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US3301869A - Methobromide and hydrochloride of 1-ethyl-3-pyrrolidyl benzilate - Google Patents

Methobromide and hydrochloride of 1-ethyl-3-pyrrolidyl benzilate Download PDF

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US3301869A
US3301869A US29156A US2915660A US3301869A US 3301869 A US3301869 A US 3301869A US 29156 A US29156 A US 29156A US 2915660 A US2915660 A US 2915660A US 3301869 A US3301869 A US 3301869A
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benzilate
pyrrolidyl
ethyl
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methobromide
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Carl D Lunsford
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AH Robins Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms

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  • the present invention relates to esters of amino alcohols, more particularly certain esters of N- or l-substituted 3-pyrrolidinols. These novel compounds are specifically identified as the N- or 1-substituted-3-pyrrolidyl benzilates.
  • the concept constituting the present invention is illustrated by the following structural formula:
  • R is a hydrocarbon radical, such as alkyl, cycloalkyl and aralkyl.
  • Nontoxic organic and inorganic acid addition salts of the compounds having the general structural formula shown above may be readily prepared as illustrated in the examples below and include salts formed with such inorganic and organic acids as hydrochloric, hydrobromic, hydriodic, sulfuric, sulfamic, phosphoric, acetic, glycolic, succinic, maleic, malic, citric, tartaric, ascorbic, benzoic, cinnamic, mandelic, benzilic, diphenylacetic and the like.
  • Quaternary ammonium salts such as alkyl salts cycloalkyl salts, aralkyl salts, and the like, of the organic bases illustratedin the general structural formula appearing above may be readily formed by treatment of the organic bases with the appropriate quaternary salt forming substances, which include, for example, methyl chloride, methyl bromide, methyl iodide, methyl sulfate, methyl benzenesulfonate, methyl p-to-luenesulfonate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, npropyl iodide, isopropyl bromide, n-butyl chloride, n-butyl bromide, isobutyl bromide, sec.-butyl bromide, n-amyl bromide, n-hexy
  • the asterisk serves to point out the asymmetric carbon atom present in the compounds of the invention.
  • the two separate stereoisomers, or optically active forms are included within the scope of the present invention. Resolution of the optically activeforms may be accomplished by combining the mixture of stereoisomers with an optically active organic acid and separating by fractional crystallization.
  • the present invention is characterized by a particular esterification of a secondary hydroxyl attached directly to a ring carbon in the three position of the pyrrolidine ring.
  • the prior art into which the compounds of the present invention fall can be distinguished.
  • United States Patent 2,655,511 to Woodrulf describes N- or l-pyrrolidyl esters where the alkanol group is extra-cyclic to the pyrrolidine ring (where there is a methylene bridge attached to the heterocyclic nitrogen); United States Patent 2,695,301 to Collinse teaches benzilates proceeding from the two position of the pyrrolidine ring but differing from the present invention in that the hydroxyl esterified is primary and extra cyclic; while United States Patent 2,735,847 to Magnoliae describes diphenylacetates proceeding from the N- or l-position in the pyrrolidine ring and involves extra-cyclic esterification.
  • the new compounds include the benzilates of 3-pyrrolidinols wherein the N- or l-position of the pyrrolidine ring is substituted by a hydrocarbon radical such as straight or branchedchain alkyl, cycloalkyl, aralkyl and the like, preferably lower-alkyl.
  • lower-alkyl is defined to include straight and branched-chain radicals of l-6 carbon atoms inclusive and includes such substituents as methyl, ethyl, isopropyl, tertiary butyl, isoamyl and the like.
  • cycloalkyl is defined to include primarily cyclic alkyl radicals containing 5 to 8 carbon atoms inclusive and encompasses such substituents as cy-clohexyl, cyclopentyl, methyl cyclohexyl, ethyl cyclopentyl, dimethyl cyclohexyl, and cycloheptyl.
