IL22905A - 4h-benzo-(4,5)-cyclohepta-(1,2-b)-thiophene derivatives and a process for their production - Google Patents
4h-benzo-(4,5)-cyclohepta-(1,2-b)-thiophene derivatives and a process for their productionInfo
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- IL22905A IL22905A IL22905A IL2290565A IL22905A IL 22905 A IL22905 A IL 22905A IL 22905 A IL22905 A IL 22905A IL 2290565 A IL2290565 A IL 2290565A IL 22905 A IL22905 A IL 22905A
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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
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
- C07D333/80—Seven-membered rings
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation
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Description
niiDi |Π3 TJinrn n PATENT ATTORNEYS · □ ' □ 10 S « 3 T I II PATENTS AND DESIGNS ORDINANCE SPECIFICATION 4H-benzo- , 5]-cyclohepta-[l , 2-b]thiophene derivatives and a process for their production Tsn*nrb-2,l3*Bsni *. t5, jiT3:.-H4 nnVm I (We) SAHDOZ A.G., a Swiss company, of Basle, Switzerland do hereby declare the nature of this invention and in what manner the same is to be performed, to be particularly described and ascertained in and by the following statement : - Case 1924 - la - The present invention relates to new heterocyclic compounds and a process for their production.
The present invention provides 4H-benzo[4,5]cyclohepta-[l,2-b]thiophene derivatives of formula I, in which R^ signifies a hydrogen atom or a halogen atom of atomic number greater than 9 but smaller than 53» a Z signifies the radical -CH=CH- or -CH2-CH2-, and their acid addition salts. The relevant halogen atoms falling within the scope of R^ are chlorine and bromine.
The present invention further provides a process for the production of compounds of formula I and their acid addition salts, characterized in that a compound of formula IV, in which and Z have the above significance, and R2 signifies a lower alkyl or lower aralkyl radical, is hydrolysed and, when an acid addition salt is required, the resulting compound I is reacted with an organic or inorganic acid.
The term "lower" as used herein designates alkyl radicals with from 1 to 4 carbon atoms inclusive and aralkyl radicals from The compounds of formula IV may be produced by reacting a 4- (5-dimethylamino-propylidene)-4H-benzo[ 4, 5]cyclohepta[ l,2-b]thiophene derivative of formula II, in which R^ and Z have the above significance, with a chloroformic acid ester of formula III, CI - CO - 0 - R2 III in which ^ has the above significance.
One advantageous method of producing the compounds of formula IV consists in that a compound II, dissolved in an inert organic anhydrous solvent, preferably benzene, toluene, heptane, carbon tetrachloride or tetrahydrofuran, is added at room temperature to a solution of a chloroformic acid ester, e.g. chloroformic acid ethyl ester or chloroformic acid benzyl ester, dissolved in more of the same solvent. To complete the reaction the mixture is further heated to the boil at reflux for 1 to 5 hours. The resulting compound IV is isolated and purified in known manner.
In order to produce compounds of formula I, the radical -C0-0-R2 in a compound of formula IV is hydrolytically replaced with a hydrogen atom. This may be effected, for example, by heating the compound IV in an alkanol of from 1 to 6 carbon atoms inclusive, preferably n-butanol, with an alkali metal hydroxide, e.g. potassium hydroxide, for several hours. The splitting off of the -C0-0-R2 radical may, however, also be effected in an acid medium, e.g. by heating with a stron inorganic acid. It is advantageous to work in obtain a better yield. The compound of formula I may be isolated from the reaction mixture in manner known per se and purified by crystallization or by conversion into a suitable salt.
The following are examples of acids which may be used for acid addition salt formation with the compounds of formula I: hydrochloric, hydrobromic, phosphoric, sulphuric, acetic, malonic, fumaric, maleic, tartaric, malic, hexahydrobenzoic and p-toluene-sulphonic acids.
Compounds of formula I are distinguished by strong effects which are characteristic for antidepressives; in tests on animals they produce inter alia, an inhibition of the vegetative and motor symptoms caused by reserpine and tetrabenazine, a potentiation of the effect of noradrenalin and certain sedative and anticholinergic effects.
