Method of preparation of new dialkylaminoalkyl ethers of the 2-alcoxy-3,5-dihalogenobenzene.
AS AFRICAN AND MALAGASY INDUSTRIAL PROPERTY PATENT P. 887 in Yaounde (Cameroon) International Patent Classification: 61 - c 07 no. 03885 has THE O. The V * corporaton scientific and industrial research residing in France. DELIVERED THE Publishes at n° of official ballot Priority: patent applications filed in France under the P-V-n° 140,294 16 February 1968 and V-P-n° 151,632 10 May 1968 on behalf of the applicant. A process for preparing novel poylesters ether of 2 alkoxy-3.5-to-dihalogenobenzene. The present invention relates to the preparation of novel poylesters ethers of 2 alkoxy-3.5-to-dihalogenobenzene, their addition salts with an inorganic or organic acid, quaternary ammonium salts thereof and the method of preparing these compounds which possess valuable pharmacological properties " in particular as spasmogens. The general formula of these compounds can be written: wherein: - n and ni are integers between 0 and 2 The R -, R-SR2 , The R ^ represent either hydrogen, or a lower alkyl radical of 1 to 5 carbon atoms such as e.g. methyl, ethyl, propyl... the N - / * the I VBE1 R., may represent a radical heterocyclic as: pyrrolidyl, piperidyl, morpholyl, piperazinyl... - X and Y are halogens such as for example: F., for Cl, brr•••• The preparation of the compounds is to acetylate a monoether pyrocatechol and then halogenating the compound obtained, then to the deacetylating and process it by a chloride-d1 the alkylamino-alkyl. The preparation of some of the compounds is described below by way of non-limiting examples. SUCH AS I L-Diethylaminoethoxy-to-2-methoxy-3" 5-dichlorobenzene STEP A : 3.5 above dichlorogafacol In a 250 ml flask equipped with a reflux condenser, is acetyl 62 g (0.5 mole) galacol using acetic anhydride in the presence of several drops of concentrated sulfuric acid. After the reaction is completed, the sulfuric acid is neutralized by sodium acetate and then upon cooling the solution is performed to chlorination of galacol acetate. In a one liter flask provided with a stirrer and thermometer, the previous solution is added 150 ml of acetic acid. Then is poured by small amounts 160 grams of chloro succinimide. The suspension is then heated to 50 and 55 degrees Celsius then held in an incubator at 55 °c for 117 hr. The reaction is complete, cooled and adds 2 liters of water while maintaining agitation. The chlorin crystallizes. It is dewatered, washed and deacetylated using 125 ml of 30% sodium hydroxide solution. The product is distilled and recrystallized in petroleum ether. 66 G of obtained 3.5-to-dichlorogalacol. (F.: 62 and 63°) (RTs: 68%). STEP B : l dléthylaminoéthoxy-to-2-methoxy-3.5-dichlorobenzene 50 g (0.25 mole) 3.5 dichlorogalacol are poured into a solution of sodium ethoxide prepared from 6 g sodium in 78 ml of absolute alcohol. Has the red solution obtained, is added 39 e (θ, 26 + 10 mole Heated gently, the solution becomes cloudy. Sodium chloride precipitates. 7 Hours then heated to reflux. Is cooled, added 300 ml of water and 25 ml of concentrated hydrochloric acid. The aqueous solution is filtered, passed to black and the base is precipitated by 40 ml of aqueous ammonia and extracted with ether. After distillation of the ether is obtained 51 e (rt.72 STEP C : L-diéthylamirdiéthylamir.oethoxy-to-2-methoxy-3.5-to-dlcblorobenzene The base obtained is dissolved in 100 ml of acetone and previously added 6 35 g of dry hydrochloric acid in 20 ml of acetone. The L-diéthylaminoethoxy and 2 a-Methoxy-phenylazo 3.5-dichlorobenzene precipitates, it is dried and washed with acetone and then dried. 