CH481124A - Process for the preparation of new, condensed heterocyclic compounds - Google Patents

Description

  

  



  Process for the preparation of new, condensed heterocyclic compounds
The present invention relates to a process for the preparation of new, condensed heterocyclic compounds.



   Compounds of general formula I,
EMI1.1
 in which R1 and R2 are hydrogen atoms, lower alkyl or alkoxy groups or halogen atoms, R5 is a hydrogen atom or a lower alkyl group, R4 and R5 are each lower alkyl, hydroxyalkyl or benzyl groups, one of which can be substituted in the phenyl nucleus by a total of at most two of the following groups, lower alkyl and / or alkoxy,
Hydroxy, halogen or methylenedioxy groups, or R4 and R5 together with the attached nitrogen atom denote the piperidino, 1-pyrrolidinyl, morpholino or 4-methyl-1-piperazinyl radical and n 1, 2 or 3 are up to now not known.

   As has now been found, these new compounds have valuable pharmacological properties, in particular anti-inflammatory, analgesic, hypotensive, spasmolytic, sedative and antitussive activity. They can be administered orally, rectally or in the form of aqueous solutions also parenterally, e.g. for the treatment of rheumatic and other inflammatory diseases, for the relief and elimination of pain, coughing or excitement of various origins.



   In the compounds of general formula I and the associated intermediates, R1 and R. are represented as lower alkyl or alkoxy groups, e.g. the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert. Butyl group or the methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or sec.



  Butoxy group, and as a halogen atom, e.g. a chlorine, bromine or fluorine atom. A lower alkyl group R3 is, for example, the methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group. R4 and R5 are independently of one another e.g. by methyl, ethyl, n -propyl, isopropyl, n-butyl, isobutyl, 2-hydroxy ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy -1-methylethyl, 2- Hydroxybutyl, 3-hydroxybutyl, 4-Hy droxybutyl, 2-hydroxy 1 -methylpropyl, 3-hydroxy 1- methylpropyl, benzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl , m-chlorobenzyl, p-chlorobenzyl, m-methylbenzyl, p-propylbenzyl, p-methoxybenzyl, p-ethoxybenzyl, 3,4-dimethoxybenzyl, 3,4-methylenedioxy-benzyl,

     embodied m-hydroxybenzyl or 3-methoxy-4-hydroxybenzyl groups.



   To prepare the compounds of the general formula I, a reactive ester of a compound of the general formula II is used,
EMI1.2
 in which Rl, R ... R5 and n have the meaning given under formula I, in particular a halide, an arenesulfonic acid or methanesulfonic acid ester, with a compound of the general formula III,
EMI2.1
 in which RX and R, independently of one another, as well as together with the attached nitrogen atom, have the meaning given under formula I, in the presence of an acid-binding agent, and converts the compound obtained into the N-oxide.

   The reactions are carried out, for example, at room temperature or at elevated temperatures of up to about 1200 in suitable solvents or diluents. such as excess amine, water, alkanols, dialkyl ethers, dioxane, tetrahydrofuran, benzene or toluene. carried out. An excess of amine of the general formula III is preferably used as the acid-binding agent; a tertiary organic base, such as triethylamine, dimethylaniline or pyridine, can also be used.



   The heterocyclic starting materials, i.e. the reactive esters of compounds of the general formula II. are in turn e.g. by converting compounds of the general formula IV,
EMI2.2
 in which R1, R. and n have the meaning given under formula I, with halides, in particular chlorides or bromides, or with anhydrides of lower α-halogen, α-arenesulfonyl or α-methanesulfonyloxyalkanoic acids in the presence or absence of suitable solution or diluents, such as Chlorobenzene or dimethylformamide, in the warm, e.g. can be prepared at the boiling point of the reaction mixture.

   The compounds of the general formula IV arise e.g. when heating o-benzoylbenzoic acids of the general formula V,
EMI2.3
 with alkanediamines of the general formula VI, - CHs - (CH2) - NH. (VI) where Rl, R and n have the meaning given under formula I, preferably at temperatures of 1201800. In the presence or absence of organic solvents, such as e.g. Chlorobenzene, o-dichlorobenzene, toluene, xylene, amyl alcohol.