Although the compounds of formula I have some neuroleptic properties, these are not very pronounced and they therefore show a specific anti-depressive effect. The toxicity of the compounds of formula I is relatively low, they are therefore indicated for use in the treatment of neurotic and psychotic disorders, especially depression conditions, and also in the therapeutical treatment of psychosomatic disorders. The compounds of formula I are especially indicated for administration in the form of their physiologically acceptable, water-soluble salts.
The compounds of formula I are indicated for use as pharmaceuticals on their own or in the form of appropriate medicinal preparations for enteral or parenteral administration. In order to produce appropriate medicinal preparations the compounds are worked up with inorganic or organic adjuvants which are inert and physiologically acceptable. Examples of such adjuvants are: tablets and drage"es : lactose, starch, talc and stearic acid; injectable solutions : water, alcohols, glycerin and vegetable oils; suppositories : natural or hardened oils and waxes.
The preparations may furthermore contain suitable preserving, stabilizing and wetting agents, solubilizers, sweetening and colouring substances and flavourings.
The present invention therefore further provides pharmaceutical preparations containing, in addition to a physiologically acceptable carrier, a compound of formula I and/or an acid addition salt thereof.
The 4H-benzo[ 4, 5]cyclohepta[ l,2-b]thiophene derivatives of formula II are described and claimed in Application Nos. 217#3 , 22639 and 226 Ο.
They may be produced by the following process: 2-thenyl-diethyl-phosphorate is condensed in a suitable anhydrous organic solvent and in the presence of an alkaline condensation agent with an o-phthal-aldehydic acid which may optionally be substituted in the 5-P°sition by a chlorine or bromine atom, the resulting 2-[ 2- (2-thienyl)-vinyl]-benzoic acid or its halogen derivative is reduced to the corresponding 2-[ 2- (2-thienyl) -ethyl]-benzoic acid or its derivative and this is subjected to an intramolecular ring closure, whereby 9,10-dihydro-4H-benzo[ 4, 5]cyclohepta[ l,2-b]thiophen-4-one or a derivative thereof substituted in the 6-position by chlorine or bromine atom are obtained. Sodium amalgam in an aqueous alcohol may, for example, be used as reducing agent and polyphosphoric acid or sulphuric acid as condensation agent for the ring closure. The dehydrogenation in the 9,10-position may, if desired, advantageously be effected as follows: The 9*10-dihydro-4H-benzo[ 4, 5]cyclohepta[l,2-b]thiophen-4-one or its obtained above, is heated with N-broraosuccinimide in absolute carbon tetrachloride and in the presence of a catalytical amount of dibenzoyl peroxide and the resulting reaction product is subsequently heated with a triallcyl amine. The resulting H-benzo[ 4, 5]cyclohepta[ 1,2-b]-thiophen-4-one derivative of formula V, tl 0 in which and Z have the above significance, is then reacted with a 3-dimethylaminopropyl-magnesium halide, in which halide signifies chlorine, bromine or iodine, the reaction product is hydrolysed and the resulting 4H-benzo[4, 5]cyclohepta[ 1,2-b]-thiophen-4-ol derivative is subsequently treated with an agent for removing water, whereby the desired compound of formula II is obtained.
In the following non-limitative Examples all temperatures are indicated in degrees Centigrade and are uncorrected.
Examgle_lj_ 4-(3-methylamino-propylidene) -9, 10-dihydro- 4H-benzo[ , 1 cyc1ohep a[1 , 2-b] thiophene . a) A solution of 5.7 g of 4-(3-dimethylamino- propylidene) -9, 10-dihydro-4H-benzo[4, 5]cyclohepta [1, 2-b] thiophene in 25 cc of absolute benzene is added dropwise to a solution of 6.5 g of chloroformic acid ethyl ester in 25 cc of absolute benzene at room temperature during the course of half an hour. The mixture is subsequently heated to the boll whilst stirring for a further 2 hourse cooling washing is effected thrice with 2N hydrochloric acid and twice more with water and the benzene solution is dried over magnesium sulphate. After evaporating the solvent, pure 4-(3-methyl-3-ethoxycarbonylamino-propylidene) -9, 10--dihydro-4H-benzo[4, 51 cyclohepta[l, 2-b] thiophene is obtained. n2^~ 1·5357· b) A solution of 6.2 g of 4-(3-methyl-3-ethoxy- carbonylamino-propylidene) -9, 10-dihydro-4H-benzo[4, 5] cyclohepta[l, 2-b] hiophene and 5 g of potassium hydroxide in 55 cc oi> n-butanol is heated to the boil whilst stirring for 6 hours in an atmosphere of nitrogen.
