Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS2956062 A
Publication typeGrant
Publication dateOct 11, 1960
Filing dateFeb 26, 1959
Priority dateFeb 26, 1959
Publication numberUS 2956062 A, US 2956062A, US-A-2956062, US2956062 A, US2956062A
InventorsCarl D Lunsford
Original AssigneeRobins Co Inc A H
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Esters of amino alcohols
US 2956062 A
Abstract  available in
Images(5)
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

Unit S wsPa U ESTERS F AlVIINO ALCOHOLS Carl D. Lnnsford, Richmond, Va., assignor to A. H. Robins Company, Inc., Richmond, Va., a corporation of Virginia No Drawing. Filed Feb. 26, 1959, Ser. No. 795,598

12 Claims. ((31. 260-3263) The present invention relates to esters of amino alcohols, more particularlycertain esters of N.- or l-substituted 3-pyrrolidinols. These novel compounds include the cycloalkyl-aryl-acetates and glycolates of 3-pyrrolidinols. The concept constituting the present invention is illustrated by the following 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, aralkyl salts, and the like, of the organic. bases illustrated in the general structural formula appearing above may be readily formed by treatment of the organic bases with the ap- 2,956,062 Patented Oct. 11, 1960,

2 acid and separating by fractional crystallization the dandl-forms.,, V

Evaluations of the compounds of the above concept by standard pharmacological tests have indicated the utility thereof as inhibitors of gastrointestinal motility, comparing favorably in potency with 'Methantheline bromide; The compounds are predominantly antagonists ofacetylcholine.

This application isa continuation-in-part of Serial No. 666,250, Lunsford, filed June 17, 1957, entitled Esters of Amino Alcohols, now abandoned.

The present invention is characterized by a particular, esterification of a secondaryalcohol attached directly to a ring carbon in the 3.,position of the pyrrolidine ring fraction. The prior art into which the compounds of the present invention fall can be distinguished. United States Patent 2,655,511, Woodruif, describes N or 1 pyrrolidyl esters where the alkanol group is extra-cyclic to the pyrrolidine ring (where there is a methylene bridge attached to the heterocyclic nitrogen); UnitedjStates Patent 2,695,301, Blicke, teaches benzilates proceeding from the 2 position of the pyrrolidine ring but differs from the present invention in that the alcohol group is primary and extra-cyclic; United States Patent 2,735,847, Blicke, describes diphenyl acetates proceeding from the N or'l position in the pyrrolidine ring and involves extracyclic esterification.

propriate quaternary salt, forming substances, which in- 1 elude, for example, methyl chloride, methyl bromide, methyl iodide, methyl sulfate, methylbenzene-sulfonate, methyl p-toluenesulfonate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, n-

propyl 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, methyl methosulfate, fonate, ethochloride, ethobromide, ethiodide, n-propochloride, n-propobromide, n-propiodide, isopropobromide, n-butochloride, n-butobromide, isobutobromide, sec.-bu tobromide, n-amobromide, n hexochloride, benzochloride, benzobromide, ethosulfate, etc.-

.In the structural formula given above, the asterisks 'serve to point out the asymmetric carbon atoms present in many of the compounds of the present invention. When two asymmetric centers are present, pairs of diastereoisomers are possible. 'with their optically active forms are included within the scope of the present invention.

The twopairs of diastereoisomers are separated and resolution of the diastereoisomers into their optically active forms may be accomplished by combining the methobenzenesulfonate, metho-p-toluenesul- These diastereoisomers, together Therefore, it is an object of this invention to provide novelcycloalkyl-aryl-acetic acid esters of 3-py1'rolidinols. It is a further object of the present invention to provide such esters wherein the alpha carbon of the acetate group may be substituted by an additional radical such as hy-. droxyl and wherein the 3-pyrrolidine portion of the molecule is substituted in the N ortl position; I It is, an additional object of the present invention to provide novel acetylcholine antagonists having 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. Members of the new group of compounds. include the alpha-cycloalkyl-aryl.aceticand glycolicacid esters of 3- pyrrolidinols where the N or 1 position of the pyrrolidine ring substituted by a hydrocarbon radical such as alkyl, cycloalkyl, aralkyl and the like,fpreferably lower alkyl. Referring to'R' in the'above structuralformula, the preferred hydrocarbon radicals are alkyl, especially straight and branched chain lower alkyl radicals, cycloalkyl and aralkyl.