  • aralkyl such radicals as lower alkylsubstituted mono-carbocyclic aryl compounds such as benzyl, phenethyl, phenpropyl and the like.
  • R is a hydrocarbon radical containing less than 8 carbon atoms and is selected from the group consisting of lower-alkyl, cycloalkyl and aralkyl.
  • the organic radical of the quaternary ammonium salts of the invention may be, for example any of the specific radicals, or types of radicals, e.g., lower-alkyl, cycloalkyl, or aralkyl, enumerated in this paragraph, the anion of the quaternary amonium salt being, for example, halogen, e.g., chloro, nitr-o (N0 sulfate (S0 or any other anion enumerated in the preceding paragraphs of this specification relating to such quaternary salts.
  • halogen e.g., chloro, nitr-o (N0 sulfate (S0 or any other anion enumerated in the preceding paragraphs of this specification relating to such quaternary salts.
  • esters of this invention are preferred in the form of their nontoxic pharmaceutically acceptable acid addition and quaternary am- Generally also, the N- or l-lower-alkyl therefore preferred.
  • the N- or l-lower-alkyl therefore preferred.
  • specifically preferred compounds are: 1-methy1-3-pyrrolidyl benzilate methobromide 1-methyl-3-pyrrolidyl benzilate hydrochloride 1-ethyl-3-pyrrolidyl benzilate hydrochloride, and 1-ethyl-3-pyrrolidyl benzilate methobromide.
  • esters of the present invention may be rolidinol of the formula:
  • the transesterification reaction is conducted in the presence of a sodium metal catalyst until the theoretical amount of lower alkanol separates.
  • the reaction conditions are similar for all variants of starting compounds, i.e., the reactants, used in approximately equimolar amounts, are heated at reflux temperatures for periods of at least about one hour and usually from one to two hours, preferably using a hydrocarbon solvent as the reaction media.
  • the resulting reaction product is extracted with dilute mineral acid, e.g., hydrochloric acid, and the resulting extract basified (e.g., with aqueous sodium hydroxide) to yield the free base upon extraction with the appropriate solvent.
  • the acid addition salts and quaternary salts are produced from the base by reaction in solvent of the base and the appropriate acid or quaternizing reagent.
  • the methobromide quaternary salt precipitated from a butanone solution of the base and excess methyl bromide after standing for 24 hours. It was crystallized from a butanone-rnethanol mixture; M.P. 169l70.5 C.
  • CiaHziNOs-HCL 10.19 10. 12 347. 83 176-177 Cl'I23NO3'IIG1 9. 80 9. 79 361. 86 148-149 C2lI-l25NO -HCL 9. 43 9.19 375. 88 191. 5-193 C72H27NO3-IICl 9. 09 9.16 389.91 179-180. 5 Czsl'lerNoz-l-lclnt 9. 00 8. 86 389. 91 155-155. 5 C 11 LmNO -HCl..- 8. 13 8.16 485. 95 201. 5-206. 5 C251I NO3- 1101... 8. 36 8.16 423. 92 154.
  • All compounds may be prepared by the alternative modifications of the procedure using either the acid or acid .chloride, or a loWer-alkyl ester of the acid, e.g., methyl.
  • Example-1-is0pr0pyl-3-pyrr0lidyl benzilate A mixture of 72 grams (0.3 mole) of methyl benzilate and 39 grams (0.3 mole) of 1-isopropyl-3-pyrrolidinol in 400 milliliters of heptane was refluxed under a Dean and Stark moisture trap with the addition of four 0.1 gram pieces of sodium at one hour intervals. When the theoretical amount of methanol had separated, the solution was extracted .with 3 N hydrochloric acid. The acid extract was basified with sodium hydroxide solution and extracted with ether. The other layer was washed, dried over sodium sulfate and concentrated, and the residue fractionally distilled :at reduced pressure. Yield: grams (54 percent); B..P. .14l143 C. at 0.2 mm.