The solvent is then evaporated, the residue is dissolved at 6o° in a mixture of 65 cc of 2N sulphuric acid and 55 cc of water and the solution is cooled. The acid solution is shaken out with 55 cc of hexane, whereby three layers are obtained. The two lower layers are separated and the upper hexane layer is washed onoe more with 20 cc of N sulphuric acid. The combined aqueous solutions are made strongly alkaline with sodium hydroxide solution and extracted thrice with ether. The combined ethereal extracts are washed with water, dried over magnesium sulphate and then evaporated The resulting residue is then dissolved in isopropanol and an isopropanolic hydrogen chloride solution is added to the resulting solution. After a number of hours the 4-(3-raethylamino-propylidene)-9i 10-dihydro-4H-benzo[4, 5Jcyclohepta[l, 2-b] thiophene hydrochloride is filtered off and recrystallized from ethanol/ isopropanol. Melting point 23 .5-238.5° (decomposition) The 4-(3-dimethylamino-propylidene) -9i 10-dihydro-4H-benzo [4, 53 cyclohepta[l, 2-b] hiophene used as starting material is produced as follows: 2-[2-(2-thienyl) -vinyl] -benzoic acid. g of powdered, well dried sodium methylate are added to a solution of 117 g of thenyl-diethyl-phosphonate (boiling point 120-124°/0.0β mm Hg) in 200 cc of freshly distilled dimethyl formaraide, whereby the temperature of the solution rises to 45-50°. The flask is then placed in an ice bath and a solution of 80 g of o_-phthalaldeh dic acid in 200 cc of dimethyl formarnide is added dropwise at such a rate that the temperature remains between 35 and 40° and stirring is then f d for a f - i r m are added to the reaction solution whilst cooling well, whereby a red oil separates. The solution is then made alkaline with potassium carbonate, whereby the oil redlssolves, the reddish brown solution is shaken out thrice with benzene and hydrochloric acid is carefully added at 10-15° to adjust the pH value of the aqueous solution to 4. After a number of hours in the refrigerator the precipitated acid is filtered off, dried and recrystallized from benzene. The resulting 2-[2-(2-thienyl) -vinyl] -benzoic acid has a melting point of I33-I350. The mother liquor is shaken out thrice with methylene chloride, the organic phase is dried over sodiurn sulphate and evaporated at 15 mm Hg. The residue is crystallized from benzene, whereby a further portion of acid, having a melting point of 133-I350, is obtained. 2-[2-(2-thienyl) -ethyl] -benzoic acid. 7.5 g of sodium are melted under anhydrous toluene, whereupon 375 g of pure mercury are added dropwise whilst shaking frequently at such a rate that the toluene boils. The mixture is then heated to 120-140° whilst Stirring and as soon as all the toluene is distilled off cooling is effected to 50°. A solution of 20 g of 2-[2-(2-thienyl) -vinyl] -benzoic acid in 1 0 cc of 9 ethanol is then poured on the homogeneous amalgam and the mixture is shaken for 30 minutes.
The mercury is then separated, washed twice with a e di through highly purified diatomaceous earth, acidified with hydrochloric acid and cooled to 5°. After several hours the precipitated acid is filtered off and crystallized from chloroform/hexane . Melting point 110-111°. 9, 10-dihydro- H-benzo [4, 5 ] cyclohepta , 2-b] thiophen-4-one. 59 cc of an3 $ phosphoric acid and 86 g of phosphorus pentoxide are first stirred at 125-130° for minutes. 20 g of powdered 2-[2-(2-thienyl) -ethyl] -benzoic acid are then added at the same temperature during the course of 30 minutes. The reaction mixture is stirred for a further 2 hours at 125-130°, poured into 1000 cc of water, the solution is filtered through highly purified diatomaceous earth and extracted thrice with methylene chloride. The organic phase is washed with 2N sodium carbonate solution, dried over magnesium sulphate, the solvent is evaporated and the residue distilled in a high vacuum, whereby 9,10-dihydro-4H-benzo [4,5] c clohe ta[1, 2-b ] thiophen-4-one distils over at 125-l4o°/0.05 mm Hg in the form of a 24 green oil. n ^ = 1.&559· 4-(3-dimethylaminopropyl) -9, 10-dihydro-4H-benzo[4i5] cyclohepta[l, -b] hiophen-4-ol. 2.2 g of magnesium which have been activated with iodine are covered with a small amount of tetra-hydrofuran and a few drops of ethylene bromide are added.
