IL29651A - Diazocycloalkenyl-isoindole derivatives and processes for he manufacture thereof - Google Patents

Description

29651/2 Diazocycloalkenyl-isoindoie derivativea ' and processes for the manufacture thereof 3PAHAMEDJCA A.Gv 0:28065 , . ^ ;■ RAN 4081/48 i ! This invention relates to a novel class of aromatic compounds novel processes and intermediates for the preparation of said novel products and derivatives thereof and to the use of said novel compounds as pharmaceuticals. More particularly, the invention in its product aspect relates to novel compounds of the formula wherein B represents an alkylene chain of 2 to 4 ' > carbon atoms in which one or more of the hydrogens ; can be replaced by lower alkyl; ^, Rg, R^ and R^ ■ ;each independently represent hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl; and RQ represents hydrogen, hydroxy or lower alkoxy. i ! · Compounds of formula I, wherein Rg represents hydroxy, can undergo a protptropic . shift to form compounds of the formula "wherein Rg, R- " R^ and B each have the same meaning as hereinabove; and R„ is lower allyl.

I In still another product aspect this application- per- !tains to novel intermediates which will be more fully des- ' 'cribed with reference to the several processes for the prepa- ration ;of compounds of formulas I and II. i · ' · · 1 j ! As used throughout this application ■ the term "lower jalkyl" denotes straight and branched chain hydrocarbons con- ! : ; taining 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec. -butyl, t. -butyl and the li..e. The term ; !"lower . alkoxy" denotes lower alkylether groups, wherein the !alkyl group is as defined above. The term "halogen" as used ! i jherein includes all four halogens, i.e., chlorine, bromine,· I ; iodine and fluorine. i ■ ■ I · · i · ' ' I Suitable salts of the compounds of formulae I and II are prepared from nontoxic organic and inorganic acids. Suitable organic acids are, for example, aleic acid, fumaric acid, ascorbic acid, tartaric acid, salicylic acid, succinic acid, citric acid and the like. Suitable inorganic acids are, for example, the hydrohalic acids, e.g., hydrochloric acid and hydrobromic acid; sulfuric acid, sulfamic acid, phosphoric acid, etc.. The acid, addition salts are readily, prepared by the usual! ■ i techniques for the preparation of acid addition salts which I . ' j are readily apparent to those skilled in the art. of the aromatic compounds of formulae I and II. is characterized ,in that.it comprises treating a compound of the formula ; wherein R^, R≥, and R^ are as defined hereinabove, !with a diamine of the formula H2 —B-NH2 XII wherein B is as defined hereinabove, cyclizing a compound of the formula wherein B, R^, ≥, R^ and R^ are as defined hereinabove b treatment with a Lewis acid or treatin a com ound of the or. a dehydro derivate thereof having the formula .'wherein B, R^ ancj ^ .are as defined hereinabove with ■ a. henylorganoraetallic derivative of the formula wherein £ is L represent hydr lower alkyl, lower alkoxy or trifluoromethyl, or treating a compound of the formula XIII with an oxidizing agent; if desired, oxidizing a resulting compound of formula I, wherein Rg represents hydrogen, to a corresponding hydroxy-substituted compound, if desired, lower •alkylating a resulting compound of formula I, wherein Rg represents hydroxy to a corresponding lower alkoxy-substituted compound, if desired, separating a racemic mixture obtained into its optically active antipodes and, if desired, converting a resulting base into an acid addition salt.

In one of its process aspects this application pertains to the preparation of compounds of formulas I and II according to the following reaction sequence. • · / . · wherein ^ Rg, R^, R^, R^ and B each have the same meaning as hereinabove.

The diol starting materials of formula V are known compounds or are readily obtainable in analogy to the prepara- , tion of the known compounds.The diol starting materials can be readily converted to the dicarbonyl intermediates of formula IV by oxidation techniques which are known per se such as, for example, using selenium dioxide and the like, as the oxidizing agent or by employing other oxidizing systems such as chromium trioxide in pyridine.

Treatment with an oxidizing agent can be conveniently carried out in an organic solvent such as, for example, di~ methylformamide, dimethylsulfoxide; hydrocarbon solvents such as benzene, toluene; alkanols, e.g., the lower alkanols, methanol, ethanol, etc.; acetic acid and the like. The oxidation reaction is preferably carried out at an elevated temperature ^suitably at a temperature between about room temperature and :about 150°C. · ί ■ ' ' .' ·■ I The intermediates . of formula IV are themselves novel The ; i of an organic solvent such as benzene, toluene; alcohols such as lower alkanols and the like. The condensation is conveniently carried out at room temperature or above, preferably at a temperature. between about 20°C and.l50°C. Alternatively, the 5 diamine reactant of formula XII can be employed as a salt . thereof in which case the reaction is conducted by heating r · the mixture of reactants to a melt.

; The reaction products, i.e., the compounds of formula 'III, can be readily oxidized, for example, by treatment with .an oxidizing agent such as hydrogen peroxide or by exposure to gaseous oxygen at room temperature to give the pei jxides of formula I-c which are readily reduced to the corresponding end products. The oxidation is conveniently carried out in an ·'. organic solvent such as alcohols, dimethylformamide , etc. at j room temperature. Higher or lower temperatures, e.g., between jabout 20°C and 100°C, can also. be employed. < · ' » Since the peroxide intermediates readily undergo re- jduction, the reaction mixture obtained upon treatment of a compound of formula III with an oxidizing agent will ordinarily 20 contain the end products of formula I-e along with the per- , oxide intermediate. of formula I-c. Complete reduction of the. peroxide can be accomplished without separating it from the ; reaction mixture and, in a preferred embodiment, the oxidation- t t 'product is submitted directly to treatment with a reducing ! agent. If desired, however, the peroxide intermediate of ί formula I-c can be separated from the reaction mixture ob- ' · I ■ · ; ' oxidizing agent by. any of the usual techniques, e.g., chromato- graphic separation, fractional crystallization, etc.

The reduction of the peroxide is conveniently carried out by employing any reducing agent conventionally used for the reduction of peroxides such as sodium sulfite, triaikyl- phosphite, etc. preferably in the presence of an organic solvent such as an alcohol, e.g., methanol, ethanol, etc.; dimethyl- formamide and the like, or when using a salt of the peroxide, .the reduction can be carried out in an aqueous solvent, e.g., in an aqueous alcoholic solvent. The reduction is suitably ! · 'carried out at room temperature or above, prefera'c-y at a jtemperature. between about 20°C and 100°C.

I t ' ' i As noted above, the hydroxyl proton of. a compound of I formula I-e can undergo a prototropic shift to form the corres-[ponding isomeric end product of formula II. In solution the jproduct obtained supon oxidation and reduction of an intermediate of formula III will ordinarily be a mixture of the •tautomeric forms I-e and II. The relative amounts of the isomeric forms present is dependent upon such factors as the • solvent system employed, the pH of the medium and the particular product, i.e., the meaning of B, R1, Rg, and R^ in ! formulas I-e and II. For example, in a solution of chloro-i . . . form the product obtained upon oxidation and reduction of 2,3-dihydro-5-phenyl-5H-imidazo [2, 1-a] isoindole contains a ; imixture of the isomers 2,3-dihydro-5-hydroxy-5-phenyl-5H-iml-■ dazo[2,l-a]isoindole and 2-(2-benzoylphenyl)-2-imidazoline in ordinary manner from the reaction product of the oxidation and reduction of 2,3-dihydro-5-phenyl-5H-imidazo[2,l-a]isoindole are" ordinarily obtained as structure II.

Compounds of formula I-d are prepared from compounds of . formula I-e by treating an acid addition salt, e.g., the hydrochloride, hydrobromide or the like, of a formula I-e compound with a lower alkanol preferably at an elevated temperature.

The etherification can be suitably carried out using the lower alkanol as solvent or in the presence of an inert organic sol- vent such as ether and the like and preferably at a temperature between about room temperature and the reflux temperature of the reaction mixture, i.e.,. up to about 150°C.

The novel compounds of formula I-d as well as the intermediates of formulas I-c and III are obtained as racemates. It is intended to include in this invention all of the stereoiso,- meric forms whether they are obtained as racemic mixtures or as the separated optically active antipodes.

' ! The intermediates of formula^ III ai¾d--i—o- are also , ■ novel compounds which constitute part of this invention.

Compounds of formula III are, in addition to being useful as intermediates in the preparation of compounds of formulas I-e j and II, also useful as psychostimulant, anti-inflammatory and anti-pyretic agents.

Alternatively, the compounds of formulas III, II and r wherein R^t 2, ^, R^ and B each have the same i meaning as hereinabove.

' ' . According to one alternative synthesis outlined above the intermediates of formula III are prepared by cyclization of a phthalimidine of formula VI. The cyclization of a phthalimidine of formula VI to form an intermediate of formula III is readily accomplished by treatment with a Lewis acid :such as titanium tetrachloride, boron trifluoride and the ;like. The oxidation and reduction of the formula III inter-mediates to form the desired end products is accomplished by the procedures described above.

!· . The reaction with Lewis acid is preferably carried out lin the presence of an inert organic solvent, e.g., hydrocarbon : solvents such as toluene, xylene and the like, and preferably ;at an elevated temperature suitably at the reflux temperature ;.of the solvent employed. A preferred temperature range for the i ■ ' - ■ I cyclization of the phthalimidines is a temperature between Iabout 50°C to about 200°C. The phthalimidine intermediates of iformula VI are prepared by condensing. a 5-phenylphthalide of 'formula VII with a diamine of formula XII. The 3-phenyl-!phthalides of formula VII and tj¾e diamines of formula XII employed as starting materials are known compounds or analogs 'of known compounds which are readily accessible in analogy ■to the known compounds.