  • Isolated guinea pig ileum studies Guinea pigs were killed by a blow on the head. The ileum was removed and terminal segments were suspended in a ml. smooth muscle bath containing Tyrodes solution which was maintained at 37 C. The bath was aerated by bubbling a continuous stream of oxygen therethrough. Intestinal activity was recorded by a balanced ink-writing lever yielding five-fold magnification on a Gorrell and Gorrell kymograph operated at speed-P.
  • Aqueous solutions of all materials were employed in these studies. Essentially, the method consisted of initially standardizing submaximal contractions of the isolated ileum to acetylcholine chloride, histamine phosphate, serotonin creatinine sulfate, and barium chloride. The test material was then introduced into the bath and two minutes later the ileum was again challenged with the various spasmogens. Tests were made at various concentrations of the compounds in the bath until it was pos- 5 sible to differentiate their relative activity as antagonists of the spasmogens.
  • the results of the pharmacological testing indicate that the compounds are predominantly acetylcholine antagonists and are effective in inhibiting gastrointestinal motility in vivo and in vitro. In general, the compounds compared favorably in potency with methantheline bromide under the conditions of these tests.

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Description

United States Patent 3,301,869 METHOBROMIDE AND HYDROCHLORIDE 0F 1-ETHYL-3-PYRROLIDYL BENZILATE Carl D. Lunsford, Richmond, Va., assignor to A. H.
Robins. Company, Inc., Richmond, Va., a corporation of Virginia No Drawing. Filed May 16, 1960, Ser. No. 29,156 2 Claims. (Cl. 260-326.3)
This application is a continuation-in-part of Serial No. 666,250, filed June 17, 1957, now abandoned, and of Serial No. 795,598, filed February 26, 1959, and now Patent No. 2,956,062.
The present invention relates to esters of amino alcohols, more particularly certain esters of N- or l-substituted 3-pyrrolidinols. These novel compounds are specifically identified as the N- or 1-substituted-3-pyrrolidyl benzilates. The concept constituting the present invention is illustrated by the following structural formula:
phenyl wherein R is a hydrocarbon radical, such as alkyl, cycloalkyl and aralkyl.
Nontoxic organic and inorganic acid addition salts of the compounds having the general structural formula shown above may be readily prepared as illustrated in the examples below and include salts formed with such inorganic and organic acids as hydrochloric, hydrobromic, hydriodic, sulfuric, sulfamic, phosphoric, acetic, glycolic, succinic, maleic, malic, citric, tartaric, ascorbic, benzoic, cinnamic, mandelic, benzilic, diphenylacetic and the like.
Quaternary ammonium salts such as alkyl salts cycloalkyl salts, aralkyl salts, and the like, of the organic bases illustratedin the general structural formula appearing above may be readily formed by treatment of the organic bases with the appropriate quaternary salt forming substances, which include, for example, methyl chloride, methyl bromide, methyl iodide, methyl sulfate, methyl benzenesulfonate, methyl p-to-luenesulfonate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, npropyl iodide, isopropyl bromide, n-butyl chloride, n-butyl bromide, isobutyl bromide, sec.-butyl bromide, n-amyl bromide, n-hexyl chloride, benzyl chloride, benzyl bromide, and ethyl sulfate, yielding respectively the methochloride, methobromide, methiodide, methosulfate, methobenzenesulfonate, methop-toluenesulfonate, ethochloride, ethobromide, ethiodide, n-propochloride, n-propobrornide, n-propiodide, is-opropobromide, n-butocblo-ride, n-butobromide, isobutobromide, sec.-butobromide, n-amobromide, n-hexochloride, benzochloride, benzobromide, ethosulfate, etc.
In the structural formula given above, the asterisk serves to point out the asymmetric carbon atom present in the compounds of the invention. The two separate stereoisomers, or optically active forms, are included within the scope of the present invention. Resolution of the optically activeforms may be accomplished by combining the mixture of stereoisomers with an optically active organic acid and separating by fractional crystallization.