After the reaction has commenced a solution of 10.8 g hydrofuran is added dropwise at such a rate that the is g of 9, 10-dihydro-4H-benzo[4, 5]cyclohepta[l, 2-b] thiophen-4-one in J>0 cc of tetrahydrofuran is added dropwise during the course of 10 minutes and heating to the boil is effected for a further 10 minutes whilst stirring. After cooling the reaction mixture is poured into a solution of 30 g f ammonium chloride in 200 cc of water, 200 cc of methylene chloride are added and the mixture is filtered through highly purified diatoraaceous earth. After separating the organic phase the aqueous portion is shaken out twice more with methylene chloride, the combined methylene chloride solutions are washed with water, dried over magnesium sulphate and evaporated at 15 mm Hg. The oily residue is crystallized The resulting from ether/petroleum ether./ 4- ( 3-dimethylaminopropyl) -9, 10-dihydro-4H-benzo[4, 5]cyclohepta[l, 2-b] thiophen-4-ol melts at 101° . 4- ( 3-dimethylamino-propylidene) -9j 10-dihydro-4H-benso [ ^, ] cyclohepta[l, 2-b] thiophene. 8 g of 4- ( 3-dlmethylaminopropyl) -9, 10-dihydro-4H-benzo[ 4, 5]cyclohepta[l, -b] thiophen-4-ol, 80 cc of glacial acetic acid and 32 cc of concentrated hydrochlo-ic acid are heated at reflux for 30 minutes, the reaction mixture is evaporated at 15 mm Hg and the residue triturated with ethanol/ether ( 1 : 1) . The precipitated hydrochloride is filtered off and recrystallized from dihydro-4H-benzo[4,53 cyclohepta[ 1, 2-b] thiophene h dro-chloride melts at 222-224° (decomposition).
E amp_le_.2j. 6-chloro-4- (g nethylamino-propylidene) - 9, 10-dihydro-4H-benzo[4, 5]cyclohepta[l, 2-b] thiophene. a) 6-chloro-4-(3-»iethyl-3-ethoxycarbonylamino-propylidene)-9, 10-dihydro-4H-benzo[4, Slcycloheptatl, 2-b] thiophene (n ^= 1.5881) is obtained from 2 g of 6-chloro- -( -dirnethylamino -propylidene ) -9, 10-dihydro-4H-benzo [4, ]cyclohepta[lJ 2-b] hiophene and 2.1 g of chloroformic acid ethyl ester in 25 cc of absolute benzene in a. manner analogous to that described in Example 1 a) . •,nen cloned in the heading of this Example b) The compound/is obtained by heating ..a solution of 2 g of 6-chloro-4-(3-methyl-3-ethoxycarbonylamino-propylidene) -9, 10-dihydro-4H-benzo[4, ]cyclohepta[l, -b] thiophene and 1.45 g of potassium hydroxide in 1β cc of n-butanol in a manner analogous to that described in Example 1 b).
The hydrochloride is produced by adding a saturated ethereal hydrogen chloride solution to the ethereal solution of the base. The precipitated 6-chloro 4-(3-methylamino-propylidene)-9, 10-dihydro-4H-benzo[4, ] cyeloheptatl, 2-b] thiophene hydrochloride melts at 215-217° (decomposition) after recrystallization from iso propanol.