51 G of product is obtained. (W: 132 - 134I C.) Calculated SUCH AS II L-dimethylaminopropoxy and 2 a-Methoxy-phenylazo 3.5-dichlorobenzene Patent is similar to that described in the example I-. STEP B : l dimethylaminopropoxy and 2 a-Methoxy-phenylazo 3.5-dichlorobenzene 63 S 3 and 5 a-dichlorogaïacol (0.32 mole) are added to a solution of sodium ethylate obtained from 7.5 g sodium and 100 ml of ethyl alcohol. Added 44 grams (10 + 0,326 mole Obtained 63 grams (rt.70 STEP C : L-dirrdirr.éthylaainopropoxy and 2 a-Methoxy-phenylazo 3.5-dichlorobenzene. The base obtained previously is dissolved in 180 ml of acetone. Added 7.85 s by hydrochloric acid dissolved in 70 ml of dry acetone. The L-dimethylaminopropoxy and 2-methoxy-3.5-dichlorobenzene precipitates. It is a white solid. (F.: 138 - 140 °C). Step a is similar to that described in the example-I STAGE 3 : l diéthylarrdiéthylarr.inoprcpoxy-to-2-methoxy-3) 5 a-dlchlorobenzene The 66 g of 3.5 to-dichlorogaïacol (0.34 mole) previously obtained are poured into a solution of sodium ethoxide prepared from 7 g sodium and 130 ml of absolute alcohol. To the solution is added red obtained 55 s diéthylaminopropyle chloride (0.34 mole + 10 Heated gently; after 5 min the solution becomes cloudy. Sodium chloride precipitates. Is then heated at reflux for 2 hours. Is cooled, admixed with water. The amine precipitates. Decanted, extract repeatedly to methylene chloride, and washed the organic solution with a sodium hydroxide solution to 4 (RTs: 95, 56). STEP C : L-diéthylamlnopropoxy-to-2-methoxy-3.5-dichlorobenzene The base obtained previously is dissolved in twice its weight of acetone. Is bubbled hydrochloric acid dry in the same volume of acetone and this solution is poured into the base to turn methyl red. The hydrochloride crystallizes. It is dewatered, washed, air dried and then oven-to 30°. It is recrystallized repeatedly in isopropanol. 51 G of obtained L-diethylaminopropoxy and 2-methoxy-3.5-dichlorobenzene. (F.: 142 °c) (rt.48 ANALYSIS Calculated L-morpholinopropoxy-to-2-methoxy-3.5-dichlorobenzene Step a is similar to that described in the example I-. STAGE 3 : l rr.orp' nolincpropoxy and 2 a-Methoxy-phenylazo 3> 5-dichlorobenzene 54 g of 3.5 (0.28 mole) dichlorogaïacol are added to sodium ethylate obtained by reacting 6.44 g sodium on 84 ml ethyl alcohol. The resulting solution is added 51 e (0.28 mole + 10 Is cooled, resumes the mixture by 300 ml of water and concentrated hydrochloric acid OJ ml. The solution obtained is filtered, adds ammonia to precipitate the base, that is extracted with ether. Is knocked ether is distilled and the vacuum residue. Obtained 73 sec. (HV, 82 STEP C : L-morpholinopropoxy-to-~méthoxy 2 and 3.5-dichlorobenzene. The base obtained is dissolved in 150 ml of previously acetone. Added 8.32 g hydrochloric acid dissolved in 50 ml dry acetone Oxalate 1 a-diéthylaminoisopropoxy-to-2-methoxy-3.5-dichlorobenzene Patent is similar to that described in the example-I STEP B : l diéthylaminoisopropoxy and 2 a-niéthoxy above 3.5-dichlorobenzene 63 g of 3.5 to-dichlorogaïacol (0,326 mole) are added to sodium ethoxide prepared by dissolving 5 g of sodium in 7 100 ml of alcohol. To the resulting solution, is added 54 seconds (10 + 0,326 mole Obtained 70 grams (RT of 7 - 10. STEP C : Oxalate 1 a-diéthylaminoisopropoxy and 2 a-irir.