IL26534A - Fused diazaheterocyclic ketone derivatives and their preparation - Google Patents

Description

26534/2 in asm P sed diaza eterooyclio ketone derivatives and their preparation J. R. mi A.Q. :25244 26534/2 The present invention concerns a process for the production of new, condensed heterocyclic compounds, these compounds as new substances, medicaments containing them as well as the use thereof.

Compounds of the general formula. I wherein R^ and e^c represent hydrogen. atoms , low alkyl or alkoxy groups or halogen atoms, R^ represents a hydrogen atom or a low alkyl group, R^ and R^ each represent low alkyl, hydroxyalkyl or benzyl groups, of which one can be substituted in the 'phenyl nucleus, by, in all, at most two of the following groups; low alkyl, low alkoxy,' and./or halogen or the methylenedioxy group,, or ^ and R^ together with the adjacent nitrogen atom represent the piperidino, 1-pyrrolidinyl, morpholino or k- 26534/2 n represents 1, 2 or 3. have not been known hitherto. It has now been found that these new compounds, their addition salts with inorganic and organic 5 acids, their quaternary salts and also their N-oxides, have valuable pharmacological properties, in particular antiinflammatory, analgetic, hypotensive, · spasmolytic , sedative and 1 antitussive activity. They can be administered orally, rectally j or, in the form of aqueous solutions, also parenterally, e.g. - 0 for the treatment of rheumatic and other inflammatory diseases, for the amelioration- and relief' of; pain,'' tussive":-l ri-feation, or conditions of agitation of various origin.

In the compounds of general formula I and the intermediate products formed in the production thereof, R-^ and R?, 1 as low alkyl or alkoxy groups, are e.g. the methyl, ethyl, n- I propyl, isopropyl, n-butyl, isobutyl or tert. butyl group or the methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy ne, the group, thyl, ethyl, l, 2- l-methyl- , m- nzyl , ybenzyl , I groups. reacting a reactive ester of a compound of general formula II wherein R-^, R^) R^ and n have the meanings given in formula I, particularly a hallde, an arene sulphonic acid ester or methane sulphonic acid ester, with a compound of the general formula III R.

/ HN (in) wherein R^ and R^ independently of each other and also together with the adjacent nitrogen atom have the meanings given in formula I, the reaction being performed in the presence of an acid -binding agent and, if desired, converting the compound obtained of general formula I into a salt with an inorganic or organic acid or into a quaternary ammonium salt or into the N-oxide. The reactions are performed, for example, at room temperature or raised temperatures up to about 120° in suitable solvents or diluents such as excess amine, water, alkanols, dialkyl ethers, dioxane, tetrahydrofuran, benzene or toluene.

Preferably an excess of amine of the general formula III is used as acid binding agent, also, for example, a tertiary dine can be used.

The heterocyclic starting materials, i.e. the reactive esters of compounds of general formula II can be produced in their turn, e.g. by reacting compounds of the general formula IV wherein R^, R2 and n have the mean'ings given in formula I, with halides, particularly chlorides or bromides, or with anhydrides of low oc-halogen- , -arene sulphonyloxy- or a-methane sulphon-yloxy- alkanoic acids. The reactions are performed in the presence or absence of suitable solvents or diluents such as chlorobenzene or dimethyl formamide, while heating, e.g. at the boiling temperature of the reaction mixture. The compounds of general formula IV are formed, e.g. on heating o-benzoylbenzoic acids of the general formula V with alkahe diamines of the general formula VI H2N - CH2 - (CH2) - NH2 (VI) wherein R^, R2 and n have the meanings given in formula I, preferably at temperatures of 120 - l80° in the presence or absence of organic solvents such as chlorobenzene , o-dichloro-benzene, toluene, xylene, amyl alcohol.

The compounds of general formula I obtained according to the process of the invention are then, if desired, converted in the usual way into their addition salts with inorganic and organic acids, or into quaternary ammonium salts or into N-oxideS.

To produce an acid addition salt, for example, the acid desired as salt component or a solution thereof is added to a solution of a compound of general formula I in an organic solvent. Preferably organic solvents in which the salt to be formed does not dissolve easily are chosen for the reaction, so that the salt can be Isolated by filtration. Such solvents are, e.g. ethanol, methanol/diethyl ether or ethanol/diethyl ether.

To produce quaternary salts, if desired, compounds of general formula I can be reacted with low alkyl halides or benzyl halides, particularly iodides, bromides and chlorides, or with low alkyl esters of sulphuric acid or of organic sul-phonic acids, the reaction being performed with or without solvent. However, both quaternary salts and acid addition salts can be obtained in one step from a reactive ester of a compound of the general formula II by reacting it with an amine of the general formula Ilia (Ilia) wherein R^ and R^ have the meanings given In formula I and R^ represents hydrogen or a group as defined for R^.

To produce N-oxides, the compounds of general formula I can be treated with an agent giving off oxygen, e.g. aqueous hydrogen peroxide. The oxidation is preferably performed in a solvent which is misclble with water and is sufficiently stable to the oxidising agent under the reaction conditions, e.g. ethanol.

For use as medicaments, instead of the free bases, the no -toxic acid addition salts can be used, i.e. salts with those acids the anions of which are pharmaceutically acceptable in the usual dosages. It is also of advantage if the salts to be used as medicaments crystallise well and are not or are only slightly hygroscopic. Hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, β-hydroxyethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid, for example, can be used for salt formation with compounds of the general formula I.

