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US3678137A - Adamantyl-substituted-alkyl 2-aminoethyl phosphates and phosphonates - Google Patents

Adamantyl-substituted-alkyl 2-aminoethyl phosphates and phosphonates Download PDF

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US3678137A
US3678137A US81109A US3678137DA US3678137A US 3678137 A US3678137 A US 3678137A US 81109 A US81109 A US 81109A US 3678137D A US3678137D A US 3678137DA US 3678137 A US3678137 A US 3678137A
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adamantyl
aminoethyl
solution
ether
substituted
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Francis R Pfeiffer
Jerry A Weisbach
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Smith Kline and French Laboratories Ltd
SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4075—Esters with hydroxyalkyl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/86—Renin inhibitors

Definitions

  • This invention relates to adamantyl-substituted-alkyl 2- aminoethyl phosphates and phosphonates.
  • Renin is an enzyme which is released from the kidney into the bloodstream where it acts upon a substrate, an 01-2- globulin, in blood plasma to form a decapeptide, angiotensin I.
  • a converting enzyme acts upon this substance to produce angiotensin II which is a very potent pressor substance.
  • a renin inhibitor is therefore useful in reducing blood pressure of renal hypertension.
  • renin substrate is incubated with renin and the compound to be tested, and the angiotensin I formed is hydrolyzed in vitro with converting enzyme to give angiotensin H and histidyl-leucine. The amount of histidyl-leucine is then measured spectrophotofluorometrically.
  • Y is an alkylene chain of one to four carbon atoms having zero to two lower alkyl substituents; R, is l-adamantoyl or 1-adamantyl-( CH Advantageous compounds of this invention are represented by Formula I in which Y is a straight alkylene chain of one to four carbon atoms.
  • Preferred compounds of this invention are represented by Formula l in which Y is a straight alkylene chain of one to four carbon atoms and R is The compounds of this invention are prepared by the following procedures:
  • R is hydroxy, hydroxy protected by, for example, 2,2,2- tn'chloroethoxycarbonyl or benzyl, or iodo and R, is hydroxy when R, is hydroxy or a protected hydroxy group, or iodo when R, is iodo.
  • adamantyl substituted intermediates of Formula III are prepared by incorporating l-adamantoyl or l-adamantyl- (CH on an alkanol starting material of Formula II by methods generally known to the art for preparing O-substituted alkanol compounds, for example as follows.
  • the compounds of Formula II] in which R, is l-adamantoyl are prepared by reacting an excess of an alkanol of Formula II in which R, is hydroxy, 2,2,2-trichloroethoxy-carbonyloxy or iodo with l-adamantoyl chloride and when R, is trichloroethoxycarbonyloxy, removing the trichloroethoxycarbonyl protecting group with acid.
  • the compounds of Formula II] in which R, is l-adamantylmethyl(or ethyl) are prepared by reacting an alkanol of Formula II, as the sodium salt, in which R, is hydroxy or benzyloxy (prepared by reacting an alkanediol with benzyl chloride in the presence of base such as potassium hydroxide in a solvent such as benzene) with a l-adamantyl-methyl(or ethyl) methylsulfonate, p-toluenesulfonate or halide and when R, is benzyloxy, removing the benzyl protecting group by hydrogenation using a catalyst such as palladium in a solvent, for example ethyl acetate or acetic acid.
  • a catalyst such as palladium in a solvent, for example ethyl acetate or acetic acid.
  • the compounds of Formula ll in which R, is l-adamantyl are prepared by reacting an alkanol of Formula II in which R, is benzyloxy with p-toluenesulfonyl chloride, reacting the resulting O-benzyl-O-p-toluenesulfonylalkanediol with the sodium salt of l-adamantanol (prepared by reacting l-adamantanol with sodium hydride in dimethylsulfoxide) and then removing the benzyl group by hydrogenation.
  • an adamantyl substituted alkanediol intermediate is treated with p-toluenesulfonyl chloride, the resulting O-adamantyl substituted O-p-toluenesulfonylalkanediol is treated with sodium diethyl phosphonate and the resulting adamantyl substituted alkylphosphonate is treated with acid or base to give the adamantyl-substituted-alkylphosphonic acid which is then converted to the optionally N-substituted aminoethyl or quaternary ammonium ethyl
  • an adamantyl substituted alkanediol intermediate is reacted with dichloro 2-bromoethyl phosphate or phosphonic acid and the resulting intermediate is reacted with an optionally N-substituted amine to give an adamantoyl-substituted-al
  • the intermediates and the products of this invention may be purified by chromatography using adsorbents such as Florisil (magnesium-silica gel), silica gel or Super-Ce] (infusorial earth).
  • adsorbents such as Florisil (magnesium-silica gel), silica gel or Super-Ce] (infusorial earth).
  • lower alkyl where used herein denotes groups having one to four, preferably one to two, carbon atoms.
  • EXAMPLE 1 A solution of 8.85 g. of l-adamantoyl chloride in 30 ml. of dry chloroform is added dropwise to a solution of 13.66 g. of 1,3-propanediol (azeotroped with benzene and dried over molecular sieves), 4.32 ml. of dry pyridine and 20 ml. of dry chloroform, cooled and stirred at 0 C. The solution is then stirred overnight at room temperature, diluted with ether, washed with dilute hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water, then dried over sodium sulfate, concentrated and chromatographed on Florisil, eluting with petroleum ether-ether. Concentrating in vacuo and recrystallizing from petroleum ether gives 3-(1-adamantoyloxy)propanol.