I . ' The preparation of the formula VI intermediates is 'amine; quinoline, ethylenediamine, etc., with acids such as an organic acid, a mineral acid, e.g., sulfuric acid, hydrohallc acid, phosphoric acid, perchloric acid, etc., or a Lewis acid, such as zinc chloride, aluminum chloride, etc. Preferred ca- ' alysts for the reaction are the salts of ethylenediamine and pyridine such as pyridinium hydrochloride and the like. It is preferred to carry out the reaction with an excess of the ethylenediamine reactant as solvent. However, inert organic •solvents such as alcohols, e.g., methanol, ethanol, etc.; hydrocarbons, e.g., benzene, toluene, etc.; ethers, e.g., ] tetrahydrofuran, dioxane, etc., can also be employed. The re-f ; action is carried out at an elevated temperature, preferably iat a temperature above 100°C. Especially suitable temperatures for carrying out this reaction are temperatures between about 180°C and about 250°C.

An alternative synthesis for compounds of formula VI comprises catalytically hydrogenating a 1,2,5* b-tetrahydro-9b phenyl-5H-imidazo [2, 1-a] isoindol-5-one .

Alternatively, the intermediates of formula III can be prepared from the corresponding diazacycloalkenylisoindolones of formula VIII by reaction with an appropriate phenyl-organo- metallic derivative of the formula • wherein RL, /and RV each have the same meaning as The reaction with a phenyl-lithium derivative of ■ formula XI can be conveniently carried, out in the presence of an inert solvent at about room temperature. Higher or lower temperatures suitably in the range of about 10°C to about 100°C can also be employed. Suitable solvents that can be utilized are, for example, the hydrocarbons such as benzene, !toluene, xylene, etc., ethers, and the like or mixtures of such solvents.

The diazacycloalkenylisoindolone' intermediates of !formula VIII ¾«*©=^Ε¾©©==^?ν-3½==^ are readily prepared by the con densation of a phthalaldehydic acid derivative of formula IX 'with an alkylene diamine of formula XII. The condensation re- . action is conveniently carried out in the presence of an inert ; organic solvent and preferably at an elevated temperature.

'Suitable temperatures for carrying out the condensation re- I action are temperatures between about 20°C and about 1006C or ί ! 1 ί the boiling point of the reaction ^mixture. As solvent for the condensation there can be suitably employed any of the usual organic solvents such as alcohols, hydrocarbons, ethers, etc.

The phthalaldehydic acid derivatives of formula IX are known starting materials or analogs of known compounds readily obtained by known processes. ι Alternatively"compounds of formula I-e can be" prepared : , from compounds of formula X by reaction of an appropriate phenylorganometallic derivative of the formula XI. The. reaction can be conveniently carried out in the presence of an inert solvent at a temperature in the range of rOom temperature, to the. reflux temperature of ■ the ■ solvent . Suitable solvents ;which can be utilized are, for example, benzene, .toluene, xylene, ether, dioxane, tet ahydrofuran and the like or mixtures 'of such solvents.

Representative of the compounds of formula XI are phenylmagnesi.umiodide,' >-(trifluoromethyl) henylmagnesiumbromide, : ό,. 'phenylmagnesiumchlyride, phenyllithium or the like.

Compounds of formula X treating a compound I of formula Vlllwith an oxidizing agent such as, for example, » diethylazodicarboxylate. The conversion reaction is conveniently carried out in the presence of an inert organic solvent such as I chloroform hydrocarbons e.g. benzene, ethers and the like. Sui-: table reaction temperatures are in the range, of about 0°C and ' I about 100°C. It is preferred to conduct the reaction at the ! boiling point of the reaction mixture, preferably with re- ; fluxing. Again, separation of the desired reaction product 1 ;can be effected utilizing known procedures.

I In still another alternative process, the end products ;of formula I can be obtained by oxidation of a l-phenyl-2- wherein B, R^, Rg, R^ and.R^ are as defined hereinabove; :and X is halogen, preferably chlorine, iodine or bromine i - · or other similar- leaving groups such as mesyloxy, tosyloxy and the like The oxidation is accomplished by treating with an ■ oxidizing agent, such as gaseous oxygen or chemical oxidants such as chromium trioxide in acetic acid and the like. ί The reaction is preferably carried out in the presence ! of an organic solvent such as, for example, hydrocarbon solvents, e.g., benzene, toluene or the like; alkanoic acids, 'e.g., acetic acid, propionic acid, etc.; ethers, alcohols and I solvents such as dimethylformamide, etc. The reaction can be suitably accomplished at room temperature or at an elevated temperature, preferably at a temperature between about 20°C i and i00°C.The l-phenyl-2-aminoalkylisoindoline intermediates ( ■ ; are prepared from the diols of formula V via a diester of i · . - . ' ; I formula V-a. The diesters are obtained by the usual teohniquesi i I for esterification, e.g., treating the diol with one of the I .

J ; ordinary esterifying agents such as a halo acid and halides 'such as phosphorous halide, thionyl haiide, tosyl halide, etc. i · : The diester of formula V-a is in turn converted to the 1-phenyl-j 2-aminoalkylisoindoline. intermediate of formula XIII by con- '< i ' '<. densing with a diamine of formula XII.

The reaction with diamine is conveniently carried out by adding the diester of formula V-a to the diamine at room 1 9 of diamine. The reaction can also be carried out at temperatures above or below room temperature, although for practical reasons It is preferred to operate at a temperature between about 0°C and 100°C. The reaction is suitably carried out in the presence of an organic solvent such as, for example, benzene, methylene chloride, ether, tetrahydrofuran and the like; or, in the case where either or both of the reactants are liquid under the conditions employed in the reaction, the reaction is conveniently carried out in the absence of a solvent.

The novel end products of this invention, i.e., the compounds of formulae I and II and their pharmaceutically .acceptable acid addition salts are useful as psychostimulants.

When administered, for example, orally, to animals such as mice, they produce a direct acting stimulant effect of long duration. Among compounds of formula I and II which have been tested.' and' found to be highly effective in tests demonstrating ye psychostimulant effects there can be named by way of exampli- fication the following: ■ ■ (. . \ 2- (2-benzoylphenyl) -2-imidazoline; ! - ( -chlorophenyl) -2,3-dihydro-5-hydroxy-5H-imidazo- ' [ ' [2,1-a] -isoindole; 2,3-dihydrp 5-hydroxy-5- (^-methoxyphenyl) -5H-imidazo- .' ; [2, 1-a] -isoindole; 2,3, ,5-tetrahydro-7-hydroxy-7-phenyl-7H-diazepino- [2, 1-a] isoindole 2, 3-dihydro-5-methoxy-5-phenyl-5H-imidazo [2, 1-a] isoindole The compounds of this invention are' thus useful as psychostimulants 1η· the treatment of depressed states, for m l n c es of im le de ression or in es of chronic ner In addition to their use as psychostimulants, the compounds of formulas Id and II"" are also useful as analgesic agents. They also show'potent aati-inflammatory activity, .anti- edema activity and muscle relaxant activity. By way of example, 2- (2-benzoylphenyl) -2-imidazoline when submitted to standard pharmacalogical tests for analgetic properties e^tihit mated activity,carpqunds of formulas I-d and II are also useful as anorexigenic agents. Compounds of this series have also demonstrated useful cardiovascular, properties.

Compounds of formula II have also been found to be [active as anti-fungal agents. For example, they have been found to be active in vitro in Candida albicans, Microsporum audoulni and Trichophyton mentagrophytes. Accordingly, these compounds can be employed as anti-fungal agents in the treatment of pathogenic diseases caused by these organisms. They can, for example, be employed in the treatment of infectious fungal diseases such as moniliasis and der atomycoses. For the treat- ■ ment of fungal infections the compounds of formula I can' be employed by applying a suitable composition. Suitable compositions are prepared by embodying a compound of formula I, or ;a pharmaceutically acceptable salt thereof in a conventional carrier suitable for topical administration.

The. novel end products of this invention are mostly ;white crystalline odorless solids melting at temperatures in the order of 200°C. They have basic properties and can be conveniently prepared in the form of their acid addition salts. Suitable salts are prepared as described hereinabove. The salts are characteristically white crystalline odorless solids I soluble in water and have good stability under ordinary conditions. · The end products of the invention preferably in the form of their acid addition salts can be formulated into preparations suitable for administration by enteral or paranteral routes. They can be embodied in pharmaceutical unit dosage forms. Parenteral formulations will ordinarily contain less of the active substance than compositions intended for enteral, e.g., oral, administration. For oral administration the products of this invention can be prepared as tablets, capsules and the like. Formulations suitable for oral administration may be such as to provide either immediate or in the alternative, sustained release of. the active drug. In general, the formulations will be prepared with pharmaceutically acceptable adjuvant materials comprising from about 60 to about 98 per cent of the weight of the compositions in oral dosage form. ■ For parenteral administration the compounds can- be formulated with a liquid diluent, for example, distilled water, in the preparation of a suitable parenteral dosage form. In general, the compounds of this invention are formulated with con- administration followin the conventional techniques and procedures of the prior art. Suitable dosage forms include tablets and capsules as well as solutions, emulsions and suspensions.

The inert adjuvants which are suitable for use in preparing the various dosage forms include liquids and solids inorganic or organic in nature such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, Vaseline, etc. Additionally, the compounds can be used in combination with preservatives, stabilizers, wetting jor emulsifying agents, salts for altering the osmotic pressure, buffers, etc. If desired, the compounds can be used also in admixture with other therapeutically valuable substances., The drug in the preferred oral dosage form, i.e., tablets or capsules will be administered under ordinary circumstances three /or four times daily. The parenteral composition will be administered ordinarily one or two times daily. Effective dosages for the administration of compounds of this invention, will, of course, depend' in all instances upon the severity and individual characteristices of each case as determined by the ' rescribing practitioner. It will be understood that dosage forms containing larger and smaller quantities of the. active drug ingredient are encompassed by the scope of this invention and that such dosage forms can be administered more or less frequently than indicated heretofore. It will be understood, that dosage forms containing inert adjuvants in quantities which are greater or less than those indicated heretofore are also encompas sed by this invention. ' ■If The invention will be more fully understood from the examples which follow. All melting points are in degrees centi-grade. Decomposition melting points may vary - 10° depending ;on the rate of heating.

