US2884426A - Basic esters of mandelic acid and a process of making same - Google Patents

Basic esters of mandelic acid and a process of making same Download PDF

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Publication number
US2884426A
US2884426A US646195A US64619557A US2884426A US 2884426 A US2884426 A US 2884426A US 646195 A US646195 A US 646195A US 64619557 A US64619557 A US 64619557A US 2884426 A US2884426 A US 2884426A
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endomethylene
cyclohexenyl
acid
mandelic acid
ether
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Kottler August
Ohnacker Gerhard
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Boehringer Ingelheim Pharma GmbH and Co KG
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Dr Karl Thomae GmbH
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    • 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
    • C07D295/10—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 doubly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • 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

Definitions

  • E indicates the 2,5-endomethylene-M-cyclohexenyl radical or the 2,5-endomethylene-cyclohexyl radical;
  • R indicates hydrogen, an alkyl radical, preferably an alkyl radical with 1 to 6 carbon atoms or an alkoxy group, preferably an alkoxy group with 1 to 4 carbon atoms;
  • R indicates hydrogen or an alkoxy group, preferably an alkoxy group with 1 to 2 carbon atoms;
  • R, and R indicate an alkyl radical, preferably an alkyl radical with 1 to 4 carbon atoms, and R and R together with the nitrogen atom to which they are attached may be a heterocyclic ring, preferably a pyrrolidine, piperidine or morpholine ring;
  • R indicates hydrogen or an alkyl or aralkyl radical, preferably an alkyl radical with 1 to carbon atoms;
  • X indicates a straight-chain or branched alkylene radical, preferably an alkylene radical with 1 to 4 carbon atoms;
  • Y indicates the anion of an inorganic or organic acid.
  • Said new basic esters of the above-given general Formula I are produced according to the present invention by reacting an a-keto carboxylic acid or its esters ofthe following formula ice wherein R and R are the same substituents as indicated above while R indicates hydrogen or an alkyl radical, with an organo-metal compound of a 2,5-endomethylene compound of the following Formulas IVa and IVb a ra wherein Z indicates alkali metal or, preferably, the magnesium halogenide radical, and hydrolyzing the resulting reaction product.
  • R R and E are the same substituents as indicated above, are then reacted with amino alkyl halogenides of the following formula /Ra Hal-X-N R4 VI wherein R R and X are the same substituents as indicated above, while Hal is halogen, or endocyclicallysubstituted rnandelic acids corresponding to Formula V as given above or their metal salts, or respectively, their alkyl esters are reacted with amino alcohols of the following formula R4 VII wherein R R and X are also the same substituents as indicated above.
  • Reaction of the organo-metal compounds of Formula IVa or lVb with a-keto carboxylic acids, or their esters of the above-given Formula III is carried out under anhydrous conditions, preferably in the presence of an inert solvent, such as ether, benzene or tetrahydrofurane.
  • an inert solvent such as ether, benzene or tetrahydrofurane.
  • said reaction is effected at elevated temperature and more advantageously at the boiling temperature of the solvent employed.
  • an especially advantageous mode of performing the reaction consists of first cooling the reaction mixture to a temperature between about 20 C. and about +5 C. and then completing the reaction by increasing the temperature, preferably to the boiling temperature of the solvent employed.
  • the resulting reaction products are hydrolyzed, for instance by the addition of ice and hydrochloric acid.
  • Esters of endocyclically-substituted mandelic acids produced by said reaction can be saponified, if desired, to the corresponding free mandelic acids of the above-given Formula V. Saponification is eifected, for instance, by boiling with alkali hydroxide or alkali carbonate in an aqueous suspension of the ester or in the presence of a suitable water-soluble solvent, for instance in the presence of ethanol.
  • reaction of endocyclically-substituted mantlelic acids of the above-given Formula V with amino alkylensues carried out in-the presence of an inert solvent, such as I isopropanol. Furthermore, said reaction is also advantageously efiected at elevated temperature, preferably at the boiling temperature of the solvent employed. Frequently it is of advantage to operate in the presence of a hydrogen halide-binding agent, for instance in the presence of an alkali alcoholate.
  • Direct esterification of endocyclically-substituted .mandelic acids of the above-given Formula V "with amino alcohols of the above-given Formula VII is carried out with or without esterification catalysts or by employing azeotropic methods to continuously remove the water formed by the esterification.
  • Reaction of alkyl esters of endocyclically-substituted mandelic acids of Formula V with amino alcohols of Formula VII is preferably effected in the presence of a basic catalyst and advantageously in the presence of alkali metal or alkali metal alcoholate. Said condensation can be carried out in the presence or absence of solvents. Suitable solvents are, for example, tolueneor xylene.
  • the reaction temperature may be as high as 150 C.
  • the preferred temperature range is between about 110 C. and about 130 C. If required, esterification can be effected under reduced pressure.
