Claims
- 1. The compound of the formula ##STR41##
- 2. The compound of the formula ##STR42##
- 3. The compound of the formula ##STR43##
Description of the Invention
This is a division of application Ser. No. 875,966 filed Feb. 8, 1978 now U.S. Pat. No. 4,202,978 issued May 13, 1980.
The present invention relates to binary .alpha.,.beta.-Adrenergic Blocking Agents of the formula ##STR5## wherein R.sub.1 is selected from the group consisting of lower alkyl; R.sub.8 is selected from the group consisting of --O--(CH.sub.2).sub.n -wherein n is 2 to 20, ##STR6## and R.sub.6 is selected from the group consisting of hydrogen or lower alkoxy, and ##STR7## wherein R.sub.1 is selected from the group consisting of lower alkyl; R.sub.8 is selected from the group consisting of --O--(CH.sub.2).sub.n -wherein n is 2 to 20, ##STR8## and R.sub.6 is selected from the group consisting of hydrogen or lower alkoxy and the racemates thereof
The presently disclosed and claimed compounds exhibit both .alpha. and .beta.-adrenergic blocking activities which are essential to their use as antihypertensive agents. They provide competitive and reversible blockade of both .alpha. and .beta. adrenoreceptors and have the unexpected property of being cardioselective, having low activity at one site (.beta..sub.2) and good activity at the .beta..sub.1 site. This selectivity has important consequences when selecting an antihypertensive agent. Further the compounds have exhibited anti-secretory, i.e. spasmolytic activity.
By the term "lower alkyl" is meant straight or branched chains of C.sub.1 or C.sub.10 length with branched chains of C.sub.3 to C.sub.4 as preferred, e.g., isopropyl or tertiary butyl.
By the term "lower alkoxy" is meant straight or branched chain saturated hydrocarbonoxy groups containing from 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy and the like.
The term "halo" or "halogen" refers to all four forms thereof, i.e., bromine, chlorine, fluorine or iodine with bromine and chlorine as preferred.
It should be noted that the racemates of the above compounds are also novel and exhibit activities similar to the preferred (S) isomers although not as quantitatively active. The racemates may also be resolved into the desired isomers when desired.
The following reaction schemes represent the methods of synthesis available to produce the novel end compounds of the present invention: ##STR9## wherein R.sub.1 is lower alkyl R.sub.2 and R.sub.3 are selected from the group consisting of hydrogen, mesyl, tosyl, brosyl or benzenesulfonyl and R.sub.4 is selected from the group consisting of halo, mesyloxy or tosyloxy ##STR10## wherein R.sub.5 is halo ##STR11## wherein R.sub.1 and R.sub.3 are as above, R.sub.6 is hydrogen or lower alkoxy, n is 2 to 20 and X is halo ##STR12## wherein R.sub.1 and R.sub.6 are as above and n is 2 to 20 ##STR13## wherein R.sub.1 and R.sub.6 are as above and n is 2 to 20 ##STR14## wherein R.sub.1 and n are as above and R.sub.7 is halo ##STR15## wherein R.sub.1, R.sub.6 and n are as above ##STR16## wherein R.sub.1 and R.sub.6 are as above ##STR17## wherein R.sub.1, R.sub.6 and n are as above
The compound of formula I which is a known compound is produced by utilizing an acid catalyzed ketal exchange reaction. The reaction is carried out utilizing a strong mineral acid, such as, sulfuric acid or p-toluenesulfonic acid or a cation exchange resin. The reaction is carried out at a temperature range of about 0.degree. C. to 100.degree. C. with room temperature as preferred. The time of the reaction to completion will vary from 1 to 16 hours depending on the reaction temperature selected.
The two step reaction to produce the compound of formula V is a known reaction, see, for example, J. Lecocq and C.E. Ballou, Biochemistry, 3, 976, (1964).
The compound of formula VI is produced by reaction of the primary alcohol (V) with a lower alkyl or aryl sulfonyl halide in the presence of a tertiary amine base. Examples of lower alkyl or aryl sulfonyl halides which may be used are mesyl, tosyl, brosyl or benzylsulfonyl chlorides or bromides. Examples of tertiary amine bases include pyridine or trialkylamines, e.g. tri-n-butyl or triethylamines. An inert solvent may be utilized to facilitate the reaction such as methylene chloride or tetrahydrofuran or pyridine. The latter functions as both reactant and solvent. The reaction temperature may vary from about -25.degree. C. to 15.degree. C. with -10.degree. C. to 15.degree. C. as preferable and 0.degree. C. to 15.degree. C. as optimum. The reaction time may range from 30 minutes to 1 hour depending on the reaction temperature chosen.