I Example 1 A solution of 21 g of o-benzoylbenzaldehyde in 250 ml iof toluene and 4 ml of ethylenediamine was refluxed for 24 hours. During this time 11.5 'ml of an aqueous phase was •separated in a Dean Stark receiver. The reaction mixture was jconcentrated in vacuo to an orange oil which was dissolved in ethyl acetate and washed twice with water. /The solution was dried and concentrated, dissolved in 200 ml of ethyl acetate / and a solution of 5.3 ml of concentrated sulfuric acid in ,100 ml of ethanol was added. A crystalline precipitate was collected which after recrystallization from a mixture of methanol and ethyl acetate gave white prisms of 2,3-dihydro-:5-phenyl-5H-imidazo[2,l-a]isoindole sulfate melting at 226-229 dec. Ultraviolet maxima (2-propanol) at 240 ιημ (£= 15,000) and 27β π)μ·(& = 5,400); infrared absorption (KBr) l66o cm-1.

Anal. Calcd. for C, 57-82; H, 4.85; N, 8 43 , Pound: C, 57.61; H, 4.8l; N, 8.73 The hydrochloride of 2,3-dihydro-5-phenyl-.jH-imidazo-: [2, 1-a] -isoindole was prepared from the corresponding base \ with aqueous 1 N hydrochloric acid. On recrystallization from a mixture of methanol and toluene, white prisms melting at 226-228° dec. were,- obtained. Nmr peaks (DMSO) at S 3.6-4.6 (4H, multiplet), at S 6.13 (1H, singlet), atS7-3- 7.9 (9H, multiplet).

The o-benzoylbenzaldehyde which was used as starting material, was prepared as follows: A mixture of 1 g of selenium dioxide and 1 g of 2-hy- droxymethylbenzhydrol in.5 ml of acetic acid was refluxed for 4 1/2 hours. The solution was cooled, filtered from selenium and the filtrate was poured into ice water and made alkaline with sodium hydroxide. Extraction with ether gave a yellow oil to which petroleum ether was added. White prisms of o- .

Ultraviolet maximum (2-propanol) at 22β/γ πΐμ (£= 15*750) and 251/2 πιμ (£= 18/500), inflexion at 294 π\μ ( = 2βθθ); infrared absorption (CHCl^) at 1665' cm"1 and 170 cm"1.

Anal. Calcd. for C, 79.98;' H, 4.79 . Pound : C, 80.00; H, 4.68 Example 2 To 1 ml of ethylenediamine was added 1 g of 2-(p-chloro- benzoyl)-benzaldehyde in small portions. An exothermic reaction !took place and after 5 minutes the reaction mixture was 'poured into ice water. A yellow solid precipitate was collected and dissolved in methylene chloride. Ether' and petroleum ether were added and the solution was shaken in air at 25°. A crystalline precipitate was obtained which after recrystallization 'from a mixture of methylene chloride and methanol gave white .needles of 2- [21 - (4-chlorobenzo-yl) phenyl] -2-imidazoline melting at I78-I8O0 dec. Ultraviolet maxima (2-propanol) at 225 mM : (£=21,250), 268 αμ (£=4500), 275 πιμ (£=4320), inflexion at .290 πιμ (1=2200); infrared absorption (KBr) at l660.cm"*1.

Anal. Calcd. for C, 67-49; H, 4.60 Found : C, 67.38; H, 4.56 The 2- [2' -(4-chlorobenzoyl) phenyl] -2-imidazoline prepared in this manner can form the isomeric 5- (4-chlorophenyl) - 2,3-dihydro-5-hydroxy-5H-imidazo [2, 1-a] isoindole .

The hydrochloride was prepared by adding a solution of hydrogen chloride in ether to a suspension of 5- ( 4-chloro- phenyl) -2,3-dihydro-5-hydroxy-5H-imidazo[ 2,l-a]isoindole. After stirring for 30 minutes- a crystalline crop was collected and recrystalllzed from a mixture of chloroform and ether to give white prisms melting at 168-171° dec. Ultraviolet inflexion ! (2-propanol) at 220 πιμ (£= 22, 000 ) , maxima at 52 ιημ (£= 12, 900) , 266 πΐμ (£= 13, 000 ) ; infrared absorption ( Br) at I670 cm Anal. Calcd.. for CI, 22.08 Pound : CI, 22. 18 The starting 2-(p-chlorobenzoyl)-benzaldehyde was prepared as follows: A solution of I8.6 g of 4 ' -chloro-2-hydroxymethyl- benzhydrol in 100 ml of acetic acid and 10.4 g selenium dioxide was refluxed for 2 hours. The mixture. as poured on ice and made alkaline 'and extracted with ether. Concentration of the ether solution and addition of petroleum ether gave. pale yellow prisms which after recrystallization from a mixture of ether and petroleum ether gave 2-(p-chlorobenzoyl)-benzalde-hyde melting at 112-113° . Ultraviolet inflexion (2-propanol) at 225 πιμ (£ = 17,500) and maximum at 259 ηιμ (S.= 22, 500) , infrared absorption (CHCl^) at 1β70 cm"1 and 1705 cm"1.

: Anal. Calcd. for C, 68.72; H, 3 -71 Pound : C, 69.12; H, 3.50 Example 3 7 , : To 4 ml of ethylenediamine was added 2 g of 2-(p- anisoyl) -benzaldehyde in small portions. The solution was stirred for 10 minutes, poured into ice water and extracted with methylene chloride. The methylene chloride solution was concentrated, the residue was dissolved .in ethano and a stream of air was passed through the solution for 18 hours.

A crystalline precipitate was collected and after recrystalli- zation from a mixture of chloroform and ether gave white prisms of 2-[2'-(4-anisoyl)phenyl]-2-imidazoline melting at ': 171-174° dec. Ultraviolet maxima (2-propanol) at 227 πιμ ■(£ = 20,200), 277 ιημ (£.=8800), 282 ταμ (£= 8750), inflexion at 292 ϊαμ (ε= 7200); infrared absorption (KBr) at ΐββθ cm"1. 1 · Anal. Calcd. for °1 ΐί1 Ν202: °' ?2·8^ H' 5-75; N, 9-99 ; Pound ■:- C, 75.07; H, 5-71; N, 9.85, The 2-[2'-(4-anisoyl)phenyl]-2-imidazoline prepared in ! jthis manner can form the isomeric 2,5-dihydro-5-hydrbxy-5-(4-methoxy-phenyl)-5H-imidazo[2,l-a]isoindole . i ■ ! i ' The starting 2- (p-anisoyl) -benzaldehyde was prepared as follows: A solution of 26 g of 4 ' -methoxy-2-hydroxymethylbenz-hydrol in 140 ml of acetic acid and 14.5 g selenium dioxide was refluxed for 2 hours. The mixture was filtered and the filtrate and was collected. Recrystallization from a mixture of methylene chloride and petroleum ether gave off-white platelets of 2- (p-anisoyl) -benzaldehyde melting at 90-91°. Ultraviolet maxima (2-propanol) at 221 πιμ (ε= 21,600), 258 πΐμ (i = 12,4-00) and 292 ηΐμ (£ = 17,000); infrared absorption (CHCl^) at ΐββθ cm ^ and at 1700 cm Anal. Calcd. for C, 74.99; H, -03 ; ' Found ,: C, 75-27; H., 5-26 Example ' To 2 ml of ethylenediamine was added 0.9 S of 2-benzoyl- 4-chlorobenzaldehyde in small portions. The. solution was •stirred for 10 minutes, poured into ice water and the solid .yellow precipitate was collected. This solid was dissolved in ether and shaken in air for minutes. A white precipitate was obtained which after recrystallization from a mixture of .'methylene chloride and methanol yielded 2- [4 ' -chloro-2 ' -benzoyl-'phenyl] -2-imidazoline melting at 200-202° dec. Ultraviolet maxima (2-propanol) at 242 πιμ (*"=17»500), 278 ιη (£= 38θθ), 286 ιημ (e= 3300), inflexions at 270 ηιμ ( £ = 3450), 295 m'M ', . ( = 2400); infrared absorption (KBr) at Ί665 cm-1. i Anal. Calcd. for Cl6H CINgO: C, 67.49; H, 4.60 ; Found ' : C, 67.42; H, 4.90 The 2- [4 ' -chloro-2 ' -benzoylphenyl] -2-imidazoline pre hydro-5-hydroxy-5-phenyi-5H-imidazo [2,1-a] isoindole.

' ' The starting 2-benzoyl- -chlorobenzaldehyde was pre- . pared as follows: . .

Absolution of 9·3 g of 5-chloro-2-hydroxymethylbenz- . hydrol in 50 ml of acetic' acid and 5· 2 g of selenium dioxide was refluxed for 3 hours. The mixture' was filtered, cooled, ,' poured on ice, made alkaline and extracted with ether. Con- centration and addition of petroleum ether gave 2-benzoyl-4- ! chlorobenzaldehyde. as prisms which after recrystallization ' from a mixture of ether and petroleum ether melted at 82-84°. : Ultraviolet maxima (2-propanol) at 230::.πιμ ((.= 19*500) and ; 257 (t= 23,500); infrared absorption (CHCl^) at 1β75 cm"1 -1 " and 1705 cm .