  • esters of Formula I can be converted, if desired, into their acid addition salts or their quaternary ammonium compounds, said salts and compounds corresponding to the above-given Formula II.
  • esters of Formula I are reacted, if required in the presence of solvents, with compounds of the following formula R Y VIII wherein R and Y are the same substituents as indicated above.
  • solvents there can be employed, for instance, ether, ethanol, acetone, acetic acid ethyl ester, benzene, and the like.
  • Salt formation and quaternization can be effected at a low temperature, if necessary with cooling, as well as at room temperature or at elevated temperature, for instance at a temperature between about 30 C. and about 150 C., and preferably at the boiling point of the solvent employed.
  • the quaternary ammonium compound can also be produced in a sealed tube.
  • the basic esters according to the present invention possess valuable therapeutic properties. They are highly effective spasmolytic agents having a neurotropically as well as a musculotropically effective component.
  • Example 1 A Grignard solution prepared from 176' gm. of 2,5- endomethylene-A -cyclohexenyl bromide and 243 gm. magnesium metal in 400 cc. anhydrous ether was added dropwise, while cooling, to'a solution of 143 gm. benzoyl formic acid ethyl ester in 200 cc. anhydrous other within the course of 2 hours.
  • the reaction mixture was stirred at room temperature for 7 hours and was subsequently heated to boiling for a-short period of time. After cooling, the reaction mixture was poured on a mixture of 7-50 gm. ice and 100 cc. 35% hydrochloric acid. Said mixture was then extracted with ether.
  • the ethereal solution was dried over anhydrous sodium sulfate, the ether was evaporated, and the residue was subjected to fractional distillation in a high vacuum. 154 gm. a-(2,5-
  • Example 2 pvMethyl benzoyl formic acid ethyl ester yielded (2,5 endomethylene-A -cyclohexenyl)-p-methyl mandelic acid having a melting point of 102 C., and its ethyl ester having a boiling point of 165-169 C./25 mm. Hg.
  • Example 3 p-Isopropyl benzoyl formic acid ethyl ester yielded a-(2,5-endomethylene-A -cyclohexenyl)-p-isopropyl mandelic acid having a melting point of 132 C., and its ethyl ester having a boiling point of 1381'40 C./ 0.4 mm. Hg.
  • Example 5 A Grignard solution prepared from 104 gm. of 2,5- endomethylene-M-cyclohexenyl bromide and 14.6 gm. of magnesium metal in 250cc. of anhydrous ether was added dropwise to -a solution of 30 gm. phenyl glyoxylic acid in 300 cc. anhydrous ether, which solution was previously cooled to --15 C. Thereafter the reaction mixture was stirred at room temperature for 1 hour, boiled under reflux for 2 hours, and cooled. The resulting granular precipitate was filtered 01f, washed with ether, decomposed with 300 cc. dilute 20% sulfuric acid, and extracted with ether.
  • Example 2 The resulting decomposition mixture was Worked up by following the procedure described in Example 1 and yielded a-(2,5-endomethylene-d -cyclohexenyD-mandelic acid as obtained according to said Example 1. The yield amounted to 62% of the theoretical yield.
  • Example 7 By using, .in place of 2,5-endomethylenerA ecyclohexenyl bromide, the equimolecular amount of 2,5-endomethylene-cyclohexyl bromide but otherwise following the I were heated under reflux for 12 hours.
  • Example 8 By following the procedure described in Example 8 while replacing the S-dimethylamino propyl chloride with equimolecular amounts of amino alkyl halides, as indicated in Examples 9 to 14 below, and by replacing the tar-(2,5 endomethylene A -cyclohexenyl) mandelic acid with equimolecular amounts of endocyclically-substituted mandelic acids, as indicated in Examples 9 to 14 below, the corresponding basically substituted mandelic acid ester compounds were obtained.
  • Example 9 a-(2,S-endomethylene-cyclohexyl)-mandelic acid prepared according to Example 7 and p-dimethylamino ethyl chloride yielded a-(2,5-endomethylene-cyclohexyl)-mandelic acid-fl-dimethylamino-ethyl ester hydrochloride. Melting point after recrystallization from methyl-ethylketone: 161 C. Yield: 68% of the theoretical yield.
  • Example 10 a-(2,5-endomethylene-A -cyclohexenyl)-p-methyl mandelic acid, prepared according to Example 2, and fl-(4- morpholino)-ethyl chloride yielded a-(2,5-endomethylene- A cyclohexenyl) p methyl-mandelic acid ,B-(4 morpholino)-ethyl ester hydrochloride. Melting point after recrystallization from a mixture of isopropanol and ether (1:2): 176 C. Yield: 74% of the theoretical yield.
  • Example 11 Example 12 a (2,5-endomethylene-A -cyclohexeny)-3,4 dimethoxymandelic acid, prepared according to Example 5, and ,8- diethylamino ethyl chloride yielded a-(2,5-endomethylene- A -cyclohexenyl)-3,4-dimethoxy-mandelic acid-p-diethylamino-ethyl ester hydrochloride. Melting point after recrystallization from isopropanol: 117 C. The compound is highly hygroscopic.
  • Example 13 Y Example 13 'a (2,5-endomethylene-A -cyclohexenyl)-mandelic acid, prepared according to Example 1, and B-(1-piperidino)- ethyl chloride yielded a-(2,5-endomethylene-A -cyclohexenyl)-rnandelic acid-p41-piperidino)-ethyl ester hydrochloride. Melting point after recrystallization from acetone: 180 Yieldi 68% of the theoretical yield.
  • Example 14 a (2,5-endomethylene-A -cyclohexenyl)-p-methyl mandelic acid, prepared according to Example 2, and B-diethyl-amino ethyl chloride yielded a-(2,5-endomethylene- A cyclohexenyl)-p-methyl-mandelic acid-p-diethylamino ethyl ester hydrochloride. Melting point after recrystallization from a mixture of acetone and ether (1:2): 166