The compound of formula IV is thereafter produced by displacement of the leaving group (the alkyl or arylsulfonyloxy group) using a primary amine such as a methyl, ethyl, isopropyl or tertiary butyl amine. The reaction can be performed with or without an inert solvent (benzene, lower alcohols or ethers may be employed). In the case of lower boiling amines, e.g. isopropylamine, the reaction should be run in a pressurized vessel. The reaction temperature may vary from room temperature to about 150.degree. C. with approximately 100.degree. C. as the preferred temperature.
A multistep sequence may also be utilized to produce a compound of formula IV in which the intermediates II and III are not isolated. The compound of formula I is oxidized to II utilizing lead tetraacetate in an inert aromatic hydrocarbon solvent, such as, benzene, toluene or xylene. The reaction temperature should be kept at room temperature or below, e.g., 0.degree. C. After one side product, Pb(OAc).sub.2, has been removed by filtration, the acetic acid which has been generated in the reaction is neutralized by the addition of an alkali metal (Na,K,etc.) carbonate or oxide, e.g., BaO.
The aldehyde (II) is thereafter reacted with a large excess of a primary amine, e.g. methyl, ethyl, isopropyl, etc. amine to form the imine (III). The reaction temperature should be at about 25.degree. C. or less and a desiccant, e.g. K.sub.2 CO.sub.3, should be used to remove any water formed and drive the reaction to completion.
Thereafter the imine (III) is hydrogenated to the secondary amine (IV) by the use of a catalyst such as noble metals (Platinum, Palladium, Ruthenium, etc.) on carbon or Raney Nickel/H.sub.2 under pressure. This reaction may be carried out at 20.degree. C.-50.degree. C. with room temperature aspreferred. The reaction may be run at 1 to 10 atmospheres depending on the catalyst chosen.
The amine (IV) is thereafter reacted with an alkyl or aryl sulfonyl halide such as a mesyl, tosyl, brosyl or benzylsulfonyl chloride or bromide in an inert aprotic solvent such as high boiling ethers, e.g., dioxane, tetrahydrofuran or methylene chloride in the presence of a tertiary amine base, e.g., triethyl or trimethylamine. The reaction is carried out at a temperature range of about -50.degree. C. to 25.degree. C. with about -10.degree. C. to 5.degree. C. as preferred.
The compound of formula VII thereafter undergoes an acid catalyzed hydrolysis of the ketal protecting group. To effect this catalysis, strong mineral acids are utilized, e.g, HCl, H.sub.2 SO.sub.4 or p-toluenesulfonic acid or a strongly acidic ion exchange resin (H.sup.+ form). The reaction solvent may be water and a miscible co-solvent, such as, a lower alcohol (methanol, ethanol, propanol, etc.) and ethers such as tetrahydrofuran or dioxane. The reaction temperature range is from about room temperature to 80.degree. C. with about 60.degree. C. to 80.degree. C. as preferred. The reaction time may range from 1 hour to 2 days depending on the temperature selected.
The diol of formula VIII is thereafter reacted with an alkyl or aryl sulfonyl halide (as previously disclosed in step V.fwdarw.VI) in the presence of a tertiary amine base (also disclosed in V.fwdarw.VI) wherein the primary hydroxyl group is selectively converted into an alkyl or aryl sulfoxy group. As disclosed previously in step V.fwdarw.VI pyridine may serve as the base and solvent or other previously disclosed solvents may be utilized (V.fwdarw.VI). The reaction temperature ranges (depending on what sulfonyloxy group) is desired may vary from about -45.degree. C. to -50.degree. C. (mesyl) to -5.degree. C. to 5.degree. C. (tosyl). When R.sub.4 of formula IX is to be halo the reaction will differ from above. The compound of formula VIII undergoes an acid catalyzed exchange reaction with a trialkylorthoacetate, e.g., trimethyl, triethyl, etc. to give the cyclic orthoacetate of the formula ##STR18## and alkanol. The alkanol is distilled from the reaction mixture as formed to facilitate reaction completion. No solvents are necessary for the reaction. The reaction temperature ranges from about 60.degree. C. to 100.degree. C. with 80.degree. C. as preferred. The time of the reaction varies from 30 minutes to 1 hour depending on the reaction temperature. The cyclic orthoacetate is thereafter reacted with trimethylhalosilane in an inert, aprotic solvent, such as, methylene chloride, giving rise to the intermediate of the formula ##STR19## which on attack by the halide ion gives the haloacetate. As solvents for this step, inert aprotic solvents such as high boiling ethers and halogenated hydrocarbons, e.g., methylene chloride, are best. The reaction may be run from about room temperature to reflux temperature for about 30 minutes. A reaction temperature of 40.degree. is preferred. Thereafter the haloacetate is reacted in an acid catalyzed hydrolysis. To carry out the reaction a solution of the substrate in a hydrolytic solvent such as alcohols, e.g., methanol, ethanol, propanol etc. or aqueous alcohol mixtures containing a catalytic amount of a mineral acid such as HCl, H.sub.2 SO.sub.4 or an acidic ion exchange resin are utilized. The reaction temperature may be varied from 0.degree. C. to reflux temperature (solvent dependent) for 30 minutes to 16 hours. Room temperature is preferred.
