GB2138812A - 8-Benzylidene-5,6,7,8-tetrahydroquinoline derivatives - Google Patents

Abstract

Compounds of formula <IMAGE> and acid addition salts thereof (wherein R represents lower alkoxy, alkanoyloxy of 2 to 7 carbon atoms or hydroxy; R<1> and R<2> independently represent hydrogen, lower alkoxy, alkanoyloxy of 2 to 7 carbon atoms, a hydroxy or lower alkyl; R<3>, R<4> and R<5> each represent hydrogen or lower alkyl with the proviso that at least one of R<3>, R<4> and R<5> is lower alkyl; and R<6> and R<7> each represent hydrogen or lower alkyl) possess anti-ulcer activity.

Description

exposure the rats were killed with intracranial alcohol and their stomachs excised and opened aiong the greater curvatures. Each stomach was washed gently free of contents with warm tap water and pinned out on a board. The condition of the gastric mucosa was then scored from 0 to 6 on the following scale: Ulcers 0-6 0 = No ulcers 1 = Pin point haemorrhaqic site

2l ~ Several discrete pin point 3( - haemorrhagic sites 51 = Large eroded sites with 6J haemorrhage The maximum possible score for each animai was 6 and for the group 36.Decrease in ulcer formation was calculated as a percentage of the control score, i.e.

Mean Control group score Mean Test Group Score Percentage Inhibition = x 100 Mean Control group score The statistical significance of the effect is assessed by Student's t-test. Experience has shown that + 45% inhibition may be taken as a threshold value below which compounds can be regarded as inactive or not sufficiently active to be considered further.

In the above mentioned test the following representative compounds of formula I were particularly active giving results as shown: Dose (mg/kg) Inhibition E-8-(3,4-Diacetoxybenzylidene) 100 93% 30 67% -5,6, 7,8-tetrahydro-3-methyliquinoline 10 40% E-8-(2-Methoxybenzylidene)-5,6,7,8- 100 87% tetrahydro-3-methylquinoline 30 21% E-5,6,7,8-Tetrahydro-8-(4-hydroxy 100 66% 30 60% -3-methoxybenzylidene)-3-methylquinoline 10 33% This invention also provides processes for preparing the compounds of formula I or acid addition salts thereof.

Accordingly a first process for preparing compounds of formula I comprises dehydrating a compound of formula

wherein one of X and Y is hydroxy, the remaining one of X and Y being hydrogen; R, R1, R2, SPECIFICATION 8-Benzylidene-5,6,7,8-tetrahydroquinoline derivatives This invention relates to heterocylic compounds, more particularly to 5,6,7,8-tetrahydroquinolines, processes for their preparation and pharmaceutical compositions containing them.

8-Benzylidene-5, 6,7, 8-tetrahydroquinolines have been described in the literature---see for example Chemical Abstracts, Volume 73, 87755d and Arch. Pharm. (Weinheim), 1980, 313, pps 826-832 by E. Reimann and co-workers. However no pharmaceutical activity is disclosed.

We have now found a novel series of 8-benzylidene-5,6,7,8-tetrahydroquinolines which possess pharmaceutical activity and in some instances are also useful as intermediates to other compounds in the series.

Accordingly this invention provides compounds of formula

wherein R represents lower alkoxy, alkanoyloxy of 2 to 7 carbon atoms or hydroxy, R' and R2 independently represent hydrogen, lower alkoxy, alkanoyloxy of 2 to 7 carbon atoms, hydroxy or lower alkyl; R3, R4 and R5 each represent hydrogen or lower alkyl with the proviso that at least one of R3, R4 and R5 is lower alkyl; and R6 and R7 each represent hydrogen or lower alkyl; and acid addition salts thereof.

The term lower as used in connection with alkyl and alkoxy means such groups containing 1 to 6 carbon atoms.

Examples of alkyl or alkoxy groups include such groups containing 1 to 4 carbon atoms, carbon atoms e.g. methyl, methoxy, ethyl, ethoxy, n-propyl, n-propoxy, etc.

Alkanoyloxy groups have 2 to 7 carbon atoms and are exemplified by acetyloxy, propionyloxy, butyryloxy, etc.

Examples of each of R3, R4 and R5 are methyl, ethyl, propyl. Preferably R3is hydrogen, most preferably R3 and R5 or R3 and R4 are both hydrogen. Examples of R6 and R7 when lower alkyl are methyl, ethyl, propyl.