The 6-chloro-4-(3-dimethylamino-propylidene)-9, 10-dihydro-4H-benzo [4, ] cyclohepta[l, 2-b] thiophene -chloro-2- [ 2- ( 2-thienyl) -vinyl] -benzoic _acid. 1 to 2 cc of a solution of 70 g of 5-chloro-phthalaldehydic acid (melting point 136-138° ) and 89 g of thenyl-diethyl phosphonate in 135 cc of dimethy 1-formarnide are added dropwise to a suspension of 5.6 g of sodium methylate in 135 cc of dimethyl formarnide, whereby the temperature of the mixture rises to 35-40°. The flask is then placed in an ice bath and the remainder of the solution of 6-chloro-phthalaldehydic acid and thenyl-diethyl phosphonate is added dropwise as rapidly as possible at such a rate that the internal temperature remains at 35-40° . The reaction mixture is then stirred for a further 3° minutes at room temperature. 3ΟΟ cc of water are added slowly to the reaction solution at 10-15° whilst cooling well and the resul ing / aqueous solution is shaken out with 300 cc of benzene. 2N hydrochloric acid is then carefully added at 10-15° to adjust the pH value of the aqueous solution to 3 to 4. After several hours the precipitated acid is filtered off and dried. Melting point 152-153° from benzene.
Melting point 134-135° from ethanol. The acid is produced in a manner analogous to that of 2-E2-(2-thienyl) -ethyl] -benzoic acid (Example 1 ) . -2hloro-9i10-dihydro-4H-benzo[4, 5]cyclohepta[l, 2-b] thiophen-4-one .
Meltin oint 1 -108° fr ether he c m dihydro- H-benzo[ i 53c3;"clohepta[lJ 2-b] thiophen-4-one (Example 1 ) . 6-chloro-4- ( 3-dimethylamino-propyl) ^9, 10-dihydro-4H-benzo[4, ] cyclohepta[l, 2-b] thiophen-4-ol.
Melting point 140.5-141.5° from ethanol. The compound is produced in a manner analogous to that of 4- (3-dimethylaminopropyl) -9, 10-dihydro-4H-benzo[4, 5 ] cyclohepta[l, -b] thiophen-4-ol (Example 1 ) . 6-chloro-4- ( 3-dimethylamino-propylidene) -9, 10-dihydro-4H-benzo[4, 5]cyclohepta[l, 2-b] thiopheneL g of the chloro compound from the preceding step are heated at reflux for one hour in a mixture of 75 cc of glacial acetic acid and 30 cc of concentrated hydrochloric acid, the reaction mixture is then evaporated at 15 mm Hg to half its volume, diluted with βθθ cc of water and made strongly alkaline with sodium hydroxide solution. The aqueous alkaline solution is then extracted thrice with methylene chloride, the combined methylene chloride extracts are washed with water and dried over magnesium sulphate. After evaporating the solvent the oily residue is crystallized from ligroin (boiling point 70-80°) . o-chloro-4- (3-dimethylamino-propylidene) -9, 10-dihydro-4H-benzo[4, ]cyclohepta [1, 2-b]thiophene melts at 106-107°. 4- ( 3-i"nethylamino-propylidene) -4H-benzo [4, ]cyclohepta[l, 2-b] thiophene. a) 4- ( 3-methyl-3-ethoxycarbonylamino-propylidene)- 4H-benzo[4, 5]cyclohepta[lJ 2-b] thiophene (n2^= 1.6075) is - Ik - 1924 formic acid ethyl ester in 40 cc of absolute benzene in a manner analogous to that described in Example 1 a) . b) 4-(3-methylamino-propylidene) -4H-benzo[4,5] cyclohepta[l, 2-b] thiophene is obtained by heating 4.2 g of 4-(3-methyl-3-ethoxycarbonylamino-propylidene) -4H-benzo[4, 5] cyclohepta[l, 2-b] thiophene and 3.40 g of potassium hydroxide in 40 cc of n-butanol.
Hydrochloride: An isopropanolic hydrogen chloride solution is added to a solution of the base in isopropanol. After several hours the precipitated hydrochloride is recrystallized from ethanol/isopropa-nol. Melting point 219-220° (decomposition).
The 4-(3-dimethylarnino-propylidene) -4H-benzo[4,5]cyclohepta[l,2-b]thiophene used as starting material is produced as follows: 9,10-dihydro-4H-benzo[4,5]cyclohepta[l, 2-b] thiophen-4-one (boiling point 125-140°/0.05 mm Hg; 24 n 1.β 5 the production of which is described in Example 1, is dehydrogenated in the 9, 10-position.
