US3048591A - 18-o-hetero-reserpates - Google Patents

18-o-hetero-reserpates Download PDF

Info

Publication number
US3048591A
US3048591A US931A US93160A US3048591A US 3048591 A US3048591 A US 3048591A US 931 A US931 A US 931A US 93160 A US93160 A US 93160A US 3048591 A US3048591 A US 3048591A
Authority
US
United States
Prior art keywords
tetrahydro
pyranyl
methyl
deserpidate
lower alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US931A
Inventor
Lucas Robert Armistead
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF Corp
Novartis Corp
Original Assignee
Ciba Geigy Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba Geigy Corp filed Critical Ciba Geigy Corp
Priority to US931A priority Critical patent/US3048591A/en
Application granted granted Critical
Publication of US3048591A publication Critical patent/US3048591A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D459/00—Heterocyclic compounds containing benz [g] indolo [2, 3-a] quinolizine ring systems, e.g. yohimbine; 16, 18-lactones thereof, e.g. reserpic acid lactone

Definitions

  • R represents lower alkyl, lower alkoxy-lower alkyl or tertiary amino-lower alkyl
  • R stands for lower alkyl
  • R represents cyclo-oxa-alkyl, particularly 2-cyclooXa-alkyl, which contains at least five atoms as ring members
  • each of the radicals R and R stands for hydrogen, lower aliphatic hydrocarbon, or a functional group, such as, for example, etherified hydroxyl, esterified hydroxyl, etherified mercapto, nit-ro, amino, halogeno or halogen-olower alkyl, or, when attached to adjacent positions and taken together, for lower :alkylene-dioxy, and R attached to either one of the positions 5 or 6, stands for hydrogen or lower alkyl, salts or N-oxides thereof, as well as process for the preparation of such compounds.
  • a lower alkyl group R containing from one to seven, preferably from one to four, carbon atoms stands, for example, for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl as Well as n-pentyl, isopentyl, n-hexyl and the like.
  • a lower alkoxy-lower alkyl group R the lower alkoxy portion contains from one to ⁇ our carbon atoms and represents, for example, methoxy, ethoxy, n-pr-opyloxy, isopropyloxy, n-butyloxy and the like.
  • the amino group of a tertiary amino-lower alkyl radical R is primarily an IJ,N-di-lower alkyl-amino group, in which lower alkyl contains from one to four carbon atoms, e.g.
  • l-morpholino and the like or an N,N-lower azaalkylene-irnino group, in which lower aza-alkylene contains preferably four carbon atoms, e.g. 4-methyl-1-piperazino and the like.
  • the lower alkyl portion of a lower alkoxy-lower alkyl or a tertiary amino-lower alkyl radical R is represented by a lower alkylene radical containing from two to seven carbon atoms, which separates the lower alkoxy group or the amino group from the carbon atom of the carboxy group by at least two carbon atoms.
  • the lower alkylene radical contains from two to three carbon atoms and separates the lower alkoxy and the amino group from the carboxy group by the same number of carbon atoms.
  • Such radicals are primarily 1,2-ethylene, l-methyl-1,2- ethylene, 2-methyl-l,2-ethylene or 1,3-propylene; other lower alkylene radicals may be, for example, 1,4-butylene or 1-methyl-1,3-propylene and the like.
  • the lower alkyl group R containing from one to four carbon atoms stands for ethyl, n-propyl, isopropyl, n-
  • the 2-cyclo-oxa-alkyl radical R attached to the oxygen atom of the position 18 of the deserpidate portion is more especially represented by a 2-cyclo-oxa-alkyl radical containing from five to seven atoms as ring members, such as a tetrahydro-Z-furanyl (Z-cyclo-oxapentyl), a tetrahydroe2- pyranyl (Z-cyclo-oxahexyl), a 2-cyclo-oxaheptyl radical and the like.
  • the carbon atoms of the cyclo-oxa-alkyl, particularly a 2-cyclo-oxa-alkyl, nucleus may be unsubstituted or substituted by lower aliphatic hydrocarbon, particularly lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, as well as, for example, lower cycloalkyl, e.g. cyclopentyl, cyclohexyl and the like, or carbocyclic aryl, such as monocyclic or bicyclic carbocyclic aryl, e.g.
