US3474095A - Beta - morpholinoethyl - alpha - phenoxy-isobutyrate hydrochloride or citrate salt - Google Patents
Beta - morpholinoethyl - alpha - phenoxy-isobutyrate hydrochloride or citrate salt Download PDFInfo
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- US3474095A US3474095A US546559A US3474095DA US3474095A US 3474095 A US3474095 A US 3474095A US 546559 A US546559 A US 546559A US 3474095D A US3474095D A US 3474095DA US 3474095 A US3474095 A US 3474095A
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- Prior art keywords
- phenoxy
- isobutyric acid
- ester
- citrate
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- 150000001860 citric acid derivatives Chemical class 0.000 title description 4
- QFBWXEMAYCOFNS-UHFFFAOYSA-N 2-morpholin-4-ylethyl 2-methyl-2-phenoxypropanoate;hydrochloride Chemical compound Cl.C1COCCN1CCOC(=O)C(C)(C)OC1=CC=CC=C1 QFBWXEMAYCOFNS-UHFFFAOYSA-N 0.000 title 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 42
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 20
- 150000002148 esters Chemical class 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- KQNPFQTWMSNSAP-UHFFFAOYSA-N alpha-isobutyric acid Natural products CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 230000000954 anitussive effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960002887 deanol Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- DZCBKUAAGVVLOX-UHFFFAOYSA-N 1-morpholin-4-ylethanol Chemical compound CC(O)N1CCOCC1 DZCBKUAAGVVLOX-UHFFFAOYSA-N 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- 229960004126 codeine Drugs 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- -1 methoxy phenoxy Chemical group 0.000 description 2
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- MADORZDTLHDDEN-UHFFFAOYSA-N 1-piperidin-1-ylethanol Chemical compound CC(O)N1CCCCC1 MADORZDTLHDDEN-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
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.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Patented Oct. 21, 1969 wherein 3,474,095 BETA MURPHULINUETHYL ALPHA PHENOXY- R is H, OCH 01' Cl TSUBUTYRA'IE HYDROCHLORIDE UR CITRATE R1 is lEnzo Marchetti, Rome, Italy, assignor to Istituto 5 Farmacologico Serono S.p.A., Rome, Italy, an Ttalian corporation No Drawing. Filed May 2, 1966, Ser. No. 546,559
Claims priority, application Italy, May 14, 1965, CH3
10,733/65 02115 lint. Cl. C07d 87/28 U5. Cl. 260-2472 1 Claim CH2CH2N CgHs CH CH ABSTRACT OF THE DISCLQSURE 2- -CH2--CH2-N CH Compounds of the formula CH CHr-CH: a /CH;CE5 -OH;CH5N 0 CH CHz wherein R is H, OCH or -Cl CH R1 i CH2-CH3OCH2-CHzN CH CH CH3CH:-N/ CZHS CH3 CH3CH3-OCH3CH2-N Cz s C2115 CH CH N or T- car-on,
CH on 0 on on N 0 CHg-CH: 2 a- 2 r .CHqCH -N /CHg OHFOH GH -CH: andXls arm-cm (300E OHzCH;-N 0 CH2 CHr-CH: Hclor /OH CH; OHa-CH:OCHr-GH2N L 00011 CHa Ha-COOH One ob ect of the present 1nvent1on consists of the sub- OHT CH2 OFOH2 GHFN stances indicated by the Formula 1 and characterized as CzHs salts (hydrochlorides or citrates), in as much as they are new products, never obtained before by synthesis, nor or described in literature.
CHFCH2 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. In and tha citrate and hydrochloride SallS ihfiI'EOf. These fact, these derivativgs havg hown in the experimental Co p have Pharmaceutical y y yimle 0f theiI animals, besides a low toxicity, an antitussive action like antitussive activitythat of codeine, but without causing the well-known side effects of the substance.
As an example, 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 administration by mouth to rats of the compounds following general formula: 0 represented by Formula 1, in doses varying from 400 to OH 800'mg./kg. daily for 50 days, has not revealed variations l a of the body weight growth curve, of the reactivity, of the OCC00 1 appetite, of the excretion and nature of urine and feces. l (3113 X Nor were any variations detected in the number and R morphological characters of the red blood corpuscles,
I leukocytes, blood clotting time and hematocrit value.
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.