The procedure is effected as follows: A mixture of 32.1 g of the dihydro compound, 2o.7 g of N-bromosuccinimide and 0.3 g of benzoyl peroxide in 250 cc of absolute carbon tetrachloride is heated to the boil for 4 hours. After cooling to 50° the reaction mixture is filtered through highly urified diatomaceous earth and the solvent is eva o heated for 2 hours together with 200 ce of criethyl-amine whilst stirring. After evaporating unconverted triethylamine 250 cc of methylene chloride are added to the residue and the resulting solution is washed thrice with 2N hydrochloric acid and twice with water. After drying the solution over magnesium sulphate the solvent is removed at reduced pressure. The residue is distilled in a high vacuum, whereby 4H-benzo[ 4, 3 cyclohepta[l, 2-b] thiophen-4-one distils over at 173-l80°/0. 1 mm Hg in the form of an oil and crystallizes upon cooling. Melting point 109-110° after recrys-tallization from ethanol. 4- ( 3-dimeth lamino-propyl-4H-benzo[4i5]cyclohepta[l, 2-b] thiophen-4-ol.
Melting point 121-122° from ethanol or ethanol/hexane. The compound is produced in a manner analogous to that of the corresponding 9, 10-dihydro compound in Example 1. 4-^3-dimethylamino-propylidene ) -4H-benzo [4, 5] cyclohepta [ 1, 2-b] thiophene.
A solution of 4 g of the compound obtained above in 250 cc of acetic anhydride is heated to the boil for 6 hours. After approximately 200 cc of solvent have been distilled off the residue is poured into 1200 cc of water whilst stirring, the aqueous solution is filtered through highly purified diatomaceous strongly earth, made/alkaline with a 20$ sodium hydroxide solution and the alkaline solution is extracted thrice are then evaporated. The resulting residue is distilled in a high vacuum, whereby 4-(3-dimethylamino-propylidene) -4H-benzo[4, 5] cyclohepta[l, 2-b] thiophene distils over at 160-165°/0.1 mm Hg. 6-chloro-4-(3»n.ethylamino-propylidene)-4H- benzo[4, 5] cyclohepta[l.2-b] thiophene. a) A solution of 5.0 g of 6-chloro-4-(3-dimethyl-amino-propylidene) -4H-benzo[4,5]cyclohepta[l, 2-b] thiophene in 4o cc of absolute benzene is added dropwise to a solu-tion of 5· 5 g of chloroformic acid ethyl ester in cc of absolute benzene at 15-20° during the course of half an hour. The mixture is subsequently heated to the boil for 2 hours whilst stirring, after cooling washing is effected thrice with 2N hydrochloric acid, then twice more with water and the benzene solution is dried with magnesium sulphate. After evaporating the solvent pure 6-chloro-4-(3-methyl-3-ethoxycarbonylarnino-propylidene) -4H-benzo[4, 5]cyclohepta[l, 2-b] thiophene is obtained, n ^= 1.6095. t>) A solution of 5·^ g of 6-chloro-4-(3-methyl- 3-ethox carbon 1amino) -propylidene-4H-benzo[4, 5] cyclo-hepta[l, 2-b] thiophene and 3.7 g of potassium hydroxide in 40 cc of n-butanol is heated to the boil in an atmosphere of nitrogen for 5 hours whilst stirring. The solvent is subsequently evaporated at 15 mm Hg, the residue is dissolved at 60° in a mixture of 65 cc of 2N sulphuric acid and 55 cc of water and the solution is cooled. are separated and the upper hexane layer is washed once more with 20 cc of 2 sulphuric acid. The combined aqueous solutions are made strongly aLkaline with sodium hydroxide solution and shaken out thrice with ether. The combined ethereal extracts which have been washed with water and dried over magnesium sulphate are then evaporated. The resulting residue is then dissolved in isopropanol and an isopropanolic hydrogen chloride solution is added to the resulting solution. After several hours at room temperature 6-chloro-4-(3-rnethylamino-propylidene) -4H-benzo[4, 5] cyclohepta [1, 2-b] thiophene hydrochloride is filtered off and recrystallized from isopropanol. Melting point 253-255° (decomposition).