Also suitable for use as medicaments are the quaternary salts, e.g. the methohalides and methosulphates , etho-halides and ethosulphates , propohalldes and the bitohalides, as well as the N-oxides of compounds of general formula I according to the invention.

As mentioned above, the new active substances can be administered orally, rectally and parenterall . The daily dosages of the free bases, of non-toxic acid addition salts, for adult patients. Suitable dosage units such as dragees (sugar coated tablets), tablets, suppositories or ampoules, preferably contain 10 - 200 mg of an active substance according to the invention. Also corresponding amounts of forms not made up into single dosages such as syrups, can be administered.

Dosage units for oral administration preferably contain between 1 - 0 of a compound of general formula I, a nontoxic acid addition salt, quaternary salt or N-oxide thereof as active substance. They are produced, e.g. by combining the active substance with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magne-slum or calcium stearate or polyethylene glycols (Carbowaxes) of suitable molecular weights, to form tablets or dragee cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum arable, talcum and/br titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance.

Dosage units for rectal administration are, e.g. suppositories which consist of a combination of an active substance or a suitable salt thereof with. a neutral fatty foundation, or also gelatine rectal capsules which contain a combination of the active substance or a suitable salt thereof with polyethylene glycols (Carbowaxes) of suitable molecular weight.

Ampoules for parenteral, particularly intramuscular, active substance in a concentration of, preferably, 0.5 - 5%, in aqueous solution, optionally together with suitable stabilising agents and buffer substances.

The following prescriptions further illustrate the pro-duction of tablets and dragees: a) 1000 g of l-(N,N-dimethylglycyl)-llb-phenyl-l,2,3,4,5, llb-hexahydro-7H-l, 3-diazepino [2, 1-a Jisoindol-7 -one are mixed with 351.60 g of lactose and 339.40 g of potato starch, the mixture is moistened with an alcoholic solution of 20 g of stearic acid and granulated through a sieve. After drying, 320 g of potato starch, 400 g of talcum, 5.00 g of magnesium stearate and 64 g of colloidal silica are mixed in and the mixture is pressed into 10,000 tablets each weighing 250 mg and containing 100 mg of active substance. If desired, the tablets can be grooved for better adaptation of the dosage. b) A granulate is produced from 250 g of l-(N-methyl-N-ethylglycyl) -1,2,3, 9b-tetrahydro-5H-imidazo [2 , 1-a ]isoindol-5-one, 175.90 g of lactose and the alcoholic solution of 10 g of stearic acid. After drying, 56.60 g of colloidal silica, 165 g of talcum, 20 g of potato starch and 2.50 g of magnesium stearate are mixed in and the mixture is pressed into 10,000 dragee cores. These are then' coated with a concentrated syrup made from 502.28 g of crystallised saccharose, 6 g of shellac, 10 g of gum arable, 0.22 g of dyestuff and 1.5 g of titanium dioxide and dried. The dragees obtained each weigh 120 mg and contain . 25 mg of active substance.

The following examples further illustrate the production of the new compounds of general formula I and of hitherto undescribed intermediate products ? but they in no way limit the scope of the invention. The temperatures are given in degrees Centigrade* Example 1 32.7 g of l-chloracetyl-9b-p enyl-l,2,3,9b~tetrahydro- 5H-imidazo[2.1-a] isoindol-5-one (see below) are slurried in. ml f dioxane and 33 g of a l% aqueous solution of dimethyl- amine are added whereupon the temperature rises from about 20° to ^0°, Whilst the starting material dissolves, two liquid phases are formed. The whole is stirred for 1? minutes after which steam is bubbled through until the smell of the amine has disappeared. On cooling, l-(N,N-dimethylglycyl)-9b-phenyl- l,2,3>9b-tetrahydro-5H-lmidazo[2.1-ajlsolndol-5-one crystallises, "~'"*"'~ 1 It is filtered under suction at 20°. After recrys- tallising once from a mixture, of 150 ml of water and 150 ml of methanol, it melts at lH7-l50°. l-(N-ethyl-N-methylglycyl)-9b-phenyl-l,2,3,9b-tetra- hydro-5H-imidazo[2.1-a]lsoindol-5-one, M.P. 120-123°, is produced analogously.

The 1-chloracetyl compound necessary in the above example is produced, for example, as follows? 22o6 g of o-benzoyl benzoic acid are added to 7-2 g of ethylenediamine and the mixture is gradually heated to lk0Q , the excess ethylenediamine and the water liberated in the reaction being distilled off. After stirring for 2 hours at 1U0°, the melt is allowed to cool and crystallised by the addition of a small amount of benzene. After recrystallisation from benzene, the pure 9b-phen l-l,2,3,9b-tetrahydro-5H-imidazo[2„l-a] isoindol-5-one is obtained, M.p. 150-151°. g of this product and 3*+.2 g of chloracetic acid anhydride in 100 ml of chlorobenzene are re fluxed for 30 minutes.

M.P. 1 6 roduct of 32.7 g of l-chloracetyl-9b-phenyl-l,2,3,9b-tetrahydro- 5H-lmidazo[2.1-a]isolndol-5-one (cf. example 1, last paragraph) and 22 g of diethylamine (100 ) are refluxed for 1 hour in 0 ml of dioxane. The diethylammonlum chloride partially crystallises. Steam is bubbled through until the excess amine and the dioxane have been removed? the crude product remains as a resih. After cooling, sodium hydroxide solution alkaline to _> is added until the reaction/is phenolphthalein alkaline and the 0 reaction product' Is dissolved by shaking in 100 ml of ether.