The term lower alkyl is defined toinclude straight and branched chain radicals of 1 -6 carbon atoms inclusive and includes such substituents as methyl, ethyl, isopropyl, tertiary butyl, isoamyl and the like. The term c-ycloalkyLis defined to includepr-irnarily cyclic alkyl radicals contain: ing 5 to 8 carbon atoms inclusive and'encompass'es such substituents as cyclohexyl, cyclopentyl, methyl cyclohexyl, ethyl cyclopentyl, dimethyl-cyclohexyl, and cycloheptyl. Included in the term aralkyl are-such radicals as lower alkyl-substituted 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. Q

Referringto R in the above structural formula the cycloalkyl hydrocarbon radicals are defined as above; preferably, the cycloalkyl radical contains at least 5 and less than 8 carbon atoms.

.Referring to R in the above structur'alformulaflfin column 1), R" is preferably an hydroxy radical. ,Gener'ally, forreasons of activity the esters in the formof nontoxic, pharmaceutically acceptable acid addition and quaternary ammonium salt compounds; where a 3 in referring to the structural formula in column 1, R is lower alkyl, R is cyclopentyl and R" is hydroxy, are preferred. Among the specifically preferred compounds are: a

1 ethyl 3 pyrrolidyl alpha-cyclopentylpheuylacetate methobrornide.

1 -'methyl 3 pyrrolidyl alpha-cyclopentyl-mandelate hydrochloride 1 methyl 3 pyrrolidyl alpha-cyclopentyl-mandelate methobrornide l-ethyl-S-pyrrolidyl alpha-cyclohexylphenylacetate hydrochloride l-methyl 3 pyrrolidyl alpha-cyclohexylphenylacetate methiodide 1 ethyl 3 -pyrrolidyl alpha-cyclohexylphenylacetate methiodide 1 benzyl 3 pyrrolidyl alpha-cyclohexylphenylacetate methobrornide The alpha carbon of the acetate group preferably is further substituted by a hydroxy radical, i.e., wherein R" is a hydroxy radical. Such compounds may be alternatively viewed as substituted glycolates or mandelates.

A highly preferred compound by reason of activity from these esters having a hydroxy radical on the alpha carbon of the acetate is the 1-rnethyl-3-pyrrolidyl alpha-cyclopentyl-mandelate methobrornide (1-methyl-3-(alpha-cyclopentylphenylhydroxyacetyloxy) pyrrolidine methobromide). This compound was found to be active at a. dilution of about one part in 100,000,000 in counter-acting spasms induced by acetylcholine in isolated intestinal strips. Other preferred compounds include l-methyl-3- pyrrolidyl alpha-cyclopentyl-mandelate hydrochloride and 1-ethyl-3-pyrrolidyl alpha-cyclopentyl-mandelate hydrochloride.

Generally, the N or 1. lower alkyl substituted compounds indicated greater activity and generally the alphacycloalkyl-mandelates were preferred.

The esters of the present invention may be prepared by reaction of a l-hydrocarbon substituted-3-pyrrolidinol of the formulawherein R is as above with an alpha. aryl acetic acid compound of the formula:

wherein R and R are as above and B isv 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 medium. Theresulting 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 the starting N-substituted-3-pyrrolidinols used in the present invention has been previously described in United States Patents 2,830,997 and 2,838,- 521, Lunsford.

The following examples illustrate the preparation of the compounds of the present invention:

All compounds may be prepared by the alternative modifications of the procedure using either the acid or acid chloride, or the lower-alkyl ester of the acid, e.g., the methyl ester.

EXAMPLE l.-1-METHYL-3 -PYRROLIDYL ALPHA- CYCLOHEXYLPHENYLACETATE To a solution of 71 grams (0.3 mole) of alpha-cyclohexylphenylacetyl chloride in toluene were added 35.5 grams (0.35 mole) of l-methyl-3-pyrrolidinol at a dropwise rate with stirring. After complete addition the mixture was refluxed for four hours, cooled and extracted with 3 N hydrochloric acid. The acid extract was basified with aqueous sodium hydroxide and extracted with chloroform. The chloroform layer was washed, dried over sodium sulfate and concentrated. The residue was distilled at reduced pressure. Yield 50 grams (55 percent); boiling point l44-l47 C. at 0.5 mm.