! I Anal. Calcd. for C, 68.72; H, 3.71 ' Found : C, 69.05; H, 3.87 Example 5 A solution of 6 g of 2- ( -bromobenzoyl) -benzaldehyde and 6.6 ml of ethylenediamine in 50 ml of toluene was refluxed i for 18 hours. During this time 0.5 ml of an aqueous phase had separated in a Dean Stark receiver. The mixture was concentrated in vacuo and the residual orange oil was dissolved in a mixture containing 15 ml of ethanol, 15 ml of methylene . chloride and 1*5 ml of a30 per cent by weight aqueous solution . from methanol gave white needles of 2- [ 2- (4-bromobenzoyl) phenyl] 2-imidazoline. melting at 187-189° dec.' Ultraviolet maxima (2-propanol) at 227 πιμ (s= 22,800), 259 ηιμ (e= 4700), 275 ιημ ' (ε= 4800), inflexion, at 292 m (ε= 2300); infrared ab-sorpiton (KBr) at ΐββθ cm"1.

. Anal. Calcd. for C^H^rl^O.: C, 8-37 H, 3.98 Pound : C, 58.27; H, 3-75 The 2-[2-(4-bromobenzoyl)phenyl] -2-imidazoline prepared in this manner can form the isomeric 5- (4-bromophenyl) -2,3-dihydro-5-hydroxy-5H-imidazo[2,l-a] isoindole .

The hydrochloride was prepared by adding ethereal hydrogen chloride to a solution of 5- (4-bromophenyl) -2, 3-di-hydro-5-hydroxy-5H-imidazo[2,l-a] isoindole in a mixture of methylene chloride and methanol. The precipitate was re-crystallized from a mixture of ethanol and ether to give white prisms melting at 155-I580 dec. Ultraviolet inflexion (2-propanol) at 22 (£=20,000), maxima at 251 πιμ (£=12,200) and 271 ηιμ (£=13,300); infrared absorption (KBr) at ΙββΟ. cm"1.

Anal. Calcd. for Cl6H1^rN20 HCl:' CI, 9-70 . Pound : CI, 9-82 The starting 2-(4-bromobenzoyl)-benzaldehyde was pre- t pared as follows: ■ „ hydride in l80 ml of tetrahydrofuran was added 0 g of 2-( -bromo ' benzoyl) -benzoic acid in the course of J>0 minutes. The mixture, after being kept at 25° for 2 hours, was cooled and 0 ml of a saturated sodium sulfate solution was added slowly. The mixture was filtered and the filtrate concentrated. The resulting oily residue was dissolved in 52 ml of acetic acid and 96 ml of xylene. This solution was added to a mixture of 17.1 g of selenium dioxide in 60 ml of. acetic acid and 120 ml of xylene and refluxed' for 17 hours. During this time about ; 22 ml of an aqueous phase had collected in a Dean Stark receiver. The solution was filtered, washed with sodium hy- ; droxide and concentrated. Addition of petroleum e'oner gave white prisms of 2-( -bromobenzoyl)-benzaldehyde melting at •.IO5-IO90. Recrystallization from a -mixture of ether and ' petroleum ether raised the melting point to 110-113°. Ultra- ; violet inflexion (2-propanol) at 225 (1=17,500) and maximum at 26l πιμ (£= 22,200); infrared absorption (CHCl^) at ' 1675 cm -1 and 1705 cm-1..

' Anal. Calcd. for C-^H^BrO^ C, 58.16; H, J.

. ! Pound : C, 57-86; H, jAi ■ Example 6 A solution of 10.5 S of 2-benzoylbenzaldehyde and 22 ml of propylene diamine in 125 ml of toluene was refluxed for 18 hr. During this time .5 ml of an aqueous phase had separated in a Dean-Stark receiver. The solution was con in a mixture of methylene chloride and ethanol and a solution ■of sulfuric acid in a mixture of tetrahydrofuran and ethanol was added. On addition of ethyl acetate a solid was obtained which after recrystallization from a mixture of ethanol and petroleum ether gave white prisms of 2, 3, , 6-Tetrahydro-6-p enyl-[ primido[ 2,l-a]isoindo.le sulfate melting at 170-172° (dec).

Ultraviolet maximum (2-propanol) at 238 ιημ(δ= 18 , 200 ) , inflexions at 246 π\μ (£= 16, 000 ) , 265 πιμ (£.= 56θθ) , 276 πιμ (€.= ^400) and 285 πιμ ( £ =2100 ) ; infrared absorption (KBr) at 1675 cm'1.

Anal. Calcd. for C, 58. 94; H, 5- C, 58. 62; H, - 9 Example 7 A solution of 10. g of 2-benzoylbenzaldehyde and '■28. 5 ml of 1,4-diaminobutane in 100 ml of toluene was refluxed ! for 18 hours. During this time 2. 5 ml of an aqueous phase had separated in a Dean Stark receiver. The solution was exposed to air for 60 hours, concentrated and diluted with 300 ml of carbon tetrachloride. A crystalline precipitate was obtained which was suspended in 40 ml of ethanol. A solution of 1 . 9 g : of oxalic acid in 40 ml of methanol was added and the solution was concentrated and diluted with ether. The precipitate was collected and recrystallized from a mixture of methanol and ether to give the oxalic acid salt as white prisms melting at ca 200° dec. This salt was suspended in a mixture of aqueous sodium carbonate solution and methylene chloride. The methylene chloride solution was concentrated and the residue was re-crystallized from a mixture of chloroform and ether to give " Ultraviolet maxima (2-propanol) at 258 πιμ (€=5000) , 2β5 πιμ (ξ=5100) , 273 ιημ (£=48θθ), inflexions at 2 0 πιμ (£=15* 000) , 290 m/x (£=2400); infrared absorption (KBr) at 1β50 cm"1.

Anal. Calcd. for ¾Ηι8 20 : C, 77 - 67 ; H, 6.52; 0, 5 - 75 Pound : C, 77-64; H, 6.75; 0, . 5-64 Example 8.

A 2-liter, J-necked, round bottomed flask was fitted with a mechanical stirrer, dropping funnel and a Dean-Stark trap fitted with a condenser. A mixture of 41.7 g '0.376 mole) of selenium dioxide in 150 ml of acetic acid and 300 ml of xylene was refluxed for 15 minutes. To the boiling mixture was added dropwise during one hour, a solution of 74. 4 g (0.3 mole) of 2-chloro-2 ' -hydroxymethylbenzhydrol in 85 ml of acetic acid and 250 ml of xylene. The Dean-Stark trap was cooled during this. time to promote separation of an aqueous phase. About 60 ml of the aqueous phase was separated during hours . The reaction mixture was refluxed for a total of 22 hours, cooled and filtered. The filtrate was added to 800 ml of ice and water, made alkaline with 50 per cent sodium hydroxide and the mixture extracted with 600 ml of ether. The extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to yield an orange oil which could not be crystalli.-' zed. Vapor phase chromatographic analysis showed the presence of two compounds. 4 . 4 Grams of the oil 2. 0. 87 mole of eth lene- diamine and 400 ml of benzene were refluxed for 5 hours in a round bottomed flask equipped with a Dean-Stark trap and a condenser. About 6 ml of aqueous phase separated in the trap. The reaction mixture was cooled, washed three times with saturated aqueous salt solution and dried over anhydrous sodium sulfate. Air was then bubbled through the benzene solution for 15 hours but only a small. amount of solid separated.

The benzene was removed under vacuo and the residue was dissolved in 150 ml of ethanol and 40 ml (0. 50 mole) of.30 per cent hydrogen peroxide. After stirring for 3 hours the ethanolj · was removed under vacuo and 300. ml of benzene was added to the residue. The aqueous phase was separated and the benzene solution was dried over anhydrous sodium sulfate and evaporated under vacuo to leave a pale yellow oil. Ether (150 ml) was added and a crystalline solid separated. The mixture was filtered to give a pale yellow solid, m.p. 164-Ιβ7° dec. The ether filtrate was stirred at room temperature, exposed to air, for two days. The precipitated solid was filtered to · give an additional pale yellow solid. Thin layer chromatography of the combined solids showed the presence of one major component, ' Rf' 0.41, and a minor component, Rf 0.67. The latter component was 2, -dihydro-5-hydroperoxy-5- (o-chlorophenyl) -5H-imidazo[2,l-a] -isoindole since the yellow solid precipitated iodine from a saturated methanolic potassium iodide solution. .

To a suspension of the yellow solid in βθ ml of refluxing methanol was added a solution of 4.28 g (0.017 mole) After refluxing for 15 minutes longer the reaction mixture •was cooled and filtered.'. The filtered solid was washed 3 times with 20 ml of v/ater and dried. Recrystallization from methanol- chloroform gave 2- [2- (2-chlorobenzoyl)phenyl] -2-imidazoline '. as colorless prisms, m.p. l8o-l8l° dec.

Anal. CalCdT for C, 67.49; H, 4.60; N, 9.84 Found : C, 6 .15 H, 4.56; N, 9.66 The 2- [2- (2-chlorobenzoyl) henyl] -2-imidazoline prepared in this manner can form the isomeric 2,3-dihydro-5-hydroxy-, 5- (2-chlorophenyl) -5H-imidazo [2,1-a] isoindole.

To a hot solution of 6.0 g (21.2 mmoles) of 2-[2-(2-' chlorobenzoyl)phenyl] -2-imidazoline in 25 ml of 6 N methanolic hydrogen chloride and 35 ml of methanol was added 200 ml. of-'ether and the solution cooled. Filtration gave 2- [2- (2-chlorobenzoyl) -phenyl] -2-imidazoline hydrochloride, m.p. I78-I8O0 dec. Dilution of the mother liquors with 200 ml of ether followed by cooling and filtering afforded an additional quantity of hydrochloride. Recrystallization from methanol- ether gave colorless prisms, m.p. 178-I8O0 dec.