  • the residue is chromatographed on 200 g. of 2:1 silica gel Super-Cel and eluted with chloroform and chloroformmethanol mixtures to give, after concentrating the 3:1 and 1:1 chloroform-methanol eluates and recrystallizing the residue from methanol-acetone, O-3-(l-adamantoyloxy)propyl 0-2- aminoethyl phosphate.
  • EXAMPLE 2 11.95 Grams of a 60.2% mineral oil dispersion of sodium hydride is suspended in 300 ml. of dry dimethylsulfoxide and the mixture is heated in an oil bath at 6570 C. for two hours under nitrogen. A solution of 22.8 g. of 1,3-propanediol in 50 ml. of dry dimethylsulfoxide is added dropwise to the hot solution and the mixture is heated and stirred for 2 hours. A solution of 12.2 g. of l-adamantylmethyl methylsulfonate (prepared from l-adamantylmethanol and methylsulfonyl chloride in pyridine) in 60 ml. of dry dimethylsulfoxide is added and the mixture is heated at C. for 3 days.
  • l-adamantylmethyl methylsulfonate prepared from l-adamantylmethanol and methylsulfonyl chloride in pyridine
  • reaction mixture is poured into ice water, extracted with ethyl acetate and washed with water.
  • the extract is dried over sodium sulfate, concentrated and chromatographed on 530 g. of Florisil eluting with petroleum ether and petroleum ether-ether mixtures to give 3-( l-adamantylmethoxy)propanol.
  • Example 1 By the procedure of Example 1,3-(l-adamantylmethoxy)- propanol in chloroform and pyridine is reacted with dichloro N-(2,2,2-trichloroethoxycarbonyl)-2-aminoethyl phosphate. The resulting intermediate is treated with zinc and acetic acid according to the procedure of Example 1 to give O-3-(1-adamantylmethoxy)propyl O-2-aminoethyl phosphate.
  • EXAMPLE 4 A suspension of 3.67 g. of a 60.2% mineral oil dispersion of sodium hydride in 100 ml. of tetrahydrofuran is dissolved by the portionwise addition of 17.9 ml. of diethyl phosphonate with stirring under reflux. To the solution is added about 5.06 g. of 3-(l-adamantylmethoxy)propyl p-toluene-sulfonate [prepared by reacting 3-( l-adamantylmethoxy)propanol, which is prepared as in Example 2, with p-toluenesulfonyl chloride in pyridine] in 25 ml. of tetrahydrofuran. The mixture is refluxed overnight.
  • reaction mixture is concentrated under reduced pressure and the residue is dissolved in ether and water and acidifiedwith dilute hydrochloric acid.
  • the aqueous phase is extracted twice with ether.
  • the combined ether extracts are washed with water, dried and concentrated to give the diethyl ester of 3-( l-adamantylmethoxy)propylphosphonic acid.
  • the filtrate is concentrated to a small volume and diluted with acetone containing 1% cyclohexylamine.
  • the solution is cooled and filtered.
  • the solid material is recrystallized from ethanol-acetone-1% cyclohexylamine to give 3-( l-adamantylmethoxy)propylphosphonic acid.
  • EXAMPLE 5 A suspension of 2.37 g. of 2-phthalimidoethyl-phosphonic acid in 25 ml. of thionyl chloride and 3 drops of dimethylformamide is stirred at room temperature overnight. The excess thionyl chloride is evaporated off and the residue is azeotroped with dry benzene. The resulting dichloro 2- phthalimidoethylphosphonic acid is dissolved in 50 ml. of dry chloroform and a solution of 2 g. of 3-[2-( l-adamantyl)- ethoxy]propanol, prepared as in Example 3, 2.65 ml. of dry pyridine and 50 ml. of dry chloroform is added dropwise at 0 C.
  • EXAMPLE 6 1.1 Mole of a 60% mineral oil dispersion of sodium hydride in 600 ml. of dry dimethylsulfoxide is heated at 65 C. for 1 hour under nitrogen. The mixture is slightly cooled and 138 g. of 1,6-hexanediol is added. The mixture is stirred at room temperature for one hour. Then a solution of 50.4 g. of 2-( l-adamantyl)ethyl methylsulfonate (prepared as in Example 3) in ml. of dimethylsulfoxide is added and the stirring is continued for 18 hours at room temperature. lce water is added and the product is extracted into 4:] (v/v) benzenechloroform and then washed with water. Chromatography on 2 kg. of Florisil with increasing concentrations of ether in petroleum ether gives 6-[2-( 1-adamantyl)ethoxy]hexanol.
  • EXAMPLE 7 O-2-aminoethyl O-2-aminoethyl
  • EXAMPLE 8 A solution of 8.3 g. of 3-( l-adamantoyloxy)propanol (prepared as in Example 1) in 35 ml. of dry chloroform and 21 ml. of dry triethylamine is added dropwise to a solution of 25.5 g. of dichloro O-2-bromoethyl phosphate in 14 ml. of dry chloroform at 5 C. with stirring. The mixture is allowed to stand overnight in the refrigerator, then stirred for 2 hours and concentrated at room temperature. To the mixture 150 ml. of 0.1N aqueous potassium chloride solution and 40 ml.
  • Silver carbonate (19 g.) is added to a solution of 9.6 g. of the above prepared ammonium bromide compound with stirring for 3 hours.
  • the mixture is filtered and perculated through a column packed with a 1:1 mixture of weakly basic anion exchange resin (hydroxyl form) and weakly acidic cation exchange resin, eluting with chloroform-methanol to give, after removing the solvent in vacuo, O-3( l-adamantoyloxy)- propyl O-Z-(trimethylammonium hydroxide)ethyl phosphate.
