Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

• a further object of the present invention consists of a process of synthesis WhlCh leads to the compounds rep- -CHz-CHgOCHz-CHN O resented by Formula 1.
• CHz-Ofi'a Still another object of the present invention relates to the therapeutical application of the said compounds.
• the following are some of the pharma- This invention relates to some new Salts of aminocological properties of the salts which are the object of alkyland aminoalcoxyalkyl esters of a-phenoxy-isoh present i ti y y-p y and The lethal oral dose in the rat, of the compounds chlorophenoxy)'isoblltyfic acid, the Process of Preparing which are the object of the present invention is in the said compounds and to the therapeutical use thereof. range between 4000 d 8000 mgjkg,
• Th se e compounds y be ftipfesented y the
• the compounds which are the object of this invention when introduced through the gastric passage in experimental animals, even in doses higher than the therapeutical ones, have never caused either a decrease in speed of the intestinal transit, unlike codeine whose constipation effect is particularly evident, or a depressive effect on respiration.
• the compounds of the present invention can be usefully applied in therapy, both alone as well as in association with other products.
• the synthesis process of the compounds represented by Formula 1 consists schematically in reacting in a suitable boiling solvent, the chlorides of a-phenoxy-isobutyric, a (o' methoxy phenoxy)-isobutyric, and a-(o-chlorophenoxy)-isobutyric acid with the aminoalcohols and aminoalkoxyalcohols corresponding to the desired product, in the presence of an organic base (for example, triethylamine).
• an organic base for example, triethylamine.
• the esters, obtained as oily liquids, are transformed into salts (for example hydrochlorides or citrates) by treating them with the relative acids.
• Example 1 A solution of 198 g. a-phenoxy-isobutyric acid chloride in 500 ml. anhydrous benzene is added, slowly and under stirring, While maintaining the temperature at 25 C. to a solution of 131 g. fi-morpholinoethanol and 202 g. triethylamine in 1500 ml. anhydrous benzene. The mixture is then heated at boiling point for 4 hours always under stirring; thereafter, it is filtered hot and the solvent is stripped at mm. and 40 C.
• the reaction product is purified by distillation at 0.01 mm. and 127-130" C.
• the B-morpholinoethyl ester of a-phenoxy-isobutyric acid is transformed into the corresponding hydrochloride by dissolving 230 g. of it in 600 ml. absolute ethanol and by passing through the solution a current of gaseous hydrochloric acid until a pH of 2 is reached.
• Example 2 Similar to Example 1, by reacting in the same conditions 89.1 g. dimethylamino-ethanol and 198 g. a-phenoxyisobutyric acid chloride there is obtained the fi-dimethylamino-ethyl ester of a-phenoxy-isobutyric acid; B.P. at 0.03 mm. 93 C.
• This ester when dissolved in 95% ethanol and treated with an equimolar amount of citric acid, by adding a double volume of ethyl ether and leaving for 12 hours at 0, yields the citrate of the fi-dimethylamino-ethyl ester of a-phenoxy-isobutyric acid: M.P. 9899 C.
• Example 3 177 g. diethylamino-ethanol is reacted in the conditions described in Example 1 with 198 g. a-phenoxy-isobutyric acid chloride to yield the B-diethylamino-ethyl ester a-phenoxy-isobutyric acid, at 0.01 mm. 107 C. B.P. which, when treated with an equimolar amount of citric acid in alcohol solution as in Example 2, yields the corresponding citrate, M.P. 134l35 C.
• Example 4 By the same method as described in Example 1, 133 g. fl-(2-dimethylamino-ethoxy)-ethanol is reacted with 198 g. u-phenoxy-isobutyric acid chloride to yield the 5-(2- dimethylamino-ethoxy)ethyl ester of a-phenoxy-isobutyric acid; B.P. 128 C. at 0.01 mm.
• This ester is transformed into the citrate by treating with citric acid in alcoholic solution as described in Example 2: M.P. 8485 C.
• Example 6 161 g. 8-(Z-diethylamino-ethoxy)-ethanol is treated with 198 g. a-phenoxy-isobutyric acid chloride, as described in Example 1 to yield the fi-(Z-diethylaminoethoxy)ethyl ester of a-phenoxy-isobutyric acid, B.P. C. at 0.01 mm.
• Example 7 By the same method described in Example 1, 175 g. fi-morpholinoethoxyethanol is reacted with 198 g. uphenoxy-isobutyric acid chloride to yield the B-morpholinoethoxyethyl ester of a-phenoxyisobutyric acid, boiling point C. at 0.01 mm. This is treated with citric acid, as described in Example 2, to yield the corresponding citrate, M.P. IOU-102 C.
• Example 8 A solution of 228 g. u-(o'-methoxy-phenoxy)-isobutyric) acid chloride in 500 ml. anhydrous benzene is added, at 25 C. and under stirring, to a solution of 129 g. epiperidinoethanol and 202 g. triethylamine in 1500 ml. anhydrous benzene. After heating at boiling point for 4 hours, the mixture is filtered through a paper filter and the filtrate is distilled first at 40 C. and 15 mm. in order to separate the solvent and then at 132-134 C. and 0.01 mm. in order to isolate the pure product, that is to say, the fi-piperidinoethyl ester of a-(o'-methoxy-phenoxy)- isobutyric acid.