The ethereal solutio is extracted at about ,30° with 30 ml of 2N hydrobromic acid and the acid solution is washed with 30 ml of fresh ether. On cooling to about 5°» l-(N,N-diethylglycyl)- 9b-phenyl-l,2,3,9b-tetrahydro-5¾-lmldazo[2„l-a]isoindol-5-one hydro'¾romide~i crystallises. It is dissolved in 100 ml of anhydrous ethanol and again precipitated by the addition of ether. In this way, the pure hydrobromide is obtained, which melts at 225-229° (with decomposition) .

The following compounds are produced analogously: 0 a) l-(N,N-dipropylglycyi)-9b-phenyl-l,2,3,9b-tetrahydro-5H- imidazo[2.1-a]isoindol-5-one hydrochloride, Μ.Ρ» 22? - 230°, b) l-(N-methyl-N-butylglyc#l)-9b-phenyl-l,2,3,9b-tetrahydro- 5H-imidazo[2.1-a]isoindol-5-one hydrochloride, MoP.20 -206°, c) l-(N,N-dibutylglycyl)-9b-phenyl-l,2,3,9b-tetrahydro-5H- 5 lmidazo[2.1-a]isolndol-5-one hydrochloride, M.P. 206-209°, d) l-(N,N-di-isopropylglycyl)-9b-phenyl-l,2,3,9b-tetrahydro- 5H-imidazo[2.1-a]lsolndol-5-one hydrochloride, M.P.263-2650 (with decomposition).

Example 3 . 32.7 g of l-chloracetyl-9b-phenyl-l,2,3,9b-tetrahydro-5H-imidazo[2.1-a]lsolndol-5-one (cf, example .1, last paragraph) are slurried in 50 ml of dioxane and 25< g of piperidine are added. An exothermic reaction causes the temperature to rise to about 75°· The whole is kept for 10 minutes at 85-90°, then cooled and 200 ml of water are added. The crude product precipitates as a resin-like mass. This is kneaded with a great amount of water and finally dissolved in dilute hydrochloric acid. The pH of the solution is adjusted to and it is brought to a volume of 2 litres. On adding dilute sodium hydroxide solution dropwise, the free base again crystallises ."^t is.__^ agaia dissolved In about 90 ml of IN hydrochloric acid and the pH of the solution is adjusted to „ After some time, the hydrochloride of l-(piperidinoacetyl)-9b~phenyl-ls2,3,9b-tetra-hydro-5H-lmldazo[2.1-ajisolndol-5-one precipitates in crystalline form0 The pure hydrochloride is obtained by filtration under suction and recrystallisatlon from ethanol and ether.

It melts at 2*+0-250° (with decomposition). &The free base melts at 96-99°. l-(Morphollnoacetyl)-9b-phenyl-l,2,3,9b"tetrahydro-5H-imidazo[2.1-a] isolndol-5-one is produced analogously, M. P. 86 -89° (from methanol) . 3*+.l g of l-chloracetyl-10b-phenyl-l,3,W,10b-tetra-hydro-pyrimido[2.1-a]isoindol-6(2H)-one (see below) are slurried in 0 ml of dioxane and 33 g of a Hl# aqueous solution of dimethylamine are added whereupon the temperature rises from about 20° to o° and two phases are formed. The whole is heated to 85 - 90° and then steam Is bubbled through the reaction mixture until all the dimethylamine has been removed. On cooling, the l-^N-dimethylglycylJ-lOb-phenyl-l^j^lOb-tetra-hydro-pyrimido[2.1-a]isoindol-6(2H)-one crystallises rand~is"~ filtered under suction at 20°.

The pure base, which melts at 172-175°» is obtained after recrystallising once from me hanol/water.

The following compounds are obtained analogously: a) l-imorpholinoacetyl^lOb-phenyl-l^j^lOb-tetrahydro-pyrimido[2.1-a]isoindol-6(2H)-one, M.P. 169-172° (from methanol/ water); b) l-(piperidlnoacetyl)-10b-pheny 1-1,3 j1†, lOb-tetrahydro-pyrimi-do[.2.1-a]isolndoi-6(2H)-one, M.P. 182-185°; c) 1- (N,N-diethylglycyl)-10b-pheny 1-1,3, HjlOb-tetrahydro-pyrlmido[2.1-a]isoindol-6(2H)-one, M.P. 101-10H°$ d) 1- (N-methyl-N-ethylglycyl)-lOb-(p-methoxyphenyD-l, 3 ,H , 10b-tetrahydro-pyrimido[2.1-a]isolndol-6(2H)-one, M.P.120- 123°$ e) l-(N,N-dlmethylglycyl)-10b-(p-methoxyphenyl)-l,3il ,10b-tetrahydro-pyrimido[2,l-aJisoindol-6(2H)-one, M.P. 155-157°; f) l-(N,N-diethylglycyl)-10b-(p-methoxyphenyl)-l,3,^,10b-tetrahydro-pyrimido[2.1-a]isoindol»6(2H)-one, M.P. 122-12U°j The chloracetyl compounds required for the production of the above end products are obtained, e.g. as follows: 22,6 g of o-benzoyl benzoic acid and 8.9 g of 1,3-propanediamine are heated within 1 hour to lUO° and then for 1 hour at this temperature. After cooling, the crude product is recrystallised from about 300 ml of ethyl acetate. In this way, lOb-phenyl-1,3 ,W , 10b-tetrahydro-pyrimido[ 2.1-a] isoindol-6(2H) -one is obtained, M.P. 176-177°. 26.k g of this compound, 100 ml of dimethyl formamide and 3^.2 g of chloracetic acid anhydride are heated for 30 minutes at 90-9?°. A large amount of water is then added to the solution and the amorphous, crude product is dissolved n benzene. This solution is dried with sodium sulphate and concentrated in vacuo. The residue is recrystallised from a mixture of about Wo ml of methanol and about kO ml of cyclohexane. 1- Ghloracetyl-lOb-phenyl-1,3,W, 10b-tetrahydro-pyrimido[ 2.1-a] iso-lndol-6(2H)-one, M.P. 157°, is obtained.