  • the product is O-3-(l-adamantoyloxy)propyl O-2-(tributylammonium bromide)ethyl phosphate which is then converted to the corresponding hydroxide.
  • EXAMPLE 1 1 Sodium hydride (l 1.5 g.) in a 60% suspension in mineral oil is suspended in 600 ml. of dry dimethylsulfoxide. The mixture is heated at 65-70 C. for 2 hours. l-Adamantanol (46.3 g.) is
  • the above prepared compound is hydrogenated in ethyl acetate in the presence of palladium at C. for 24 hours to give after filtering and removing the solvent in vacuo 3-( ladamantyloxy)propanol.
  • EXAMPLE 12 By the prOcedure of Example 8, using dichloro 2- bromoethylphosphonic acid in place of dichloro 0-2- bromoethyl phosphate, the product is O-3-(1-adamantoyloxy)propyl 2-(trimethylammonium broniide)ethylphosphonate which is then converted to the corresponding hydroxide.
  • EXAMPLE 1 3 3-( l-Adamantylmethoxy)propylphosphonic acid, prepared as in Example 4, is reacted with 2-methylaminoethanol in the presence of excess trichloroacetonitrile and pyridine (to make the mixture basic) in acetonitrile with stirring at about 50 C. for hours. Water is added and the mixture is acidified with dilute hydrochloric acid, then extracted with ether. The ether extract is chromatographed on silica gel Super-Ce] to give 0- 2-( N-methylamino)ethyl 3-( l-adamantylmethoxy)propylphosphonate.
  • the product is O-Z-(trimethylammonium hydroxide)ethyl 3-( l-adamantylmethoxy)propylphosphonate.
  • Y is an alkylene chain of one to four carbon atoms having zero to two lower alkyl substituents;
  • R is l-adamantoyl or 1-adamantyl-(CH n is 0 to 2;
  • R2 is -Ol-O-Cll:CllzR ,O1CllzCllzIl or l
  • Cll ClI R.1 ()ll 01 I nt R (B 6 R315 N or N(Rs)a R and R are hydrogen or lower alkyl; R is lower alkyl and X is a pharmaceutically acceptable anion.

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Abstract

Adamantoyl, adamantyl or adamantylalkyl-oxyalkyl 2-aminoethyl phosphates and phosphonates having renin inhibitory activity.

Description

United States Patent Pfeiffer et al.
15] 3,678,137 1 July 18, 1972 [54] ADAMANTYL-SUBSTITUTED-ALKYL 2- AMINOETHYL PHOSPHATES AND PHOSPHONATES [72] Inventors: Francis R. Pfeiffer, Cinnaminson; Jerry A.
21 Appl. No.: 81,109
[52] US. Cl. ..260/944, 260/61 1 R, 260/617 R, 260/945, 260/968, 260/974, 260/978, 260/982,
[51] Int. Cl. ..C07f 9/08, C07f 9/28, A6lk 27/00 [58] Field of Search ..260/944, 945
[56] References Cited UNITED STATES PATENTS 3,124,508 3/1904 Nordmann ..260/944 x Primary Examiner.loseph Rebold Assistant Examiner-Anton H. Sutto Attorney-William H. Edgerton, Richard D. Foggio, Joan S. Keps, Alan D. Lourie and Joseph A. Marlino 57] ABSTRACT Adamantoyl, adamantyl or adamantylalkyl-oxyalkyl 2- aminoethyl phosphates and phosphonates having renin inhibitory activity.
9 Claims, No Drawings This invention relates to adamantyl-substituted-alkyl 2- aminoethyl phosphates and phosphonates.
The compounds of this invention have renin inhibitory activity. Renin is an enzyme which is released from the kidney into the bloodstream where it acts upon a substrate, an 01-2- globulin, in blood plasma to form a decapeptide, angiotensin I. A converting enzyme acts upon this substance to produce angiotensin II which is a very potent pressor substance. A renin inhibitor is therefore useful in reducing blood pressure of renal hypertension.
The activity of the compounds of this invention as renin inhibitors is demonstrated by biochemical assay and rat bioassay procedures.
In the biochemical assay procedure, renin substrate is incubated with renin and the compound to be tested, and the angiotensin I formed is hydrolyzed in vitro with converting enzyme to give angiotensin H and histidyl-leucine. The amount of histidyl-leucine is then measured spectrophotofluorometrically.
In a rat bioassay procedure, as described by Pickens et al., Circulation Research 17:438-448 (1965 and Sen et al., Biochemistry 6:1572-1581 (I967), activity of the compounds of this invention is demonstrated at about 2 to 10 mg./ml. Briefly, according to this procedure, the compound to be tested, renin and renin substrate are allowed to react in vitro and the angiotensin I formed during the in vitro procedure is measured by pressor effects in anesthetized rats elicited by the angiotensin II formed by the animals converting enzyme.
The compounds of this invention are represented by the following formula:
FORMULA I in which:
Y is an alkylene chain of one to four carbon atoms having zero to two lower alkyl substituents; R, is l-adamantoyl or 1-adamantyl-( CH Advantageous compounds of this invention are represented by Formula I in which Y is a straight alkylene chain of one to four carbon atoms.
Preferred compounds of this invention are represented by Formula l in which Y is a straight alkylene chain of one to four carbon atoms and R is The compounds of this invention are prepared by the following procedures:
The terms Y, R, and R are as previously defined; R, is hydroxy, hydroxy protected by, for example, 2,2,2- tn'chloroethoxycarbonyl or benzyl, or iodo and R, is hydroxy when R, is hydroxy or a protected hydroxy group, or iodo when R, is iodo.
