 6-dihydro-3-hydroxy-2 -(m-fluorophenyl)-thiazolo [3. 2-a] thieno [2, 3-c] pyridinium hydroxide (internal : af) from 6,7-dihydrothieno [3. 2-c] pyridine-7 (6H)-thione and 1-phenyl-2, 2-dicyano-oxirane there is obtained 5,6-dihydro-3-hydroxy-2-phenylthiazolo [3, 2-ajthieno [3, 2-c] pyri- dinium hydroxide (internal salt) of m. p. 198-202 (dec.).
Example 2 aa) Method A: 23.65 g of 3. 4-dihydroisoquinoline-1 (2H) -thione are dissolved in 750 ml of chloroform, whereupon the solution is treated at room temperature while cooling firstly with 54 g of a-bromophenylacetyl chloride and 90-minutes later with 53 ml of triethylamine and the mixture is stirred at room temperature overnight. The reaction mixture is washed with water, dried over mag- nesium sulphate and evaporated in vacuo. There is obtained 5, 6-dihydro-3-hydroxy-2-phenylthiazolo [2, 3-a] isoquinol-i-. nium hydroxide (internal salt) of m. p. 210 (dec.) (from acetonitrile/dioxan). ab) Method B: 2.96 g of 7-chloro-3,4-dihydroisoquinoline -1 (2H)-thione and 3.7 g of 1- (p-chlorophenyl)-2. 2-dicyanooxirane are stirred overnight in 60 ml of acetone. The separated red crystalline precipitate is filtered off under suction and recrystallized from dioxan. There is obtained 9-chloro-2- (p-chlorophenyl)-5, 6-dihydro-3 -hydroxythiazolo [2, 3-a] isoquinolinium hydroxide (internal salt) of m. p. 276 (dec.).
In an analogous manner, ac) from 7-chloro-3, 4-dihydroisoquinoline-1 (2H)-thione and a-bromophenylacetyl chloride (method A) or 1-phenyl-2, 2 -dicyanooxirane (method B) there is obtained 9-chloro-2 -phenyl-5, 6-dihydro-3-hydroxythiazolo [2. 3-a] isoquinolinium hydroxide (internal salt) of m. p. 296 (dec.): ad) from 7-chloro-3,4-dihydroisoquinoline-1 (2H)-thione and l- (o-chlorophenyl)-2,2-dicyanooxirane there is obtained 9-chloro-2- (o-chlorophenyl)-5. 6-dihydro-3-hydroxythia- zolo [2. 3-a] isoquinolinium hydroxide (internal salt) of m. p. 260-262 (method B, dimethylformamide as the solvent).
Example 3 aaa) 38.9 g of methyl 3, 3'-dithiobis-thiophene-2-carboxy- late are suspended in 1500 ml of 1N sodium hydroxide solution and 700 ml of ethanol, whereupon the suspension is heated under reflux until the reaction has finished.
After cooling in an ice-bath the mixture is acidified with 25 percent hydrochloric acid, whereby the product crystal lizes out. By recrystallization from water there is obtained 3,3'-dithio-bis-thiophene-2-carboxylic acid as colourless crystals of m. p. 256-257 . aab) 41.3 g of 3, 3'-dithiobis-thiophene-2-carboxylic acid are suspended in 340 ml of thionyl chloride, whereupon the suspension is heated under reflux for 2.5 hours. The excess thionyl chloride is removed in vacuo and the residue is suspended in 700 ml of dioxan. Ammonia is now conducted into the solution. After cooling in an ice-bath the mixture is filtered and the crystals are stirred in 1500 ml of water for 30 minutes. The crystals are filtered off. By recrystallization from n-butanol/dioxan there is obtained 3, 3'-dithiobis-thiophene-2-carboxamide as colour less crystals of m. p. 222-223 . aac) 77.5 g of 3, 3'-dithio-bis-thiophene-2-carboxamide are suspended in 1200 ml of dioxan, whereupon the suspension is warmed to 45 under an inert gas. 46.4 g of sodium borohydride are added portionwise to the suspension at 45-48 . After the evolution of hydrogen has finished the mixture is heated under reflux until the disulphide has disappeared. 450 ml of water are now added dropwise while cooling and the mixture is subsequently acidified with 2N hydrochloric acid. After dilution of the solution with 1800 ml of water and saturation with sodium chloride it is extracted exhaustively with ether. The combined extracts are dried over sodium sulphate, filtered and evaporated.