In an analogous way, on using o- (p-anisoyl) -benzoic acid, 10b-(p-methoxyphenyl)-l,3? ,10b-tetrahydro-pyrimido[2.1-a] isoindol-6(2H)-ohe, M.P. 162-163°, is obtained and, from this, 1-chloracetyl-lOb- ( -methoxyphenyl)-1,3,k , 10b-tetrahydro-pyrimido[2.1-aJisoindol-6(2H)-one, M.P. 135-138°, is obtained.

Structural formula of the first end product of example k: Example 5 3^.1 g of 1-chloracetyl-lOb-pheny1-1,3 >*+> 10b-tetra-hydro-pyrimido[2.1-a]isolndol-(62H)-one (cfe example , penultimate paragraph) are slurried in 70 ml of dioxane and 30„0 g of 1-methyl-piperazine are added0 The whole is heated within 30 minutes to 95-100° and kept at this temperature for 15 minutes. Sodium hydroxide solution is then added to the solutio and the smeary product which separates is dissolved, after, cooling, by repeated extraction with ether „ The ether solutions are dried with sodium sulphate and then concentrated „ The glassy crude product is recrystallised from about 1 00 ml of methylcyclohexane. ' l-[ (U-methyl-l-piperaz'inyl)-acetyl -lOb-phenyl-l^^jlOb-tetrahydro-pyrimidot ol-ajisoin-dol-6(2H)-one is obtained, M.P. 135-137°» gxample $ .5 g of 1-chloracetyl-llb~pheny1-1, 2 3, 5^ 1 ™ hexahydro-7H~l,3-dlazeplno[2.1-a]lsolndol-7-one are slurried in O ml of dloxane and 33 g of a l aqueous solution of dimethylamine are added. The whole is heated within 30 minutes to 90° and steam is bubbled through the solution until all the dimethylamine has been removed . The product, which is at first smeary, crystallises on cooling. It is iltered .. " and re-crystallised, first from methanol, then from ethyl acetate. 1- (N,N- Dimethylglycyl)-llb-phenyl-1,2,3,^, 5,llb-hexahy The following compounds are obtained analogously: a) l-(morpholinoacetyl)-llb-phenyl-1,2,3 , 5»Hb=hexahydro-7H-l,3-diazepino[20l-a]lsoindol-7-one, M.P, 220-223° (from metha-nol)i b) 1- (piperidinoacetyl)-llb-phenyl-l , 2,3 ?5» llb-hexahydro-7H-l,3-diazeplno[2ol-a]isoindol-7-one, M.P. 211-213° (from methanol)-, c) l-(N,N-diethylglycyi)-llb-phenyl-l,2,3,l+,5,Ilb-hexahydro-7H-l,3-diazepino[2.1-a]lsolndol-7-one, M.P. d) l-(N-methyl-N-ethylglycyl)-llb-pheri l-l,2,3| ,5,llb-hexa-hydro-7H-l,3-diazepino[2.1-a]lsoindol-7-one, M.P. l60-l65°.

To produce the 1-chloracetyl compound of this example, 22.6 g of o-benzoyl benzoic acid and 10.1 g of l, ~butane-diamine are heated within 2 hours to 179° with 100 g of 0-dichlorobenzene, the reaction water being distilled off with a small amount of o-dichlorobenzene . After concentrating in vacuo, the crystalline residue is recrystallised from benzene. 27.8 g of this compound and 3^.2 g of chlorace lc acid anhydride in 100 ml of dimethyl formamide are heated for 30 minutes at 90-95°. The solution is then poured into 1000 ml of water and the partially crystallised product is iltered under suction and recrystallised from methanol. 1-Ohioracety1-llb-phenyl-1,2 , 3, *+ , 5j llb-hexahydro-7H-l , 3-diazepino[ 2„ 1-a] lso-indol-7-one is obtained, M.'P. 203-207°.

Structural formula of the first end product o example 6: Example 7 39.9 g of l-(2-bromobutyryl)-9b-phenyl-l,2,3,9b-tetra-hydro-5H-lmldazo[2.1-a] isoindol- 5-one (see below) are slurried in 50 ml of dioxane and 3*+ g of a l$ aqueous solution of dimethylamlne are added. The mixture is refluxed for 15 minute and then excess dimethylamlne is removed with steam0 The amorphous crude product is crystallised by the addition of a small amount of methanol and then recrystallised from dilute methanol. l-[ 2- (Dimethylamino)-butyryl]-9b-phenyl-l, 2,3 , 9b-tetrahydro-5H-lmidazo[2.1-a]lsoindol- 5-one is obtained, _~ - 144.5°.