This procedure is carried out as disclosed previously by a prior art method.
The hydroxyl group of the compound of formula V is protected as its benzyl ether by producing the compound of the formula XI. The reaction is one of the alcohol (V) with an alkali metal hydride, e.g., Na, Li, K, etc., to form the alkoxide which then is reacted with an alkylating agent, i.e. a benzyl halide (Cl or Br) to give the benzyl ether (XI). Solvents suitable for such a reaction include anhydrous dimethylformamide, dimethylsulfoxide and high boiling ethers such as tetrahydrofuran or dioxane. The reaction temperature may range from about room temperature to 100.degree. C. with about room temperature as preferred.
The compound of formula XII is thereafter produced by an acid catalyzed hydrolysis of the ketal protecting group. Reagents and reaction parameters are the same as in previously disclosed step VII.fwdarw.VIII.
The diol of formula XII is converted into the haloacetate of formula XIV via the compound of formula XIII and the intermediate of the formula ##STR20## by following the steps and utilizing the reactants and reaction parameters disclosed previously in step VIII.fwdarw.IX. This series of reactions are performed because selective alkyl or aryl sulfonyloxy of the primary hydroxyl group in XII is difficult due to the similar reactivity of both of the hydroxyl groups in XII.
The compound of formula XIV thereafter undergoes a two step reaction wherein the acetate (XIV) is saponified to give the intermediate halohydrin of the formula ##STR21## which is then converted under basic conditions into the epoxide of formula XV. The reaction is carried out utilizing an alkali metal, e.g., Na or K, hydroxide in a solvent of H.sub.2 O plus an inert water miscible co-solvent such as a lower alcohol, e.g., methanol, ethanol, propanol, etc. The reaction temperature may vary from about -10.degree. C. to 25.degree. C. with a range of about 0.degree. C. to 10.degree. C. as preferred. It should be noted that the above reactions preserve the stereochemistry of the asymmetric carbon atom throughout.
This reaction is a two step sequence wherein a compound of the formula IX under basic reaction conditions is converted into the epoxide of the formula ##STR22## wherein R.sub.1 and R.sub.3 are as above. This compound acts as the alkylating agent in the ensuing reaction with the phenol (XVI) under basic catalysis conditions to form the ether (XVI). The base utilized in the reaction is an alkali metal hydroxide, e.g., NaOH or KOH and the reaction temperature ranges from about room temperature to 100.degree. C. The reaction time may vary from about 2 hours to several days depending on the reaction temperature chosen. The solvents utilized may be dimethylsulfoxide, tetrahydrofuran and lower alcohol/water mixtures.
This reaction is similar to XVI.fwdarw.XVII except a large excess of hydroxyphenol is utilized to minimize any dialkylation which might occur. As in XVI.fwdarw.XVII the effective alkylating agent is the epoxide (see above). The reagents and reaction parameters are as above (XVI.fwdarw.XVII).
The compound of formula XVII thereafter undergoes hydrogenolysis to a compound of formula XVIII. Catalysts for the reaction may be noble metals such as Platinum, Palladium, Rhodium or Ruthenium on carbon. Suitable solvents include lower alcohols (methanol, ethanol, etc.), esters (ethyl or butyl acetate) and ethers (dioxane or tetrahydrofuran). The reaction temperature may be varied from about 0.degree. C. to 100.degree. C. with room temperature preferred.