Anal. Calcd. for C^H^Cl^O: CI, 22.08 Found · : CI, 22.00 The starting '2-chloro-2 ' -hydroxymethyl-benzhydrol was prepared as follows: To 250 ml of concentrated sulfuric acid was added, with stirring and slight cooling, 37· 5 S (0·545 mole) of sodium nitrite. To this was added 120.5 g (0.50 mole) of 2-(2-amino- benzoyl)benzoic acid at such a rate that the temperature of the, · reaction mixture remained between 30-40°. After the addition was complete the reaction mixture was stirred for one hour and then poured into one liter of ice and water and filtered. The filtrate was added rapidly to a stirred solution of 55 g (Ο.55 mole) of cuprous chloride, 150 g of sodium chloride, 250 ml of concentrated hydrochloric acid and 300 ml of water, i The precipitated gum was extracted with chloroform and the extracts were washed twice with water, dried over anhydrous sodium sulfate 'and evaporated under vacuo to leave a red ; oil which crystallized upon scratching. Recrystallization from 200 ml of ethyl acetate gave 2- (2-chlorobenzoyl)benzoic acid 'as a pink solid. A sample recrystallized three times from ethyl acetate gave colorless prisms, double m. p. 112-116° . ;and 124-126° .

To a stirred suspension of 22.8 g (0.60 mole) of lithium \ aluminum hydride in 700 'ml of dry tetrah drofurah was added ■ 104 g (0.40 mole) of 2- (2-chlorobenzoyl)benzoic acid prepared as above in portions keeping the reaction mixture temperature- between 15-30° with ice cooling. After the addition was complete the reaction mixture was stirred for one. hour. Ether '.' (400 ml) was added followed by the slow addition of 80 ml of ■ water, with ice cooling. The mixture was filtered through a large sintered glass funnel which contained a matting of Celite •furan and the combined filtrates were evaporated under vacuo to a yellow oil which crystallized upon scratching. The material was recrystalUzed from 150 ml of isopropyl ether to ■ give 2-chloro-2' -hydroxymethyl-benzhydrol as a slightly pink solid, m.p. 85-870. A sample was recrystallized three times from isopropyl ether to' give .colorless prisms, m.p. 86-87°.

Example 9 , ' A solution of 1.2 ml of titanium";tetrachloride in >0 ml 'of xylene was addend at 25° to a stirred solution of 2.5 g of 2-(2-aminoethyl) -J-phenylphthalimidine in.150 ml' o. xylene.

The mixture was refluxed for 18 hours, cooled and washed with I ' an aqueous ; solution of' sodium carbonate. The xylene solution was extracted ;Wi!th 2N hydrochloric acid. The acidic extract was poured on ice and made alkaline with sodium hydroxide. The solution was extracted with ethyl acetate and the extract was ; concentrated. Addition of a solution of sulfuric acid in a 'mixture of ethanol and tetrahydro uran and further dilution with ethyl acetate gave a crystalline precipitate. Recrystalli- zation from a mixture of methanol and ethyl acetate gave 2,3- '· ■ dihydro-5-phenyl-5H-imidazof2,l-a]isoindole sulfate as white : prisms melting at 225-228° dec.

The 2- (2-aminoethyl) -J-phehylphthalimidine which was used i starting material, was prepared as follows: A solution- of 25 g (0.1 mole) of l,2,3,9b-tetrahydro-9b- ' containing 2.5 g of hydrogen chloride was shaken under one atmosphere of hydrogen at 25° using 0.5 g of platinum oxide as catalyst. In the course of 7. hours, 3000 ml of hydrogen (theory ca. 2500 ml) was absorbed and the rate of uptake- had slowed down considerably. The solution was poured into ice water, basified with ammonia and extracted with methylene chloride. .The organic phase was dried and concentrated. The , residue crystallized with ether and after recrystallization from a mixture of methylene chloride and petroleum ether gave white prisms of 2- (2-aminoethyl) -J-phenylphthalimidine melting at 90-93°. 7coC13 = l685 279 , fc= 1900.

Anal. Calcd. for C1 H15N20: C' 76.16; H, 6.39 Found : C, 75-81; H, 6.32 Example 10 A solution of 7.5 g of phthalaldehydic acid in 30 ml of !ethanol and 34 ml of ethylenediamine was refluxed for 16 hours. The solution was concentrated in vacuo and the residue was dissolved in methylene chloride. The solution was washed with water, dried and concentrated. The residue was distilled in a bulb tube at 0.3 mm at a bath temperature of I5O-I8O0. A colorless oil was obtained which was dissolved in methanol and on addition of ethereal hydrogen chloride gave white prisms of l,2,3,9b-tetrahydro-5H-imidazo[2,l-a]iso'indol-5-one hydrochloride, m.p. 222-224°..dec.

The sal obtained in the preceding experiment was treated with aqueous potassium carbonate solution. Extraction with methylene chloride gave an . oil of which 0.9 g was dissolved in a mixture of 25 ml of benzene and 10 ml of ether. To this solution was added 5· 5 ml of a 2 N solution of phenyl lithium in a mixture of benzene and ether (7:3)· After stirring at 25° for 1 hour the solution was poured into ice water and extracted with ethyl acetate. This solution was concentrated and the residue was exposed to air for. 48 hours. On addition of methylene chloride crystals were obtained which were dissolved in methanol. Addition of ethereal hydrochloric acid gave white prisms which ^after recrystallization from a mixture of methanol and ether gave crystals of 2-(2-benzoyl- phenyl) -2-imidazoline hydrochloride, melting at 173-175° dec.

Example 11 A solution of 3. g of chromium trioxide and 5.· 9 g of : 2-(2-aminoethyl) -1-phenylisoindoline in 250 ml of acetic acid was stirred at 55-60° for 18 hours. The solution was cooled, : poured on. ice and made alkaline. Extraction with methylene chloride and removal of the solvent gave a brown oil which partly crystallized. Recrystallization from a mixture of · chloroform and ethyl acetate gave 2- (2-benzoylphenyl) -2-imidazoline as white prisms melting at 19 -196° dec.

The starting 2- (2-aminoethyl) -1-phenylisoindoline was prepared as follows: A solution of.127 S (0.59 mole) of 2-hydroxymethylbenz- hydrol.was dissolved in 900ml of benzene, 80 g of anhydrous magnesium sulfate was added and the mixture was cooled in an ice bath. Hydrogen bromide. was bubbled into the stirred so- . ilution until saturation which took about > minutes. During thi time the temperature of the solution was kept at 15-18° . The ice bath was removed and the temperature was allowed to rise to 35° in the course of 1 hour. The mixture was heated for another hour at 40-45° on a steam bath. During the whole time hydrogen bromide was passed into the solution to keep it saturated. The mixture was filtered and the solution was concentrated in vacuo to give a red oil which was dissolved in 200 ml of benzene and added to J42 g (5 · 7· moles) of ethylene diamine in the course of 15 minutes. During1 the addition the' mixture was stirred and cooled to maintain a temperature of • ca 40°. The mixture was stirred at .25° for 70 minutes. Two layers were obtained and separated. The benzene layer was . washed with water and concentrated in vacuo. The residual oil was dissolved in 250 ml of ether. This solution was extracted ; twice with 300. ml of cold IN hydrochloric acid. The acidic .aqueous phase .was made alkaline with aqueous sodium hydroxide ; !and extracted with 550 ml of ether. The ethereal solution was washed with 250 ml of water, dried and concentrated. The ; residue was an amber oil which crystallized on scratching. This material melted up to ca 45° . ' ' By analogy there were also prepared the following: 2- (3-aminopropyl) -1-phenylisoindoline 2- (2-aminoethyl) -1- (p-me hox henyl) isoindoline · .2-(4-aminobutyl) -1-phenylisoindoline 2- (2-amino-2-methylpropyl) -l-phenylisoindoline 2- (2-aminopropyl) -1-phenylisoindoline' ; 2- (2-aminoethyl) -1- (p-hydroxyphenyl) isoindoline.

Example 12 The base liberated from 16. 6 g of 2,3-dihydro-5-phenyl- 5H-imidazo [2,1-a] isoindole sulfate was dissolved in 50 ml of ethanol and 11 ml- of a 30 per cent by weight aqueous solution . of hydrogen peroxide was added. The mixture was st_rred at '. 25° for 40 hours. A crystalline crop was collected and placed : on a column containing 250 g of silicagel. Elution with ar'mixtu- : e of 1 part of methanol (volume) and 1 part of chloroform (vo- 'lume) gave fractions from which on concentration a crystalline : esidue was obtained. Recrystallization' from a mixture of methanol and chloroform gave 2, -dihydro-5-hydroperoxy-5-phenyl- ; H-imidazo- [2,1-a] isoindole as white prisms melting at 167- 168° dec. Ultraviolet inflexions (2-propanol) at 2 2 πι · (e= 14,000) and 290 πιμ (*=2β00), maxima at 2β9 πιμ (t=4000) and .' 275 πιμ (€.=4400), infrared absorption (KBr) at 1665 cm"1.

Anal. Calcd. for c 1^i1i^2°2 : C' 72,l6; H' 5'^0; Ν>10·52 Found: C, 72.09; H, 5.3 N,10.22 The hydrochloride of 2,3-dihydro-5-hydroperoxy-5-phenyl- 5H-imidazo[2,l-a] isoindole was prepared with methanolic hy ■methanol and ether gave white platelets melting at 158-159° dec. Ultraviolet maxima (2-propanol) at 2 5 πΐμ (S.=l4,800) and 278 χημ (£,=520.0) ; infrared absorption (KBr) at l680 cm ^ .