The 6-chloro-4-(3-dimethylamino-propylidene) - H-benzo [4, 5] cyclohepta[1, 2-b] thiophene used as starting material is produced as follows: 1.0 g of magnesium which has been activated with iodine is covered with tetrahydrofuran and a few drops of ethylene bromide are added. After the reaction has commenced a solution of 4.5 g of 3-dimethylamino-propyl chloride in 10 cc of tetrahydrofuran is added dropwise at such a rate that the solvent boils and heating to the boil is effected for a further 2 hours. A solution of 3.8 g of 5-chloro-4H-benzo[4, 5]cyclo-hepta[l, 2-b] thiophen-4-one in 15 cc of tetrahydrofuran is then added dropwise at 20° during the course of 5 reaction mixture is poured into 200 cc of a 20$ ammonium chloride solution and the aqueous solution is shaken out thrice with ether. The combined ether extracts are washed twice more "ith water, dried over sodium sulphate and the solvent is evaporated at 15 mm Hg.
The oily residue is crystallized from ethanol. 6-chloro-4-( 3-dimeth lamino-propyl) -4H-benzo[4, 53cyclohepta [l, 2-b]thiophen-4-ol melts at l64-l55°.
A solution of δ.Ο g of 6-chloro-4-( 3-dimethyl-amino-propyl) -4H-benzo[4, 5]cyclohepta[l, -b] thiophen-4-ol in 10 cc of isopropanol, 5 cc of ethanol and cc of a βΝ isopropanolic hydrochloric acid is stirred at S0° for half an hour. The solvent is evaporated at 15 mm Hg and the residue is dissolved in 3 oc of acetone. After standing the 6-chloro-4-(3-dimethyl-amino-propylidene) -4H-benzo[4,5]cyclohepta[l, 2-b] thiophsne hydrochloride precipitates; it is filtered off and recrystallized from isopropanol. Melting point I83-186° (decomposition).
Claims (11)
1. A process for the production of H-benzo[ , 5]cyclohepta[l,2-b]-thiophene derivatives of formula I, in v;hich R^ signifies a hydrogen atom or a halogen atom of atomic number greater than 9 but smaller than 55* and Z signifies the radical -CH=CH- or -CH2-CH2-, and their acid addition salts, characterized in that a compound of formula IV, in which R^ and Z have the above significance, and R^ signifies a lower alkyl or lower aralkyl radical, is hydrolysed and, when an acid addition salt is required, the resulting compound I is reacted with an organic or inorganic acid.
2. A process according to Claim 1, in which the compound of formula IV is produced in such a way that a 4- (5-dimethylamino-propylidene)-4H-benzo[ 4, 5]cyclohepta[l,2-b]thiophene derivative of formula II, in which R.. and Z have the significance stated in Claim 1, » 4 - 20 - 192 is reacted with a chlordformic acid ester of formula III, CI - CO - 0 - R III in which ^ has the significance stated in Claim 1.
3. A process for the production of the compounds of formula I stated in Claim 1 and their acid addition salts substantially as herein 5 described with reference to any one of the Examples.
4. The compounds of formula I stated in Claim 1 and their acid addition salts whenever produced by the process claimed in any one of Claims 1-3.
5. · The compounds of formula I stated in Claim 1 and their acid 10 addition salts.
6. 4- (3-methylami.no-propylidene) -9,10-dihydro-4H-benzo[ , 5] - cyclohepta[l,2-b]thiophene.
7. . 6-chloro-4- (3-methylamino-propylidene) -9, 10-dihydro-4H- benzo[ , 5]cyclohepta[ l,2-b]thiophene.
8. 15 8. 4- (3-methylamino-propylidene)-4H-benzo[ 4, 5] cyclohepta- [ 1,2-b]thiophene.
9. 6-chloro-4- (3-methylamino-propylidene)-4H-benzo[ 4, 5]cyclohepta- [ l,2-b]thiophene.