éthoxy above 3.5-dichlorobenzene . The base obtained previously is dissolved in 1j0 ml of absolute alcohol; added 21 g of oxalic acid previously dissolved in 40 ml of alcohol. L1 oxalate 1 a-diéthylaminoisopropoxy-to-2-methoxy-3.5-dichlorobenzene precipitates, it is wrung out, alcohol washed and dried. ANALYSIS 6 Calculated %: c-H-n-LC 17.93 48.48 5.81 3.53 found 7.: C. 48.28 hr 5.98 LC 17.80 3.39 N. EXAMPLE VI. Bromométhylate L-diethylaminopropoxy and 2-methoxy-3.5 dichloridebenzene The base is prepared and far more 11 is described in steps a and b of the such as III. Is poured a methanolic solution of methyl bromide (18 gm brr HM ^ for 161 ml solution, either 0.17 mole + 10% excess) in 51 grams (0.17 mole) of L-diethylaminopropoxy and 2-methoxy-3.5-dichlorobenzene dissolved in 100 ml of methanol. The solution is held at room temperature for 90 hours. The alcohol is distilled under vacuum to a constant weight. Is recrystallized in acetone. The crystals are wrung, washed with acetone and dried at 55 °c. 43 G of crystals are obtained white bromométhylate L-diethylaminopropoxy and 2-methoxy-3.5-dichlorobenzene. This material is highly hygroscopic. aLyM ^:4 "115 DEGREESc) (RTs: 63%) * Calculated %: C. 44.89 hr 5.98 brr 19.95 LC 17.70% n-3.49 found: C. 44.76 hr 6.10 brr 20.03 LC 17.56 3.28 N. The studies which follow are exposed as an indicator. Acute toxicities studied in mouse showed that the compounds prepared according to the present invention have a toxicity that is readily compatible with therapeutic use. The table below is exemplary: 1 Degrees) the action spasmogenic compounds prepared in the invention was examined on the guinea pig isolated ileum. On a frangment of guinea pig isolated ileum, measured the height of contractions caused by increasing doses of the product to be studied: 0.1 pg/ml - 0.2 ml - 0.4 jjig/GP/platform of the vehicle. This study has identified the spasmogenic exhibiting potent compounds. 2 Degrees) antagonistic action to atropine was examined also on. the guinea pig isolated ileum. A fragment of ileum is suspended in the liquid Tyrode aerated. L-diethylaminopropoxy and 2-methoxy-3.5-to-dichlorobsnzene 2.10.7 concentration (the O, 2 pg/ml) is left in contact for 30 seconds with the muscle. Contractions are recorded and thus caused repeated every six minutes up to stabilization of the response. Atropine is added to the liquor In addition to their propriétésles drugs 1 of1 irir.ver.tion have various propriétésintéressantes summarized in the following table aorès: The experimental results were confirmed in clinic where the products have been administered in the form of tablets and ampoules a pharmacologically acceptable salt. 1,251,695. Aminoalkyl ethers of 2-(alkoxy) - 3,5-dihalobenzenes. SOC. D'ETUDES SCIENTIFIQUES ET INDUSTRIELLES DE L'ILE-DE-FRANCE. 13 Feb., 1969 [16 Feb., 1968; 10 May, 1968], No. 7933/69. HeadingC2C. Novel compounds of the Formula (I) and their acid-addition salts with a mineral or organic acid and their quaternary ammonium salts, wherein n and m each is 0, 1 or 2, R, R l and R 2 each is H or C 1-5 alkyl, R 3 is C 1-5 alkyl, or the group NR 1 R 2 represents a heterocyclic radical, and X and Y are halogens, are obtained by acetylating a monoether of pyrocatechol, then halogenating the product, de-acetylating the halogenated product and treating the dihalo-pyrocatechol monoether with an appropriate (substituted amino) alkyl chloride, and optionally forming acid or quaternary ammonium salts. Pharmaceutical compositions, useful as spasmogenie agents, contain compounds of Formula (I) above as active ingredients, and may be formulated as tablets or solutions. 