Examples of groups for R are hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, acetoxy, propionyloxy and butyryloxy.

Examples of groups for R1 or R2 are methyl, ethyl, propyl, methoxy, ethoxy, n-propoxy, acetoxy, propionyloxy, butyrloxy and hydroxy.

When R2 is hydrogen examples of R and R1 are respectively acetoxy, acetoxy; hydroxy, hydroxy: acetoxy, methoxy and methoxy, hydroxy.

Preferably R and A1 represent one of the following: 3, 4-diacetoxy; 3, 4-dihydroxy; 3-acetoxy-4-methoxy; 3-hydroxy-4-methoxy; 3-methoxy-4-hydroxy; 2-hydroxy-3-methoxy, when R' and R2 are both hydrogen R is preferably 2-methoxy, 2,3 or 4acetoxy or 3-hydroxy.

The compounds of formula I form salts with inorganic organic acids. Examples of acid addition salts are those formed with one of the following: hydrochloric, hydrobromic, hydriodic, sulphuric, nitric, phosphoric, methanesulphonic, acetic, maleic, citric, fumaric, tartaric, malonic or formic acids.

The compounds of formula I possess anti-ulcer activity as measured by a standard test procedure and accordingly are useful for the treatment of ulcers in mammals.

Anti-ulcer activity was determined by the stress-induced erosion test of Senay and Levine, Proc. Soc. Exp. Biol. Med., 124, 1221-3 (1967). The procedure used was as follows.

Male rats, weighing between 80 and 1 20 gms. were fasted overnight with water ad lib. The rats were then divided into groups of six and dosed orally with the test drug in the form of a solution or with the vehicle alone, 0.5% carboxymethylcellulose, in a volume of 10 ml/kg. After 30 minutes the rats were inserted into aluminium restraining tubes measuring 1 5/8 inches in diameter by 5 inches and placed in the cold (4 + 1"C) for 3 hours. Immediately after cold R3, R4, R5, R6 and R7 are as defined above, R, R1 and R2 each also represent hydroxy groups protected by a protecting group and removing any protecting group.

By "hydroxy group protected by a protecting group" is meant such groups other than lower alkoxy or alkanoyloxy of 2 to 7 carbon atoms.

The dehydration may be carried out with usual dehydrating agents, e.g. polyphosphoric acid or with an organic acid anhydride, e.g. acetic anhydride, (in which case an acetylated derivative may be formed, from which acetic acid is eliminated to give the compound of formula 1). Use of an acid anhydride to effect dehydration may also acylate any R, R' or R2 hydroxy groups in which case hydrolysis may be used if desired as an after process to revert to hydroxy substituents. Also if desired any hydroxy substituents in the compound of formula II may be protected by any group known in the art for protecting hydroxy groups and then removing such protecting groups.

In this connection attention is directed to well known textbooks on peptide chemistry which illustrate such hydroxy protecting groups and methods for their removal-see for example E.

Schroder and K. Lubke, "The Peptides", Volume 1, Acadamic Press, New York and London, 1965.

The compounds of formula II wherein X is H and Y is OH may be prepared by treatment of a compound of formula Ill

wherein R3, R4, R5, R6 and R7 are as defined in connection with formula I, and M is hydrogen, an alkali metal (e.g. sodium, potassium or lithium) or MgHal, where Hal is chlorine, bromine or iodine, with an aldehyde of formula IV

wherein R, R' and R2 are as defined in connection with formula 11, if necessary (e.g. when M is an alkali metal) followed by treatment with a proton source, e.g. dilute acid.

When M is hydrogen the reaction may be carried out at room temperature or below in a suitable solvent, e.g. acetic acid and/or in the presence of a Lewis acid e.g. zinc chloride. If the aldehyde of formula IV and the tetrahydroquinoline of formula Ill (wherein M is H) are reacted simultaneously under dehydrating conditions then it is possible to produce the compounds of formula I directly without isolation of an intermediate hydroxy compound of formula Il wherein X is H and Y is OH. Examples of suitable conditions for effecting such a reaction are the presence of a dehydrating agent such as an organic acid anhydride (including mixed anhydrates) e.g. acetic anhydride preferably at elevated temperature. Polyphosphoric acid or the like may also be used as the dehydrating agent. Hydroxy substituent groups may be protected in similar manner to that described in connection with the dehydration of compounds of formula II described above.