The hydrochloride was precipitated from an ethereal solution of the base with ethereal hydrogen chloride and crystallized from butanone; melting point l53.5154.5 C.

The methiodide quaternary precipitated from an ethereal solution was the base and excess methyl iodide after standing for several hours. It was crystallized from butanone; melting point 169.5-170.5 C.

EXAMPLE 2.--l-n-BUTYL-3-PYRROLIDYL ALPHA- CYCLOPENTYLPHENYLACETATE To a solutionof 89 grams (0.4 mole) of alpha-cyclm pentylphenylacetyl chloride in benzene were added 71.5 grams (0.50 mole) of l-n-butyl-3-pyrrolidinol at a dropwise rate with stirring. After complete addition the mixture was refluxed for two hours, cooled and extracted with 3 N hydrochloric acid. The acid extract was basified with aqueous sodium hydroxide and extracted with ether. The layer was washed, dried over sodium sulfate, and concentrated. The residue was distilled at reduced pressure. Yield grams (67 percent); boiling point -155 C. at 0.1 mm.

The hydrochloride was precipitated from an ethereal solution of the base with ethereal hydrogen chloride and crystallized from butanone; melting point 107.5l09.5 C.

The methobrornide quaternary was precipitated from an ethereal solution of the base and excess methyl bro mide after standing for thirty-six hours. it was crystallized first from an ethyl acetate-ether mixture and then from butanone; melting point 104-106 C.

EXAMPLE 3 .l-BENZYL-3-PYRROLIDYL ALPHA- CYCLOHEXYLPHENYL-ACETATE To a solution of 71 grams (0.3 mole) of alpha-cyclohexylphenylacetyl chloride in toluene were added 62 grams (0.35 mole) of 1-benzyl-3-pyrrolidinol, at a dropwise rate with stirring. After complete addition the mixture was refluxed for four hours, cooled and extracted with 3 N hydrochloric acid. The acid extract was basified with aqueous sodium hydroxide and extracted with chloroform.

70 The chloroform layer was washed, dried over sodium sulfate and concentrated. The residue was distilled at reduced pressure. Yield 45.5 grams (40 percent); boiling point l8718'9 C. at 0.01 mm.

The hydrochloride was precipitated from an ethereal splution of: the base with ethereal hydrogen chloride and crystallized from butanone; melting point 142-143.5 C.

The methyl bromide quaternary precipitated from an ethereal solution of the base and excess methyl bromide, after standing for twenty-four hours, as an oil. This was crystallized from an ethyl acetate-ethermethanol mixture; melting point 183-185 C.

EXAMPLE 4.1-METHYL-3 -PYRROLIDYL ALPHA- CYCLOPENTYLPHENYLACETATE To a solution of 52 grams (0.244 mole) of alpha-cyclopentylphenylacetyl chloride in benzene were added 25 grams (0.248 mole) of 1-methyl-3-pyrrolidinol, at a dropwise rate, with stirring. After complete addition the mixture was refluxed for two hours, cooled and extracted with 3 N hydrochloric acid. The acid extract was basified with aqueous sodium hydroxide and extracted with ether. The ether layer was washed, dried over sodium sulfate, and concentrated. Theresidue was distilled at reduced pressure. Yield 40 grams (63 percent); boiling point 144-147? C. at 0.2 mm. s

The hydrochloride was precipitated as an oil from an ethereal solution of the base with ethereal hydrogen chloride. This was crystallized from a methonol-ethyl acetate mixture and melted at 114-l15 C.