1)* L-invention concerns the preparation of a member of the group consisting of dialkylamino alkyl ethers of the novel 2 alkoxy-3.5-dihalo benzene of the formula: as well as their addition salts with an inorganic or organic acid and their quaternary ammonium salts. In the above formula: - n and m are integers between 0 and The R -, SR r2, the rg represent either hydrogen, or a lower alkyl radical of 1 to 5 carbon atoms such as for example: methyl, ethyl, propyl... the moiety - n can represent a radical heterocyclic such as for example: pyrrolidyl, piperidyl, morpholyl, piperazinyl... - X and Y are halogens such as for example: F., for Cl, brr... 2) L-Diethylaminoethoxy-to-2-methoxy-3.5-dichlorobenzene. 3) L-dimethylaminopropoxy and 2-methoxy-3.5-dichlorobenzene. 4) L-diethylaminopropoxy and 2-methoxy-3.5-dichlorobenzene. 5) L-morpholinopropoxy-to-2-methoxy-3.5-dichlorobenzene. 6) Oxalate-L diéthylaminoisopropoxy-to-2-methoxy-3.5-dichlorobenzene. 7) Bromométhylate L-diethylaminopropoxy and 2-methoxy-3.5-dichlorobenzene. 8) A process for preparing the products according to 1) to 7) consisting basically to acetylate a monoether pyrocatechol, then halogenating the compound obtained, then to the désacétylei and process it by a chloride of alkylaminoalkyl. 9) A preparing method according to 8) of: of 1 a-Diethylaminoethoxy-to-2-methoxy-3j 5~dichlorobenzène• 10) A preparing method according to 8) of: l-diméthylan) inopropaxy and 2 a-niéthoxy and 3.5 to-uichlorobenzene. 11) A preparing method according to 8) of: of 1 a-boa thylaminopropoxy-to-2-ma polymerizable thoxy-to-3.5 dichlorobenzene. 12) A preparing method according to 8) of: l-morpholinopropoxy and 2 a-niéthoxy-a 3" 5 a-uiehlorobenzene. 13) A preparing method according to 8) of: l diéthylaminoisopropoxy and 2 a-mathoxy and 3.5 to-uichlorobenzene. 14) A preparing method according to 8) of: l-diethylaminopropoxy and 2-methoxy-3.5-dichlorobenzene. hydrochloride hydrochloride hydrochloride hydrochloride bromométhylate oxalate Office CAZENAVEANALYSIS
Calculated 45.79 c. Hr 5.72 33.86 LC NR 4.45 Found c. 45.59 Hr 5.79 35.72 LC NR 4.30 THE EXE K. ? L-PART III Chlcrr therein. ■drate l-dléthvla . minopropoxy-to-2-methoxy-3.5 - - dichlorobenzè: ketone and dried. ( 73 grams) (RTs 94. . (Ρ, ·ΐ 83 - 184 °c). ANALYSIS Calculated : C. 47.12 H 5.61 LC 29.87 N. 3.93 Found : C. 47.33 H 5.72 LC 29.77 N. 3.92 EXEM L-P-I Y : COMPOUND In mg/kg in 50 df: (compound in the base form): VI: THE IP cS: ipo! 9.ï-L-diethylaminopropoxy and 2 - 34.8! 181 608 i-737: ii methoxy-3.5-dichlorobenzene 31.3 1 •E • • •• Agents to spasmogens 50 Attopine dosage antagonist average GP/ml. l diethylaminopropoxy and 2-methoxy-3.5-to-dichlorobenz ene dosage spasmogenic: 2.10 - 7 1.9 (has) Acetylcholine 1.10 ' 7 0,010 (has) (has) determined on 12 measurements, each piece of ileum being subjected successively to the action spasmogenic L-diethylaminopropoxy and 2-methoxy-3.5 dichlorobenzene and acetylcholine. Technical Animals Mgs/kg per dose Path 1 a-diéthylarainopropoxy-to-2 Me thoxy-a 3.5 to-dichlorobenzè - does Gastrointestinal transit measured 40 mnmn.après delivering of the medium: coal plant Mouse OF 50 S.C.. Null effect of 0,001 mg/kg to 200 mg/kg. Antiemetic activity measured 30 min (SC) or 1 hr. (orally) after administration of the product. Medium: GP/kg in 100 apcmorphine SC in Dog OF 50 s.c.. 16 Effect Cataleptic activity measured at most the effect either 3c0 mnmn.après 360 to administration of the drug. Rats OF 50 S.C.. 30 Effect Technique 30 measured tensile