• Example 9 By the same method as described in Example 8, 89.1 g. dimethylamino-ethanol is reacted with 228 g. tat-(o'- methoxy-phenoxy)-isobutyric acid chloride to yield the p-dimethylamino-ethyl ester of u-(o'-methoxyphenoxy)- isobutyric acid, having a boiling point of 118 C. at 0.01 mm.
• This ester is treated in alcoholic solution with citric acid, as indicated in Example 8, to yield the corresponding citrate having a M.P. 86-88 C. 7
• Example 10 117 g. diethylamino-ethanol is reacted in the same conditions as described in Example 8, with 228 g. tat-(o'- methoxy-phenoxy)-isobutyric acid chloride to yield the B-diethylamino-ethyl ester of m-(o-methoxy-phenoxy)- isobutyric acid, having a B.P. of 128 C. at 0.01 mm.
• the corresponding citrate is obtained, having a M.P. of 106-108" C.
• Example 1 By reacting 131 g. morpholinoethanol with 228 g. a- (o'-methoxy-phenoxy)-isobutyric acid chloride in the conditions described in Example 8, there is obtained the fi-morpholinoethyl ester of u-(o'-methoxy-phenoxy)-isobutyric acid, having a B.P. of 134 C. at 0.01 mm. This is treated with citric acid to yield the corresponding citrate having a M.P. of 100-102 C.
• Example 13 By the method described in Example 8, 175 g. fi-rnorphoh'noethoxyethanol is reacted with 228 g. a-(o'-methoxyphenoxy)-isobutyric acid chloride to obtain the B-morpholinoethoxyethyl ester of m-(omethoxyphenoxy) -isobutyric acid, having a B.P. of 145 C. at 0.01 mm.
• This ester is salified with citric acid as indicated in Example 8, to yield the citrate having a M.P. of 77- 79 C.
• Example 15 133 g. B-(Z-dimethylaminoethoxy)-ethanol and 202 g. triethylamine are dissolved in 1500 ml. anhydrous benzene; then, a solution of 233 g. a-(o'chloro-phenoxy)- isobutyric acid chloride in 500 ml. anhydrous benzene is added slowly under stirring at a temperature of 25 C. The mixture is warmed to boiling point for 4 hours, under stirring; then, it is filtered hot and the solvent is stripped at 15 mm. and 40 C.
• the crude fl-(Z-dimethylamino-ethoxy)-ethyl ester of a-(o'chloro-phenoxy)-isobutyric acid, as obtained, is purified by distilling it at 0.02 mm. and 130-135 C.
• Example 16 Analogously to Example 15, 89.1 g. dimethylaminoethanol is reacted with 233 g. u-(o'ch1oro-phenoXy)-isobutyric acid chloride to yield the B-dimethylamino-ethyl ester of a-(o'chloro-phenoxy)-isobutyric acid having a B.P. of 123 C. at 0.01 mm.
• Example 17 117 g. diethylarnino-ethanol is reacted in the same conditions as described in Example 15, with 233 g. a-(o'chloro-phenoxy)-isobutyric acid chloride to yield the p-diethylamino-ethyl ester of a-(ochloro-phenoxy)- isobutyric acid having a B.P. of 126 C. at 0.01 mm. This is treated in alcoholic solution with an equimolar amount of citric acid to yield the corresponding citrate having a M.P. of 131-133 C.
• Example 18 129 g. piperidinoethanol is treated with 233 g. a- (o-chloro phenoxy)-isobutyric acid chloride, as described in Example 15, to yield the fl-piperidinoethyl ester of CL- (o'-chloro-phenoxy)-isobutyric acid having a B.P. of 132 C. at 0.02 mm.
• the citrate, obtained as in Example 8, has a M.P. of 6266 C.
• Example 19 As in Example 15, 131 g. morpholinoethanol is reacted with 233 g. a-(ochloro-phenoxy)-isobutyric acid chloride to yield the B-morpholinoethyl ester of u-(o'chlorophenoxy)-isobutyric acid having a B.P. of 142 C. at 0.01 mm.
• This ester is transformed into the citrate by treating it with citric acid as described in Example 15; M.P. 87 C.
• Example 20 As in Example 15, 161 g. B-(Z-diethylamino-ethoxyethanol is reacted with 233 g. a-(o'chloro-phenoxy)-isobutyric acid chloride, to yield the fl-(Z-diethylaminw ethoxy)-ethyl ester of a-(o-chl0ro-phenoxy)-isobutyric acid, having a B.P. of 138 C. at 0.01 mm.
• the corresponding citrate has a M.P. of 72-74 C.
• Example 21 By the same method as described in Example 15, g. fl-morpholinoethoxyethanol is reacted with 233 g. a.- (o'chloro-phenoxy)-isobutyric acid chloride to yield the p-morpholinoethoxyethyl ester of a-(o'-chloro-phenoxy)- isobutyric acid having a B.P. of 139 C. at 0.02 mm. This ester is treated with citric acid, as described in Example 15, to yield the corresponding citrate having a M.P. of 75-77 C.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Peptides Or Proteins (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=11134408

Family Applications (1)

Country Status (3)

Cited By (1)

• 1966
  • 1966-05-02 US US546559A patent/US3474095A/en not_active Expired - Lifetime
  • 1966-05-06 GB GB20254/66A patent/GB1154244A/en not_active Expired
  • 1966-05-11 FR FR1588156D patent/FR1588156A/fr not_active Expired

Non-Patent Citations (1)

Also Published As

Similar Documents