The adamantyl substituted intermediates of Formula III are prepared by incorporating l-adamantoyl or l-adamantyl- (CH on an alkanol starting material of Formula II by methods generally known to the art for preparing O-substituted alkanol compounds, for example as follows.
The compounds of Formula II] in which R, is l-adamantoyl are prepared by reacting an excess of an alkanol of Formula II in which R, is hydroxy, 2,2,2-trichloroethoxy-carbonyloxy or iodo with l-adamantoyl chloride and when R, is trichloroethoxycarbonyloxy, removing the trichloroethoxycarbonyl protecting group with acid.
The compounds of Formula II] in which R, is l-adamantylmethyl(or ethyl) are prepared by reacting an alkanol of Formula II, as the sodium salt, in which R, is hydroxy or benzyloxy (prepared by reacting an alkanediol with benzyl chloride in the presence of base such as potassium hydroxide in a solvent such as benzene) with a l-adamantyl-methyl(or ethyl) methylsulfonate, p-toluenesulfonate or halide and when R, is benzyloxy, removing the benzyl protecting group by hydrogenation using a catalyst such as palladium in a solvent, for example ethyl acetate or acetic acid.
The compounds of Formula ll in which R, is l-adamantyl are prepared by reacting an alkanol of Formula II in which R, is benzyloxy with p-toluenesulfonyl chloride, reacting the resulting O-benzyl-O-p-toluenesulfonylalkanediol with the sodium salt of l-adamantanol (prepared by reacting l-adamantanol with sodium hydride in dimethylsulfoxide) and then removing the benzyl group by hydrogenation.
The intermediates of Formula III are converted to the phosphate and phosphonate compounds of this invention by the following procedures:
intermediate is reacted with dichloro N-(2,2,2-trichloroethoxycarbonyl)-2-aminoethyl phosphate in the presence of a base such as pyridine and the resulting intermediate is treated with zinc in acetic acid to give the adamantyl-substituted-alkyl 2- By the method of procedure ll, an O-adamantoyl iodoalkanol is reacted with silver t-butyl N-(t-butyloxy-carbonyl)-2- aminoethyl phosphate and the resulting intermediate is treated with acid to give the adamantoyloxyalkyl Z-aminoethyl phosphate.
III.
( nn-on (Cl)2l ClI:ClI:N(C()) CGH4CE;G RT' Y 3HzOl CHzCH2NII2 OH According to procedure 11], an adamantyl substituted alkanediol is reacted with dichloro 2- phthalimidoethylphosphonic acid and the resulting intermediate is treated with hydrazine to give the adamantyl-substituted-alkvl ester of 2-aminoethyl-phosphonic acid.
According to procedure lV, an adamantyl substituted alkanediol intermediate is treated with p-toluenesulfonyl chloride, the resulting O-adamantyl substituted O-p-toluenesulfonylalkanediol is treated with sodium diethyl phosphonate and the resulting adamantyl substituted alkylphosphonate is treated with acid or base to give the adamantyl-substituted-alkylphosphonic acid which is then converted to the optionally N-substituted aminoethyl or quaternary ammonium ethyl According to procedure V, an adamantyl substituted alkanediol intermediate is reacted with dichloro 2-bromoethyl phosphate or phosphonic acid and the resulting intermediate is reacted with an optionally N-substituted amine to give an adamantoyl-substituted-alkyl optionally N-substituted aminoethyl or quaternary ammoniumethyl phosphate or an adamantyl-substituted-alkyl ester of optionally N-substituted aminoethyl-or quaternary ammoniumethylphosphonic acid.
In the above procedures 1 to V, the terms Y, R and R are as previously defined and R, is l-adamantoyl.
As indicated in the following examples the intermediates and the products of this invention may be purified by chromatography using adsorbents such as Florisil (magnesium-silica gel), silica gel or Super-Ce] (infusorial earth).
The term lower alkyl where used herein denotes groups having one to four, preferably one to two, carbon atoms.
The following examples are not limiting but are illustrative of compounds of this invention and methods of preparing them.
EXAMPLE 1 A solution of 8.85 g. of l-adamantoyl chloride in 30 ml. of dry chloroform is added dropwise to a solution of 13.66 g. of 1,3-propanediol (azeotroped with benzene and dried over molecular sieves), 4.32 ml. of dry pyridine and 20 ml. of dry chloroform, cooled and stirred at 0 C. The solution is then stirred overnight at room temperature, diluted with ether, washed with dilute hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water, then dried over sodium sulfate, concentrated and chromatographed on Florisil, eluting with petroleum ether-ether. Concentrating in vacuo and recrystallizing from petroleum ether gives 3-(1-adamantoyloxy)propanol.
A solution of 8.92 g. of dichloro N-(2,2,2-trichloroethoxycarbonyl)-2-aminoethyl phosphate in 50 ml. of dry chloroform is stirred and cooled under nitrogen and a solution of 2 g. of 3-( l-adamantoyloxy)propanol, 2 ml. of pyridine and 50 ml. of dry chloroform is added dropwise over 1.5 hours. The solution is stirred overnight at room temperature, then diluted with ether, washed with dilute hydrochloric acid and water, dried over sodium sulfate and concentrated to give 0- 3-(1-adamantoyloxy)propyl O2-[N-(2,2,2-trichloroethoxycarbonyl)amino]ethyl phosphate. This intermediate is stirred overnight with 20 g. of activated zinc, 30 ml. of ether and 30 ml. of acetic acid. The reaction mixture is filtered, the filter cake washed with chloroform and the filtrates concentrated. The residue is dissolved in chloroform, washed with small volumes of brine, dried over sodium sulfate and concentrated. The residue is chromatographed on 200 g. of 2:1 silica gel Super-Cel and eluted with chloroform and chloroformmethanol mixtures to give, after concentrating the 3:1 and 1:1 chloroform-methanol eluates and recrystallizing the residue from methanol-acetone, O-3-(l-adamantoyloxy)propyl 0-2- aminoethyl phosphate.