The methyl bromide quaternary was precipitated from an ethereal solution of the base and excess methyl bromide after standing for seventy-two hours. It was purified by recrystallization from butanone and melted at 166.5- 168 C. r

EXAMPLE 5.-1-n-BUTYL-3-PYRROLIDYL ALPHA- CYCLOPENTYLMANDELATE A mixture of 54 grams (0.216 mole) of methyl alphacyclopentylmandelate and 39 grams (0.272 mole) of l-n-butyl-Bpyrrolidinol in 500 ml. of heptane was refiuxed under a Dean and Stark moisture trap, with the addition of four 0.1 gram pieces of sodium at one hour intervals. After five hours refluxing the solution was concentrated at one half volume, diluted with ether and washed with water. The ether layer was dried over sodium sulfate and concentrated. Theresidue was fractionally distilled at reduced pressurel Yield 60 grams (80.5 percent); boiling point 160-165 C. at 0.04 mm.

The hydrochloride was precipitated from an ethereal solution of the base with ethereal hydrogen chloride as an oil. It was crystallized from butanone and melted at 129-130 C.

Analysis.Calcd for C H NO 1-HCl: or, 9.28.

Analysis.Calcd for C H NO -CH Br: Br, 18.15.

Found: Br, 17.98.

A mixture of 42.5 grams (0.17 mole) of methyl alphacyclopentyl mandelate and 18 grams (0.175 mole) of 1-methyl-3-pyrrolidinol in 500 ml. of heptane-was refiuxed under a Dean and Stark moisture trap, with the addition of four 0.1 gram pieces of sodium at one hour intervals. After five hours refluxing the solution was concentrated to one half volume, and extracted with cold 3 N HCl. The acid extract was made alkaline with aqueous sodium hydroxide and extracted with ether which was washed, dried over sodium sulfate, filtered and concentrated. The residue was fractionated at reduced pressure. Yield 33 grams (64%); boiling point 151154 C./0.2 mm. 11 1.5265.

The hydrochloride salt was precipitated as an oil from an ethereal solution of the base with ethereal hydrogen "chloridei It' was crystallized from butanone; melting EXAMPLE 7.--1-ETHYL-3-PYRROLIDYL ALPHA- CYCLOPENTYLMANDELATE HYDROCHLORIDE This compound was prepared according to the method outlined for the methyl derivative above (see Example 6). The base boiled at 162-165 C./0.25 mm. After recrystallization from butanone :the salt melted 160- 161.5 C.

Analysis.--Calcd for C H NO Cl, 10.02. Found: Cl-, 9.82.

EXAMPLE 8.1 CYCLOHEXYL-3-PYRROLIDYL ALPHA CYCLOPENTYLMANDELATE HYDRO- CHLORIDE.

This compound was prepared according to the method outlined for the methyl derivative above as in Example 6. The base boiled at 193-195 C./0.038 mm. After recrystallization from butanone and absolute ethanol the salt melted 2l2213.5 C.

Analysis.Calcd for C H NO -HC1: Cl", 8.69. Found: Cl, 8.81.

EXAMPLE 9.lMETHYL-3-PYRROLIDYL ALPHA- CYCLOHEXYLMANDELATE A mixture of 10 grams (0.0403 mole) of methyl alphacyclohexylmandelate and 5 grams (0.0493 mole) of N- rnethyl-3-pyrrolidin0l' in ml. of n-heptane was refluxed for five hours under a Dean and Stark moisture trap. At approximately equal intervals starting at zero time three approximately 0.1 gram pieces of sodium metal were added to the reaction. At completion of the reflux time the heptane solution was extracted wtih icecold 3 N hydrochloric acid. The acid extract was basi-. fied with saturated aqueous potassium carbonate and extracted with ether. The ether extract was washed, dried over magnesium sulfate and concentrated. The residual oil was distilled at -163 C./ 0.3 mm. giving an amber oil product. Yield 8.7 grams (68%).

The hydrochloride salt was precipitated as a crystalline solid from an ethereal solution of the base with ethereal hydrogen chloride. It was crystallized from a butane methanol mixture; M.'P. 206-207 C. a I

Analysis.-Calcd for C H NO -HCl: C-l"',- 10.02. Found: c1,10.00. I I

The methyl bromide quaternary was prepared-by saturating a solution of the free base in dry'- ethyl etherfwith methyl bromide and allowing the solution to stand 15 The product precipitated as white crystals' 'and hours. was recrystallized from butanone; M.P. 253-255 C (d).

This decomposition range varies with the rate at which the sample is heated.