This reaction consists of the O-alkylation of the phenol of formula XVI with a compound of the formula ##STR23## wherein X is a leaving group selected from the group consisting of halogen, tosyloxy and mesyloxy, R.sub.6 is hydrogen or alkoxy and n is 2 to 20, utilizing an alkali metal hydroxide (NaOH, KOH, etc.) in an inert water miscible solvent, e.g., a dimethylsulfoxide/H.sub.2 O mixture. The reaction temperature may vary from about room temperature to 60.degree. C. with 60.degree. C. as preferred with a reaction time from 1-2 hours to several days depending on the reaction temperature. Alternate O-alkyation systems which may be utilized in conjunction with the phenylpiperazine include alkali metal alkoxides in lower alcohols e.g., sodium methoxide in methanol or potassium carbonate in acetone.
The compound of formula XVIII is reacted with a compound of the formula
The reaction which is an O-alkylation of a phenol (XVIII) with an .alpha.,.omega.-dihaloalkane (for example) is carried out utilizing an alkali metal carbonate, such as, potassium or sodium carbonate in, as preferred, refluxing acetone. The reaction temperature may vary from room temperature to reflux with reflux as preferred.
This reaction follows the same reaction parameters and utilizes the same reagents as previously disclosed in step XVI.fwdarw.XIX.
The compound of formula XVIII is thereafter reacted with a compound of the formula ##STR24## wherein X is as above and R is lower alkyl.
This O-alkylation of the phenol (XVIII) with the alkyl .omega.-haloalkanoate, for example, ethyl-6-bromohexanoate or ethyl bromoacetate, using as a base an alkali metal alkoxide, such as, potassium tert-butoxide, methoxide or ethoxide in a lower alcohol, e.g., methanol, ethanol, etc., at a temperature range of about 0.degree. C. to 100.degree. C. with 60.degree. C. to 80.degree. C. as preferred. The product is subsequently saponified to give the acid (XX). The saponification is usually carried out at between room temperature to 65.degree. C. for a period of 3 to 40 hours.
The compound of the formula XVIII is reacted with an alkylating agent of the formula ##STR25## wherein X, n and R.sub.6 are as before, such as, 1-(.omega.-haloalkanoyl)-4-phenylpiperazine, in an alcohol/water mixture or tetrahydrofuran or dimethylsulfoxide/water mixture containing an alkali metal hydroxide, e.g., NaOH or KOH. The reaction is carried out at from about room temperature to 100.degree. C. with 75.degree. C.-80.degree. C. as preferred.
The compound of formula XIX undergoes hydrogenolysis of the benzyl ether portion by utilizing a noble metal catalyst, e.g., Palladium, Platinum, Rhodium, etc. on carbon. The solvent for such a reaction may be an alcohol (methanol, ethanol, etc.) or acetic acid containing a small amount of mineral acid such as HCl or H.sub.2 SO.sub.4. The reaction temperature may vary from about 0.degree. C.-100.degree. C. with room temperature as preferred. The compound of formula XXI thereafter undergoes an O-alkylation using an alkylating agent (IX) in the presence of an alkali metal hydroxide as a base. The reagents and reaction parameters for this reaction are as previously disclosed for step XVI.fwdarw.XVII.
The acid of the formula XX is converted to the activated intermediate ##STR26## wherein R.sub.1, R.sub.3 and n are as above on treatment with ethyl chloroformate under anhydrous conditions in an aprotic solvent, e.g. tetrahydrofuran or dioxane, at a low temperature e.g., about 0.degree. C. to 5.degree. C. in the presence of a tertiary amine base, e.g. trialkylamine. This mixed anhydride is treated in situ with a phenylpiperazine of the general formula ##STR27## wherein R.sub.6 is as above to give the tertiary amide. This reaction is carried out at between about 10.degree. C. to 25.degree. C.
The compound of formula XXIV undergoes a reductive cleavage of the --R.sub.3 protecting group utilizing as the reducing agent a 60-70% solution of sodium bis-methoxyethoxy aluminum hydride in an inert aromatic hydrocarbon solvent such as benzene or toluene. Inert aprotic solvents such as tetrahydrofuran or dioxane may also be utilized. The reaction may be carried out at from about room temperature to 100.degree. C. with a range of about 80.degree. C. to 100.degree. C. as preferred.
The compound of formula XXII undergoes a reductive cleavage of the --R.sub.3 protecting group with a concommitant reduction of the amide function to an amino group. The reagents and reaction parameters for this reaction are as previously disclosed in step XXIV.fwdarw.XXV with the exception that a proportionately greater amount of the hydride reducing agent is employed.