EXAMPLE 2 11.95 Grams of a 60.2% mineral oil dispersion of sodium hydride is suspended in 300 ml. of dry dimethylsulfoxide and the mixture is heated in an oil bath at 6570 C. for two hours under nitrogen. A solution of 22.8 g. of 1,3-propanediol in 50 ml. of dry dimethylsulfoxide is added dropwise to the hot solution and the mixture is heated and stirred for 2 hours. A solution of 12.2 g. of l-adamantylmethyl methylsulfonate (prepared from l-adamantylmethanol and methylsulfonyl chloride in pyridine) in 60 ml. of dry dimethylsulfoxide is added and the mixture is heated at C. for 3 days.
The reaction mixture is poured into ice water, extracted with ethyl acetate and washed with water. The extract is dried over sodium sulfate, concentrated and chromatographed on 530 g. of Florisil eluting with petroleum ether and petroleum ether-ether mixtures to give 3-( l-adamantylmethoxy)propanol.
By the procedure of Example 1,3-(l-adamantylmethoxy)- propanol in chloroform and pyridine is reacted with dichloro N-(2,2,2-trichloroethoxycarbonyl)-2-aminoethyl phosphate. The resulting intermediate is treated with zinc and acetic acid according to the procedure of Example 1 to give O-3-(1-adamantylmethoxy)propyl O-2-aminoethyl phosphate.
EXAMPLE 3 A solution of 12.6 g. of 2-( l-adamantyl)ethanol in 70 ml. of anhydrous pyridine is cooled to 0 C. and treated dropwise with 12.0 g. of methylsulfonyl chloride. The mixture is stirred at 0 C. for 2 hours and at 25C. for 4 hours, then diluted with 500 ml. of ether and washed rapidly with cold water, iced dilute hydrochloric acid, water, cold 5% aqueous sodium bicarbonate solution and water. The solution is dried over sodium sulfate and concentrated to give 2-( l-adamantyl)ethyl methylsulfonate.
11.39 Grams of a 60.2% mineral oil dispersion of sodium hydride in 200 ml. of dry dimethylsulfoxide is heated at 65-70 C. for one hour under nitrogen. A solution of 21.74 g. of 1,3-propanediol in 25 ml. of dimethylsulfoxide is added to the cooled solution and the mixture is stirred at room temperature overnight. A solution of 12.3 g. of 2-(l-adamantyl)ethyl methylsulfonate in 25ml. of dimethylsulfoxide is added dropwise and the mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with ice water and extracted wit ethyl acetate. The ethyl acetate extract is washed with water, dried over sodium sulfate, concentrated and chromatographed on 540 g. of Florisil eluting with 2:1 petroleum ether-ether and 1:1 petroleum ether-ether and ether to give 3-[2-( l-adamanty1)ethoxy]propanol.
According to the procedure of Example 1, 3-[2-( l-adamantyl)ethoxy]propanol is reacted with dichloro N-(2,2,2- trichloroethoxycarbonyl)-2-aminoethyl phosphate in chloroform and pyridine and the resulting intermediate is treated with zinc and acetic acid to give O-3-[2-(l-adamantyl)-ethoxy]propyl O-2-aminoethyl phosphate.
EXAMPLE 4 A suspension of 3.67 g. of a 60.2% mineral oil dispersion of sodium hydride in 100 ml. of tetrahydrofuran is dissolved by the portionwise addition of 17.9 ml. of diethyl phosphonate with stirring under reflux. To the solution is added about 5.06 g. of 3-(l-adamantylmethoxy)propyl p-toluene-sulfonate [prepared by reacting 3-( l-adamantylmethoxy)propanol, which is prepared as in Example 2, with p-toluenesulfonyl chloride in pyridine] in 25 ml. of tetrahydrofuran. The mixture is refluxed overnight. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in ether and water and acidifiedwith dilute hydrochloric acid. The aqueous phase is extracted twice with ether. The combined ether extracts are washed with water, dried and concentrated to give the diethyl ester of 3-( l-adamantylmethoxy)propylphosphonic acid.
11.6 Grams of the diethyl ester of 3-( l-adamantylmethoxy)propylphosphonic acid is refluxed for 3 hours with 40 ml. of ethanol and 40 ml. of aqueous sodium hydroxide solution. The reaction mixture is concentrated and the aqueous phase is extracted with ether. The aqueous phase is acidified, extracted with 4:1 ethyl acetate-chloroform and the organic extract is washed with brine, dried over sodium sulfate and concentrated. The residue is dissolved in acetone and treated with cyclohexylamine until basic, then cooled to -30 C. overnight and filtered. The solid material is dissolved in 20 ml. of ethanol and the solution is filtered. The filtrate is concentrated to a small volume and diluted with acetone containing 1% cyclohexylamine. The solution is cooled and filtered. The solid material is recrystallized from ethanol-acetone-1% cyclohexylamine to give 3-( l-adamantylmethoxy)propylphosphonic acid.