Most of the products represented by Formula 1 have shown a decrease in coughing, when administered by mouth in suitable doses to suitably treated rats.
Due to their particular antitussive activity, low toxicity, and lack of unfavorable side effects, 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). The esters, obtained as oily liquids, are transformed into salts (for example hydrochlorides or citrates) by treating them with the relative acids.
The following examples serve to illustrate more fully the new compounds as obtained according to this invention, and their methods of preparation. However, it is understood that such examples have only an illustrative and not a limitative nature, since variations of the schemes given in the examples will be obvious to the experts in the art, and therefore they should be considered as comprised in the field of the invention.
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, as obtained, 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. By adding 1000 ml. anhydrous ethyl ether and leaving at 0 for 12 hours there are obtained crystals of fi-morpholinoethyl ester of a-phenoxy-isobutyric acid hydrochloride; M.P. 143-145 C.
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.
4 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.
This is transformed into the citrate in the same manner as described in Example 2: M.P. 83-84 C.
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.
A solution of 225 g. of the ester, as obtained, in 500 m1. absolute ethanol is added to a solutiom of 134.5 g. citric acid in 300 ml. absolute ethanol. The mixture is stirred, 1500 ml. anhydrous ether is added and'the whole is kept at 0 for 12 hours.
Thus, the citrate of the p-piperidinoethyl ester of a- (o-methoxy-phenoxy)-is0butyric acid is obtained. Melting point 5456 C.
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. By treating this ester with citric acid, as indicated in Example 8, the corresponding citrate is obtained, having a M.P. of 106-108" C.
Example 1 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.
Ex ample 12 Following Example 8, 133 g. p-(Z-methylaminoethoxy)-ethanol is reacted with 228 g. a-(o'-methoxyphenoxy)-isobutyric acid chloride to yield the fi-(Z-dimethylamino-ethoxy)-ethy1 ester of u-(o'-methoxyphenoxy) -isobutyric acid, having a B.P. of 133 C. at 0.01 mm.
This ester is transformed to the citrate as described in Example 8, and the corresponding salt melts at 70-71 0.
Example 13 Example 14 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.
250 g. of the pure product is dissolved in 500 ml. absolute ethanol and is treated with a solution of 146 g. citric acid in 300 ml. absolute ethanol; then, 1500 m1. anhydrous ether is added and the whole is left for 12 hours at 0 to yield the citrate of the B-(Z-dimethylaminoethoxy)-ethyl ester of a-(ochloro-phenoxy)-isobutyric acid, melting at 73-75 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.
By treating this ester in alcoholic solution with an equimolar amount of citric acid there is obtained the citrate of the fi-dimethylamino-ethyl ester of the oc- (ochloroaphenoxy)-isobutyric acid having a M.P. of 88-90 C.
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.
Iclaim:
1. The hydrochloride or citrate salt of the fi-morpholinoethyl ester of u-phenoxy-isobutyiic acid.
References Cited Aktiebolag Hassle, Chemical Abstracts, vol. 62, pp. 485-86, (1965).
Marchetti et al.: Chemical Abstracts, vol. 65, pp. 15, 263, (1966).
ALEX MAZEL, Primary Examiner JOSE TOVAR, Assistant Examiner U.S. Cl. X.R.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1073365 | 1965-05-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3474095A true US3474095A (en) | 1969-10-21 |
Family
ID=11134408
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US546559A Expired - Lifetime US3474095A (en) | 1965-05-14 | 1966-05-02 | Beta - morpholinoethyl - alpha - phenoxy-isobutyrate hydrochloride or citrate salt |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US3474095A (en) |
| FR (1) | FR1588156A (en) |
| GB (1) | GB1154244A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5412112A (en) * | 1994-06-14 | 1995-05-02 | Industrial Technology Research Institute | Derivatives and preparation of 2,2-dimethyl-5-substituted phenoxy-pentanoic acids |
-
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)
| Title |
|---|
| None * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5412112A (en) * | 1994-06-14 | 1995-05-02 | Industrial Technology Research Institute | Derivatives and preparation of 2,2-dimethyl-5-substituted phenoxy-pentanoic acids |
Also Published As
| Publication number | Publication date |
|---|---|
| FR1588156A (en) | 1970-04-10 |
| GB1154244A (en) | 1969-06-04 |
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