Analysis.Calcd for C H NO -Br: Br 19.38. Found: Br", 19.27. i a As pointed out in column 1, those compounds which have two asymmetric centers are capable of existing in two diastereoisomeric forms. These two-forms can be separated by fractional crystallization as shown in the following exam l ture trap. At approximately equal intervals, starting at zero time, three approximately 0.1 gram pieces of sodium metal were added to the reaction. At completion of the reflux time the heptane solution was extracted with ice cold 3 N hydrochloric acid. The acid extract was basified with aqueous sodium carbonate and extracted with ether. The ether extract was washed, dried over sodium sulfate and concentrated. The residual oil was distilled at 1571-60 C./0.05- mm., giving an amber oil product. Yield 31.7 grams (56%). V

This material was converted to the hydrochloride salt by precipitation as a crystalline solid from an ethereal solution of the base with ethereal hydrogen chloride. This material was fractionally crystallized from methyl ethyl ketone and from an ethyl acetate methanol mixture. High and low melting isomers were obtained:

Other compounds within the scope of the invention are shown in Table I. In each instance the free base as well as the indicated acid addition or quaternary salt was prepared.

Table I R C Hz-N-R C-C O O CH I A CH2CH7 R R A Salt Calculated f01'- Pegcient Found M.W M.P., C

CH3 Cy-CsHu H HCI CwHwNOrHCl 16. 49 10. 46 337. 88 153. 5-154. 5 C 115 cy-CsHu H 1101 CzoHzoN'Oz-HCl 10. 01 10. 14 351. 91 125 -127. 5 i-CsH'; CY-CaHn H HCI CzrHmNOz-HCI 9. 69 9. 67 365. 9.1 164 -167 D-C4Ha Cy-CaHu H H01 CwzHmNOz H01 9: 34 9. 28 379. 96 100 -151 i-C4Ho Cy-CsHn H H01 CHHKJNO: H01 9. 34 9. 27 379. 96 139. 5-1415 t-C4H9 (Dy-C 11 H I'ICI CzzHzgNOz H01 9. 34 9. 43 379. 96 141 -142 (By-0 11 1 cy-OuH H HCl C24H3 NO2 HCl 8. 73 8. 62 405. 98 226 -227. 5 CaHsCHz Cy-CeHrr H V HCl C25H31NO HC1 8. 57 8. 69 413. 93 142 -143. 5 CH3 CY-CgHq H H01 C15H25NO2 HCl 10. 95 10. 93 323. 85 114 -115. 5 C2115 CY-C5H9 H 1101 OmHzrNOz-HCI 10. 49 10. 31 337. 88 113 --114 11-C4H9 Cy-CsHa H H01 C2iH31NO2-HC1 9. 69 9. 67 365. 93 107. 5-109. 5 CY-CsHn (.y-C5Hq H H01 Cz3H33NOz-HC1 9. Q5 8. 90 391. 97 191 192. 5 C5H CH2 Cy-C5H9 H H01 CttHtONOz-HCl 8. 86 8. 70 399. 94 138 -139 CH3 Cy-CuHu H. CH3]: CZOHKUNO'g-I 28. 62 28. 67 443. 37 169. 5-176 5 CH3 cy-O5H H CHsBI' C aHaoNOa-Bl 26. 16 20. 2S 2116. 36 177. 5-179 C2115 Cy-CgH H CH3]: CmHazNOrI 27. 74 27. 70 457. 40 130 133 1-C4H9 Cy-CaHn H CHaBI CnHaeNOrBl 18. 23 17. 93 4'33. 168. 5-170 t-CtHe Cy-CuHn H CH3B1 CggHaaNOg- B1 18. 23 18. 12 438. 45 177 -178 CoH5CHz Cy-CaHn H CHaB! CznHuNOz-BI 16. 92 16. 62 472. 46 183 -185 H3 cy-O H H CHzBI CmHzgNOz-Br 20. 96 21. 13 382. 34 166. 5-163 CgH5 try-C514 H CHsBI CZUHanNOzBl 26. 16 26. 14 396. 37 152. 5-154 n-C Hq Cy-C H9 H CHaBI' CMHIHNOziBI 18. 83 18. 72 424. 42 167. 5-108. 5 cy-CgHn 0y-C5H9 H CHaBI HHMNOL'BT 17. 74 18. O1 448. 45 191. 5-193 CeH5CHz cy-C H H CHaBr Cz5H32NO2-Br 17. 51 17. 67 407. 43 175. 5-176. 5 H3 (By-C5119 OH H01 CrgH aNOa-HCI 10. 43 10. 30 509. 85 170 -171. 5 C2115 (fly-C 119 OH HCl CmHzlNOs-HCJ 16. 62 9. 82 .553. 88 160 -161. 5 H'CJHQ (By-C5119 OH 1101 CmHgzNOg-HCI 9. 2S 9. 17 381. 93 129 -13[) (fly-05H ey-C H OH H01 CuHsaNOrHCl 8. 69 8. 81. 467. 97 212 -213. 5 CH3 (III-C 11 OH CHzBI CnHrsNOa-BI 26. 66 19. 78 398. 3-1 193 494. 5 D'C-IHG (y-C5110 OH CHaBI' CzgHzqNOa-BI 18. 15 17. 98 140. 42 176 -177. 5 CBH5CH2 Cy-C H9 OH CHaBr C251'I32NO3BI' 16. 84 16. S3 474. 43 173 -175 cy-CuHn CY-C H9 OH CHaBr C24H35NO3'B1' 17. 13 16. 93 466. 4.5 193 196 CH3 C"-C6Hr1 OH HC1 CIQHQ'INOZ'HCl 10. 02 10. O0 353. S6 206 -2U7 CH3 (By-09H OH CHgBl CzuHeuNOz-Br 19. 38 19.27 412. 36 253 255 0211561401111) cyIhI-In OH H01 C1aH2gNO3-C1 9. 64 9. 68 367. 91 184 185 CgHaQi-fOlfll) (Dy-C51 1 OH IIC-l CzoHzqNOs- C1 9. 64 9. 65 367. 91 219 -220. 5 021-15 cy-C H OH CHaBl' CzrHtzNOyBt 18. 74 18. 59 426. 39 181 -182. 5