  • Example 15 5 gm. a-(2,S-endomethylene-A -cyclohexenyl)-p-(nbutoxy) -mandelic acid, prepared according to Example 4, 2.3 gm. ii-diethylamino ethyl chloride, and 60 cc. of ism propanol were heated under reflux for 12 hours. The resulting solution was filtered while still hot. Isopropanol was removed from the filtrate by vacuum distillation. The residue was dissolved in a small amount of water. Saturated potassium carbonate solution was added thereto and the mixture was extracted with ether. The ethereal extract was dried over anhydrous sodium sulfate and the ether was evaporated.
  • the remaining basic ester was dissolved in 5 cc. isopropanol.
  • the equimolecular amount of an 0.875 molar citric acid solution in ism propanol (18 cc.) was added thereto while heating.
  • the resulting solution was allowed to stand at 0 C. for
  • Example 16 3 gm. 18-(1-piperidino)-ethyl chloride dissolved in 10 cc. isopropanol were added dropwise to a boiling solution of 5 gm. a-(2,5-endornethylene-A -cyclohexenyl)-p-methyl-mandelic acid and 0.45 gm. sodium ill 60 cc. isopropanol within the course of one hour. The reaction mixture was boiled for additional 2 hours. The mixture was filtered while still hot. Isopropanol was removed from the filtrate by distillation in a vacuum. The residue was dissolved in ether.
  • Example 17 27 gm. a-(2,S-endomethylene-A -cyclohexenyl)-mandelic acid-ethyl ester, prepared according to Example 1, were heated with 25 gm. diethylamino ethanol and about 0.05 gm. sodium in an oil bath to a temperature of C. until the ethanol set free during said esterification reaction was distilled off through a column of a length of 20 cm. and a diameter of 1 cm. 6 to 8 hours were required to complete the reaction. The residue was freed from excess diethylamino ethanol by heating in a vacuum and was dissolved in 2 N hydrochloric acid. The solution was washed with ether and was rendered alkaline by the addition of saturated potassium carbonate solution.
  • Example 18 Following the procedure described in Example 17 but using, in place of diethylamino ethanol, an equimolecular amount of dimethylamino ethanol as the one reaction component, yielded the corresponding a-(2,5-endomethylene-A -cyclohexenyl)-mandelic acid B dimethylamino ethyl ester hydrochloride. Melting point after recrystallization from acetone: 184 C. I
  • Example 19 4 gm. a-(2,5-endomethylene-A -cyclohexenyl)-mandelic acid-p-diethylamino-ethyl ester hydrochloride, prepared according to Example 17, were converted into the free base. Twice the required-amount of methyl bromide was '7 added to and admixed with said free base at a temperature of -40 C. The mixture was allowed to stand for 2hours at said temperature and was then kept at C.
  • Example 20 4 gm. a-(2,5-endomethylene-A -cyclohexenyl') mande'lic acid- -dimethylamino-ethyl ester hydrochloride, prepared according to Example 18, were converted into the free base. Twice the required amount of methyl bromide was added and admixed with said free base, and the mixture was reacted and worked up as described in Example 19. 3.9 gm. a-(LS-endOmethyIene A cyclohexeny1)- mandelic acid-n-diethylamino-ethyl ester bromomethylate were'obtained. Melting point after recrystallization from ,iSQPITOPaHOII 170 C. Yield: 82% of the theoretical yield.
  • Example 21 I by vacuum distillation. The residue was dissolved in 2 N hydrochloric acid and the solution was extracted with other. A saturated potassium carbonate solution was then added and the resulting mixture was again extracted with ether. The latter ethereal extraction solution was dried over anhydroussodiurn sulfate and the ether was then evaporated, The remaining basic ester was converted into the corresponding hydrochloride by passing dry hydrogen chloride into an anhydrous ethereal solution of the base. Recrystallization of the reaction product from amixture of methyl-ethyl-ketone and isopropanol (10:1) yielded 32 gm. a-(2,5-endomethylene-A -cyclo hexenyl)- mandelic acid-fi-pyrrolidinoethyl ester hydrochloride, which had a melting Point of 165 C.
  • Example 2 By reacting a-(2,5-endomethylene-A -cyclohexenyl)spmethyl-mandelicacid, prepared in accordance with Example 2 a e, with"fl-py rolid c yl hlorid i a manner analogous to that described In Exam le 24, 42,5-
  • Example 22 1 gm. a-(2,5aendomethylene-A -cyclohexenyl') -mandelic acid-B-dimethylaminoethylester' hydrochloride, prepared acid-B-dimethylaminoethylester decylobromate were ob-.
  • Example '23 3.2 gm. a-(2,5:endomethylene-d -cyclohexenyl).-mandelic acid-,B-dimethylamino-ethyl ,esterhydrochloride,prepared in accordance with Example '18 above, were ,converted into the free base. Twice the required amount of benzylbromide was added thereto, and the mixture was then maintained at 130 C. for about half an hour. After cooling, the excess benzylbromide was removed from the reaction mass by distillation in vacuo. . The residue was admixed with ether, the mixture was filtered, the filter cake was Washed withflether and recrystallized from a mixture of acetone and ether (2:1).
  • Example 24 29:5 gm. a-(2,S-endornethylene+A scyclohexeuyl) man delie acid, prepared in accordance with Example 1. above,
  • Example 27 13.8 gm. 0: 2,5-endomethylene-M-cyclohexenyl) pmethyl-mandelic acid-fi-pyrrolidinoethyl ester, prepared in accordance with Example '25 above, were converted into the correspondingfr ee base. Twice the required amount of methylbromide and 100 cc. ethyl acetate were added to the free base while maintaining the mixture at -20 C.; thereafter, the reaction'mixture was maintained at 0 C. for about 48 hours. The reaction product was filtered ofi, washed with ether and recrystallized from a mixture of methyl-ethylketone and isopropanol (10:1).
  • the new basic esters and especially their acid addition salts and quaternary ammonium compounds are excellent spasmolytic agents. They canbe activity similar to ;that.of-papaverine. .Such compounds are, for instance, a:(2,S-endomethylene-A rcyclohexenyl).-