10. The acid addition salts of the compounds claimed in any one of 20 Claims 6-9.
11. Pharmaceutical preparations containing, in addition to a physiologically acceptable carrier, a compound of formula I and or an acid addition salt thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH127564A CH440321A (en) | 1964-02-04 | 1964-02-04 | Process for the preparation of new heterocyclic compounds |
| CH1324664 | 1964-10-13 | ||
| CH806165A CH473138A (en) | 1964-02-04 | 1965-06-09 | Process for the preparation of new 9,10-dihydro-4H-benzo (4,5) cyclohepta (1,2-b) thiophene derivatives |
| CH1519165A CH473146A (en) | 1964-02-04 | 1965-11-03 | Process for the preparation of new 4H-Benzo (4,5) cyclohepta (1,2-b) thiophene derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL22905A true IL22905A (en) | 1969-01-29 |
Family
ID=27428140
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL22905A IL22905A (en) | 1964-02-04 | 1965-02-03 | 4h-benzo-(4,5)-cyclohepta-(1,2-b)-thiophene derivatives and a process for their production |
Country Status (12)
| Country | Link |
|---|---|
| BE (2) | BE659178A (en) |
| BR (2) | BR6566936D0 (en) |
| CH (2) | CH473138A (en) |
| DE (2) | DE1238040B (en) |
| ES (1) | ES332985A2 (en) |
| FI (1) | FI42216B (en) |
| FR (4) | FR1441486A (en) |
| GB (2) | GB1089483A (en) |
| IL (1) | IL22905A (en) |
| NL (2) | NL125442C (en) |
| OA (1) | OA01524A (en) |
| SE (1) | SE306323B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU195800B (en) * | 1983-10-13 | 1988-07-28 | Sandoz Ltd | Process for producing 4h-benzo/4,5/cylopenta/1,2-b/ thiofene derivatives and pharmaceutical compositions containing them |
| EP1218007B1 (en) | 1999-09-13 | 2011-07-20 | Bridge Pharma, Inc. | Optically active isomers of ketotifen and therapeutically active metabolites thereof |
-
1965
- 1965-01-26 GB GB3355/65A patent/GB1089483A/en not_active Expired
- 1965-01-28 OA OA51413A patent/OA01524A/en unknown
- 1965-01-29 NL NL6501154A patent/NL125442C/xx active
- 1965-02-01 DE DES95277A patent/DE1238040B/en active Pending
- 1965-02-02 FI FI0244/65A patent/FI42216B/fi active
- 1965-02-02 BE BE659178A patent/BE659178A/xx unknown
- 1965-02-02 FR FR4164A patent/FR1441486A/en not_active Expired
- 1965-02-03 IL IL22905A patent/IL22905A/en unknown
- 1965-02-03 SE SE1405/65A patent/SE306323B/xx unknown
- 1965-02-04 BR BR166936/65A patent/BR6566936D0/en unknown
- 1965-04-30 FR FR15304A patent/FR4369M/fr not_active Expired
- 1965-06-09 CH CH806165A patent/CH473138A/en unknown
- 1965-08-09 BE BE668052A patent/BE668052A/xx unknown
- 1965-08-09 NL NL6510326A patent/NL6510326A/xx unknown
- 1965-08-10 FR FR27925A patent/FR91208E/en not_active Expired
- 1965-11-03 CH CH1519165A patent/CH473146A/en unknown
-
1966
- 1966-10-21 GB GB47266/66A patent/GB1159480A/en not_active Expired
- 1966-10-28 DE DE19661620420 patent/DE1620420A1/en active Pending
- 1966-10-31 BR BR184229/66A patent/BR6684229D0/en unknown
- 1966-11-02 FR FR82202A patent/FR92121E/en not_active Expired
- 1966-11-02 ES ES332985A patent/ES332985A2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR1441486A (en) | 1966-06-10 |
| NL6501154A (en) | 1965-08-05 |
| BR6684229D0 (en) | 1973-12-26 |
| SE306323B (en) | 1968-11-25 |
| BE659178A (en) | 1965-08-02 |
| NL6510326A (en) | 1966-12-12 |
| CH473138A (en) | 1969-05-31 |
| BE668052A (en) | 1966-02-09 |
| ES332985A2 (en) | 1968-03-16 |
| FR91208E (en) | 1968-05-03 |
| CH473146A (en) | 1969-05-31 |
| FR92121E (en) | 1968-09-27 |
| BR6566936D0 (en) | 1973-08-14 |
| FI42216B (en) | 1970-03-02 |
| FR4369M (en) | 1966-08-22 |
| DE1620420A1 (en) | 1970-03-12 |
| GB1089483A (en) | 1967-11-01 |
| DE1238040B (en) | 1967-04-06 |
| NL125442C (en) | 1968-06-17 |
| GB1159480A (en) | 1969-07-23 |
| OA01524A (en) | 1969-07-21 |
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