Accordingly this invention also provides a process for preparing a compound of formula I as hereinbefore defined which comprises reacting a compound of formula Ill wherein M is hydrogen with an aldehyde of formula IV as herein before defined under dehydrating conditions, and if required removing one or more hydroxy protecting groups.

Compounds of formula II wherein X is OH and Y is hydrogen may be prepared by reacting a compound of formula

wherein R3, R4, R5, R6 and R7 are as hereinbefore defined with a compound of formula

wherein R, R' and R2 are as hereinbefore defined in connection with formula II and Z is an alkali metal or MgHal where Hal is chlorine, bromine or iodine, followed by treatment with a proton source, e.g. dilute acid.

A further process for preparing compounds of formula I employs the Peterson reaction (J.

Organic Chem. 1968, 780; Carey and Toler ibid, 1976, 41, 1966, Hudrik s Peterson J. Amer.

Chem. Soc. 1975, 97, 1464)-see the scheme below

The process comprises reacting a compound of formula V as defined above with a silicon compound of formula VII

wherein R, R1 and R2 are as defined above, M' is an alkali metal especially lithium or Mg Hal where Hal is chlorine, bromine or iodine and (R8)3 represents three R8 radicals the same or different selected from alkyl, cycloalkyl, aralkyl, aryl or electron donating substituents such as alkoxy, cycloalkoxy, aralkoxy, aryloxy, alkylthio, cycloalkylthio, aralkylthio or arylthio, the group RbRCN- wherein Rb and Rc are selected from alkyl, cycloalkyl, aryl and aralkyl or Rb and Rc may be joined to form a heterocyclic ring with the nitrogen atom (e.g. a piperidinyl or pyrrolidinyl ring, which may be substituted e.g. by alkyl), to give a silyl compound VIII which is treated under acidic or basic conditions to give compound I. If the conditions of work up are acidic (e.g.

sulphuric acid or trifluoroacetic acid) then compound VIII will usually be converted first into a compound VIII where M' is H, but basic conditions (e.g. sodium or potassium hydride) and use of fluoride ions (e.g. KF or LiF) usually result in direct formation of compound I. As before protecting groups for hydroxy substituents are removed as required.

Preferably R8 in the compound of formula VII is an alkyl radical of 1 to 6 carbon atoms, most preferably methyl, or an aryl radical, most preferably phenyl.

The silicon compound VII starting materials may be prepared from corresponding compounds of formula

by standard methods. The starting materials of formula V may be prepared as described in U.K.

Patent Specification 1460457 or by analogous methods.

In a variation of the above reaction the compounds for formula I may be prepared according to the following scheme

A silicon compound of formula IX, where R3, R4, R5, R6, R7 and R8 are as previously defined in connection with formula V and X' is hydrogen, sodium, potassium or lithium is reacted with an aldehyde compound of formula IV as hereinbefore defined to obtain a silyl intermediate of formula X which is converted to compound I by acid or base treatment as described for the previous reaction scheme, and removing any protecting groups as required. The starting compound IX may be prepared as described in our U.K. Patent Publication No. 2122629 published 18th January 1984 or by analogous methods.Briefly a compound of formula

where M2 is sodium, potassium or lithium is treated with a silylating agent of formula (RB)3SiHaI where R8 is as defined above and Hal is chlorine, bromine or iodine, to obtain a compound of formula IX wherein X1 is hydrogen and if desired treating this with a metal compound R*M2 where M2 is sodium, potassium or lithium and R is alkyl, cycloalkyl, aralkyl or aryl or an amine residue to obtain a compound of formula i)( where X' is sodium, potassium or lithium.

Althernatively compounds of formula I may be prepared by the Wittig reaction (see Peterson loc cit for references thereto) according to the scheme below

in which formulae Rt, R2, R3, R4, R5, A6 and R7 are as defined in connection with the previous reaction scheme, and removing any hydroxy protecting groups as required.

The Wittig phosphorus reagent of formula XII used in this reaction may be prepared by reacting Ph3P with an appropriate compound of formula

followed by reaction with a suitable base.

Once a compound of formula I is prepared in which any of R, R' and R2 is alkanoyloxy then such compounds may be hydrolysed to give corresponding hydroxy compounds of formula I.