The following compounds are obtained analogously: a) l-[2-(methylethylamino)-butyryl]-9b-phenyl-l,2,3,9b-tetra-hydro-5H-imidazo[2.1-a]isoindol- 5-one, M.P. 108-112°, and b) l-(2T-morpholinobutyryl)-9b-phenyl-l,2,3,9b-tetrahydro-5H-imidazo[2.1-a]isoindol- 5-one, M„P. 120-122°o To produce the 1- (2-bromobutyryl) compound, 2 g of 9b-phenyl-l,2,3,9b-tetrahydro-5H-imldazo[2cl-a]isoindol- 5-one (cf. last paragraph of example 1) and l8„ 5 g of 2-bromobutyry] chloride in 100 ml of chlorobenzene are refluxed for 1 hour.

The reaction solution is washed several times with water, dried with sodium sulphate and concentrated in vacuo. The residue is recrystallised twice from methanol. l~(2-bromobutyryl)-9b-phenyl-l,2,3,9b-tetrahydro-5H-imidazo[2.1-ajisoindol-5-one is obtained, M.P. I61-16W0. 39.9 g of l- ( 2-bromobutyryl) -9b-phenyl-l, 2 , 3 , 9b-tetra-hydro-5H-lmldazo[ 2.1-a] lsoindol-5-one (see example 7 , last paragraph) are slurried in 65 ml of dioxane and, with 22. g of diethylamlne , refluxed for 1 hour. The solution is poured into 500 ml of water and the amorphous crude product is dissolved in ether. The ethereal solution is concentrated to about 50 ml and then left to stand whereupon a small amount of 1-crotonyl-9b-phenyl-l, 2 , 3 , 9b-tetrahydro-5H-imida«oC2.1-a]isoindol-5-one separates out as side product.

The filtered ether solution is concentrated, the residue is dissolved in 2H hydrobromic acid and the solution is cooled to 0°. The hydrobromids. of 1- (2-diethylaminobutyryl)- 9b-phenyl-1.2.3 o 9b-tetrahydro-5H-imida2o[ 20l-ajisoindol- -one crystallises. After recrystallisatlon from ethanol/ether , the pure hydrobromlde is obtained, M.P. 223-225° (with decomposition). 38. g of l-(2-bromopropionyl)-9b-phenyl-l,2,3,9b- tetrahydro-5H-imidazo[2,l-a]isoindol-5-one (M.P. 157-159°, produceci analogously to the process described in the last paragraph of example 7), are slurried in 0 ml of dioxane and 31* g of a l aqueous solution of dimethylamine are added.

The mixture is refluxed for 20 minutes, after cooling, it is diluted with 500 ml of ether, washed with water, the washing water is removed,' the mixture .is dried with sodium sulphate and concentrated in vacuo. Cn- riturating wit fresh ether, the crude product crystallises. After recrystallisation from a mixture of ethyl acetate and hexane, l-(N,N~dimethylalanyl)-9b- phenyl-l,2,3,9b-tetrahydro-5H-imidazo[2ol-a]isoindol-5-one is • obtained, M.P.139-1^1°. f . The following compounds are produced analogously: . a) 1- (N-methyl-N-ethylalanyl)-9b-phenyl-1,2,3, 9b- 1etrahydro- 5H-imldazo[2ol-a]isoindol-5-one, M.P. 150-153°; b) l-(N,N-diethylalanyl)-9b-phenyl-l,2,3,9b-tetrahydro-5H-• imidazo[2„l-a]isoindol-5-one hydrochloride, M.P. 205-215° . (with decomposition). 36.1 g of l-chloracetyl-9b-(p-chlorophenyl)-l,2,3,9b-tetrahydro-;ni-imidazo[2.1-a]isolndol-5-one, (M.P.163-165.5°, see below) are slurried in Uo ml of dioxane and, after the addition of 3^+ g of a l$ aqueous dimethylamine solution, refluxed for 1 minutes. After cooling, it is diluted with ether and washed with water,, The ether solution is dried with sodium sulphate and concentrated in vacuo. The honey-like crude product obtained Is dissolved In anhydrous ether and converted into the hydrochloride by the introduction of hydrogen chloride. This is recrystallised from a mixture of ethanol and ether „ 1-(N,N-dimethylglyc^l) -9b- (p-chlorophenyl)-1, 2,3 , 9b-tetrahydro- 5H-imidazo[2.1-a]isoindol-5-one hydrochloride is obtained, (it decomposes at about 255°)· The following compounds are produced analogously: a) l-(N,N-diethylglycyl)-9b-(p-chlorophenyl)-l,2,3,9b-tetra-hydro-5H-imidazo[2„l-a]isoindol-5-one hydrochloride, M0P0 22 -232° (with decomposition) j b) l-(N-methyl-N-ethylglycyl)-9b-(p-chlorophenyl)-l,2,3,9b-tetrahydro~5H-imidazo[2„l-a]isoindol-5-one hydrochloride, M0P0 213-220° (with decomposition.

The 1-chloracetyl compound necessary for this example is produced analogously, to the process described in the last paragraph of example 1, starti g from o-(p-chlorobenzoyl)-benzoic acid, by way of 9b-(p-chlorophenyl)-l,2,3,9b-tetrahydro-5H-imidazo[2el-a]lsolndol-5-one, MeP» I66-I680.