Evaluation of the compounds of the invention by standard pharmacological tests has indicated their utility as inhibitors of gastrointestinal motility, comparing favorably in potency with methantheline bromide. The compounds are predominantly antagonists of acetylcholine.
' monium salts.
substituted compounds indicated greater activity and are Patented Jan. 31, 1967 The present invention is characterized by a particular esterification of a secondary hydroxyl attached directly to a ring carbon in the three position of the pyrrolidine ring. The prior art into which the compounds of the present invention fall can be distinguished. United States Patent 2,655,511 to Woodrulf describes N- or l-pyrrolidyl esters where the alkanol group is extra-cyclic to the pyrrolidine ring (where there is a methylene bridge attached to the heterocyclic nitrogen); United States Patent 2,695,301 to Blicke teaches benzilates proceeding from the two position of the pyrrolidine ring but differing from the present invention in that the hydroxyl esterified is primary and extra cyclic; while United States Patent 2,735,847 to Blicke describes diphenylacetates proceeding from the N- or l-position in the pyrrolidine ring and involves extra-cyclic esterification.
Therefore, it is an object of this invention to provide novel benzilates of 3-pyrrolidinols.
It is a further object of the present invention to provide such esters wherein the 3-pyrrolidine portion of the molecule is substituted in the N- or l-position.
It is an additional object of the present invention to provide novel acetylcholine antagonists having a high degree of activity and satisfactory activity when compared with known compounds currently in use as inhibitors of gastrointestinal motility.
Other objects of the invention will become apparent to those skilled in the art to which this invention pertains.
The new compounds include the benzilates of 3-pyrrolidinols wherein the N- or l-position of the pyrrolidine ring is substituted by a hydrocarbon radical such as straight or branchedchain alkyl, cycloalkyl, aralkyl and the like, preferably lower-alkyl.
The term lower-alkyl is defined to include straight and branched-chain radicals of l-6 carbon atoms inclusive and includes such substituents as methyl, ethyl, isopropyl, tertiary butyl, isoamyl and the like. The term cycloalkyl is defined to include primarily cyclic alkyl radicals containing 5 to 8 carbon atoms inclusive and encompasses such substituents as cy-clohexyl, cyclopentyl, methyl cyclohexyl, ethyl cyclopentyl, dimethyl cyclohexyl, and cycloheptyl. Included in the term aralkyl are such radicals as lower alkylsubstituted mono-carbocyclic aryl compounds such as benzyl, phenethyl, phenpropyl and the like. Preferably, R is a hydrocarbon radical containing less than 8 carbon atoms and is selected from the group consisting of lower-alkyl, cycloalkyl and aralkyl. On the other hand, the organic radical of the quaternary ammonium salts of the invention may be, for example any of the specific radicals, or types of radicals, e.g., lower-alkyl, cycloalkyl, or aralkyl, enumerated in this paragraph, the anion of the quaternary amonium salt being, for example, halogen, e.g., chloro, nitr-o (N0 sulfate (S0 or any other anion enumerated in the preceding paragraphs of this specification relating to such quaternary salts.
Generally, for reasons of activity, the esters of this invention are preferred in the form of their nontoxic pharmaceutically acceptable acid addition and quaternary am- Generally also, the N- or l-lower-alkyl therefore preferred. Among specifically preferred compounds are: 1-methy1-3-pyrrolidyl benzilate methobromide 1-methyl-3-pyrrolidyl benzilate hydrochloride 1-ethyl-3-pyrrolidyl benzilate hydrochloride, and 1-ethyl-3-pyrrolidyl benzilate methobromide.
Since the alpha carbon of the acetate group is substituted by a hydroxyl radical, the compounds may alternatively be viewed either as benzilates or phenyl-substituted 'mandelates. The esters of the present invention may be rolidinol of the formula:
wherein R is as indicated above, with an alpha-phenylmandelic [benzylic] acid compound of the formula:
phenyl phenyl( ]C OB 6H wherein B is hydroxy, halogen or lower-alkoxy.
