Patent GB-767163-A (GB)
Title: New 5:6-dihydro-benzo(c)cinnoline derivatives and a process for their preparation
IPC: C07D487/04
Filed: 1955-01-13
Abstract: The invention comprises compounds of the formula:-<FORM:0767163/IV(b)/1> wherein R is hydrogen, a hydrocarbon group or an organic radical containing at least one ether grouping -C-O-C, including cyclic ether groupings, and wherein R contains at most 10 carbon atoms, and salts thereof with bases; and their preparation by condensing, preferably in an inert atmosphere, 5 : 6-dihydrobenzo(c)cinnoline, unsubstituted or substituted in the 5 and/or 6 positions by alkali metal atoms or acyl groups, with a compound X.CO.CHR.CO.Y wherein X and Y are hydroxyl, alkoxyl or halogen, the condensation being effected in one or two stages depending on the relative reactivities of X and Y.  When the above-mentioned 5 and 6 substituents are absent or are acyl groups and X and Y are alkoxy groups the condensation may be effected at elevated temperatures in the presence of an alkaline condensing agent such as sodium ethoxide, sodium amide or phenyllithium, but when X and Y are both hydroxy groups an acid condensing agent such as PCl3 or SOCl2 is preferably used.  In the modification where free 5 : 6-dihydrobenzo(c)cinnoline, the alkali metal derivative thereof, or the salt thereof is condensed with a malonyl halide, an acid binding agent such as pyridine or diethylaniline is used.  The group R may be introduced after these condensations by, for example, alkylation with an alkyl halide in the presence of a hydrogen halide binding agent such as sodium ethoxide, or with a sulphonic or sulphuric acid ester, or by condensation with an aldehyde or ketone with hydrogenation of the resulting alkylidene derivative, or by reductive alkylation in the presence of a hydrogenation catalyst and a condensing agent such as piperidine acetate or ammonium acetate.  Bases which form salts with the compounds of the invention include potassium, lithium, barium, trimethylammonium and triethylammonium hydroxides and a ,o -bis (trimethylammonium)-hexane dihydroxide.  Examples describe the preparation, by one or more of the above methods, of compounds of the invention in which R is hydrogen, n-butyl, methyl, isopropyl, sec.-butyl, benzyl, n-hexyl, tert.-butyl, 3-methoxybutyl, 4-ethoxybutyl, b -ethoxyethyl, tetrahydrofurfuryl, ethyl, n-propyl, furfuryl, tetrahydropyran-2-methyl, n-butoxyethyl, b -phenoxyethyl, cyclopentyl, cyclohexyl and allyl, the catalytic hydrogenation of the last-mentioned compound to the n-propyl derivative also being described.  Starting materials and intermediates.  N-acyl-and N : N1 - diacyl - 5 : 6 - dihydrobenzo(c)cinnolines are prepared by treating 5 : 6-dihydrobenzo(c)cinnolines with acylating agents or by hydrogenating acylation of benzo(c)cinnoline. Benzo(c)cinnoline is prepared by the catalytic reduction of 2 : 21-dinitrodiphenyl with air oxidation of the 5 : 6-dihydro-benzo(c)cinnoline first formed, the latter compound being formed again on hydrogenation.  Diethyl 3-methoxybutylmalonate is prepared by reaction of diethyl-malonate with 3-methoxybutyl benzene sulphonate, itself prepared from 3-methoxybutanol and benzene sulphonyl chloride. Diethyl tetrahydropyran-2-methylmalonate is prepared from diethyl malonate and tetrahydropyran-2-methyl benzenesulphonate, itself prepared from tetrahydropyran-2-methanol and benzenesulphonyl chloride.  N : N1 - (cyclopentylidenemalonyl)- and N : N1 - (cyclohexylidenemalonyl) - 5 : 6 - dihydrobenzo(c)cinnolines are prepared from N : N1-malonyl - 5 : 6 - dihydrobenzo(c)cinnoline and, respectively, cyclopentanone and cyclohexanone.ALSO:A pharmaceutical preparation, suitable for combating inflammatory affections, comprises a compound of the formula <F\1> where in R is hydrogen, a hydrocarbon group or an organic radical containing at least one ether grouping-, C - O - C -, including cyclic ether groupings and wherein R contains at most 10 carbon atoms, or a salt thereof with organic or inorganic base, together with an inert pharmaceutical carrier such as water, gelatin, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, polyalkylene glcols, petroleum jelly and cholesterol. The preparations may be made up as tablets, dragees, solutions, suspenions or emulsions and may contain preservatives, stabilizing, wetting or emulsifying agents, salts which modify the osmotic pressure, or buffer substances.  They may also contain other therapeutically valuable substances such as 2:3 - dimethyl - 1 - phenyl-5-pyrazolone, procaine, p  o -diethylamino- 2:6-aceto-xylidide, saliclamide, ascorbic acid, the calcium complex salt of the disodium salt of ethylene diamine tetraacetic acid, p-(di-n-propyl-sulphamyl) - benzoic acid or methionine-methylsulphonicum iodide.  It is also stated that water soluble salts of the compounds of the above general formula may be used to prepare concentrated aqueous solutions of sparingly water-soluble pharmaceuticals such as amido pyrine.