Anal. Calcd. for C, 6 .47 H, 4.99;C1 11.71 Found . : C, 63.63; H, 4.83;C1 11.79 A solution of 0.7 g of sodium sulfite heptahydrate in 3 ml of water was added to 0.5 g of 2,3-dihydro-5-hydroperoxy- 5-phenyl-5H-imidazo[2,l-a] isoindole. in 7 ml of dimethy 1formamide . ;The solution was heated to 100° for 15 minutes. On cooling and addition of 20 ml of water, 2- (2-benzoylphenyl; -2-imidazoli- ne was obtained. • i Example 13 ' • A solution of 0.1 g of 2,3-dihydro-5-hydroperoxy-5- 5 ■ ! phenyl-5H-imidazo [2, 1-aJ isoindole and 0.33 g of triethyl- ' phosphite in 20. ml of ethanol was kept on a steam bath for :5 minutes, then l8 hours at 25°.: The solution was concentrated •in vacuo and on addition of water 2- (2-benzoylphenyl) -2- ' imidazoline was obtained. .; ; Example 14 1 g of 2- (p-chlorobenzoyl) -berizaldehyde was thoroughly mixed with 0.9 g of ethylenediamine . toluene sulfonate and heated in a metal bath (bath temperature, 120-125°) for 1 / •which on addition of methylene chloride, ethyl acetate and ; petroleum ether gave a crystalline precipitate which was treated with ice cold aqueous sodium hydroxide. The mixture was extracted with ether and the extract was exposed to air at 25° for 18 hours. A crystalline crop was collected and suspended in methylene chloride. Addition of ethereal hydrogen • chloride gave a crystalline material which after recrystallization from a mixture of methanol and ether gave white prisms of 5- (p-chlorophenyl) -2,3-dihydro-5-hydroperoxy-5H-imidazo[2,l-a] ; isoindole hydrochloride melting at 175-177° ..dec. Ultraviolet inflexion (2-propanol) at 223 ∞M (*=21,800) and 279 ιημ (£=5β00) , maximum at 43 πιμ ( ≤. =15*500); infrared absorption (KBr) at : 1670 cm"1.

Anal. Calcd. for C, ,-H. ClNo0o-HCl : C, 56,99 H, 4.18; iD 1-? .. ci,21,03; N, 8.31 ! Pound : C, 57.1 ·· H, 4.15; ; CI,21.02; N, 8.30 i - Example 15 ■ To a suspension of 8.5 g of 2,3-dihydro-5-phenyl-5H- I imidazo[2,l-a] isoindole sulfate in water wasvadded 50 ml of ' IN aqueous sodium hydroxide. Extraction with methylene chloride . and concentration gave an orange oil which was dissolved in a mixture of 30 ml of methylene chloride and 30 ml of re'thanol-- To this solution was added 2.3 ml of 30 per cent by weight [ 'hydrogen peroxide.' After stirring at 25° for 18 hours, a precipitate was collected which after recrystallization from melting at 194-196° dec. Ultraviolet inflexions (2-propanol) at 225 W (£= 15,500) and 290 πιμ (£=2250), maxima at 269 τημ (£=4100) and 276 πιμ ( =4250); infrared absorption (KBr) l660 ' -1 cm Anal. Calcd. for C, 76.78 H, 5-64; N, 11.19 Found : C, .76.42; H, 5.79; N, 11.13.

The 2- (2-benzoylphenyl) -2-imidazoline prepared in this manner can form the isomeric 2,J-dihydror5-hydroxy-5-phenyl- 5H-imidazo- [2,1-a] isoindole.

The hydrochloride was prepared by adding a solution of hydrogen chloride in methanol to a suspension of 2- (2-benzoylphenyl) -2-imidazoline in methanol. Ether was added and the ■crystalline precipitate was collected. Recrystallization from a mixture of methanol and ether gave white prisms melting at 173-176° dec. Ultraviolet maximum (2-propanol) at 252 πιμ (£.= 13,600); infrared absorption (KBr) at 1665 cm 1- Anal. Calcd. for CI,.12.36 Found : CI, 12.22.

The hydrobromide was prepared by adding an aqueous so- ■ lution of hydrobromic acid to a suspension of 2-(2-benzoylphe-. nyl) -2-imidazoline in ethanol. Addition of ether gave a precipitate which after recrystallization from a mixture of ethanol and ether gave white- platelets melting at 193-194° dec.

Anal." Calcd. ~ for C^H^-^O-HBr: Br, 2 . 13 Found :' Br, 2 .15 Example 16 A solution of 5 g of 2- (2-behzoyl henyl) ^-imidazoline.' ydro- chlprjd_in 5Q.ml of methanolwas refluxed for 18 hours. The solution was concentrated in vacuo, dissolved in 20 ml of methanol and • 60 ml of ether was added. Crystals precipitated and were identified as starting material. The mother liquor was concentrated and the residue was recrystallized from a mixture [ of methanol, methylene chloride and ether to give 2,3-dihydro-'5-methoxy-5-phenyl-5H-imidazo[2,l-a] -isoindole hydrochloride as white orisms melting at 139-1 1° dec. Ultraviolet maxima (2-propanol) at 2 4 πιμ (¾-=ΐ4, 4θθ) and 278 πιμ (¾ =5100) ; infrared absorption ( Br) at 1β70 cm Anal. Calcd. for C 7H fiN-O-HCl: 0, 67. 83 H, 5- 70; 11 0 OCH^, 10.32 ! Pound : C,' 67.84; H, 5- 6l; i 0CH,, 10.44 ' . 3 The corresponding base was obtained as a colorless oil by liberating it from the hydrochloride obtained as above with !alkali. Ultraviolet inflexions (0.1N KOH) at 230 πιμ (S= 14, 600) , :'290 η\μ ( £ =2700) , maxima at 269 πιμ (s= 4200) and 275 πιμ (έ,= 4600) . . ■ > .

Infrared absorption (smear) at I660 cm and nmr Example 17 A solution containing 100 g. of phthalaldehydic acid in . 1200 ml. of methanol and 225 nil. of ethylenediamine was - refluxed for 17 hours. The solution was . concentrated in vacuo and the residual oil was dissolved in 1000 ml. of chloroform.

This solution was washed successively with concentrated aqueous ·: ■ solutions of. potassium carbonate and sodium chloride, dried and concentrated. The residual yellow oil was dissolved in ethanol, a solution of 57 g. of maleic acid in ethanol was added and on ' addition of ether a crystalline crop of a maleate s obtained ■,■ which after recrystallization from a mixture of methanol and ether gave white jprisms. This product was . suspended in · i V From, a solution containing 7.4 g. of 1,2 ,3 , 9b-tetrahydro- 5H-imidazo[ J,l"-a]isoindol~5-*one in 550 ml. · of benzene 25 ml. ' of " solvent was remo ed by distillation. After cooling 25 g. of diethylazodiearboxyl&ve was added and the solution was refluxed, for 6 hours. The mixture was chilled and the hydrazoester was removed by filtration.' The orange filtrate was concentrated i vacuo and the residue .was recrystalllzed from a mixture of tetrahydrofuran and petroleum ether to give 2 ,3-dlhydro-5H- . imidazo[2,l-a]isoindol-5-one as white needles having a melting ■· point of 139- l4l°. Ultraviolet maxima (2-propanol) at 215 ny. ( e = 37.000) 218 'κΐμ (e= 36 , 900 ) 252 Βμ (e= 12 ,500) , 303 πιμ (e= 4,300) , inflexions at 2 ½ Βΐμ (e—- 11,500) 0 m" (e 9,500)5 infrared absorptions at 1670 cm" (C=N) and 1725 cm. (C= 0) . · .

Anal.' Calcd. for CioHsN20 : C, 69.75 ; H, 4.63; N, 16.27 Found:; C, 9. H, 4. ½ N, 15. 93 To a solution containing 0. 85 g, of 2,5-dihydro~5H~ imidazo[2,l~a]isoindol"5-one in 15 ml. of benzene cooled to 5" 10° was. added 12 ml. of a 2N solution of phenylllthium in a . mixture of 7 parts of benzene and 3 parts of ether. The mixture was stirred at 20° for 1 hour and poured into ice water..

Extraction with methylene chloride gave a crystalline crop which after recrystallizatloh from a mixture of methanol and methylene chloride gave 2 ,3~dihydro-5-phenyl-5H-imidazo[2,l-a] isoindol~5"ol(or 2~ (2-benzoylphenyl)~2-imidazoline) as white ;· prisms having a melting point of 194-196° (dec.),.

Example 18 A solution containing 22 g. of J-bromobenzotrifluoride . in 50 ml. of ether was added slowly to 2.4 g. of magnesium turnings /stirred in 20 ml. of ether. The mixture was refluxed gently fo 1 hour and cooled in an ice "bath. A solution containing 5. g. ( of 2 ,2-dihydro-5H-imldazo[2 -a isoindol-5-one in 50 ml. of · '' , "benzene was added slowly. The resulting brown solution was '.. kept at 25* for 17 hours and poured into an aqueous solution of: : ammonium chloride. The .organic phase was removed and on ■·"/' ; dilution with ether gave a crystalline material which after ' recrystallization from a mixture of methanol and eth^l acetate gave 2 ,3-dlhydro-5-(a,a,a -trifluoro-m-tolyl)-5H-imldazo[2,l-a] isoindol-5-ol (or 2- [2- (a,a,a -trifluoro-m-toluoyl)phenyl]-2- · · ··.: imidazoline) as tan plates having a melting point of 199-202° i' V multiplet, N-CHg) , 4.2-4.5 (2H, multiplet,' =N-CH2) , S> =7.1-8.0 (9H,. multiplet,. aromatic CH) .