When B is lower-alkoxy, the transesterification reaction is conducted in the presence of a sodium metal catalyst until the theoretical amount of lower alkanol separates. With this exception, the reaction conditions are similar for all variants of starting compounds, i.e., the reactants, used in approximately equimolar amounts, are heated at reflux temperatures for periods of at least about one hour and usually from one to two hours, preferably using a hydrocarbon solvent as the reaction media. The resulting reaction product is extracted with dilute mineral acid, e.g., hydrochloric acid, and the resulting extract basified (e.g., with aqueous sodium hydroxide) to yield the free base upon extraction with the appropriate solvent. The acid addition salts and quaternary salts are produced from the base by reaction in solvent of the base and the appropriate acid or quaternizing reagent.
The preparation of starting N-substituted-3-pyrrolidinols used in the present invention has been previously de- The hydrochloride was precipiated from an ethereal solution of the base with ethereal hydrogen chloride and crystallized from a dry ethyl acetate-ethanol mixture; M.P. 1915-193 C.
The methobromide quaternary salt precipitated from a butanone solution of the base and excess methyl bromide after standing for 24 hours. It was crystallized from a butanone-rnethanol mixture; M.P. 169l70.5 C.
In the same manner as given in the preceding example, by reacting the appropriate 1-hydrocarbon substituted- 3-pyrrolidinol with the appropriate esterifying agent, additional compounds within the scope of the general structural formula are prepared.
Representative products prepared from the chosen starting materials are as follows:
l-phenethyl-3-pyrro1idyl benzilate hydroiodide 1-phenethyl-3-pyrrolidyl benzilate sulfate 1-phenpropyl-3-pyrrolidyl benzilate succinate 1-dimethylbenzyl-3-pyrrolidyl benzilate citrate 1-cycloheptyl-3-pyrrolidyl benzilate methobromide 1-phenethyl-3-pyrrolidyl benzilate tartrate 1-phenpropyl-3-pyrrolidyl benzilate benzoate 1-phenethyl-3-pyrrolidyl benzilate methochloride 1-phenpropyl-3-pyrrolidyl benzilate ethyl iodide l-di-methylbenzyl-3-pyrrolidyl benzilate ethosulfate 1-phenethyl-3-pyrroliclyl benzilate l-phenpropyl-3-pyrrolidyl benzilate imethobenzene sulfonate.
Other compounds within the scope of the invention are shown in Table X. In each instance the free base as well :as the indicated acid addition or quaternary salt was prepared.
TABLE X ph enyl C H2NR phenyl-OO O-OC H 0 H O H2O H2 R Salt Calculated for Percent Found M..W. M. P., C.
CiaHziNOs-HCL" 10.19 10. 12 347. 83 176-177 Cl'I23NO3'IIG1 9. 80 9. 79 361. 86 148-149 C2lI-l25NO -HCL 9. 43 9.19 375. 88 191. 5-193 C72H27NO3-IICl 9. 09 9.16 389.91 179-180. 5 Czsl'lerNoz-l-lclnt 9. 00 8. 86 389. 91 155-155. 5 C 11 LmNO -HCl..- 8. 13 8.16 485. 95 201. 5-206. 5 C251I NO3- 1101... 8. 36 8.16 423. 92 154. 5-150 1:1 CIIQB C'g0I'12lNO3-BI' 10. (5G 19. 79 406. 32 211-212. 5 CHaBr CMHQGNOQBLMH 19.01 19. 420. 34 150-152 e CHaBr. C22H2sNOs-Br- 18. 48 18. 33 432. 36 169-170. 5 ClIaBr czaHaoNos-Brnut 17. 82 17.97 448. 40 170-180. 5 CH BrNn CQQHmNOa-BLMH 17. 82 17.62 448. 40 153. 5-155 01131313.-- C2aHa2NOa-Br 16. 84 16. 48 474. 46 185. 5-187 CtIIaC z CHaBr C2sHzsNOaBr 16. 57 16. 23 482. 41 186-187. 5
scribed in United States Patents 2,830,997 and 2,838,521 of Lunsford.