3-( l-Adamantylmethoxy)propylphosphonic acid (487 mg.) and 734 mg. of N-(2,2,2-trichloroethoxycarbonyl)ethanolamine are dissolved in 20 ml. of pyridine and 4 ml. of trichloroacetonitrile- The resulting mixture is heated at 50 C. for 30 hours, then concentrated in vacuo. The residue is diluted with water and extracted with ether. The aqueous layer is acidified and extracted with ether. The ether extracts are combined, washed with water and then concentrated in vacuo. The residue is stirred in 20 ml. of 95% acetic acid with 2 g. of activated zinc for 24 hours, then filtered and the filter cake is washed with 4:1 ether-chloroform. The filtrate is washed with water and then chromatographed on 2:1 silica gel Super-Ce], eluting with 9:1 to 7:3 chloroform-methanol mixtures to give O-Z-aminoethyl 3-( l-adamantylmethoxy)propylphosphonate.
EXAMPLE 5 A suspension of 2.37 g. of 2-phthalimidoethyl-phosphonic acid in 25 ml. of thionyl chloride and 3 drops of dimethylformamide is stirred at room temperature overnight. The excess thionyl chloride is evaporated off and the residue is azeotroped with dry benzene. The resulting dichloro 2- phthalimidoethylphosphonic acid is dissolved in 50 ml. of dry chloroform and a solution of 2 g. of 3-[2-( l-adamantyl)- ethoxy]propanol, prepared as in Example 3, 2.65 ml. of dry pyridine and 50 ml. of dry chloroform is added dropwise at 0 C. The mixture is stirred at room temperature for 18 hours, diluted with ether, washed with dilute hydrochloric acid and brine, dried over sodium sulfate and concentrated to give O-3- [2-( l-adarnantyl)ethoxy]propyl 2phthalimidoethylphosphon ate.
The above prepared phosphonate is dissolved in 50 ml. of ethanol and the resulting solution is treated with 2.43 ml. of 50% aqueous hydrazine and stirred at room temperature overnight. The mixture is concentrated and the residue is stirred with chloroform and filtered and the filtrate is concentrated. The residue is chromatographed on 250 g. of 2:1 silica gel Super-Ce! to give O-3-[2-( l-adamantyl)ethoxy]propyl 2- aminoethylphosphonate.
EXAMPLE 6 1.1 Mole of a 60% mineral oil dispersion of sodium hydride in 600 ml. of dry dimethylsulfoxide is heated at 65 C. for 1 hour under nitrogen. The mixture is slightly cooled and 138 g. of 1,6-hexanediol is added. The mixture is stirred at room temperature for one hour. Then a solution of 50.4 g. of 2-( l-adamantyl)ethyl methylsulfonate (prepared as in Example 3) in ml. of dimethylsulfoxide is added and the stirring is continued for 18 hours at room temperature. lce water is added and the product is extracted into 4:] (v/v) benzenechloroform and then washed with water. Chromatography on 2 kg. of Florisil with increasing concentrations of ether in petroleum ether gives 6-[2-( 1-adamantyl)ethoxy]hexanol.
A solution of 3.12 g. of 6-[2-(1-adamantyl)ethoxy]-hexanol, 4.48 ml. of anhydrous pyridine and 30 ml. of anhydrous chloroform is added dropwise to a cooled and stirred solution of 5.93 g. of dichloro N-(2,2,2-trichloroethoxycarbonyl)-2- aminoethyl phosphate in 30 ml. of chloroform. The solution is stirred at room temperature for 18 hours, then worked up by the procedure described in Example 1 and chromatographed on 500 g. of 2:1 (w/w) silica gel Super-Cel to give 0-6-[2-(1- adamantyl)ethoxy]hexyl O-Z-aminoethyl phosphate which after recrystallization from methanol-acetonitrile melts at 22923 1 C.
EXAMPLE 7 O-2-aminoethyl O-2-aminoethyl EXAMPLE 8 A solution of 8.3 g. of 3-( l-adamantoyloxy)propanol (prepared as in Example 1) in 35 ml. of dry chloroform and 21 ml. of dry triethylamine is added dropwise to a solution of 25.5 g. of dichloro O-2-bromoethyl phosphate in 14 ml. of dry chloroform at 5 C. with stirring. The mixture is allowed to stand overnight in the refrigerator, then stirred for 2 hours and concentrated at room temperature. To the mixture 150 ml. of 0.1N aqueous potassium chloride solution and 40 ml. of :1 ether-methanol are added at 0 C. with stirring for 1 hour. The mixture is diluted with 800 ml. of ether and acidified with concentrated hydrochloric acid to pH 2. The ether solution is washed with water, dried over sodium sulfate and concentrated and the residue is azeotroped with benzene to give 0-3- l-adamantoyloxy)propyl O-2-bromoethyl phosphate.
A solution of g. of dry gaseous trimethylamine in 200 ml. of 2-butanone is added to 14.7 g. of O-3-(l-adamantoyloxy)propyl O-2-bromoethyl phosphate and the mixture is stirred at 50 C. for 18 hours, then concentrated to one-half of its original volume, refrigerated, filtered and dried in vacuo to give O-3-( l-adamantoyloxy)propyl O-2-(trimethylammonium bromide)-ethyl phosphate.
Silver carbonate (19 g.) is added to a solution of 9.6 g. of the above prepared ammonium bromide compound with stirring for 3 hours. The mixture is filtered and perculated through a column packed with a 1:1 mixture of weakly basic anion exchange resin (hydroxyl form) and weakly acidic cation exchange resin, eluting with chloroform-methanol to give, after removing the solvent in vacuo, O-3( l-adamantoyloxy)- propyl O-Z-(trimethylammonium hydroxide)ethyl phosphate.