Suitably protected the optically active 2,3-epoxypropanol (XV) is thereafter reacted with a substituted phenol of the formula XVI in an O-alkylation using an alkali metal alkoxide, e.g., sodium or potassium methoxide or ethoxide, as the base in a lower alcohol solvent (methanol, ethanol, etc.). Also useful as a base in the above reaction would be an alkali metal hydroxide, e.g., NaOH or KOH in an aqueous alcohol, tetrahydrofuran, dioxane or dimethylsulfoxide solvent. The reaction temperature may range from room temperature to reflux for the chosen solvent with 60.degree. C.-80.degree. C. as preferred.
The benzyl ethers of the formula XXX thereafter undergo a hydrogenolysis utilizing a catalyst of a noble metal such as Palladium, Platinum, Ruthenium etc. on carbon. Suitable solvents include alcohols (methanol, ethanol, propanol, etc.) or acetic acid containing a small amount of a mineral acid such as H.sub.2 SO.sub.4 or HCl. The reaction temperature may range from about 0.degree. C. to 100.degree. C. with room temperature as preferred. The hydrogenolysis may also be run under pressure up to 10 atmospheres if a catalyst such as H.sub.2 /Raney Nickel is chosen.
The reagents and reaction parameters for this step have been previously disclosed in step XII.fwdarw.XIII.fwdarw.XIV.
The acetate (XXXIII) thereafter undergoes an acid catalysed hydrolysis wherein the acetate reacts in a hydrolytic solvent, such as, alcohols, e.g., methanol, ethanol, etc. or alcohol/water mixtures which contain a catalytic amount of a mineral acid such as H.sub.2 SO.sub.4 or HCl or an acidic ion exchange resin. The reaction may be carried out at from about 0.degree. C. to reflux of the chosen solvent with a range of about room temperature to 60.degree. C. as preferred.
The halohydrin (XXXIV) is therefore reacted with a phenylpiperazine of the formula ##STR28## wherein X is halo.
This reaction involves two separate and unrelated base-induced transformations, i.e., (1) conversion of the halohydrin into an epoxide and (2) the O-alkylation of the phenol with the selected phenylpiperazine. The reaction is carried out under basic conditions utilizing an alkali metal hydroxide, e.g., NaOH or KOH in an aqueous dimethylsulfoxide, tetrahydrofuran or alcohol (methanol, ethanol, etc.) solvent. The reaction is carried out from about 0.degree. C. to 40.degree. C. with higher temperatures, e.g., 40.degree. C. as preferred.
The epoxide of formula XXXV is reacted with a monoalkylamine such as isopropyl, t-butyl, etc. amine to produce the amino alcohol. Solvents for such a reaction are alcohols (C.sub.1 -C.sub.4) with methanol preferred or ethers, such as, tetrahydrofuran or dioxane. The reaction may be run from about 0.degree. C. to 100.degree. C. with about 65.degree. C. as preferred.
The compound of formula XVII undergoes a reductive cleavage of the N-protected amine to give the secondary amine. Reagents and reaction parameters for this reaction have been previously disclosed for step XXIV.fwdarw.XXV.
The benzyl ether of formula XXXVI thereafter undergoes hydrogenolysis in a catalyzed reaction. Suitable catalysts include noble metals (as previously disclosed) on carbon in a solvent such as lower alcohols (C.sub.1 to C.sub.4) e.g., methanol or ethanol at a temperature range of from about 0.degree. C. to 100.degree. C. If H.sub.2 /Raney Nickel is chosen as the catalyst, the reaction should be run under pressure, e.g., up to 10 atmospheres.
The phenol (XXXVII) undergoes a base induced O-alkylation with a phenylpiperazine of the formula ##STR29## wherein n and R.sub.6 are as above. in an aqueous dimethylsulfoxide, tetrahydrofuran or dioxane solvent. Suitable bases include alkali metal hydroxides, such as, NaOH or KOH. The reaction temperature ranges from about 0.degree. C. to 100.degree. C. with about 60.degree. C. as preferred.
The compound of the formula XLII is reacted with a compound of the formula ##STR30## to produce the compound of the formula XLIII. The reactants and reaction parameters have been previously disclosed in step XV.fwdarw.XXX.
The compound of formula XLIII thereafter undergoes a hydrogenolysis as previously disclosed and with the same reagents and reaction parameters as step XXX.fwdarw.XXXI.
The compound of formula XLIV is converted to a compound of formula XLVI utilizing the same reagents and reaction parameters as previously disclosed in step XII.fwdarw.XIII.fwdarw.XIV.