2.5 grams of material, M.P. 184185, and 13.8 grams of material melting 219-2205". A mixture of these two isomers melted at 178182 C.

Analysis of high melting is0mer.Calcd for C H NO -HCl: C, 65.29; H, 8.22. Found C, 65.55; H, 8.33.

Analysis of low melting is0mer.Calcd for c, H,,N0 -Hc1; C, 65.29; H, 8.22. Found: C, 65.45; H, 8.39.

The low melting isomer is designated the alpha (0:) form and the high melting isomer is referred to as the beta (13) form in Table I.

In the same manner as given in the preceding examples, by reacting the appropriate l-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:

alpha-cyclopentylphenylacetate In evaluating the compounds of the present invention pharmacologically the following experimental testing procedure was utilized.

ISQLATED 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 bubling a continuous stream of oxygen through it. 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 acetylchlorine 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 possible 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 eflective 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. A compound selected from the group consisting of esters of B-pyrrolidinols having the structural formula wherein R is a hydrocarbon radical selected from the group consisting of lower alkyl, phenylalkyl containing up to nine carbon atoms inclusive, and cycloalkyl containing five to eight carbon atoms inclusive and having five to seven carbon atoms inclusive in the ring.

R is a cycloalkyl hydrocarbon radical containing five to eight carbon atoms inclusive and having five to seven carbon atoms inclusive in the ring, and

R" is a radical selected from the group consisting of hydrogen and hydroxyl; and nontoxic acid addition and lower-alkyl and benzyl quaternary ammonium salts thereof.

2. l-methyl- 3 -pyrrolidyl alpha-cyclopentylmandelate methobromide.

3. 1-methyl-3 -pyrrolidyl alpha-cyclopentylmandelate hydrochloride.

4. 1-ethyl-3-pyrrolidyl alpha-cyclopentylphenylacetate methobromide.

5. l-methyl 3 pyn'olidyl alpha cyclohexylphenylacetate methiodide.

6. l-methyl 3 pyrrolidyl alpha cyclohexylphenylacetate hydrochloride.

7. l-ethyl 3 py-rrolidyl alpha cyclohexylphenylacetate methiodide.