Example 19 · Tablet Formulation Per Tablet 2- (2-benzoylphenyl) -2-imidazoline 10.0 mg ; Lactose 113*5 mg Corn Starch 70.5 m Pregelatinized Corn Starch 8.0 mg Calcium Stearate 3.0 mg Total Weight 205.0 mg ! Procedure: 2(2-Benzoylphenyl) -2-imidazoline was mixed with the lactose, corn starch, and pregelatinized corn starch in a suitable size mixer. The mix was passed through a comminuting machine. The mix was returned to the mixer and moistened with wate to a thick paste. The moist mass was passed through a screen and the moist granules were dried at 40°C. The granules were compressed at a tablet weight of 200 mg, using 1 standard concave punches having a diameter of 8 mm.

Example 20 Suppository Formulation Per 1.3 Gram Suppository 2- (2-benzoylphenyl) -2-imidazoline Hydrogenated. coconut oil Procedure: The hydrogenated coconut oil. and the car-nauba wax were melted in a suitable size glass-lined container (stainless steel may also be used) , mixed well and cooled to'. 5°C. 2- (2-Benzoylphenyl) -2-imidazoline, which had been reduced to a fine powder with no lumps, was added and stirred until completely and uniformly dispersed. The mixture was poured into suppository molds to yield suppositories having an individual weight of l.jj grams. The suppositories were cooled and removed from molds. They .were individually wrapped in wax paper for packaging. (Foil may also be used).

Example 21 Capsule Formulatidn Per Capsule 2- (2-benzoylphenyl) -2-imidazoline 25 mg Lactose 158 mg Corn Starch 57 m Talc ■ 5 mg ' ! 2 \ Total Weight 2#5 mg Procedure: 2- (2-Benzoylphenyl) -2-imidazoline was mixed with the lactose and corn starch in a suitable mixer. The mixture was further blended by passing through a comminuting j machine. The blended powder was returned to the mixer, the talc added and blended thoroughly. The mixture was then filled into hard shell gelatin capsules on a capsulating machine.

Example 22 Parenteral Formulation Per ml 2- (2-benzoylphenyl) -2-imidazoline 2.5 mg Tartaric Acid q.s. ad pH J>.0 Phenol Anhydrous 4.5 mg Water for Injection q.s. ad 1.0 ml Procedure: 2- (2-Benzoylphenyl) -2-imidazoline was slurried ! · in part of the water for injection. 2r (2-Benzoylphenyl)-2- •10 imidazoline was solubilized by slowly adding the tartaric acid to a pH of approximately 3·0. The phenol anhydrous was • then added, and the solution was filtered and allowed to stand . for 2 hours. It was then filtered through a porous candle. The solution was filled into desired size ampuls and sealed under ,151 · an atmosphere of nitrogen. All ampuls were inspected; those ' ·.. ! containing excessive amounts of fibers were rejected.: In another formulation procedure, the drug was prepared in duplex, ampuls, one containing the dry drug and the other containin the special diluent: •20 '' · Dry Fill Ampul 5 ml 2- (2-benzoylphenyl) -2-imidazoline- ■ 25 mg , A parenteral grade of the drug, fiber-free, was filled into the ampul. The ampuls were sealed and sterilized at •125°C for 2 hours.

Immediately before use the powder was solubilized with the following solution: · , ' ' _ ; Special Diluent 2 ml per ml . Tartaric acid 16 mg .

Water for Injection q.s. to 1.0 ml In a suitable container under an atmosphere of nitrogen the tartaric acid was dissolved in part of the water for injection. The solution was made to volume, filtered through a porous candle filter and filled into 2 ml flint ampuls. The filling should be done under an atmosphere of nitrogen. The ampuls were sealed and sterilized at 100°C for 30 minutes. The ampuls were then inspected and "those that leaked or contained fibers were discarded. . ,

Claims (1)