The compound of formula XLVI undergoes a three step reaction under basic conditions as follows:
The activated ester of formula XLVIII is produced by treatment of the acid (XLVII) with an excess of a haloacetonitrile (Halo--CH.sub.2 C.tbd.N) in the presence of a tertiary amine base, such as, trialkylamine, e.g., triethyl-or trimethylamine. The reaction temperature may range from about 0.degree. C. to 70.degree. C. with a range of about 25.degree. C.-70.degree. C. as preferred. The activated ester may be utilized to undergo condensation reactions, such as reactions with amines to form amides at a much faster rate than the ordinary methyl or ethyl esters.
The ester of formula XLVIII is thereafter condensed with a primary amine of the formula ##STR31## to form the amide (XLIX). An inert solvent, such as, tetrahydrofuran or dioxane, may be utilized at a temperature range of about 0.degree. C. to 100.degree. C. with room temperature as preferred.
The epoxide of formula XLIX is thereafter reacted with a primary amine e.g., an amine of the formula
The alkene portion of the formula LI* compound is reacted with a hypohalous acid (generated in situ from an N-Halosuccinimide in aqueous acetone containing a catalytic amount of HClO.sub.4) to give a mixture of halohydrins, i.e., LII and the compound of the formula ##STR32##
The bromohydrins (LII and LII') are thereafter converted under basic conditions to the epoxide (LIII). As a base, an alkali metal (Na, K, etc.) hydroxide may be utilized. Suitable solvents for the reaction include ethers, such as, dioxane or tetrahydrofuran and alcohols (C.sub.1 to C.sub.4) e.g., methanol, ethanol, etc. The reaction may be run at from about 0.degree. C. to 40.degree. C. with room temperature as preferred.
The acid portion of the compound of formula LI is esterified by treatment of LI with an excess of an alkylating agent, CH.sub.3 -Halo, e.g., CH.sub.3 I, CH.sub.3 Br, in the presence of an alkali metal (Na, K) carbonate in a solvent, such as, acetone, dimethylformamide, dimethylsulfoxide or hexamethylphosphoramide to give the ester of formula LIV. The reaction temperature is not critical but about room temperature is preferred for its ease.
The acid portion of the epoxide (LIII) may also be esterified by using diazomethane in the presence of a solvent such as ethers (tetrahydrofuran) or a C.sub.1 to C.sub.4 alcohol. As above, this reaction is preferably run at room temperature.
The alkene portion of the compound of formula LIV is thereafter reacted with an aromatic or aliphatic peracid, such as, m-chloroperbenzoic acid, peracetic acid, performic acid, trifluoroperacetic acid, permaleic acid, perbenzoic acid, monoperphthalic acid, o-sulfoperbenzoic acid or p-nitroperbenzoic acid. The reaction utilized as a solvent any inert halogenated aliphatic hydrocarbon, such as, methylene chloride or chloroform. The reaction temperature may range from about 0.degree. C. to reflux with room temperature as preferred.
The epoxide portion of the compound of formula LV is thereafter reacted with a primary amine of the formula NH.sub.2 R.sub.1, wherein R.sub.1 is as above, in a suitable solvent, such as, C.sub.1 to C.sub.4 alcohols or ethers, such as, dioxane or tetrahydrofuran. The reaction temperature may vary from about 0.degree. C. to room temperature with room temperature as preferred.
The ester portion of LVI is thereafter condensed with a primary amine of the formula ##STR33## wherein n and R.sub.6 as as above, to form the amide. No solvent is necessary for this step. The reaction temperature may be from about 100.degree. C. to 150.degree. C. with a preferred range of from about 140.degree. C. to 145.degree. C.
The phenol portion of XVI undergoes an O-alkylation with an epihalohydrin, e.g., epichlorohydrin, using as a base, an alkali metal hydroxide, e.g. KOH or NaOH in a mixture of H.sub.2 O and dioxane, tetrahydrofuran or dimethylsulfoxide. The reaction may be carried out from about 0.degree. C. to 100.degree. C. with about room temperature as preferred.
The epoxide portion of LXII is thereafter reacted with an amine of the formula
The benzyloxy portion of the compound of formula LXIII is converted to the phenol function by utilizing the reagents and reaction parameters previously disclosed for the isomer, see, step XXXVI.fwdarw.XXXVII.
The phenol portion of LXIV is reacted with a phenylpiperazine as previously disclosed in step XXXVII.fwdarw.XXV along with the reagents and reaction parameters.