Example 11 .6 g of l-chloroacetyl-9b-(p-methoxyphenyl) -1 , 2 , 3 , 9b- tetrahydro-5H-imidazo[2,l-a]isoindol-5-one (does not crystallise, see below), 40 ml of dloxane and 34 g of a 41% aqueous dimethylamine solution are refluxed for 15 minutes. After cooling, the reaction solution is diluted with ether, washed with water and evaporated to dryness. The honey-like residue is dissolved in 500 ml of anhydrous ether. Hydrogen chloride is then introduced until saturation. The hydrochloride of 1-(N,N- dimethylglycyl) -9b-(p-methoxyphenyl) -1,2,3, 9b-tetrahydro-5H- 10 imidazo [2.1-a ]isoindol-5-one immediately crystallises. It is recrystallised from a mixture of ethanol and ether, M.P. 240 - 243° (with decomposition). _J -a^ 3^Ji~meJ^J^^½^ -J^' keHW y:d→?^ The following compounds are produced analogously: a) l-(N-methyl-N-ethylglycyl) -9b-(p-methoxyphenyl) -1,2,3, 9b-tetrahydro-5H-imidazo [2 , 1-a ]isoindol-5-one hydrochloride , M.P. 225 - 228° (with decomposition); b) l-(N,N-diethylglycyl) -9b-(p-methoxyphenyl) -1,2,3,9b- tetrahydro-5H-imidazo [2 , 1-a ]isoindol-5-one hydrochloride, M.P. 210 - 220° (with decomposition) c) l-(N.,N-dimethylglycyl) -9b-(p-ethoxyphenyl) -1,2,3,9b- 25 tetrahydro-5H-imidazo [2 , 1-a ]isoindol-5-one hydrochloride, M.P. 225 - 230° (with decomposition); d) l-(N-methyl-N-ethylglycyl) -9b-(p-ethoxyphenyl) -1,2,3,9b- tetrahydro-5H-imidazol [2 , 1-a ]isoindol-5 -one hydrochloride, M.P. 230° ^with decomposition) e) l-(N,N-diethylglycyl) -9b-(p-ethoxyphenyl) -1,2, 3, 9b-tetrahydro-5H-imidazo [2, 1-a ]isoindol-5-one hydrochloride, M.P. 220° (with decomposition) .

The starting materials for the production of the above compounds are obtained analogously to the scheme of reactions described in the last paragraph to Example 1. Starting from 0-(p-anisoyl) -benzoic acid and ethylene diamine, the reaction proceeds by way of 9b-(p-methoxyphenyl) -1, 2, 3 , b-tetrahydro-5H-imidazo[2,l-a ]isoindol-5-one (M.P. 160 - 161°), and starting from o-(p-ethoxybenzoyl) -benzoic acid and ethylene-diamine, it proceeds by way of 9b-(p-ethoxyphenyl) -1, 2, 3, b-tetrahydro-5H-imidazo[2,l-a]isoindol-5-one (M.P. 158 - 159°). The 1-chloroacetyl-9b-(p-ethoxyphenyl) -1,2,3, b-tetrahydro-5H-imidazo [2, 1-a ]isoindol-5-one, as immediate starting material for the compounds mentioned under c) , d) and e) , melts at 132 - 135°.

Example 12 .5 g of l-chloracetyl-9b-(3,l+-xylyl)-l52,3s9b-tetra hydro- 5H-imidazo[ 2„ 1-a] isoindol-5-one (it does not crystallise see below) are dissolved in kO ml of dioxane and, after the addition of a kl% aqueous solution of dimethylamlne , the whole is refluxed for 15 minutes 0 f ter TcooTing" "' "i ' Iute ith 100 ml of /ether and the solution is washed with water. 1- ( N,N- dime thy 1- glycyl) - 9b- (3 ^- ylyD-l, 2,3 ,9b-tetrahydro-5H-imidazo[ 2o 1-aJ is ;·"'"' indo - 5- o e crystallises out, M„P. 157- l60° from ethanol.

The following compounds are produced analogously: a) l-(N-methyl-N-ethylglycyl)-9b-(3,l+-xylyl)-l»2s3?9b-tetra- hydro-5H-imidazo[2.1-a]isoindol-5-one hydrochloride, MoP0230 - 235° (with decomposition), and b) 1- (N,N-diethylglycyl)-9b- (3 , -xylyl) -1, 2,3 , 9b-tetrahydrc~ 5H-imldazo[2.1-a] isoindol-5-one hydrochloride, M0P .230-235° (with decomposition) „ The 1-chloracetyl compound required as starting material is produced analogously to the scheme of reactions described in example 1, starting from o- (3, H-xyloyl) -benzoic acid and ethylenediamine by way of 9b»(3,l+-xylyl)~l, 93,9b~ tetrahydro-5H-imidazo[2ol-a]lsoindol-5-one, M0P.ll+9-l520o Example 13 34.1 g of 1-chloracetyl-lOb-phenyl-l, 3 , 4 , lOb-tetrahydro-pyrimido[2,l-a]isoindol-6(2H)-one (cf. Example 4, last paragraph) are dissolved in 25 ml of dioxane and 22.5 g of 2-methylamino-ethanol are added. The whole is heated for 15 minutes at 90 - 100° and then concentrated in vacuo. The amorphous residue is washed with water and dissolved in ethyl acetate. The solution is dried with sodium sulphate and concentrated. The crude product which slowly crystallises is re-crystallised first from ethyl acetate and then from a mixture of benzene/hexane. l-[N-(2-hydroxyethyl) -N-methylglycyl ]-10b-phenyl-1 ,3,4, 10b-tetrahydro-pyrimido[2, 1-a ]isoindol-6(2H) -one is obtained, M.P. 114 - 117°.