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US646195A 1954-08-05 1957-03-15 Basic esters of mandelic acid and a process of making same Expired - Lifetime US2884426A (en)

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DE1954T0009816 DE1001261C2 (de) 1954-08-05 1954-08-05 Verfahren zur Herstellung von basischen Estern endocyclisch substituierter Mandelsaeuren und ihren Salzen

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CH (1) CH337519A (de)
DE (1) DE1001261C2 (de)
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GB (1) GB776717A (de)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3144464A (en) * 1959-02-27 1964-08-11 Bayer Ag Beta-phenyl-beta-hydrocarbon-hydracrylic acid-2-nu, nu-diethylamine ethyl esters
US3192209A (en) * 1963-03-11 1965-06-29 Robins Co Inc A H Amino acid esters of 4-hydroxyalkyl-2-pyrrolidinones and 4-hydroxyalkyl-2-thionpyrrolidinones
US3192207A (en) * 1963-03-11 1965-06-29 Robins Co Inc A H Aminoalkyl esters of 4-carboxyalkyl-2-pyrrolidinones and 4-carboxyalkyl-2-thionpyrrolidinones
US3218328A (en) * 1963-02-18 1965-11-16 U S Vitamin & Pharmacentical C Heterocyclic amino phenoxyacetic acids, acid addition salts and quaternary ammonium salts thereof
US3256316A (en) * 1963-06-11 1966-06-14 Pittsburgh Plate Glass Co Adducts of cyclopentadiene ketals
EP1205464A3 (de) * 2000-11-07 2003-03-26 SUMIKA FINE CHEMICALS Co., Ltd. Herstellungsverfahren zur 2-Cyclohexyl-2-hydroxy-Phenylessigsäure, Zwischenprodukt dafür und Herstellungsverfahren davon
US20090036436A1 (en) * 2005-01-26 2009-02-05 Bertrand Leblond 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroaryl-3-hydroxy-2-amino-propionic acid amides and related compounds having analgesic and/or immuno stimulant activity