Similarly compounds of formula I wherein any of R, R1 and R2 is hydroxy may be acylated, e.g.

using alkanoyl halides to give corresponding alkanoyl compounds of formula 1. When any of R, R1 and R2 is alkoxy then such compounds may be dealkylated using standard procedures to give corresponding hydroxy compounds of formula I. Accordingly compounds of formula I are intermediates for other compounds of formula I.

In any of the aforementioned reactions compounds of formula I may be isolated in free base form or as acid addition salts as desired.

The compounds of formula I and their acid addition salts may be used in pharmaceutical compositions.

For the pharmaceutical compositions any suitable carrier known in the art can be used. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents,binders, or tablet disintegrating agents; it can also be encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.

In tablets the active ingredient is mixed with a carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredient. Suitable solid carrier are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax and cocoa butter. The term "composition' is intended to include the formulation of anactive ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carriers, which is thus in assocation with it.

Similarly cachets are included.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. In other instances compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil.

Preferably the pharmaceutical composition is in unit dosage form, the composition is subdivided in unit doses containing appropriate quantities of the active ingredient; the unit dosage form can be a packaged composition, the package containing specific quantities of compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in packaged form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from 10 to 500 mg or more, e.g. 25 mg to 250 mg, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.

The anti-ulcer compositions of the invention will be administered orally in either liquid or solid composition form. These compositions may include one or more antacid ingredients, e.g.

aluminium hydroxide, magnesium hydroxide or bismuth carbonate, aluminium glycinate, calcium carbonate, magnesium trisilicate, sodium bicarbonate or the alumina gel described in British Specification No. 1,284,394.

In another aspect the invention provides as an anti-ulcer agent a compound of formula I or an acid addition salt thereof as defined above.

The following examples illustrate the invention: EXAMPLE 1 E-8-(4-Acetoxy-3-methoxybenzylidene)-5, 6, 7, 8-tetrahydro-4-methylquinoline A mixture of 5,6,7,8-tetrahydro-4-methylquinoline (5.2g), vanillin (5.37g), zinc chloride (0.3g) and acetic anhydride (50ml) were refluxed under nitrogen for 16 hours. The solvent was removed by evaporation and the resulting residue was neutralised (Na2CO3) in the presence of ethyl acetate and was then extracted with ethyl acetate.

The ethyl acetate solution was extracted with 2N HCI and this extract was washed with ethyl acetate, basified (Na2CO3) and the product extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4) and evaporated. The resulting residue was repeatedly extracted with hot hexane and the extracts allowed to cool. The resulting white solid was filtered, washed with cold hexane and finally dried to give the title compound (3.3g). m.p. 110-112"C.

Analysis: Found: C, 74.7; H, 6.95; N, 4.4% C20H21NO3 C, 74.3; H, 6.55; N, 4.3% EXAMPLE 2 E-5, 6, 7, 8-Tetrahydro-8j4-hydroxy-3-methoxybenzylldenej-4-meThylquinollne E-8-(4-Acetoxy-3-methoxybenzylidene)-5,6,7,8-tetrahydro-4-methylquinoline, HCI (from Example 1) (1.3g) was dissolved in 2N HCI (20ml) and heated at 90"C for 4 hours. The resulting red solid was removed by filtration, washed with a small amount of ether and finally dried to give the title compound as the hydrochloride salt (1.15g) m.p. 285-287"C.

Analysis: Found: C, 67.6; H, 6.4; N, 4.3% C18H19NO2HCl requires C, 68.0; H, 6.3; N, 4.4% EXAMPLE 3 E-8-(3, 4-Diacetoxybenzylidene)-5, 6, 7, 8-tetrahydro-4-methylquinoline A mixture of 5,6,7,8-tetrahydro-4-methylquinoline (5.2g), 3,4-dihydroxybenzaldehyde (4.88g), zinc chloride (0.39) and acetic anhydride (50ml) were refluxed under nitrogen for 16 hours.

The solvent was removed by evaporation and the resulting residue was neutralised (Na2CO3) in the presence of ethyl acetate and was then extracted with ethyl acetate. The ethyl acetate solution was extracted with 2N HCI and this extract was washed with ethyl acetate, basified (Na2CO3) and the product extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4) and evaporated. The resulting residue was repeatedly extracted with hot hexane and then extracts allowed to cool giving a white solid.

This was filtered, washed with cold hexane and dried to give the title compound as the quarterhydrate (2.6g). m.p. 126-128"C.