The following example illustrates the preparation of the compounds of the present invention, but is in no way to be construed as limiting:
All compounds may be prepared by the alternative modifications of the procedure using either the acid or acid .chloride, or a loWer-alkyl ester of the acid, e.g., methyl.
Example-1-is0pr0pyl-3-pyrr0lidyl benzilate A mixture of 72 grams (0.3 mole) of methyl benzilate and 39 grams (0.3 mole) of 1-isopropyl-3-pyrrolidinol in 400 milliliters of heptane was refluxed under a Dean and Stark moisture trap with the addition of four 0.1 gram pieces of sodium at one hour intervals. When the theoretical amount of methanol had separated, the solution was extracted .with 3 N hydrochloric acid. The acid extract was basified with sodium hydroxide solution and extracted with ether. The other layer was washed, dried over sodium sulfate and concentrated, and the residue fractionally distilled :at reduced pressure. Yield: grams (54 percent); B..P. .14l143 C. at 0.2 mm.
In evaluating the compounds of the invention pharmacologically, the following experimental testing procedure was utilized.
Isolated guinea pig ileum studies Guinea pigs were killed by a blow on the head. The ileum was removed and terminal segments were suspended in a ml. smooth muscle bath containing Tyrodes solution which was maintained at 37 C. The bath was aerated by bubbling a continuous stream of oxygen therethrough. Intestinal activity was recorded by a balanced ink-writing lever yielding five-fold magnification on a Gorrell and Gorrell kymograph operated at speed-P.
Aqueous solutions of all materials were employed in these studies. Essentially, the method consisted of initially standardizing submaximal contractions of the isolated ileum to acetylcholine chloride, histamine phosphate, serotonin creatinine sulfate, and barium chloride. The test material was then introduced into the bath and two minutes later the ileum was again challenged with the various spasmogens. Tests were made at various concentrations of the compounds in the bath until it was pos- 5 sible to differentiate their relative activity as antagonists of the spasmogens.
The results of the pharmacological testing indicate that the compounds are predominantly acetylcholine antagonists and are effective in inhibiting gastrointestinal motility in vivo and in vitro. In general, the compounds compared favorably in potency with methantheline bromide under the conditions of these tests.
Various modifications may be made in the compounds of the present invention Without departing from the spirit and scope thereof, and it is to be understood that the invention is limited only by the scope of the appended claims.
I claim:
1. 1-ethyl-3-pyrrolidyl benzilate hydrochloride.
2. 1-ethyl-3-pyrrolidyl benzilate methobromide.
References Cited by the Examiner UNITED STATES PATENTS 2,792,339 5/1957 Ekenstam et al. 260--326.3 2,816,895 12/1957 Ehrhart et al. 260294.3
6 2,844,591 7/ 1958 Feldkamp et al. 260-326.3 2,918,406 12/1959 Biel 260294.3 2,918,407 12/ 1959 Biel 260294.3 2,918,408 12/ 1959 Biel 260294.3 2,987,517 6/1961 Martin et a1. 260326.3 3,157,671 11/1964 Bowman et al 260326.3
FOREIGN PATENTS 483,258 4/ 1938 Great Britain.
555,178 8/1957 Belgium.
159,630 7/1957 Sweden.
OTHER REFERENCES Richters Organic Chemistry, volume 3, pages 3 to 4 (1923).
Biel et al.: J. Am. Chem. Society, lvolume 74, pages 1485-88 (1952).
ALEX MAZEL, Primary Examiner.
20 H. I. LIDOFF, Examiner.
JOSE TOVAR, Assistant Examiner.