Citations (3)

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US2265184A (en) * 1938-08-05 1941-12-09 Ciba Pharm Prod Inc Basic esters and process of preparing same
US2490964A (en) * 1945-11-02 1949-12-13 Ciba Pharm Prod Inc Basic esters of trisubstituted acetic acids
US2789110A (en) * 1953-03-14 1957-04-16 Knoll Ag Amino alcohols substituted by bicycloalkyl residues and a process of making same

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Publication number Priority date Publication date Assignee Title
NL68704C (de) * 1900-01-01
US2477796A (en) * 1943-01-28 1949-08-02 Westinghouse Electric Corp Heat-treating furnace
US2554511A (en) * 1949-05-20 1951-05-29 Schieffelin & Co Basic esters of 2-aryl-2-(1-hydroxycyclopentyl) ethanoic acid and acid addition salts of the same
US2558020A (en) * 1949-05-20 1951-06-26 Schieffelin & Co Basic esters of 2-aryl-2-(1-hydroxycyclohexyl) ethanoic acid and acid addition salts of the same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2265184A (en) * 1938-08-05 1941-12-09 Ciba Pharm Prod Inc Basic esters and process of preparing same
US2490964A (en) * 1945-11-02 1949-12-13 Ciba Pharm Prod Inc Basic esters of trisubstituted acetic acids
US2789110A (en) * 1953-03-14 1957-04-16 Knoll Ag Amino alcohols substituted by bicycloalkyl residues and a process of making same

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3144464A (en) * 1959-02-27 1964-08-11 Bayer Ag Beta-phenyl-beta-hydrocarbon-hydracrylic acid-2-nu, nu-diethylamine ethyl esters
US3218328A (en) * 1963-02-18 1965-11-16 U S Vitamin & Pharmacentical C Heterocyclic amino phenoxyacetic acids, acid addition salts and quaternary ammonium salts thereof
US3192209A (en) * 1963-03-11 1965-06-29 Robins Co Inc A H Amino acid esters of 4-hydroxyalkyl-2-pyrrolidinones and 4-hydroxyalkyl-2-thionpyrrolidinones
US3192207A (en) * 1963-03-11 1965-06-29 Robins Co Inc A H Aminoalkyl esters of 4-carboxyalkyl-2-pyrrolidinones and 4-carboxyalkyl-2-thionpyrrolidinones
US3256316A (en) * 1963-06-11 1966-06-14 Pittsburgh Plate Glass Co Adducts of cyclopentadiene ketals
EP1205464A3 (de) * 2000-11-07 2003-03-26 SUMIKA FINE CHEMICALS Co., Ltd. Herstellungsverfahren zur 2-Cyclohexyl-2-hydroxy-Phenylessigsäure, Zwischenprodukt dafür und Herstellungsverfahren davon
US6777576B2 (en) 2000-11-07 2004-08-17 Sumika Fine Chemicals Co., Ltd. Production method of 2-cyclohexyl-2-hydroxy-2-phenylacetic acid intermediate therefor and production method thereof
US20090036436A1 (en) * 2005-01-26 2009-02-05 Bertrand Leblond 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroaryl-3-hydroxy-2-amino-propionic acid amides and related compounds having analgesic and/or immuno stimulant activity
US8288556B2 (en) 2005-01-26 2012-10-16 Allergan, Inc. 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroaryl-3-hydroxy-2-amino-propionic acid amides and related compounds having analgesic and/or immuno stimulant activity
US8927589B2 (en) 2005-01-26 2015-01-06 Allergan, Inc. 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroaryl-3-hydroxy-2-aminopropionic acid amides and related compounds having analgesic and/or immuno stimulant activity

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CH337519A (de) 1959-04-15
DE1001261C2 (de) 1957-07-04
DE1001261B (de) 1957-01-24
GB776717A (en) 1957-06-12
FR1169527A (fr) 1958-12-29

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