Analysis: Found: C, 71.0; H, 6.2; N, 3.95% C21H21NO4.iH2o requires C, 70.9; H, 6.1; N, 3.9% EXAMPLE 4 E-5, 6, 7, 8-Tetrahydro-8-[3, 4-dihydroxybenzylidene]-4-methylquinolin E-8-(4-Acetoxy-3-methoxybenzylidene)-5, 6,7, 8-tetrahydro-4-methylquinoline, HCI (1. Og) (from Example 1) was dissolved in 2N HCI (20ml) and heated at 90 C for 4 hours. The resulting red solid was removed by filtration, washed with a small amount of ether and finally dired to give the title compound as the hydrochloride quarterhydrate salt (0.75g), m.p. 278-280"C.

Analysis: Found: C, 65.9; H, 6.2; N, 4.7% C,7H,7NO2.HCI iH20 requires C, 66.2; H, 6.05; N, 4.5% EXAMPLE 5 E-8-(3, 4-Diactoxybenzylidene)-5, 6,7, 8-tetrah ydro-3-meth ylquinoline A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 ml), 3,4-dihydrobenzaldehyde (20g) and acetic anhydride (50ml) was heated at 100' for 48 hours. Further acetic anhydride (50ml) and ZnCl2 (1 g) were added and the mixture was heated at reflux for 1 6 hours. The solvent was removed by evaporation, the residue was neutralised (NaCO3) in the presence of ethyl acetate and extracted with ethyl acetate.The ethyl acetate solution was extracted with 2N HCI and this extract was washed with ethyl acetate, basified (NaeCO3) and extracted with Et2O. The ether solution was dried (MgSO4) and evaporated and the residue triturated with hexane and recrystallised from di-isopropyl ether to give the title compound (229) m.p. 100-1"C.

Analysis: Found: C, 71.85; H, 5.9; N, 3.9% C21H21N04requiresC,71.8; H, 6.0; N, 4.0% EXAMPLE 6 E-5, 6, 7, 8-tetrahydro-8-(3, 4-hydroxybenzylidene]-3-methylquinoline A solution of E-8-(3, 4-diacetoxybenzylidene)-5, 6,7, 8-tetrahydro-3-methylquinol ine (prepared according to Example 5) (39) in 2N HCI (50ml) was heated at 80 for 1+ hours. The precipitated crystals were removed by filtration and dried to give the title compound as the hydrochloride, quarterhydrate (2.6gel) m.p. 265"C decomp.

Analysis: Found: C, 66.1; H, 6.4; N, 4.4% Ct7H,7NO2,HCI. *H20 requires C, 66.2;; H, 6.0; N, 4.5% EXAMPLE 7 E-8-(2-Acetoxybenzylidene)-5, 6, 7, 8-tetrahydro-3-methylquinoline A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20ml), salicylaldehyde (20ml) and acetic anhydride (40ml) was heated at 100" for 48 hours. Further acetic anhydride (50ml) and ZnCI2 (19) was added and the mixture was heated at reflux for 16 hours. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate, neutralised with Na2CO3 solution and extracted with ethyl acetate. The extracts were extracted with 2N HCI and the extract washed with ethyl acetate basified (Na2CO3) and extracted with diethyl ether.The solution was dried (MgS04) and evaporated to give an oil which was triturated with n-hexane and recrystallised from n-hexane to give the title compound (129) m.p. 85-7"C.

Analysis: Found: C, 78.1; H, 6.5; N, 4.5% C,9H19NO2 requires C, 77.8; H, 6.5; N, 4.8% EXAMPLE 8 E-8- (4-A cetoxy-3-methoxybenzylidene)-5,6,7, E3-tetrah ydro-jl-meth ylquinoline A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20ml), vanillin (2 5g), acetic anhydride (50ml), and zinc chloride (1g) was heated at reflux for 30 hours. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. This solution was shaken with 2N HCI and a crystalline solid was deposited. This was removed by filtration, washed with diethyl ether and propan-2-ol/diethyl ether. The product was then dried to give the title compound as the hydrochloride salt (34g) m.p. 223-5"C.