After drying there is obtained crude 3-mercaptothiophene- -2-carboxamide of m. p. 116-120 . aad) 11.1 g of 3-mercapto-thiophene-2-carboxamide, 2.2 g of 95 percent paraformaldehyde and 13.3 g of p-toluenesulphonic acid monohydrate are heated together under reflux with 300 ml of mesitylene. After the reaction has finished the mixture is left to cool and the solvent is removed in vacuo. After chromatography of the residue on silica gel and recrystallization from ethyl acetate there is obtained 2, 3-dihydro-4H-thieno [2. 3-e] [1, 3] thiazin-4-one as yellowish crystals of m. p. 153-155 . aae) 19.6 g of 2, 3-dihydro-4H-thieno [2. 3-e] [1. 3]-thiazin -4-one are heated under reflux together with 23.1 g of Lawesson reagent in 200 ml of acetonitrile until all of the starting material has reacted. The reaction mixture is cooled and the crystallized-out product is filtered off.
By recrystallization from ethyl acetate there is obtained pure 2, 3-dihydro-4H-thieno [2, 3-e] [1, 3] thiazine-4-thione of m. p. 136-138 . Additional material can be obtained by evaporation of the mother liquor and recrystallization. aba) In an analogous manner, from 4, 5, 6, 7-tetrahydro-8H- -thieno [2, 3-c] azepin-8-one there is obtained 4, 5,6,7 -tetrahydro-8H-thieno [2. 3-c] azepine-8-thione of m. p. 103-104 (from ethyl acetate). aca) Method A: 17.4 g of methyl 3-mercapto-thiophene-2 -carboxylate are dissolved in 350 ml of toluene under an inert gas atmosphere, whereupon tte solution is treated with 20.5 g of 2-aminoethyl bromide hydrobromide and then with 100 ml of 3N sodium methylate solution in methanol.
The mixture is stirred at room temperature for 30 minutes and thereafter heated under reflux until the reaction has finished. The mixture is evaporated in vacuo, the residue is taken up in 300 ml of water, acidified with 2N hydrochloric acid and the crystals are filtered off. By recrystallization from chloroform there is obtained 3, 4-di- hydro-thieno [2#3-f] [l4] thiazepin-5-(2H)-one as white crystals of m. p. 186-188 .
Method B: 65.4 g of methyl 3-meccapto-thiophene-2- -carboxylate are dissolved in 800 ml of ethanol, whereupon the solution is treated with 19.4 ml of ethyleneimine.
After the reaction has finished the reaction mixture is cooled in an ice-bath and the hydrochloride is precipitated by introducing dry hydrogen chloride. The crystals are filtered off and the filtrate is evaporated, whereby fur ther crude product is obtained. By recrystallization from methanol/ethyl acetate there is obtained methyl 3- [ (2 -aminoethyl) thio]-2-thiophenecarboxylate hydrochloride as white crystals of m. p. 174-176 .
1.0 g of methyl 3- [ (2-aminoethyl) thio]-2-thiophene carboxylate hydrochloride are suspended in 20 ml of toluene under argon, whereupon 9.4 ml of 1N sodium methylate solution in methanol are added. After the reaction has finished the mixture is evaporated in vacuo and the residue is treated with 20 ml of water. The crystals are filtered off, washed with water and dried. By recrystallization there is obtained 3, 4-dihydro-thieno [2, 3-f] [l, 4] thiazepin-5 (2H)-one as white crystals of m. p.