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,301,869 January 31, 1967 Carl D. Lu-nsford It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 1, lines 20 to 26, the formula should appear as shown below instead of as in the patent: I
henyl phenyl-C-CO-Of-j R Signed and sealed this 28th day of November 1967.
(SEAL) Attest:
EDWARD M.FLETCHER,JR. EDWARD J BRENNER Attesting Officer Commissioner of Patents

Claims (1)

1. 1-ETHYL-3-PYRROLIDYL BENZILATE HYDROCHLORIDE.
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Cited By (3)

* Cited by examiner, † Cited by third party
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US4990683A (en) * 1986-10-27 1991-02-05 A. H. Robins Company, Incorporated Process for preparing 3-pyrrolidinols
WO2003087094A3 (en) * 2002-04-16 2004-03-18 Almirall Prodesfarma Sa Pyrrolidinium derivatives as antagonists of m3 muscarinic receptors
WO2022111500A1 (en) * 2020-11-26 2022-06-02 Rezubio Pharmaceuticals Co., Ltd Anticholinergic agents

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US2816895A (en) * 1954-11-30 1957-12-17 Hoechst Ag Basic benzilic esters and a process of preparing them
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US2918408A (en) * 1957-04-08 1959-12-22 Lakeside Lab Inc Anti-spasmodic compositions specific for treating spasm of the colon
US2918406A (en) * 1957-04-08 1959-12-22 Lakeside Lab Inc Anti-spasmodics specific for peptic ulcer
US2918407A (en) * 1957-04-08 1959-12-22 Lakeside Lab Inc Anti-spasmodics specific for upper gastrointestinal pain and spasm
BE555178A (en) * 1956-02-22 1960-02-12 Parke Soc NEW CHEMICAL COMPOUNDS HAVING USEFUL THERAPEUTIC PROPERTIES AND METHODS FOR PREPARING THEM.
US2987517A (en) * 1954-04-20 1961-06-06 Cilag Chemie Alpha aryl-3-methyl-pentanoic acid-nu-lower alkyl heterocyclic esters
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US3157671A (en) * 1964-11-17 Ljl-diethyl-a-hydroxypyrrolidimum
GB483258A (en) * 1936-06-08 1938-04-14 Arthur George Bloxam Manufacture of basic esters of polyarylacetic acids
US2792339A (en) * 1952-12-31 1957-05-14 Standard Oil Co Rotary sludge coker wearing ring
US2987517A (en) * 1954-04-20 1961-06-06 Cilag Chemie Alpha aryl-3-methyl-pentanoic acid-nu-lower alkyl heterocyclic esters
US2816895A (en) * 1954-11-30 1957-12-17 Hoechst Ag Basic benzilic esters and a process of preparing them
US2844591A (en) * 1955-10-14 1958-07-22 Mead Johnson & Co 1-substituted-3-pyrrolidylmethyl benzilates and salts thereof
BE555178A (en) * 1956-02-22 1960-02-12 Parke Soc NEW CHEMICAL COMPOUNDS HAVING USEFUL THERAPEUTIC PROPERTIES AND METHODS FOR PREPARING THEM.
US2918408A (en) * 1957-04-08 1959-12-22 Lakeside Lab Inc Anti-spasmodic compositions specific for treating spasm of the colon
US2918406A (en) * 1957-04-08 1959-12-22 Lakeside Lab Inc Anti-spasmodics specific for peptic ulcer
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4990683A (en) * 1986-10-27 1991-02-05 A. H. Robins Company, Incorporated Process for preparing 3-pyrrolidinols
WO2003087094A3 (en) * 2002-04-16 2004-03-18 Almirall Prodesfarma Sa Pyrrolidinium derivatives as antagonists of m3 muscarinic receptors
US20050282875A1 (en) * 2002-04-16 2005-12-22 Maria Prat Quinones Pyrrolidinium derivatives
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CN116669721A (en) * 2020-11-26 2023-08-29 宁康瑞珠生物制药(珠海)有限公司 anticholinergic drugs
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