A therapeutic method utilizing a choleretically active composition containing a morpholino derivative
4 United States Patent [191 Fourneau et al.  
 [ Apr. 8, 1975 [541 A THERAPEUTIC METHOD UTILIZING A CHOLERETICALLY ACTIVE COMPOSITION CONTAINING A MORPHOLINO DERIVATIVE [75] Inventors: Jean-Pierre Fourneau; Jean DeLourme, both of Paris, France [73] Assignee: Laboratoires Houde, Paris, France [22] Filed: Sept. 25, I972 [21] Appl. No.: 292,099  
  Related US. Application Data [62] Division of Ser. No. 856,5l8, Aug. 4. I969,  
 UNITED STATES PATENTS 3,160,557 l2/l964 Mauvcrnay ..424/248 3.228.96l 1/1966 Vargha et al. 260/3263 Primary E.\&#39;aminerSam Rosen Attorney, Agent, or Firm-Zalkind, Horne &amp; Shuster [57] ABSTRACT A therapeutic composition having, in particular, a choleretic action, comprising 2-morpholino-ethyl O- acetylvanillate of formula OCH CH CO-O coo-cu -CH N O (I) or a pharmaceutically acceptable acid addition salt thereof.  
 3 Claims, No Drawings 1 2 A THERAPEUTIC METHOD UTILIZING A added, it melts instantaneously at 161C (7.8 g; Yield: CHOLERETICALLY ACTIVE COMPGSITION 36%). It is slightly hygroscopic and soluble in about 5 CONTAINING A MORPHOLINO DERIVATIVE parts of water.  
 . Analysis This application is a Division of our application Ser. 5 Calculated for C H CINO C% 53.40; H% 6.46; No. 856,518, filed Aug. 4, 1969, now abandoned. Cl% 9.85; N% 3.89  
  This invention relates to a therapeutic composition having, in particular, a choleretic activity comprising, Acute toxlclty as active ingredient, The LD values, in mice, of 2-morpholino-ethyl O- Z-morpholino-ethyl O-acetylvanillate of formula acetylvanillate hydrochloride are: 220 mg/kg by the in- OCH3 or a pharmaceutically acceptable acid addition salt tra-venous route, 1000 mg/kg by the intraperitoneal thereof. route and 2700 mg/kg per os.  
 2-morpholino-ethyl O-acetylvanillate and its acid addition salts are new compounds. Tolerance tests m rat:  
  Another ester of O-acetylvanillic acid, namely 2- lst test: The following dosages were administered by diethylamino-ethyl O-acetylvanillate hydrochloride has a gastric catheter to a lot of 10 rats: already been described as chemical compound but the 500 mg/ g aily during 3 days pharmacological properties as set forth here have never 1000 mg/kg daily during the following 3 days been described heretofore. 2000 mg/kg daily during the following 3 days.  
  Indeed, it was found that 2-morpholino-ethyl O- The animals were kept under observation during 2 acetylvanillate and its acid addition salts possess a surweeks after the end of the treatment, and were then prisingly high choleretic activity. sacrificed and autopsied. No disorder of the behavior,  
  To prepare 2-morpholino-ethyl O-acetylvanillate, O- no modification of the weight increase curve with reacetylvanilloyl chloride is condensed with 2- spect to the untreated animals and no alteration of the morpholino-ethanol. principal organs were observed.  
  This condensation is advantageously carried out in a 2nd test: 1 g/kg was administered orally daily to a lot non-polar solvent such as benzene, with stirring, under of 5 rats during 5 consecutive days. No weight loss was moisture free conditions and at room temperature, noted in the treated lot. All animals were sacrificed and using the reactants in stoichiometric proportions. autopsied 3 hours after the last administration: no in- The reaction is generally carried out during 12-24 jury of the gastro-intestinal system was detected in the hours at room temperature, or during several hours at 40 treated animals. refluxing conditions. Tolerance tests in dog:  
 The following example illustrates; the preparation of The following dosages were administered orally to 3 beagles: 2-MORPHOLlNO-ETHYL ()-ACETYLVANILLATE 30 mg/kg daily during 3 days HYDROCHLORIDE 75 mg/kg daily during the following 3 days In a 250 ml three-necked flask fitted with a reflux 150 mg/kg daily during the following 3 days. condenser (provided overhead with a calcium chloride As in rat, no particular symptomatology was noted. trap), a dropping funnel and a good mechanic stirrer, Systemic effects:  
 are added 13.7 g (0.06 mole) of O-acetylvanilloyl chlo- As early as the l mg/kg i.v. dosage, the compound of ride dissolved in 50 ml of anhydrous benzene. 2- example 1 produces in rat a transient hypotension Morpholino-ethanol (7.9 g; 0.06 mole) dissolved in anwhich is proportional .to the dosage administered and hydrous benzene (35 ml) is added portionwise through is non modified by atropine, and a brief stimulation of the dropping funnel, with stirring. The reaction mixture respiration which may reach 80% after 10 mg/kg. The is then refluxed during 6 hours. After allowing to rest effects produced by acetylcholine, noradrenaline and overnight in the refrigerator, the crystals which have isoprenaline on blood pressure are not modified, but separated are suction filtered and then dried. 14 g of adrenaline-induced hypertension is reinforced. Similar impure 2-morpholino-ethyl O-acetylvanillate hydrophenomena are noted in guinea pig or in rabbit. chloride are thus obtained. I The compound prepared in example 1 has no sub- The material i di olv d in water, made alkaline with stantial central effects in the following tests: nocturnal sodium bicarbonate and the base is extracted with activity of mice, potentiation or antagonism on penether. Evaporation of the solvent leaves 9.4 g of light tobarbital-induced narcosis or on strychnine-, pentetyellow oily base which is converted to the hydrochlorazoleor electroshock-induced convulsions, or on resride by addition of the calculated amount of anhydrous erpine-induced ptosis.  