Analysis: Found: C, 66.5; H, 6.1; N, 3.8% C20H21NO3.HCI requires C, 66.8; H, 6.2; N, 3.7% EXAMPLE 9 E-5, 6,7, 8-Tetrahydro-8-(4-hydrnxy-3-methoxybenzylldenej-3-methylquinollne A mixture of E-5, 6,7, 8-tetrahydro-8-(4-acetoxy-3-methoxybenzylidene)-3-methylquinoline HCI (prepared according to Example 8) (3.09) and 2N HCI (50ml) were heated for 1 hour on a steam bath. After cooling the yellow crystals were removed by filtration, washed with diethyl ether and then dried to give the title compound as the hydrochloride salt (2.5g). m.p. 257-60 C.

Analysis: Found: C, 67.95; H, 6.6; N, 4.3% Cr8H19NO2HCI requires C, 68.0; H, 6.3; N, 4.4% EXAMPLE 10 E-8-(3-Acetoxy-4-methoxybenzylidene)-5, 6, 7, 8-tetrahydro-3-methylquinoline A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20ml), isovanillin (259), acetic anhydride (50ml) and ZnCI2 (19) was heated at reflux for 1 7 hours. The solvent was removed by evaporation and the residue dissolved in ethyl acetate. The solution was acidified with 2N HCI, a yellow solid being obtained. This was washed with diethyl ether and then dried to give the title compound as the hydrochloride, sesquihydrate (33g) m.p. 222-4 C.

Analysis: Found: C, 62.0; H, 6.1; N, 3.7% Q0H21NO.HCI. H20 requires C, 62.1; H, 6.25; N, 3.6 EXAMPLE ii E-5, 6,7, 8- Tetrahydro-8-(3-hydroxy-4-methoxybenzylidene)-3-methylquinoline E-8-(3-Acetoxy-4-methoxybenzylidene)-5, 6, 7,8-tetrahydro-3-methylquinoline (prepared accord- ing to Example 10) (3g) in 2N HCI (50ml) was heated at 80"C for 1 hour. The resulting yellow solid was removed by filtration and washed with diethyl ether and hexane and dried to obtain the title compound as the hydrochloride, quarterhydrate salt (2.29). m.p. 233-5"C.

Analysis: Found: C, 66.7; H, 6.3; N, 4.3% C,8HgNO2.HCl.iH20 requires C, 67.1; H, 6.4; N, 4.3% EXAMPLE 12 E-8-(2Methoxybenzylidene)-5, 6, 7, 8-tetrahydro-3-methylquinoline 5,6,7,8-Tetrahydro-3-methylquinoline (6.69) was added to o-anisaldehyde (8.169) in acetic anhydride (1Oml) and was heated to reflux for 14 4 hours after which the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (some) and was added to 2N HCI (150ml), the aqueous layer was basified (Na2CO3) and extracted with ethyl acetate (4 X 100ml) dried (mgSO4) and evaporated under reduced pressure.The residue was washed with several aliquots of hot hexane and was then dissolved in a small volume of boiling propan2-ol and etherial hydrogen chloride was added in excess. On cooling a precipitate formed and was removed by filtration, washed with ether and dried under vacuum to give the title compound as the hydrochloride salt (2.6g) m.p. 221-222.5 C.

Analysis: Found: C, 71.5; H, 6.6; N, 4.5% Ct8H19NO.HCI requires C, 71.6; H, 6.7; N, 4.6% EXAMPLE 13 E-8-(2-Hydroxy-3-methoxybenzylidene)-5, 6,7, 8-tettrahydro-3-methylquinoline 5,6,7,8-Tetrahydro-3-methylquinone (20ml), vanillin (259), acetic anhydride (50ml), and ZnCI2 (1g) were heated at reflux for 17 hours. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate (100ml) and acidified with 2N HCI solution. The solid obtained was removed by filtration and the aqueous layer was basified with Na2CO3 and shaken with diethyl ether. A solid was obtained in the ether layer which was removed by filtration.The combined solids were dissolved in 1 N sodium hydroxide and the solution was extracted with ethyl acetate. The extracts were dried over MgSO4 and the solvent was removed by evaporation.

The crystals obtained were washed with hexane and dried to give the title compound (6g) m.p.

149-1 53'C.

Analysis: Found: C, 76.7; H, 6.8; N, 5.0% C18H18NO2 requires C, 77.1; H, 6.5; N, 5.0% EXAMPLE 14 E-8-(3-Acetoxybenzylidene)-5, 6,7, 8-tetrah ydro-3-m eth ylquinoline A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20ml), m-hydroxybenzaldehyde (209), acetic anhydride (50ml) and ZnCl2 (1g) was heated at reflux for 3+ hours. The solvent was removed by evaporation and the residue dissolved in ethyl acetate (300ml). The solution was extracted with 2N HCI, and the acidic phase was washed once with ethyl acetate. It was then basified (Na2CO3) and the product extracted into a mixture of diethyl ether and ethyl acetate.