mnmn.après product dispensation. Mouse OF 50 s.c.. 197 PP.O. Effect of 40 1 Potentiation of barbituric 60 mg/kg in narcosis roject Administration has an IP Mouse 2 Indexes II.P. 55.4 measured 30 Mn after the product has. Medium: pentobarbitone PP.O. Indexes: 200 mg/kg of 1.23 to Spontaneous motility measured 15 min (intraperitoneal injection) or 60 min (lane PO) after administration of the product Test Flataker Winter and Mouse OF 50 II.P. 49.1 PP.O. 200 Mg/lambdag null effect to Activographe Mouse OF 50 II.P. 16.1 - 19.7 PP.O. 105 Activity measured antimescaline 13 min after administration of the product medium: 50 mg/kg in mushroom ii.m. Mouse OF 50 II.P. 30 Effect Technical 1 Animals Mgs/kg per dose Path 1-diethylamino-butoxy-to-2-methoxy - Y, 5 dichlorobenzene Anti-apomorchine ' (testing of Janssen) measured 80 min. after administration of the product medium: 1.25 mg/kg of apomorphine in I.V. Rats OF 50 S.C.. Effect of OJ antimorphine activity (testing Straub) measured 60 to 120 min after administration of the product medium: mgs/kg of morphine to OJ s.c.. Mouse OF 50 PP.O. 313 antitrémorine activity (technique expensive) measured 60 min after administration of the product medium: 7.5 mg/kg of trémorine ii.m. Mouse OF 50 II.P. 9 ^, 7 Rotating stem test Mouse OF 50 II.P. 71.5 measured 10 to OJ min after administration of the product PP.O. 18 Effect Testing the evasion (Kneipp wading technique) measured 1 hour after administration of the product Mouse OF 50 II.P. 75.9 Antiserotonin acting: reduction relative to control hypertension caused by serotonin: 25/kg to I.V therein. Dog OF 50 I.V. 19 Anticonvulsant activity Seizure electrical measured at the peak effect Mouse OF 50 SC PP.O. 37.1 143 - anticonvul activity Chemical attack An agent! Cardiazol Mouse OF 50 II.P. 84.9 sivante measured JQm after administration of the product. 70 mg/kg in I.V. PP.O. 200 Mg/kg in null effect to Medium: 2 mg/kg of nicotine to I.V. Mouse OF 50 II.P. 31.3 PP.O. 92.9 1' Technical Animals Mgs/kg per dose Path 1 a-diéthylaminc-butoxy-to-2 Me thoxy-a 3.5 to-dichlorobenzèns - sivanteanticcnvul activity Audiogenic seizure measured OJ min after administration of the product Mouse OF 50 II.P. 18, 8 - 19, 7 PP.O. 67 - analgési activity Mechanical stimulus (tester HAFF * the SR!) Mouse OF 50 II.P. 71.5 that measured at the peak effect PP.O. Activity Chemical stimulus II.P. Effect #22 analgesic (Test the phénylbenzoquinone) Mouse OF 50 to 90 mg/kg. measured at the peak effect PP.O. 30 Effect GBP - UEs analgési activity Thermal stimulus flat hot dog (according to the technique of CJD, w001-Fe and McDonald) measured at the peak effect S.C.. 45 Effect Mouse OF 50 PP.O. - Minic antihista activity Hypotensive histaminic $reduction relative to control hypotension Dog 32, 16 8, 4 2, 1 I.V. R=50 to 60 Ortho - cool thic Carotid occlusion during 30 seconds. Dog 16, 8 4, 2 1 I.V. R - 35 Reduction or reversal # adrenaline relative to control hypertension Dog OF 30 ; I.V. 12 Technical Animals Mgs/kg per dose ii ? 1-diethylamino - propoxy-to-2-methoxy -, 3.5 and i.d. chlorobenzene derivatives Ortho - cool - thic va. Snri Dog OF 50 ; 1 iV The nicotine 16 ! THE R ≈ 4 8 THE R= 15 ratio to 1' - hyperbranched Dog 4 I.V. THE R ≈ 3 reference voltage 2 ; THE R= 0 1 THE R= the Ta System Acetylcholine 16 THE R= 33, ¾ 8 THE R= 37 the para - the hypo - ratio Dog 4 I.V. THE R= 15 cool - reference voltage 2 THE R= 5 1 THE R= 0 thic Exciting 16 THE R= 51 vagal 8 THE R= 21 Dog 4 I.V. THE R= 11 the hypo - ratio 2 THE R= 0 reference voltage 1 THE R= 0