The phenol portion of the bromoethoxy phenol undergoes an O-alkylation with an alkylating agent, such as, allyl halide, e.g. chloride or bromide, in the presence of an alkali metal (Na,K) carbonate in refluxing solvent, such as, acetone. The reaction temperature should be about or at reflux of the solvent.
The alkene portion of the compound of formula LVIII is thereafter converted to the halohydrins of formulas LIX and LIX' by utilizing the reagents and reaction parameters set forth in step LI.fwdarw.LII.
The halohydrins (LIX and LIX') are thereafter converted to the epoxide of formula LX by utilizing the reagents and reaction parameters set forth in step LII.fwdarw.LIII.
The epoxide (LX) is thereafter reacted with a primary amine of the formula NH.sub.2 -R.sub.1 wherein R.sub.1 is as above, to give the aminoalcohol (LXI). Suitable solvents include C.sub.1 to C.sub.4 alcohols, ethers such as tetrahydrofuran or dimethylsulfoxide or dimethylformamide. The reaction may be carried out from about room temperature to 60.degree. C. with a range of about room temperature to 55.degree. C. as preferred.
The halogen portion of LXI is thereafter displaced with a secondary amine of the formula ##STR34## wherein R.sub.6 is as above to produce a compound of formula XXV'. Solvents suitable for this reaction include C.sub.1 to C.sub.4 alcohols and ethers, such as, dioxane and tetrahydrofuran. The reaction may be carried out at from about 0.degree. C. to 100.degree. C. with 80.degree. C. to 100.degree. C. as preferred.
A compound of the formula LXV is reacted with an appropriately substituted amine of the formula ##STR35## wherein R.sub.6 is as above in a C.sub.1 to C.sub.4 alcohol. The temperature of the reaction may be varied from room temperature to the boiling point of the selected alcohol. A preferred alcohol is ethanol and the preferred reaction temperature is its boiling point.
The compound of formula LXVI is thereafter converted to a compound of formula LXVII by treatment with a base such as an alkali or alkaline earth metal hydroxide (NaOH, KOH, Ba(OH.sub.2) in a solvent such as water, C.sub.1 to C.sub.4 alcohols or dimethylformamide or alkali metal (K,Na) salts of lower alcohols in solvents such as dimethylformamide or C.sub.1 to C.sub.4 alcohols. To this reaction mixture containing the salt of LXVI is added epihalohydrin to generate LXVII.
The compound of formula LXVII is treated with an amine of the formula
The compound of formula LXVIII can alternatively be prepared from LXIX by treatment with a propenoyl halide in an inert solvent e.g., dioxane, dimethylsulfoxide, etc. at from about 0.degree. C. to 50.degree. C. The intermediate is treated in situ with an appropriately substituted amine of the formula ##STR36## wherein R.sub.6 is as above The reaction conditions are as in step LXV.fwdarw.LXVI above. The compound of formula LXX Is generated by mixing maleic acid with LXVIII in an inert solvent.
The haloalkanoyl halide of formula LXXI is reacted with 4-aminophenol in the presence of excess 4-aminophenol or an equivalent of a tertiary amine, such as, pyridine, triethylamine or the like in an inert solvent, such as, an ether, e.g., tetrahydrofuran or dioxane or a polyhalogenated hydrocarbon, e.g., methylene chloride at a temperature of from about 0.degree. C. to 100.degree. C. A preferred reaction system for this conversion is dioxane in the presence of excess 4-aminophenol at room temperature.
The compound of formula LXXII is reacted with an appropriately substituted amine of the formula ##STR37## wherein R.sub.6 is as above in the presence of a hydrogen halide scavenger, such as excess reagent or a less reactive amine such as triethylamine or pyridine in an inert solvent e.g., C.sub.1 to C.sub.4 alcohol. The reaction temperature may vary from about room temperature to 100.degree. C.
Conversion of the compound of formula LXXIII into that of formula LXXV is the same for reagents and reaction parameters as previously disclosed in steps LXVI.fwdarw.LXVII.fwdarw.LXVIII.fwdarw.LXX
The end compounds of the subject invention may be converted to their pharmaceutically acceptable salts which exhibit comparable pharmacological activity. The end products have three amine functions, but only two of these groups are sufficiently basic to form stable salts. Accordingly they form diacid salts with various organic and inorganic acids. Some of the useful organic or inorganic acids include maleic acid, fumaric acid, tartaric acid, citric acid, hydrochloric acid, hydrobromic acid and sulfuric acid. A typical preparation of one of these salts entails the mixture of a solution of the base end product, for example, XXV in a C.sub.1 to C.sub.4 alcohol with a solution of a pharmaceutically acceptable acid as outlined above, also in a C.sub.1 to C.sub.4 alcohol. The salt thus formed crystallizes spontaneously from solution or does so on the addition of a suitable co-solvent, for example, ethyl acetate, ether, acetone, or halogenated hydrocarbons, such as, chloroform, 1,2-dichloroethane, etc.