EXAMPLE 9 By the procedure of Example 8, O-3-(1-adamantoyloxy)- propyl O-2-bromoethyl phosphate is reacted with triethylamine to give O-3-(l-adamantoyloxy)propyl O-2- (triethylammonium bromide)ethyl phosphate which is then converted by the procedure described in Example 8 to 0-3-(1- adamantoyloxy)propyl O-Z-(triethylammonium hydroxide)ethyl phosphate.
By the same procedure, using tributylamine in place of triethylamine, the product is O-3-(l-adamantoyloxy)propyl O-2-(tributylammonium bromide)ethyl phosphate which is then converted to the corresponding hydroxide.
EXAMPLE 10 O-3-[2-( l-adamantyl)ethoxy]propyl O-2-(N- ethylamino)ethyl phosphate O-3-[2-( l-adamantyl)ethoxy]propyl O-Z-(N-butylamino)ethyl phosphate O-3-[2-( l-adamantyl)ethoxy]propyl O-2-( N,N-
dimethylamino)-ethyl phosphate O-3-[2-( l-adamantyl)ethoxy]propyl O-2-(N,N-
dipropylamino)-ethyl phosphate O-3-[2-( l-adamantyl)ethoxy]propyl O-2-( N,N-dibutylamino)-ethyl phosphate.
EXAMPLE 1 1 Sodium hydride (l 1.5 g.) in a 60% suspension in mineral oil is suspended in 600 ml. of dry dimethylsulfoxide. The mixture is heated at 65-70 C. for 2 hours. l-Adamantanol (46.3 g.) is
added and the resulting mixture is stirred at room temperature for 30 minutes. To the mixture is added 96.2 g. of 3-benzyloxypropyl p-toluenesulfonate (prepared by reacting 3-benzyloxypropanol with p-toluenesulfonyl chloride) in 100 ml. of 5 dimethylsulfoxide. The resulting mixture is heated with stirring at 65 C. for 2 hours, then poured into water and extracted with ethyl acetate. The extract is washed with water and chromatographed over Florisil eluting with ether-petroleum ether mixtures to give 1-(l-adamantyloxy)-3-benzyloxypropane.
The above prepared compound is hydrogenated in ethyl acetate in the presence of palladium at C. for 24 hours to give after filtering and removing the solvent in vacuo 3-( ladamantyloxy)propanol.
By the procedure of Example I, 3-( l-adamantyloxy)- propanol is reacted with dichloro N-(2,2,2-trichloroethoxycarbonyl)-2-aminoethyl phosphate and the resulting intermediate is treated with zinc and acetic acid to give O3-( ladamantyloxy)propyl O-Z-aminoethyl phosphate.
EXAMPLE 12 By the prOcedure of Example 8, using dichloro 2- bromoethylphosphonic acid in place of dichloro 0-2- bromoethyl phosphate, the product is O-3-(1-adamantoyloxy)propyl 2-(trimethylammonium broniide)ethylphosphonate which is then converted to the corresponding hydroxide.
EXAMPLE 1 3 3-( l-Adamantylmethoxy)propylphosphonic acid, prepared as in Example 4, is reacted with 2-methylaminoethanol in the presence of excess trichloroacetonitrile and pyridine (to make the mixture basic) in acetonitrile with stirring at about 50 C. for hours. Water is added and the mixture is acidified with dilute hydrochloric acid, then extracted with ether. The ether extract is chromatographed on silica gel Super-Ce] to give 0- 2-( N-methylamino)ethyl 3-( l-adamantylmethoxy)propylphosphonate.
By the same procedure, using choline in place of 2- methylaminoethanol, the product is O-Z-(trimethylammonium hydroxide)ethyl 3-( l-adamantylmethoxy)propylphosphonate.
What is claimed is:
l. A compound of the formula:
(|)lI:0-R1 I CII2R2 in which:
Y is an alkylene chain of one to four carbon atoms having zero to two lower alkyl substituents; R is l-adamantoyl or 1-adamantyl-(CH n is 0 to 2;
t) (I) 0 R2 is -Ol-O-Cll:CllzR ,O1CllzCllzIl or l ()Cll ClI R.1; ()ll 01 I nt R (B 6 R315 N or N(Rs)a R and R are hydrogen or lower alkyl; R is lower alkyl and X is a pharmaceutically acceptable anion.
2. A compound according to claim 1 in which Y is a straight alkylene chain of one to four carbon atoms.
3. A compound according to claim 1 in which Y is a straight alkylene chain of one to four carbon atoms and R is 4. A compound according to claim 1 in which Y is CH R is l-adamantoyl and R is v CH R is l-adamantylmethyl and R is 6. A compound according to claim 1 in which Y is 7. A compound according to claim 1 in which Y is CH R. is l-adamantylmethyl and R is 8. A compound according to claim 1 in which Y is CH R is 2-(1-adamantyl)ethyl and R is 9. A compound according to claim 1 in which Y is

Claims (8)

  1. 2. A compound according to claim 1 in which Y is a straight alkylene chain of one to four carbon atoms.