8. l-benzyl-3-pyrrolidyl alpha-cyclohexylphenylacetate methobromide.

9. 1-lower-alkyl-3 pyrrolidyl cycloalkylmandelate having the structural formula:

cycloalkyl lLwer-alkyl wherein the cycloalkyl radical contains five to eight carbon atoms, inclusive, and has five to seven carbon atoms, inclusive, in the ring.

10. Non-toxic acid addition salt of a compound of claim 9.

11. Non-toxic lower-alkyl quaternary ammonium salt of a compound of claim 9.

12. l-methyl 3-pyrrolidyl alpha-cyclopentylmandelate.

References Cited in the file of this patent Richters Organic Chemistry, vol. 3, pp. 3 to 4 (1923).

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2317804 *May 28, 1940Apr 27, 1943Hans KraikallzN-vinyl lactams
US2792399 *May 24, 1955May 14, 1957Bofors AbAnilides of heterocyclic compounds
US2799679 *Jul 28, 1955Jul 16, 1957Bofors AbProcess of preparing amides of heterocyclic carboxylic acids
US2816895 *Nov 30, 1954Dec 17, 1957Hoechst AgBasic benzilic esters and a process of preparing them
BE555178A * Title not available
GB483258A * Title not available
GB532943A * Title not available
GB788126A * Title not available
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3091570 *Aug 8, 1960May 28, 1963Lakeside Lab IncAntidepressant: 3-pyrrolidyl glycolates
US3138614 *Dec 18, 1961Jun 23, 1964Lilly Co EliSalts of 1, 1-dimethyl-3-pyrrolidyl phenyl-2-thienylglycolate
US3211747 *Oct 10, 1961Oct 12, 1965Union Carbide CorpN-carbamylmethyl-maleimides
US4990683 *Jan 11, 1988Feb 5, 1991A. H. Robins Company, IncorporatedProcess for preparing 3-pyrrolidinols
US6307060 *May 11, 1999Oct 23, 2001Christian NoeEnantiomerically pure basic N-heterocyclic arylcycloalkylhydroxycarboxylic esters, processes for their preparation and their use in medicaments
US6395757Jul 23, 1999May 28, 2002Arthur M. BobroveMethod for treating hot flashes in humans
US6420392Jan 6, 1995Jul 16, 2002Millennium Pharmaceuticals, Inc.Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders
US6433003Apr 19, 2000Aug 13, 2002Arthur M. BobroveMethod for treating hyperhidrosis in mammals
US7192978Apr 11, 2003Mar 20, 2007Almirall Prodesfarma AgPyrrolidinium derivatives
US7253182 *Jun 23, 2003Aug 7, 2007Sofotec Gmbh & Co. KgEnantiomerically pure basic arylcycloalkylhydroxycarboxylic esters, processes for their preparation and their use in medicaments
US7465751Dec 23, 2002Dec 16, 2008Ranbaxy Laboratories Limited1-substituted-3-pyrrolidine derivatives as muscarinic receptor antagonists
US8153669 *Dec 22, 2005Apr 10, 2012Novartis AgQuaternary ammonium salts as M3 antagonists
US8309732Apr 6, 2009Nov 13, 2012Saltigo GmbhProcess for preparing quaternary salts of piperidyl esters of mandelic acid
US8324266Oct 26, 2011Dec 4, 2012Pearl Therapeutics, Inc.Compositions, methods and systems for respiratory delivery of two or more active agents
US8703806Dec 3, 2012Apr 22, 2014Pearl Therapeutics, Inc.Compositions, methods and propellant-based systems for respiratory delivery of glycopyrrolate and one or more active agents
US8808713May 28, 2010Aug 19, 2014Pearl Thereapeutics, Inc.Compositions for pulmonary delivery of long-acting β2 adrenergic receptor agonists and associated methods and systems
US8815258May 17, 2011Aug 26, 2014Pearl Therapeutics, Inc.Compositions, methods and systems for respiratory delivery of two or more active agents