186-188 . The reaction can also be carried out with 1.1 mol equivalents of potassium tert-butylate solution in toluene. acb) 1.0 g of 3, 4-dihydro-thieno [2, 3-f] 11, 4] thiazepin- -5 (2H)-one are heated under reflux for 5 hours together with 15 ml of pyridine and 1.35 g of phosphorus pentasulphide. After cooling the mixture is poured into 90 ml of water and the crystals are filtered off. After chromatography on silica gel the product is recrystallized from ethyl acetate. There is obtained 3, 4-dihydro-thieno [2. 3-f] [1, 4] thiazepine-5 (2H)-thione as yellow crystals of m. p. 138-139 . ada) 288 g'of thieno [2. 3-cjpyridine are dissolved in 5.3 1 of methylene chloride and an equivalent amount of m-chloroperbenzoic acid is added portionwise at-5 to 0 .
The mixture is stirred until the reaction has finished.
The addition of 800 ml of saturated ethereal hydrogen chloride solution precipitates the product as white crystals which are washed with ether. The thus-obtained thieno [2. 3-cjpyridine 6-oxide hydrochloride is sufficiently pure for use in the next step, m. p. 202 . adb) 671.5 g of thieno [2, 3-c] pyridine 6-oxide hydrochloride are suspended in 4000 ml of dioxan under argon and 655 ml of phosphorus oxychlorid-e are added. The mixture is heated on an oil-bath until the exothermic reaction has set in. After the exothermic reaction has faded away the mixture is heated to reflux for a further 10 minutes. The mixture is concentrated in vacuo and the residue is taken up in 2000 ml of toluene. The solution is then treated with 300 ml of water while cooling slowly.
The mixture is neutralized by the portionwise addition of sodium carbonate. The organic phase is separated and the aqueous phase is extracted with 1000 ml of toluene. After washing with water the combined organic solutions are dried over sodium sulphate, filtered and evaporated, whereby crude 7-chloro-thieno [2, 3-c] pyridine is obtained as a brown oil. adc) 4.85 g of 7-chloro-thieno [2. 3-c] pyridine are dissolved in 15 ml of dimethylformamide and 3.18 g of sodium hydrogen sulphide monohydrate are added under argon. The mixture is heated to 110-115 for one hour, a further 1.06 g of sodium hydrogen sulphide monohydrate are added and the mixture is held at the temperature indicated above for a futher hour. The mixture is poured on to 150 ml of ice-water and acidified with 1N aqueous hydrochloric acid solution. After stirring at 2 for a short time the yellowish crystals are filtered off. After recrystallization from a toluene/ethyl acetate mixture there is obtained pure thieno [2, 3-cjpyridine-7 (6H)-thione, m. p. 187-189 . ba) 16.7 g of thieno [2, 3-cjpyridine-7 (6H)-thione are suspended in 1000 ml of methylene chloride under an inert gas atmosphere, whereupon 15.3 ml of about 90 percent a-bromophenacetyl chloride are added dropwise. After completion of the addition the mixture is stirred at room temperature for about a further half hour and then added dropwise to 27.8 ml of triethylamine. The mixture is subsequently stirred at room temperature for 30 minutes.
The solution is washed twice with 750 ml of water each time, dried over sodium sulphate, filtered and evaporated in vacuo. The red crystals obtained are purified by chromatography and recrystallization from chloroform/ ether/hexane. There is obtained 3-hydroxy-2-phenylthia- zolo [3. 2-a] thieno [2. 3-cjpyridinium hydroxide (internal salt) as red crystals of m. p. 195-200 (dec.).
In an analogous manner. bb) from 2. 3-dihydro-4H-thieno [2, 3-e] [1. 3] thiazine-4 -thione and a-bromophenacetyl chloride there is obtained 7-hydroxy-8-phenyl-SH-thiazolo [3,2-c] thieno [2,3-e] [1, 3]- thiazinium hydroxide (internal salt) of m. p. 194-197 (from methanol): bc) from 4. 5. 6, 7-tetrahydro-8H-thieno [2. 3-c] azepine-8 -thione and a-bromophenacetyl chloride there is obtained 5, 6-dihydro-e-hydroxy-9-phenyl-4H-thiazolo [3. 2-a] thieno [2. 3-c] azepinium hydroxide (internal salt) of m. p.