An alternative method which may be useful in the case of compounds, such as the end product L, comprises the treatment of two parts of the base with an excess of hydrochloric acid in methanol. The solvent is then removed in vacuo to drive off the excess acid which gives the unstable trihydrochloride salt. The salt is then redissolved in methanol and one part of free base added to the solution. The dihydrochloride salt is then precipitated from solution on the addition of a co-solvent, such as disclosed above.
Preferred among the compounds disclosed herein are those of the formula ##STR38## wherein R.sub.1 is selected from the group consisting of lower alkyl; R.sub.8 is selected from the group consisting of --O--(CH.sub.2).sub.n -wherein n is 2 to 20, ##STR39## and R.sub.6 is selected from the group consisting of hydrogen or lower alkoxy, the racemates thereof and pharmaceutically acceptable salts thereof. Especially preferred are those compounds wherein R.sub.1 is a branched chain alkyl, such as, isopropyl or tertiary butyl, R.sub.8 is the group --O--(CH.sub.2).sub.n -- or ##STR40## wherein n is 2 to 10, most preferably 2, and R.sub.6 is hydrogen.
The compounds of the present invention and their pharmaceutically acceptable salts are useful as .alpha. and .beta. adrenergic blocking agents when utilized particularly in oral preparations. As contemplated by this invention the novel end products of the present invention and their pharmaceutically acceptable salts can be embodied in pharmaceutical dosage formulations containing from about 0.1 to about 50 mgs., most preferably 1-50 mg. with dosage adjusted to animal species and individual requirements. The novel end products and their pharmaceutically acceptable salts can be administered internally, for example, parenterally or enterally, in conventional pharmaceutical dosage forms. For example, they can be incorporated in conventional pharmaceutical dosage forms. For example, they can be incorporated in conventional liquid or solid vehicles such as water, gelatin, starch, magnesium stearate, talc, vegetable oils and the like to provide tablets, elixirs, capsules, solutions, emulsions and the like according to acceptable pharmaceutical practices. Although less preferred intravenous and intramuscular delivery systems may be utilized to provide the above novel compounds.
The disclosed compounds are in the general class of 1-aryloxy-3-alkylaminopropan-2-ols, many examples of which have been shown to possess .beta.-adrenergic blocking activity. Since the class of compounds has an asymmetric center there are two enantiomeric forms. It has been found that the .beta.-blocking activity of such compounds is to a large extent found in the isomer having the S-absolute configuration i.e. that isomer that is stereochemically equivalent to the naturally occurring .beta.-agonist (R)-(-) epinephrine, whereas the racemic form exhibits approximately half of this activity, see, for example,
The desired S-isomer of the disclosed compounds are available in two ways:
(a) by resolution of the racemic material via a fractional crystallization of its diastereoisomeric salts formed with an optically active acid, such as tartaric acid.
(b) by asymmetric synthesis using an optically active synthon of the appropriate absolute configuration. Two such synthons, IX and XV, which are readily available from D-mannitol, a naturally occurring sugar, have been used to construct the oxypropanolamine side chain in the disclosed compounds. Synthon IX is restricted to the syntheses of .alpha., .beta.-blockers, wherein the functionality of the final compound is compatable with the conditions required to remove the amine protecting group, R.sub.3 i.e. reductive cleavage using a mixed metal hydride. When the functionality of the final compound is not compatable with these conditions, e.g. the amido group in compound L, the synthon XV is used to incorporate the oxypropanolamine side chain.
Applicants, in setting forth the disclosure of the above specification have cited the teaching of various articles and U.S. Patents. Such citations are meant to incorporate the teachings of these references for completeness of disclosure.
US Referenced Citations (3)
| Number |
Name |
Date |
Kind |
| 4016179 |
Fujimoto et al. |
Apr 1977 |
|
| 4150235 |
Cragoe et al. |
Apr 1979 |
|
| 4178460 |
Berkelhammer et al. |
Dec 1979 |
|
Divisions (1)
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Number |
Date |
Country |
| Parent |
875966 |
Feb 1978 |
|
Patent Grant
4247710