US8846954Mar 3, 2006Sep 30, 2014Sosei R&D Ltd.Crystallisation and purification of glycopyrronium bromide
US9006461Sep 11, 2013Apr 14, 2015Dermira, Inc.Crystalline glycopyrrolate tosylate
US9006462Aug 29, 2014Apr 14, 2015Dermira, Inc.Glycopyrrolate salts
US20120022127 *Apr 7, 2010Jan 26, 2012Thomas AllmendingerProcess for preparing pyrrolidinium salts
CN101133021BMar 3, 2006Jan 19, 2011索塞R&D有限公司Crystallisation and purification of glycopyrronium bromide
DE102008020746A1Apr 25, 2008Oct 29, 2009Saltigo GmbhVerfahren zur Herstellung von quarternären Salzen von Piperidyl Estern der Mandelsäure
EP2112137A1Apr 9, 2009Oct 28, 2009Saltigo GmbHMethod for producing quarternary salts from mandelic acid piperidyl esters
EP2607351A1Dec 22, 2011Jun 26, 2013Cerbios-Pharma S.A.Continuous process for the alkylation of cyclic tertiary amines
EP2682100A2Jul 4, 2013Jan 8, 2014Sanovel Ilac Sanayi ve Ticaret A.S.Inhalation Compositions Comprising Muscarinic Receptor Antagonist
EP2682103A2Jul 4, 2013Jan 8, 2014Sanovel Ilac Sanayi ve Ticaret A.S.Compositions Comprising Muscarinic Receptor Antagonist and Sorbitol
EP2682129A2Jul 4, 2013Jan 8, 2014Sanovel Ilac Sanayi ve Ticaret A.S.Compositions Comprising Muscarinic Receptor Antagonist and Glucose Anhydrous
WO1998021183A1 *Nov 11, 1997May 22, 1998Christian R NoePure enantiomer basic aryl-cycloalkyl-hydroxycarboxylic acid esters, process for preparing the same and their use in medicaments
WO2003087094A2 *Apr 11, 2003Oct 23, 2003Almirall Prodesfarma SaPyrrolidinium derivatives as antagonists of m3 muscarinic receptors
WO2004056767A1 *Dec 23, 2002Jul 8, 2004Jang Bahadur Gupta1-substituted-3-pyrrolidine derivatives as muscarinic receptor antagonists
WO2006092617A1 *Mar 3, 2006Sep 8, 2006Sosei R & D LtdCrystallisation and purification of glycopyrronium bromide
WO2008000482A1Jun 28, 2007Jan 3, 2008Novartis AgCompositions of glycopyrronium salt for inhalation
WO2010115937A1Apr 7, 2010Oct 14, 2010Novartis AgProcess for preparing pyrrolidinium salts
WO2010138868A2May 28, 2010Dec 2, 2010Pearl Therapeutics, Inc.Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting b2 adrenergic receptor agonists and associated methods and systems
WO2011076842A2Dec 22, 2010Jun 30, 2011Chiesi Farmaceutici S.P.A.Aerosol formulation for copd
WO2011076843A2Dec 22, 2010Jun 30, 2011Chiesi Farmaceutici S.P.A.Combination therapy for copd
WO2011157387A1Jun 13, 2011Dec 22, 2011Chiesi Farmaceutici S.P.A.Crystal form of glycopyrronium chloride
WO2011157536A1May 30, 2011Dec 22, 2011Chiesi Farmaceutici S.P.A.Process for the preparation of glycopyrronium chloride
WO2012106575A1Feb 3, 2012Aug 9, 2012Novartis AgDry powder formulations of particles that contain two or more active ingredients for treating obstructive or inflammatory airways diseases
WO2014007769A1Jun 28, 2013Jan 9, 2014Sanovel Ilac Sanayi Ve Ticaret Anonim SirketiCompositions comprising muscarinic receptor antagonist and glucose anhydrous
WO2014062143A2Oct 11, 2013Apr 24, 2014Mahmut BilgicAnticholinergic agent combinations
WO2014077787A1Oct 11, 2013May 22, 2014Mahmut BilgicCombinations including abeta2 agonist and glycopyrrolate
WO2014147541A3 *Mar 16, 2014Feb 19, 2015Mahesh KandulaCompounds and compositions for the treatment of peptic ulcers and gastrointestinal diseases
Classifications
U.S. Classification548/556
International ClassificationC07D207/12
Cooperative ClassificationC07D207/12
European ClassificationC07D207/12