  2. 3. A compound according to claim 1 in which Y is a straight alkylene chain of one to four carbon atoms and R3 is
  3. 4. A compound according to claim 1 in which Y is
  4. 5. A compound according to claim 1 in which Y is
  5. 6. A compound according to claim 1 in which Y is
  6. 7. A compound according to claim 1 in which Y is
  7. 8. A compound according to claim 1 in which Y is
  8. 9. A compound according to claim 1 in which Y is
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Cited By (13)

* Cited by examiner, † Cited by third party
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WO1980000567A1 (en) * 1978-09-18 1980-04-03 Dainippon Pharmaceutical Co Phosphorylethanolamine derivatives,process for preparing same,and medicinal composition containing same
US4283542A (en) * 1978-11-30 1981-08-11 Mona Industries Process for the preparation of phosphobetaines
US4329302A (en) * 1980-06-27 1982-05-11 Board Of Regents, The University Of Texas System Synthetic phosphoglycerides possessing platelet activating properties
US4504474A (en) * 1980-06-27 1985-03-12 Board Of Regents, The University Of Texas System Synthetic phosphoglycerides possessing platelet activating properties
US20090042933A1 (en) * 2005-05-20 2009-02-12 Carlos Puig Duran Derivatives of 4-(2-amino -1-hydroxyethyl)phenol as agonists of the Beta2 adrenergic receptor
US20090082378A1 (en) * 2006-04-27 2009-03-26 Carlos Puig Duran Derivatives of 4-(2-amino-1-hydroxiethyl)phenol as agonists of the b2 adrenergic receptor
US20100093681A1 (en) * 2007-02-09 2010-04-15 Carlos Puig Duran Napadisylate salt of 5-(2--1-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one as agonist of the beta 2 adrenergic receptor
US20100324000A1 (en) * 2007-11-28 2010-12-23 Victor Giulio Matassa Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the beta2 adrenergic receptors
US20110028442A1 (en) * 2008-02-28 2011-02-03 Carlos Puig Duran Derivatives of 4-(2-amino-1-hydroxyethyl) phenol as agonists of the beta2 adrenergic receptor
US8524908B2 (en) 2009-03-12 2013-09-03 Almirall, S.A. Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one
US8563731B2 (en) 2008-12-22 2013-10-22 Almirall, S.A. Mesylate salt of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]jamino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one as agonist of the β2 adrenergic receptor
US9108918B2 (en) 2011-10-07 2015-08-18 Almirall, S.A. Process for preparing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one via a novel intermediate
US9346759B2 (en) 2012-03-20 2016-05-24 Almirall, S.A. Polymorphic crystal forms of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one, heminapadisytlate as agonist of the β2 adrenergic receptor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3124508A (en) * 1964-03-10 N-methylaminoethyl

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3124508A (en) * 1964-03-10 N-methylaminoethyl

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1980000567A1 (en) * 1978-09-18 1980-04-03 Dainippon Pharmaceutical Co Phosphorylethanolamine derivatives,process for preparing same,and medicinal composition containing same
US4283542A (en) * 1978-11-30 1981-08-11 Mona Industries Process for the preparation of phosphobetaines
US4329302A (en) * 1980-06-27 1982-05-11 Board Of Regents, The University Of Texas System Synthetic phosphoglycerides possessing platelet activating properties
US4504474A (en) * 1980-06-27 1985-03-12 Board Of Regents, The University Of Texas System Synthetic phosphoglycerides possessing platelet activating properties
US8242177B2 (en) 2005-05-20 2012-08-14 Almirall, S.A. Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the β2 adrenergic receptor
US20090042933A1 (en) * 2005-05-20 2009-02-12 Carlos Puig Duran Derivatives of 4-(2-amino -1-hydroxyethyl)phenol as agonists of the Beta2 adrenergic receptor
US8420669B2 (en) 2005-05-20 2013-04-16 Laboratories Almirall, S.A. Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the BETA2 adrenergic receptor
US7964615B2 (en) 2005-05-20 2011-06-21 Almirall, S.A. Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the β2 adrenergic receptor
US20090082378A1 (en) * 2006-04-27 2009-03-26 Carlos Puig Duran Derivatives of 4-(2-amino-1-hydroxiethyl)phenol as agonists of the b2 adrenergic receptor
US20100093681A1 (en) * 2007-02-09 2010-04-15 Carlos Puig Duran Napadisylate salt of 5-(2--1-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one as agonist of the beta 2 adrenergic receptor
US8283342B2 (en) 2007-02-09 2012-10-09 Almirall S.A. Napadisylate salt of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy) hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one as agonist of the β2 adrenergic receptor
US20110195943A9 (en) * 2007-02-09 2011-08-11 Carlos Puig Duran Napadisylate salt of 5-(2--1-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one as agonist of the beta 2 adrenergic receptor
US8178679B2 (en) 2007-11-28 2012-05-15 Almirall, S.A. Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the β2 adrenergic receptors
US20100324000A1 (en) * 2007-11-28 2010-12-23 Victor Giulio Matassa Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the beta2 adrenergic receptors
US20110028442A1 (en) * 2008-02-28 2011-02-03 Carlos Puig Duran Derivatives of 4-(2-amino-1-hydroxyethyl) phenol as agonists of the beta2 adrenergic receptor
US8563731B2 (en) 2008-12-22 2013-10-22 Almirall, S.A. Mesylate salt of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]jamino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one as agonist of the β2 adrenergic receptor
US8524908B2 (en) 2009-03-12 2013-09-03 Almirall, S.A. Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one
US9108918B2 (en) 2011-10-07 2015-08-18 Almirall, S.A. Process for preparing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one via a novel intermediate
US9346759B2 (en) 2012-03-20 2016-05-24 Almirall, S.A. Polymorphic crystal forms of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one, heminapadisytlate as agonist of the β2 adrenergic receptor

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