205-208 (from chloroform/diethyl ether) : bd) from 3, 4-dihydrothieno [2, 3-f] [1, 4] thiazepine-5 (2H) -thione and a-bromophenacetyl chloride there is obtained 5, 6-dihydro-8-hydroxy-9-phenyl-thiazolo [3, 2-d] thieno [2, 3-f] [1, 4] thiazepinium hydroxide (internal salt) of m. p.
196-198 (from chloroform/diethyl ether).
Example4 The compound described in Example 3bd) can also be prepared as follows: 0.6 g of 3. 4-dihydro-thieno [2, 3-f] [1, 4] thiazepine -5 (2H)-thione and 1.0 g of a- (tosylhydrazono) phenyl acetyl chloride are stirred for a long time in 50 ml of methylene chloride at room temperature and in the presence of 0.84 ml of triethylamine. The solvent is removed in vacuo and the residue is chromatographed on silica gel.
There is obtained 5, 6-dihydro-8-hydroxy-9-phenyl-thia- zolo [3, 2-d] thieno [2, 3-f] [1. 4] thiazepinium hydroxide (internal salt) of m. p. 190-195 .

Claims (3)

  1. Patent Claims 1. Compounds of the general formula
    wherein Q1 and the nitrogen atom together signify a group of the formula > N-CH2CH2- (a), > N-CH2CH2CH2- (b), > N-CH=CH- (c), > N-CH 2-CH=CH- (d), > N-CH 2-S (O) p- (e) > N-CH2CH2-S(O)p - (f) or > N-CH=CH-S(O)p - (g). p signifies the number 0, 1 or 2, Re signifiies a phenyl, pyridyl or thienyl group which is optionally substituted by halogen, trifluoromethy nitro, lower alkyl or lower alkoxy, Rb and Rc together with the carbon atom denoted by a signify a group of the formula > Cα-S-CH=CH- (h). > Cα-CH=CH-S- (i) or > Cα-CH=CH-CH=CH- (j) which is optionally substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino or mono-or di (lower alkyl) amino, and the dotted line signifies an additional bond.
  2. 2. Compounds according to claim 1, wherein Q1 and the nitrogen atom together signify the group of the formula > -N-CH2CH2- (a) or > N-CH=CH- (c).
  3. 3. Compounds according to claim 1 or 2, wherein Ra signifies a phenyl group which is optionally substituted by m-halogen or m-trifluoromethyl.
    3. Compounds according to claim 1 or 2, wherein Ra signifies a phenyl group which is optionally substituted by m-halogen or m-trifluoromethyl.
    4. Compounds according to claim 3, wherein Ra signifies phenyl.
    5. Compounds according to any one of claims 1 to 4, wherein Rb and Rc together with the carbon atom denoted by a signify a group of the formula > C-S-CH=CH-or > C-CH=CH-CH=CH-which is optionally substituted by halogen and the dotted line signifies an additional bond.
    6. Compounds according to claim 5, wherein Rb and Rc together with the carbon atom denoted by a signify the group of the formual > Cα-S-CH=CH- or > C -CH=CCl-CH=CH-.
    < l
    7.5,6-Dihydro-3-hydroxy-2-phenylthiazolo [3, 2-a] thieno [2,3-e] pyridinium hydroxide (internal salt).
    8.9-Chloro-2-phenyl-5,6-dihydro-3-hydroxythiazolo [2, 3-a] isoquinolinium hydroxide (internal salt).