 hydrochloric acid dissolved in ether. Suction filtering, U0 and 300 mg/kg i.p. lower the central temperature washing with ether and drying gives 10.2 g of crude hyof rat by an average of 2C during about 20 minutes. drochloride melting at C. On recrystallization from 1 g/kg per os protects against tremorine-induced 500 ml of acetone to which 50 ml of ether have been symptoms.  
  150 and 300 mg/kg per os decrease by 55% the number of wriggling fits induced in mice by intraperitoneal injection of acetic acid, which corresponds to an analgesic activity.  
  On the isolated ileum of guinea-pig, the concentration reducing by 50% the histamineand barium chloride-induced contractions is 2X10? Thus, spasmolytic activity is low. Furthermore, the peristalsis of the intestine of guinea-pig in situ is not modified by 5-20 mg/kg i.v., and the intestinal transit in mice is not modified by 4080 mg/kg per os.  
  The compound of example l has no local anesthetic activity on the cornea of rabbit up to the very high concentration of 4%.  
 Choleretic activity in rat:  
  As early as the dosage of 20 mg/kg, the compound of example 1, administered by the intraduodenal route, produces an increase of more than 50% of the biliary rate of flow, with respect to the original rate of flow. With 40 mg/kg, the increase is within 60 and 100%. At the higher dosages (60 and 80 mg/kg), the increase is not proportional to the dosage administered and does not exceed 110%. The compound is at least as active as sodium dehydrocholate which, administered in the same tests at the dosage of 60 mg/kg, increased the rate of flow by 50 to 110%.  
 Clinical experimentation The compound was experimented in two different hospital services, the therapeutical preparation being administered in the form of enteric coated tablets containing each 200 mg of active principle.  
  l. 25 patients were treated with 2-6 tablets daily during a period of time of -35 days. The subjects suffered from various functional hepatic disorders, with or without lithiasis of the gallbladder: nausea, epigastric flatulence, alternating diarrhea and constipation, frontal headaches, true migraines, slow digestion, bitter taste in the mouth, anorexia.  
  Tolerance is excellent. No effect on blood pressure or on sleep was ever noted. The therapeutical composition was well tolerated in the four cases of lithiasis of the gallbladder, without appearance of biliary colic.  
 The following results were obtained:  
 Disapperance of symptoms 9 Strong improvement 10 Substantial improvement 6 2. 20 patients suffering from functional hepatic disorders similar to those described above were treated with 6 tablets daily during 10-30 days. The therapeutical composition was perfectly well tolerated, without any side effects on blood pressure or sleep, and excellent results were obtained in cases and substantial results -CO-O were obtained in 5 cases. The best results were noted in sequelae of cholecystectomy, in simple biliary dyspepsia and true migraines.  
  It is apparent from the tests reported above that the therapeutical composition may be administered benefically in human therapeutics, in particular to control the functional disorders due to a hepato-biliary insufficiency such as nausea, epigastric flatulence, alternating diarrhea and constipation, frontal headaches, migraines, slow digestion, bitter taste in the mouth, anorexia, sequelae of cholecystectomy and pains in the right hypochondriac area.  
  In such applications, the therapeutical composition is advantageously formulated for the oral administration of about -1500 mg and, on the average, of 500 mg of active principle per 24 hours, the latter being associated with a vehicle or excipient suitable for such route of administration.  
  The therapeutical composition may be administered at the rate of 1-3 doses per day during 30 day periods, as liquid formulations such as drops, syrups, elixirs or solutions containing about l5% by weight of active principle, or as solid formulations such as tablets, capsules, granules, and the like, each solid unit dose containing, for example, about 100-600 mg of active prin- I ci le.  
  2m example of formulation of the therapeutical composition is given below:  
 Enteric coated tablets:  
  Morpholinoethyl acetylvanillate hydrochloride 200 mg Excipient: sugar, starch, prepared silica and talc, q.s. for a tablet finished at about 0.42 g  
 Enteric coating: polymethacrylate, q.s.  
  Having now described our invention, what we claim as new and desire to secure by Letters Patent is:  
  1. A method of increasing the biliary rate of flow from patients suffering from hepato-biliary insufficiency comprising administering to said patients an effective amount of an active ingredient selected from the group consisting of 2-morpholino-ethyl O- acetylvanillate of the formula OCH and its pharmaceutically acceptable inorganic acid addition salts.  
  2. The method as claimed in claim 1, wherein said inorganic acid addition salt is hydrochloride.  
  3. The method as claimed in claim 1, wherein said effective amount is of from 100 mg to 1500 mg of active ingredient per 24 hours.