The solvent was removed by evaporation and the residue crystallized from di-isopropyl ether, washed twice with hexane and then dried to give the title compound as the hemihydrate (7.49).

m.p. 66-8"C.

Analysis: Found: C, 75.7; H, 6.5; N, 4.6% C,9H19NO2.+H20 requires C, 75.5; H, 6.7; N, 4.6% EXAMPLE 15 E-5, 6,7, 8-Tetrahydro-8-(3-hydroxybenzylidenej-3-methylquinoline The product of Example 14, E-8-(3-Acetoxybenzylidene)-5,6,7,8-tetrahydro-3-methylquinoline (39) in 2N HCI (50ml) was heated at 80"C for 1 hour. On cooling crystals were removed by filtration, washed with diethyl ether and dried to give the title compound as the hydrochloride salt (2.2g). m.p. 264-6"C.

Analysis: Found: C, 71.0; H, 6.3; N, 4.9% Cl7H,7NO.HCi requires C, 70.95; H, 6.3; N, 4.9% EXAMPLE 16 E-8-(4-Acetoxybenzylidene)-5, 6, 7, 8-tetrahydro-3-methyIquinoline 5,6,7,8-Tetrahydro-3-methylquinoline (6.6g) was dissolved in acetic anhydride (10ml) and 4hydroxybenzaldehyde (7.35g) was added. The mixture was allowed to reflux for 18 hours after which the solvent was removed under reduced pressure. The residue was added to 1 M NaOH (300ml) and the solid extracted with dichloromethane (3 X 150ml) and dried (Na2SO4). Solvent was removed under reduced pressure. The solid residue was recrystallised from ethyl acetate to give the title compound (4.59). m.p. 119-122"C.

Analysis: Found: C, 78.0; H, 6.7; N, 4.7% CtgH19NO2 requires C, 77.8; H, 6.5; N, 4.8% EXAMPLE 17 E-5, 6,7, 8-Tetrahydro- 7-(4-hydroxybenzylidenej-3-methylquinoline A mixture of 5,6,7,8-tetrahydro-3-,methylquinoline (20ml), p-hydroxybenzaldehyde (209), acetic anhydride (50my), and ZnCl2 (lg) was heated at reflux for 25 hours. The solvent was removed by evaporation and the residue dissolved in ethyl acetate. This solution was acidified with 2N HCI and a crystaline solid precipitated. The solid was removed by filtration, washed with diethyl ether and then dried to give the title compound as the hydrochloride, quarterhydrate (289), m.p. 265"C decomp.

Analysis: Found: C, 69.85; H, 6.2; N, 4.8% C,7H,7NO.HCI. kH2O requires C, 69.9; H, 6.4; N, 4.8%

Claims (23)

1. A compound of formula

or an acid addition salt thereof, wherein R represents lower alkoxy, alkanoyloxy of 2 to 7 carbon atoms or hydroxy; R' and R2 independently represent hydrogen, lower alkoxy, alkanoyloxy of 2 to 7 carbon atoms, hydroxy or lower alkyl; R3, A4 and R5 each represent hydrogen or lower alkyl with the proviso that at least one of R3, R4 and R5 is lower alkyl; and A6 and R7 each represent hydrogen or lower alkyl.

2. A compound of formula 1 as claimed in Claim 1 wherein R represents hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, acetoxy, propionyloxy or butyryloxy.

3. A compound of formula I as claimed in Claim 2 wherein R1 and R2 independently represent hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, n-propoxy, acetoxy, propionyloxy, butyryloxy and hydroxy.

4. A compound of formula I as claimed in Claim 3 wherein R2 is hydrogen and R and R1 are both acetoxy; both hydroxy; or R is acetoxy and R1 is methoxy; or A is methoxy and R' is hydroxy.

5. A compound of formula I as claimed in any one of claims 1 to 4 wherein one of R3, R4 and R5 is methyl, ethyl or n-propyl and the remainder are both hydrogen.