Example Ik 32.7 g of l-chloracetyl-9b-phenyl-l,2,3,9b-tetrahydro-5H-imidazo[ 2,1-a] isoindol- -one (production see example 1), HO.5 g -of N-ethyl-benzylamine and o ml of dioxane are heated to 100°. After 15 minutes, the reaction mixture is allowed to cool and is then extracted with 20 ml of water and 300 ml of ether. On concentrating the ether phase, 1- (N-ethyl-N-benzyl-glycyl)-9b-pheny1-1, 2,3 ,9b-tetrahydro-5H-imidazo[ 2,1-a] isoindol-5-one crystallises. After recrystalllsation from ethyl acetate and hexane it melts at 126-128°.

The following compounds are produced analogously: a) l-(N-methyl-N-be zylglycyl)-9b-phenyl-l,2,3,9b-tetrahydro-5H-imidazo[2,l-a] isolndol- 5-one, M.P. 157-159°; b) l-[N-ethyl-N-(p-chlorobenzyl)-glyc^l]-9b-phenyl-l,2,3,9b-tetrahydro-5H-imidazo[ 2,1-a] isoindol-5-one; c ) 1-[ N-me hyl-N- ( -chlorobenzyl) -glycyl] -9b-phenyl-1 , 2 , 3 , 9b-tetrahydro-5H-imidazo[2,l-a]isoindol-5-one, M.P. 112-115°; d ) 1-[N-methyl-N- (p-methoxybenzyl) -glycyl] -9b-pheny1-1,2,3,9b-tetrahydro-5H-imidazo[2,l-a] isoindol-5-one, M.P. 117-120°; e ) 1- [ N-ethyl-N- (p-methoxybenzyl) - lycyl]-9b-phenyl-1, 2,3 , 9b-tetrahydro-5H-imidazo[ 2,1-a] isoindol- 5-one hydrochloride, M.P. 2 ^° (with decomposition) ; ) 1- (N-propyl-N-benzylglycyl)-9b-phenyl-l, 2,3 , 9b-tetrahydro-5H-lmidazo[2,l-ajiso.indol-5-one, M.P. 117-119°; g) l-(N-ethyl-N-benzylglycyl)-9b-(p-chlorophenyl)-l, 2,3,9b- . tetrahydro-5H-imidazo[ 2,1-a] isoi dol- 5-one , M.P . 95-100°; , h) l-(N-methyl-N-benzylglycyl)-9b-(3,H-dimethoxyphenyl)-1,2, 3, b-tetrahydro-5H-imidazo[ 2,1-a] isoindol- -one hydrochlor- 1,2,3, b-te rahydro- 5H- imidazo[ 2 , 1-a] isoi dol- -one ydrochlor- k) l-[N-methyl-N- (p-methoxybenzyl)-glycyl]-9b- (3 ^-dimethoxy-phenyl) -1,2, 3 ,9b-tetrahydro- H-imidazo[ 2, 1-a] isoindol- 5-one hydrochloride', 1) l-[N-ethyl-N- (p-methoxybe zyl)-glycyl] -9b- (3 ,U-dimethoxy-phenyl)-l, 2,3 , 9b-tetrahydro- H-imidazo[ 2, 1-a] isoindol- - one hydrochloride, M.P. l?9-l80°; m) l-[N-methyl-N- (p-chlorobenzyl)-glycyl]-9b- (3 , H-dimethoxy-phenyl)-l, 2,3 ,9b-tetrahydro-5H-imidazo[ 2, 1-a] isoindol- 5-one hydrochloride, M.P. 197-198°; n) l-[N-e hyl-N- (3 ,H-dimethoxybe zyl) -glycyl]-9b- (3 ,H-dimethoxy phe yl) -1, 2,3,9b-tetrahydro-5H-imidazo[ 2, 1-a] isoindol-5-one hydrochloride; o) l-(N-propyl-N-benzylglycyl)-9b-(3,^-dimethoxyphenyl)- 1, 2,3,9b-tetrahydro-5H-imidazo[ 2, 1-a] isoindol- -one hydrochlor- p) 1-[N-me hyl-N- (3 , -dimethoxybenzyl)- lycyl]-9b- (3 , -dimeth-oxyphe yl)-1, 2,3, b-tetrahydro- H-lmidazo[ 2, 1-a] isoindol- 5-one hydrochloride; '.'.;'.·-■- ' q) l-[N-ethyl-N-(3,I+-methylenedioxybenzyl)-glycyl]-9b-(3,I+-dimethoxyphenyl)-l, 2,3, 9b-tetrahydro-5H- imidazo[ , 1-a] isoindol-5-one hydrochloride*, . -r) 1- (N-ethyl-N-benzylalanyl)-9b-phenyl-l,2,3 ,9b-tetrahydro-5H-imidazo[2,l-a]isoindol-5-one hydrochloride, M.P. I96-I980; s ) l-[N-ethyl-N- (3 ,U-dimethoxybenzyl) -glycylJ-9b-phenyl-1, 2,3 ,9b-tetrahydro- H- imidazo[ 2 , 1-a] isoindol- -one j t) l-[N-methyl-N- (p-methoxybenzyl)-glycyl]-9b- (p-methoxyphe y)-l,2,3,9b-tetrahydro-5H-imidazo[2,l-a]isoindol-5-one, M.P. 130 - u) 1- [ N-met yl-N- (3 ,V-meth le nedioxybenzy1) -glycy1] -9b- (3 ,U-dimethoxyphenyl)-1,2,3 ,9b-tetrahydro-5H- lmldazo[ 2,1-a] Isolndol-5-one hydrochloride, M.P. 192-193°.