    9. The use of compounds according to any one of claims 1-8 for the manufacture of therapeutically active substances.
    10. The use of compounds according to any one of claims 1-8 for the manufacture of compounds of the general formula
    wherein Ra, Rb, Rc, Q1 and the dotted line have the above significance and Rd signifies cyano, nitro or the group of the formula -CO-(Q2A2)Q-R1, q signifies the number O or 1, A signifies lower alkylene or a direct bond, Q signifies an oxygen atom or the group-NR2-. R1 signifies hydrogen, hydroxy, cyano, nitro, halogen, lower alkoxy, lower alkyl, lower alkoxycarbonyl, aryl, a group of the formula -NR3R4 or a 5-membered, saturated, partially unsaturated or aromatic heterocycle which is attached via a carbon atom and which is optionally substituted by one or two lower alkyl groups and optionally substituted by a (C3-6)-cycloalkyl, hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, lower alkoxycar- bonyl, lower alkanoyl, carbamoyl, mono-or di (lower alkyl) carbamoyl. oxo or alkylenedioxy group, R2 signifies hydrogen, lower alkyl or aryl, R3 and R4 each signify hydrogen, lower alkyl, lower alkoxyalkyl, lower dialkoxyalkyl, lower alkylenedioxyalkyl, lower cyanoalkyl, lower haloalkyl, lower hydroxyalkyl, lower dihydroxyalkyl, lower alkanoyl, lower alkoxycarbonyl or a (C-)-cycloalkyl group which is optionally substituted by hdyroxy, lower alkoxy, lower alkanoyloxy. lower hydroxyalkyl. lower alkoxyalkyl, lower alkanoyloxyalkyl. oxo. carbamoyl. mono-or di (lower alkyl) carbamoyl or by lower alkylenedioxy or together with the nitrogen atom signify a 3-to 7-membered, saturated N-heterocycle which is optionally substituted by one or two lower alkyl groups and optionally substituted by one or two hydroxy, lower alkoxy, lower alkanoyloxy. lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, lower alkoxycarbonyl. lower alkanoyl, carbamoyl, mono-or di (lower alkyl) carbamoyl, oxo or lower alkylenedioxy groups and which can contain as a ring member an oxygen or sulphur atom or the group > N-R. and R signifies hydrogen, lower alkyl, lower hydroxyalkyl. lower alkoxyalkyl. lower alkanoyloxyalkyl, lower alkanoyl, lower alkoxycarbonyl. carbamoyl or mono-or di (lower alkyl) carba- moyl, with the proviso that R1 has a significance different from hydroxy, cyano, nitro, halogen, lower alkoxycarbonyl, lower alkoxy and -NR3R4 when q signifies the number 1 and A2 signifies a direct bond, and of pharmaceutically acceptable acid addition salts of compounds of formula I which have one or more basic substituents.
    Amendments to the claims have been filed as follows 1. Compounds of the general formula
    wherein Q1 and the nitrogen atom together signify a group of the formula > N-CH2CH2- (a), > N-CH2CH2CH2- (b). > N-CH=CH- (c), > N-CH2-CH=CH- (d), > N-CH2-S (O) p- (e), > N-CH2CH2-S (O) p- (f) or > N-CH=CH-S (O) p- (g). p signifies the number 0,1 or 2, Ra signifies a phenyl, pyridyl or thienyl group which is optionally substituted by halogen, trifluoromethyl nitro, lower alkyl or lower alkoxy, Rb and Rc together with the carbon atom denoted by a signify a group of the formula > C&alpha;-S-CH=CH- (h). > C&alpha;-CH=CH-S- (i) or > C&alpha;-CH=CH-CH=CH- (j) which is optionally substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, amino or mono-or di (lower alkyl) amino, and the dotted line signifies an additional bond.
    2. Compounds according to claim 1, wherein Q1 and the nitrogen atom together signify the group of the formula N-CH2CH2- (a) or > N-CH=CH- (c).
GB8805796A 1984-11-06 1985-11-05 Tricyclic pyridine derivatives Expired GB2200117B (en)

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Application Number Priority Date Filing Date Title
CH530484 1984-11-06
CH383685 1985-09-05
GB8527196A GB2169288B (en) 1984-11-06 1985-11-05 Tricyclic pyridine derivatives

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GB2200117A true GB2200117A (en) 1988-07-27
GB2200117B GB2200117B (en) 1989-05-24

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