6. E-5,6,7,8-tetrahydro-8-[3,4-dihydroxybenzylidene]-4-methylquinoline.

7. E-8-(3,4-diacetoxybenzylidene)-5,6,7,8-tetrahydro-3-methyiquinoline.

8. E-8-(4-acetoxy-3-methoxybenzylidene)-5, 6,7, 8-tetrahydro-3-methylquinoline.

9. E-5,6,7,8-tetrahydro-8-(3,4-dihydroxybenzylidene)-3-methylquinoline.

10. E-5,6,7,8-tetrahydro-8-(4-hydroxy-3-methoxybenzylidene)-3-methylquinoline.

11. E-5,6,7,8-tetrahydro-8-(3-hydroxy-4-methoxybenzylidene)-3-methylquinoline.

12. E-8-(2-methoxybenzyiidene)-5,6,7,8-tetrahydro-3-methylquinoline.

1 3. E-8-(2-hydroxy-3-methoxybenzylidene)-5, 6,7, 8-tetrahydro-3-methylquinoline.

14. E-8-(2-acetoxybenzylidene)-5, 6,7, 8-tetrahydro-3-methylquinoline.

1 5. E-5,6,7,8-tetrahydro-8-(3-hydroxybenzylidene)-3-methylquinol ine.

16. E-8-(4-acetoxybenzylidene)-5,6,7,8-tetrahydro-3-methylquinoline.

1 7. A compound as claimed in any one of Claims 1 to 16 when in the form of a salt with an acid selected from hydrochloric, hydrobromic, hydroiodic, sulphuric, nitric, phosphoric, meth anesulphonic, acetic, maleic, citric, fumaric, tartaric, malonic, or formic acid.

18. A process for preparing a compound of formula I as defined in Claim 1 which comprises dehydrating a compound of formula a)

wherein R, R1, R2, R3, R4, R5, A6 and R7 are as defined in Claim 1; R, R1 and R2 each also represent a hydroxy group protected by a protecting group; and one of X and Y is hydroxy, the remaining one of X and Y being hydrogen; and if required removing any hydroxy protecting group; or b) reacting under dehydrating conditions a compound of formula IV

wherein R, R1 and R2 are as defined above in connection with formula II, with a compound of formula Ill

wherein R3, R4, R5, R6 and R7 are as defined in Claim 1 and M is hydrogen and if required removing hydroxy protecting groups; or c) reacting a compound of formula V

wherein R3, R4, R5, A8 and R7 are as defined in Claim 1 with a compound of formula (VII)

wherein R, R1, and R2 are as defined above in connection with formula II, M1 is an alkali metal or Mg Hal where Hal is chlorine, bromine or iodine, and (R8)3 represents three R8 radicals the same or different selected from alkyl, cycloalkyl, aralkyl, aryl or electron donating substituents such as alkoxy, cycloalkoxy, aralkoxy, aryloxy, alkylthio, cycloalkylthio, aralkylthio or arylthio, the group RbRCN-wherein Rb and Ac are selected from alkyl, cycloalkyl, aryl and aralkyl or Rb and Ac may be joined to form a heterocyclic ring with the nitrogen atom, which may be substituted; followed by treatment under acidic or basic conditions, and if required removing hydroxy protecting groups, or d) reacting a compound of formula IX

wherein R3, R4, R5, R6 and R7 are as defined in Claim 1, (R8)3 is as defined hereinbefore, and X' is hydrogen, sodium, potassium or lithium, with a compound of formula IV

wherein R, R' and R2 are as defined above in connection with formula II; followed by treatment under acidic or basic conditions, and if required removing hydroxy protecting groups; or e) reacting under Wittig reaction conditions a compound of formula (V) as defined above with a compound of formula

wherein R, R' and R2 are as defined in connection with formula II and if required removing hydroxy protecting groups; or f) converting a compound of formula I wherein at least one of R, R' or R2 is a reactive substituent group to give a different compound of formula l; or g) converting a compound of formula I to an acid addition salt or vice versa.

1 9. A process for preparing a compound of formula I substantially as hereinbefore described with reference to any one of Examples 1 to 1 7.

20. A compound of formula I whenever prepared by a process as claimed in Claim 18 or Claim 19.

21. A compound as claimed in any one of Claims 1 to 17 for use as an antiulcer agent.

22. A pharmaceutical composition comprising a compound of formula I or an pharmaceutically acceptable acid addition salt thereof as claimed in any one of Claims 1 to 1 7 and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition as claimed in Claim 22 when in unit dosage form.