Example 15 34.0 g of l-chloracetyl-10b-phenyl-l,3,4,10b-tetrahydro-pyrimido [2 , 1-a ]isolndol-6 ( 2H) -one , (production see Example 4), are dissolved in 40 ml of dioxane and the solution is heated for 10 minutes at 100° with 36.3 g of N-methyl-benzylamine .

After cooling, the reaction mixture is extracted with 20 ml of water and 300 ml of ether. On concentrating the ether phase, the l-(N-methyl-N-benzylglycyl) -10b-phenyl-l,3,4 l0b-tetra-hydro-pyrimido[2,l-a ]isoindol-6(2H) -one is isolated. Recrystal-lised from ethyl acetate and hexane, it melts at 126 - 127.5°. l-(N-Ethyl-N-benzylglycyl)-lOb-phenyl-1 ,3,4, lOb-tetra-hydro-pyrimido [2 , 1-a ]isoindol-6 ( 2H) -one, M.P. 141 - 144° is produced analogously.

Example 16 a) 33.5 g of l-(N,N-dimethylglycyl)-9b-phenyl-l,2,3,9b-tetra-hydro-5H-imidazo [2 , 1-a ]isoindol-5-one (produced according to Example 1) are dissolved in 500 ml of ethyl acetate and 100 g of methyl iodide are added at room temperature. The quaternary ammonium salt immediately precipitates in oily form and crystallises on washing with hexane. M.P. 233° (with decomposition). b) The methochloride is obtained on reacting 32.7 g of 1-chlor-acetyl -9b-phenyl-1 , 2,3, 9b-tetrahydro-5H-imidazo [2 , 1-a Jisoindol-5-one with a solution of 50 ml of trimethylamine in 500 ml of ether.

Example 17 34.1 g of l^chloracetyl-10b-phenyl-l,3,4,10b-tetrahydro-pyrimido [2 , 1-a ]isolndol-6 ( 2H) -one are dissolved in 50 ml of dioxane and the solution is heated for 1 hour at 90° with 36 g of N-methyl-diethanolamine. After cooling, the crude product is precipitated with petroleum ether and recrystallised from alcohol. In this way l-(N,N-bishydroxyethyl-glycyl) -10b-phenyl-1 ,3,4, lOb-tetrahydro-pyrimido [2 , 1-a ]isoindol-6 ( 2H) -one methochloride is obtained. Decomposition point: 200°.

Example 18 36.3 g of l-(N,N-diethylglycyl) -9b-phenyl-l,2,3,9b-tetrahydro-5H-imidazo [2 , 1-a ]isoindol-5-one (see Example 1) are dissolved in 250 ml of ethanol and 12 ml of a 2Q% aqueous solution of hydrogen peroxide are added. The mixture is re-fluxed for 2 hours. On carefully concentrating, the N-oxide crystallises.

Claims (7)

26534/2

1. Process for the production of new, condensed hetero cyclic co wherein R-^ and each represent hydrogen atoms , low alkyl or . ... alkoxy groups or halogen atoms, ■- R3 represents a hydrogen atom .or a low alkyl group, R4 and '' g each represent low alkyl, ■ hydroxyalkyl or benzyl groups, of which one can be substituted in the phenyl" nucleus by, in all, at most two of the following groups,' low alkyl, low alkoxy',- -and/or halogen or the methylenedioxy group, or 4 and g together with the adjacent nitrogen atom represent or the piperidino, 1-pyrrolidinyl , morpholino./ 4- ' methyl-1-pipe azinyl , : ■ ' - radical , and n represents 1, 2 or 3, their acid addition salts, their quaternary, salts and their N-oxides, characterised by reacting a reactive ester of a "compound of the general formula II ' wherein R^, R2, R3 and n have the meanings given in formula I, with a compound of the general formula III R, H - N (III) Rc wherein R^ and R^ independently of each other and also together with the adjacent nitrogen atom have the meanings given in formula I, the reaction being performed in the presence of an acid binding agent and, if desired, converting the compound of the formula I into an acid addition salt or into a quaternary salt or into an N-oxide.

2. Process according to claim 1 for the production of acid addition salts and quaternary salts of compounds of the general formula I, characterised by reacting a reactive ester of a compound of the general formula II, defined in claim 1, with a compound of the general formula Ilia R. R6 - N (Ilia) wherein R^ and R^ independently of each other or together with the adjacent nitrogen atom, have the meanings given in formula I, and R6 represents hydrogen or a group as defined for R^.

3. Compounds of the general formula I, given in claim 1, wherein R- R2, R3, ^, 5 and n have the meanings given therein, and their acid addition salts, their quaternary salts and their -oxides. ■ -' .

4. Acid addition salts and quaternar salts, of compounds of the general formula Ϊ, given in claim 2, wherein. R- 2, R3, R4> > R6 and n have tne meanings given therein. .

5. .Process for the production of compounds of' the general formula I, their acid addition salts, their quaternar salts and their N-oxides , · defined' in claims 1 and 2, as herein-described with reference to and as illustrated in any of the foregoing examples.

6. Compounds of the general formula I, their acid additio salts, their quaternary salts and their N-oxides, defined in claims 3. and 4, as herein described with reference to and as illustrated in any of the foregoing examples. .'

7. '. Therapeutical preparations for . the treatment, of rheumatic and other inflammatory diseases, for the amelioration and relief of pain, tussive irritation and conditions of agitation of various origin, characterised by a content' of a compound.,of the. general formula I, a pharmaceutically acceptable acid addition salt, quaternary salt or N-oxide of such a compound in combination .with an inert carrier and, optionally, further additives.