1. Having how particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is: · 1. Process for the manufacture of-&&Q fa<?-G mpG^ of the general formula wherein B represents an alkylene chain of .2 to 4 carbon atoms in which one or more- of the hydro-j gens can be replaced by lower alkyl; R^, R≥, j ' and R^ each independently represents hydrogen, halogen, i lower alkyl, lower alkoxy, hydroxy or trifluoro- ' methyl; and Rg represents hydrogen, hydroxy or lower alkoxy, of tautomers of those compounds wherein Rg represents hydroxy, 29651/2 and having the formula and of acid addition salts of all the preceding compounds which comprises treating a compound of the formula - 55a - Y wherein R. , R_, R_ and R,, are as defined hereinabove, 1 5 4 with a diamine of the formula H≥N-B-NH2 XII wherein B is as defined hereinabove, or cyclizing a compound of the formula ; wherein B, R R , R-, and Hk are as defined t hereinabove by treatment with a Lewis acid, or treating a compound of the formula or a dehydroderivative thereof having the general formula wherein B, R-^ and are as defined hereinabove with a phenylorganometallic derivative of the. formula wherein R^' and R^' represent hydrogen, halogen, lower alkyl, lower alkoxy or trifluormethyl and Z is Li,. I gBr, Mg-ypr MgCl or treating a compound of the formula ; wherein B, R^, g, R^ and R^ are as defined herein-; above, 'with an oxidizing agentj if desired, oxidizing a r sulting -compound of formula' I, wherein Rg represents hydrogen, to ·' a corresponding hydroxy-substituted compound, if desired, lower alkylating a resulting compound of formula I, wherein , Rg represents hydroxy, to a corresponding lower alkoxy-substi : tuted compound, if desired, separating a racemic mixture ' obtained into its optically active antipodes and, if desired, converting a resulting base into an acid addition salt. · - 2. Process as claimed in Claim 1 wherein a compound of the formula ■ " wherein'R^, R^, ,R^' and. ^ each independently represents •hydrogen, halogen, lower alkyl,' lower alkoxy, hydroxy- . or trifluormethyl- ■ . . .. is reacted with a diamine of the formula H2N-B-NH2 XII wherein B represents an alkylene chain of 2 to 4 , carbon atoms in which one or more of the hydrogens i j can be replaced by lower alkyl; ; or a compound of the formula - wherein B, R^, R^, ^ and R^ are as defined hereinabove is cyclized by treatment with a Lewis acid;, or a compound. of the formula ■-.·■- . -· wherein- B, R^, Rg andR^' are as defined herein- above, .is treated with an oxidizing agent; if desired, oxidizing a resulting compound o . formula I, wherein Rg represents hydrogen, to a corresponding hydroxy-substituted compound, if desired, lower alkylating a resulting compound of formula Ί, where'in Rg represents hydroxy,' to a corresponding lower alkoxy-substi-" .tuted compound, if desired, converting a resulting base into an acid addition salt; : j5. A process as claimed in Claim 1 wherein a compound :of the general formula ; wherein B represents an alkylene chain of 2 to 4 carbon ' atoms in which one or more of the hydrogen atoms can be replaced by lower alkyl and ^ and .^ each independently represents hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy o ' trifluoromethyl treated with a phenylorganometallic derivative .of the formula ■-.·—· wherein R.-.' ■ and R^ ' each independently represents . . hydrogen, halogen, lower alkyl,' lower alkoxy or tri- fluoromethyl and-Z is Li, MgBr, Mg^ or gCl '■and if' desired^ separating a racemic mixture obtained' into its optically active . antipodes and if desired, converting a :product obtained into its acid addition salt. ; i ■ . ' ■4. Process according to claim 1 or 2, wherein the compound I of the formula VI is treated with titanium tetrachloride or 'boron trifluoride. t ■ ■ i 5· Process according to Claim- 1 or 2, wherein the com- · i pound of the formula XIII is treated with chromium, trioxide or gaseous oxygen. : 6. Process according to Claim 1 or 2, wherein the oxi- •dation of the compound of formula I, wherein. Rg represents hydrogen, to the corresponding hydroxy-substituted compound . ■includes the treatment of the intermediately formed, corresponding hydroperoxy-substituted compound with a reducing ■agent. 7· Process according to any one of Claims 1, 2' and 6, wherein the oxidation of a compound of formula I, wherein Rg represents hydrogen. is effected with hydrogen peroxide or gaseous oxygen. .8. Process according to Claim 6, wherein the reducing agent is sodium sulfite or triethyl phosphite. ;'. 9· Process according to Claim 1 or 2, wherein "the lower alkylation of the compound of formula I, wherein Rg represents 'hydroxy, is. effected wi'th the acid of a lower alkanol. 10. Process according to any one of Claims 1-9, wherein 'a compound of formula I is produced wherein RQ is hydroxy. 11. Process according to any one of Claims 1-10, wherein ( g and' R^ and R^, respectively are each hydrogen. 12.' Process according to any one of Claims 1-11 wherein :B represents the ethylene group. 13. Process according to any one of Claims 1-12 wherein j is hydrogen or chlorine and R^ and R^V respectively is hydrogen, chlorine; bromine or methoxy. 14. Process according to any one of Claims 1, 2, 4, 6 to 13 wherein o-benzoylbenzaldehyde is treated with ethylene- , diamine or 2- (2-aminoalkyl) -3-phenylphthalimidine is cyclized by treatment with a Lewis acid and the resulting compound is oxidized and if desired, converted into an acid addition salt. 15. Process according to anyone of Claims 1,3, , 6-13 wherein' " azo 1* 2,3,9b-tetrahydro-5H-imid&a«- [2,1-a] isoindol-5-one is treated with an unsubstituted phenylorganome allic derivative, the resulting compound is oxidized and, if desired, converted into an acid addition salt. .16..Process according to any one "of Claims 1·, 2, 5 and 9-13* wherein' 2- (2-aminoethyl ) -1-phenylisoindoline is treated with an oxidizing agent and, if desired, the resulting compound is converted into an acid addition salt. 1'7. Process according to any one of Claims 1, 2, 4, 6 to 13, wherein 2:- (p-chlorobenzoyl) -benzaldehyde is treated with ethylenediamine or 2- (2-aminoethyl) -3- (p-chlorophenyl) -phthalimidine is cyclized by treatment with a Lewis acid and the resulting compound is oxidized and if desired, converted into an acid addition salt. 18. Process according to any one of Claims 1, * ^ and ; 6-13 wherein l,2,3*9b-tetrahydro-5H-imidazo [2,1-a] isoindol-5-one is treated with a p-chloro-substituted phenyl-organo-metallic derivative, and the resulting compound is oxidized and, if desired, converted into an acid addition salt. 19. Process according, to any one of Claims 1 and 10-13 wherein 2,3-dihydro-5-phenyl-5H-imidazo [2, 1-a] isoindol-5-one is treated with an unsubstituted phenylorganometallic derivative and? if desired the resulting compound is converted into an acid addition salt. 20. Process according to' any one of Claims 1, 2, 5 and 9-13* wherein 2- (2-aminoethyl )-l- (p-chlorophenyl) isoindoline is treated with an oxidizing agent and, if desired, the resultin compound is converted into an acid addition salt. 21. Process according' to any one of Claims 1 , 2, 4, 6 to 1.3 j wherein 2- (p-anisoyl) -benzaldehyde is treated with ethylene diamine or 2- (2-aminoethyl) -3- (p-methoxyphenyl)phthalimidine is cyclized by treatment with a Lewis acid and the resulting compound is oxidized and^if desired^ converted into an .acid .addition salt. ! 22. A process according to any one of Claims 1 , 3* and. ι β-13, wherein 1 , 2, 3, 9b-tetrahydro-5H-imidazo [ 2, 1-a] isoindol-j ' : 5-one is treated with a p-methoxy- substituted phenyl'organo-:metallic derivative, the resulting compound is oxidized and, ■if desired, converted into an acid addition salt. 23· Process according to any. one of Claims 1 , 2, 5 ' and 9-13 wherein 2- (2-aminoethyl) -l-(p-methoxyphenyl)isoindoline is :treated with an oxidizing agent and, if desired, the resulting !compound is converted into an acid addition salt. 24. 'Process according to any one of Claims 14 to 17 , ■ therein the resulting product is methylated, and if desired, the resulting compound is oonverted into an acid addition salt. compounds of . the formula given in Claim 1 -©©fipewift4B- 25. Process for the preparation of/ ai ema^l^t ompetff-^^ |as hereinbefore particularly described, especially with 'reference to the foregoing Examples. 2β . Process for the manufacture of preparations having psychostimulant, analgesic, anti-inflammatory, anti-edema, anti- n · cardiovascular ,/ ., pyretic, muscle relaxant, . anorexigemc, /¾ype»¾eft€4V« and/or anti wherein B represents an alkylene chain of 2 to carbon atoms in which one or more of the hydro- . · gens can be replaced by lower alkyl; R, , R , R_ 1 and' R^_ each independently represents hydrogen, halogen, lower alkyl', lower alkoxy, hydroxy or trifluoro- methyl; and Rg represents hydrogen, hydroxy or lower alkoxy? a tautomer of a compound of formula I, wherein RA represents and having the formula II in Claim 1 0 hydroxy or a pharmaceutically acceptable acid addition salt 'of any of the preceding compounds is mixed, as. active substance, with nontoxic, inert, therapeutically compatible solid or liquid carriers, commonly used in such preparations, and/or excipients. '. 27.. Compositions having psychostimulant, analgesic, anti-inflammatory, anti-edema, antipyretic,muscle 'relaxant, cardiovascular anore igenic irypepfceHeive and/or antifungal properties, containing an aromatic compound of the general formula . " I wherein B represents an alkylene chain of .2 to 4 ι Icarbon atoms in which one or more of the hydrogens- can be replaced by lower alkyl; R^, R≥, R^ and ^ each independently represents hydrogen, halogen 'lower alkyl, lower alkoxy> hydroxy or trifluoro- ί 'methyl; and Rg represents hydrogen, hydroxy or ''lower alkoxy"; _ ... a tautomer of a- compound of formula I, wherein Rfl represents and having the formula II in Claim 1 ° hydroxy or a pharmaceutically acceptable acid addition salt of any. of the preceding compound, in admixture with a pharmaceutically acceptable carrier. Aromatic compounds of the general formul ■wherein B represents an alkylene chain o .2 to ■ carbon atoms in which one or more- of the hydrogens can be replaced by lower alkyl;. R^, R2> R-^ : nd R^ each independently represents hydrogen, halogen, Ilower alkyl, lower alkoxy, hydroxy or trifluoro- ' !methyl; and RQ represents hydrogen, hydroxy or i . ! lower alkoxy; tautomers , of those compounds wherein RQ represents hydroxy, ; and having the formula II in Claim 1 /and- acid addition salts of all the preceding compounds, . whenever prepared according to the process claimed in any ' ' one of Claims 1.·" 9 -and 25 or by an obvious chemical equivalent thereof. 29· Aromatic compounds according to the formula in Claim 28 and acid addition salts thereof, whenever prepared according to the process of any one of Claims 2, 4-9 and 25 or by an obvious chemical equivalent thereof. ,25 or by an obvious chemical equivalent thereof. " ' 31. Aromatic compounds according to Claim:"28 having the formula wherein R^, R^, R^, R^_ and B each have the same. meaning as in Claim 28, 'whenever prepared according to the process claimed in Claim ;10 or by an obvious chemical equivalent thereof. 32. Aromatic compounds according to the formula in Claim 28 wherein R^ and R^ are each hydrogen, whenever prepared according to the process claimed in Claim 11 or by an obvious chemical equivalent thereof. 33. Aromatic compounds according to the formula in Claim 28 wherei B represents the ethylene group, whenever prepared According to the process claimed in Claim 12 or by an obvious chemical equivalent thereof. 3 . Aromatic compounds according to the formula in Claim 28 bromine or me hoxy, 'whenever prepared according to the process claimed in Claim 13 or by an obvious chemical equivalent thereof. 35. 2, -Dihydro-5-hydroxy-5-phenyl-5H-imidazo [2, 1-a] iso-indole and acid addition salts thereof whenever prepared according to the process claimed in an one of Claims 14 and 16 or by an obvious chemical equivalent there_f. 36. 2,3-Dihydro-5-hydroxy-5-phenyl-5H-imida¾o[2,l-a] isoindole and the tautomer thereof, i.e. 2-(2-benzoylphenyl)-2- ■ imidazoline, and acid addition salts of any of said compounds,, whenever prepared according to the process claimed in Claim 15 or by an obvious chemical equivalent thereof. o 37· 2,3-Dihydro-5-hydroxy-5- (; -chlor^henyl) -5H-imidazo ' [ 2, 1-a] isoindole and acid addition salts thereof, whenever prepared according to the process claimed in any one of Claims 17 and 20 or by an obvious chemical equivalent thereof. 38. 2,3-Dihydro-5-hydroxy-5- ( -chlorophenyl) -5H-imidazo [2, 1-a] isoindole and the tautomer thereof, i.e. 2-[2-( -chlorobenzoyl) phenyl] -2-imidazoline and acid addition salts of any of said compounds,' whenever prepared according to the process claimed in Claim l8 or by an obvious chemical equivalent thereof. 39. '2,3-Dihydro-5-hydroxy-5-phenyl-5H-imidazo [2, 1-a] isol nd .the t ut m r thereof and acid addition salts of an of claimed in Claim 19 or by an obvious chemical equivalent thereof. 40. 2 , 3-Eihydro-5-hydroxy-5-(4-methox )-5H-imidazo[ 2 ,1-a] isoindole and acid addition salts thereof, whenever prepared according to the process claimed in any one of Claims 21 and 23 or by an obvious chemical equivalent thereof. 41. 2 , 3-Dihydro-5-methoxy-5-phenyl-5H-imidaao[ 2 ,1-a] isoindole and acid addition salts thereof, whenever prepared according to the process claimed in Claim 24 or by an obvious chemical equivalent thereof. 42. Tautomers of compounds as defined in Claims 30-35, 37 and 40 and having the formula I in Claim 1 whenever prepared according to the process claimed in any one of Claims 10 to 14, 16, 17, 19, 20, 21 and 23 or by an obvious chemical equivalent thereof. 43. Diazocycloalkenyl-isoindole compounds of the general formula I in Claim 1 and their acid addition salts. 44. Compounds according to Claim 43 having the formula wherein R^, R2, R^, R^ and B each have the same meaning as in Claim 3 and their acid addition salts. 45· Compounds of the formula II in Claim 1 being tautomers of the compounds of formula I-e in Claim 44, and their acid addition salts,. 46. Compounds according to any one of Claims 43 to 45 wherein and R^ are each hydrogen. 47* Compounds according to amy one of Claims 43 - 46 wherein B represents the ethylene group. 48. Compounds according to any one of Claims 43 - 47, wherein is hydrogen or chlorine and R^ is hydrogen, chlorine, bromine or methoxy. 49. 2,3-Pihydro-5-hydroxy-5-phenyl-5H-imidaaoL2,l-a] isoindole and acid addition salts thereof. 50. 2,3-Pihydro-5-hydroxy-5-(4-chlo70phenyl)-5H-imidazo [ 2,1-a]isoindole and acid addition salts thereof. 51. 2 ,3-Dlhydro-5-hydroxy-5-( -methoxyphenyl)-5H-imidazo[2,1-a]isoindole and acid addition salts thereof. 52. 2 , 3-Dihydro-5-methoxy-5-phenyl-5H-imidazo[2 ,1-a] Isoindole and acid addition salts thereof. 53. Tautomers according to Claim 5 of the compounds according to any one of Claims 44 and 46 - 51 and acid addition salts thereof. For the Applicants AM) BARTM-iiS