   To prepare N-oxides, the reaction products obtained by reacting compounds of general formula II with compounds of general formula III can be treated with an oxygen-releasing agent, for example aqueous hydrogen peroxide. The oxidation is preferably carried out in a water-miscible solvent which is sufficiently stable to the oxidizing agent under the reaction conditions, e.g. Ethanol.



   For use as drugs, non-toxic acid addition salts can be used in place of free bases, i. E. Salts with acids whose anions are pharmaceutically acceptable at the dosages in question. It is also advantageous if the salts to be used as medicinal substances are readily crystallizable and have little or no hygroscopic properties. For salt formation with compounds of the general formula I, e.g. the hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanol sulfonic acid, .B -hydroxyethanesulfonic 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.



   Also suitable for use as drugs are quaternary salts e.g. the methohalides and methosulphates, ethohalides and sulphates, the propohalides and the butohalides, and the N-oxides of the compounds of the general formula I.



     As mentioned above, the new active ingredients are administered orally, rectally and parenterally. The daily doses range between 10 and 1000 mg for adult patients. Suitable dosage unit forms, such as dragees, tablets, suppositories or ampoules, preferably contain 10-200 mg of an active ingredient according to the invention. Furthermore, the use of corresponding amounts of non-single-dose application forms, such as syrups, is also possible.



   Unit dosage forms for oral use contain as active ingredient preferably between 1-9007o a compound of the general formula I.



   To produce them, the active ingredient is combined e.g. with solid powdery carriers. such as lactose, sucrose, sorbitol, mannitol; Starches such as potato starch, corn starch or amylopectin. furthermore laminaria powder or citrus pulp powder; Cellulose derivatives or gelatin, optionally with the addition of lubricants. such as magnesium or calcium stearate or polyethylene glycols (carbowaxene) of suitable molecular weights to form tablets or dragee cores. The latter is coated, for example, with concentrated sugar solutions, which e.g. Arab gum, talc and / or titanium dioxide, or with a paint dissolved in volatile organic solvents or solvent mixtures.

   Dyes can be added to these coatings, e.g. for labeling different doses of active ingredients.



   Unit forms for rectal use are e.g. Suppositories which consist of a combination of an active ingredient or a suitable salt thereof with a neutral fat base. or also gelatine rectal capsules which contain a combination of the active ingredient or a suitable salt thereof with polyethylene glycols (carbowaxene) of suitable molecular weight.



   Ampoules for parenteral, especially intramuscular administration preferably contain a water-soluble salt of an active ingredient in a concentration of preferably 0.5-50%, optionally together with suitable stabilizing agents and buffer substances, in aqueous solution.



   The following instructions are intended to explain the manufacture of tablets and coated tablets in more detail: a) 1000 g 1- (N, - (N, N-diethylglycyl) -9b-phenyl- 1, 2,3,9b- -hexahydro-SH-imidazof2, 1 -a] isoindol-5-one-N-oxide 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 talc, 5.00 g of magnesium stearate and 64 g of colloidal silicon dioxide are mixed and the mixture is pressed into 10,000 tablets, each weighing 250 mg and 100 mg active ingredient content, if desired with partial notches for a finer adjustment of the Dosage can be provided. b) From 250 g of 1- (N, N-diethylglycyl) -l, 2,3,9b-tetrahydro - 5 H - imidazol [2, 1-a] isoindol-5-one-N-oxide, 175, 90 g
Lactos and the alcoholic solution of 10 g of stearic acid are made into granules which, after drying, are mixed with 56.60 g of colloidal silicon dioxide, 165 g of talc, 20 g of potato starch and 2.50 g of magnesium stearate and pressed to form 10,000 coated tablets . These are then crystallized with a concentrated syrup of 502.28 g.

   Sucrose, 6 g shellac, 10 g gum arabic, 0.22 g dye and 1.5 g titanium dioxide coated and dried. The coated tablets each weigh
120 mg and each contain 25 mg of active ingredient.



   The following example explains the preparation of the new compounds of the general formula I and of intermediates not previously described, but is not intended to restrict the scope of the invention in any way. The temperatures are given in degrees Celsius.



   Example 32.7 g of 1-chloroacetyl-9b-phenyl-1,2,3,9b-tetrahydro -SH-imidazo [2,1 -a] isoindoi-5-one are treated with 22 g of diethylamine 100% in 50 ml of dioxane for one hour boiled under reflux. Dac diethylammonium chloride partially crystallizes out. Steam is now passed through. until the excess amine and dioxane are removed while the crude product remains as a resin. After cooling, sodium hydroxide solution is added until a phenolphthalein-alkaline reaction is achieved, and the reaction product is dissolved in 100 ml of ether with shaking.



   The ethereal solution is extracted at about 300 with 30 ml of 2N hydrobromic acid. and washed the acidic solution with 30 ml of fresh ether. On cooling to approx. 50, the 1 - (N, N-diethylglycyl) -9b-phenyl- - 1,2,3,9b-tetrahydro-SH-imidazol2,1 .a] isoindol.5-one hydrobromide crystallizes out. It is dissolved in 100 ml of anhydrous Etha nol and precipitated again by adding ether. Pure hydrobromide with a melting point of 2252290 (with decomposition) is obtained in this way. The free base is obtained from the aqueous solution of the hydrobromide by adding sodium hydroxide solution, shaking out with ether and evaporating the ether from the dried extract.



   36.3 g of 1 - (N, N-diethylglycyl) -9b-phenyl-1,2,3,9b-tetra-hydro-SH-imidazo [2, 1-a] isoindol-5-one are in 250 ml of ethanol dissolved and mixed with 12 ml of a 28% own aqueous solution of hydrogen peroxide. The mixture is refluxed for 2 hours. Upon careful concentration, the N-oxide crystallizes out.



   The 1-chloroacetyl compound required in the above example is e.g. manufactured as follows:
22.6 g of o-benzoylbenzoic acid are introduced into 7.2 g of ethylenediamine and the mixture gradually increases
1400 heated, the excess ethylenediamine and the water released during the reaction distilling off.



  After stirring for two hours at 1400, the melt is allowed to cool and crystallized by adding a little benzene. After recrystallization from benzene, pure 9b-phenyl-1,2,3,9b-tetrahydro.5H.imidazo [2,1-a] isoindol-5-one with a melting point of 150 1510 is obtained.



   25 g of the aforementioned product are refluxed for 30 minutes with 34.2 g of chloroacetic anhydride in 100 ml of chlorobenzene. After evaporation in vacuo, the residue is recrystallized from ethyl acetate, the 1-chloroacetyl-9b-phenyl-1, 2,3,9b-tetrahydro-SH-imidazo [2,1-a] isoindol-5-one of mp 156-1580 received.

 

Claims (1)

PATENT CLAIM Process for the preparation of new, condensed heterocyclic compounds of the general formula I. EMI3.1 in which R1 and R each are hydrogen atoms, lower alkyl or alkoxy groups or halogen atoms, R5 is a hydrogen atom or a lower alkyl group, Rg and R5 are each lower alkyl or hydroxyalkyl. or benzyl groups, one of which can be substituted in the phenyl nucleus, by a total of at most two of the following groups, lower alkyl and / or alkoxy, Hydroxy, halogen or the methylenedioxy groups, or R, and R5 together with the adjacent nitrogen atom the piperidino. 1-pyrrolidinyl, morpholino or 4-methyl-1-piperazinyl radical and n is 1, 2 or 3, characterized in that a reactive ester of a compound of the general formula II, EMI4.1 in which Rt, R5, R5 and n have the meaning given under formula I, with a compound of the general formula III, EMI4.2 in which R4 and R5, independently of one another or together with the attached nitrogen atom, have the meaning given under formula I, are reacted in the presence of an acid-binding agent and the compound obtained is converted into the N-oxide.