  • phenyl, naphthyl and the like or carbocyclic aryllower aliphatic hydrocarbon, such as monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the like.
  • Two of the carbon atoms of the cyclo-oxa-alkyl nucleus may also be part of a second, especially of a carbocyclic, ring system fused onto the cyclo-oxa-alkyl nucleus; carbocyclic rings, which may be fused onto the :cyclo-oxa-alkyl nucleus, may be represented, for example, by cycloalkyl containing from five to seven carbon atoms, e.g. cyclopentyl, cyclohexyl, cycloheptyl and the like, or carbocyclic aryl, such as monocyclic or bicyclic carbocyclic aryl, e.g. phenyl, naphthyl and the like.
  • substituents attached to any of the available carbon atoms of the cyclo-oxa-alkyl, particularly the Z-cyclooxa-alkyl, radical are, for example, halogen atoms, e.g. fluorine, chlorine, bromine and the like, as well as other functional groups.
  • the group R may, therefore, be represented by tetrahydrofuranyl (cyclo-oxapentyl) radicals, particularly tetrahydro-Z-furanyl (Z-cyclo-oxapentyl) radicals, e.g.
  • tetrahydro-Z-furanyl (Lcyclo-oxapentyl), 4-methyl-tetrahydro-2- furanyl (4-methyl-2-cyclo-oxapentyl), S-methyl-tetrahydro- Z-furanyl (S-methyl-Z-cyclo-oxapentyl), 3-chloro-tetrahydro-Z-furanyl (3-chloro-2-cyclo-oxapentyl) and the like, tetrahydropyranyl (cyclo-oxahexyl) radicals, particularly tetrahydro-Z-pyranyl (2-cyclo-oxahexyl) radicals, e. g.
  • tetrahydro-Z-pyranyl (Z-cyclo-oxahexyl), 4-methyl-tetrahydro- 2-pyranyl (4-methyl-2-cyclo-oxahexyl), 6-methyl-tetrahy dro-Z-pyranyl (6-methyl-2-cyclo-oxahexyl), fi-phenyl-tetrahydro-Z-pyranyl (6-phenyl-2-cyclo-oxahexyl), hexahydrobenz[e]tetrahydro 2 pyranyl (bicyclo[4,4,0]-2-oxa-3- decyl), benZ[e]dihydro-2-pyranyl (2-benz[e]cyclo-oxahexyl), 3-chloro-tetrahydro-2-pyranyl (3-chloro-2-cyclooxahexyl), 3-bromo-tetrahydro-2-pyranyl (3-bromo-2- cyclo
  • the substituents R and R may represent hydrogen or any of the groups mentioned hereinabove.
  • groups are, for example, lower aliphatic hydrocarbon, primarily lower alkyl containing from one to four carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl and the like, or functional groups, such as, for example, etherified hydroxy, particularly lower alkoxy containing from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, i-butyloxy, and the like, as well as cycloalkyloxy, e.g.
  • carbocyclic aryloxy such as monocyclic carbocyclic aryloxy, e.g. phenyloxy and the like
  • carbocyclic aryl-lower alkoxy such as monocyclic carbocyclic aryl-lower alkoxy, for example, phenyl-lower alkoxy, e.g. benzyloxy and the like
  • esterified hydroxyl particularly lower alkoxy-carbonyloxy, e.g. methoxycarbonyloxy, ethoxycarbonyloxy and the like, or lower alkanoyloxy, e.g.
  • radicals R and R when taken together may also form a cyclic substituent; such substituent may be represented, for example, by lower alkylene-dioxy, e.g. methylenedioxy, or any other analogous substituent.
  • the radical R stands preferably for hydrogen; when representing lower alkyl, such radical may stand for 'methyl, as well as ethyl and the like.
  • Salts of the compounds of this invention are primarily therapeutically acceptable acid addition salts with inorganic or organic acids, particularly with mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like.
  • the compounds may also be present in the form of their N-oxides.
  • the latter may :be obtained in the form of a mixture of racemates, racemates or optically pure compounds.
  • the new compounds of this invention have antihypertensive properties, as well as sedative and tranquilizing eflects on the central nervous system. They are characterized by a quick onset of the physiological action. Furthermore, tests show that animals, treated with the compounds of the present invention, recover faster and more completely from the pharmacological effects than those treated with known, naturally occurring Rauwolfia alkaloids, for example, with reserpine, deserpidine or rescinnamine. In addition, certain quantitative difierentiations may be observed within the group of the new compounds of this invention.
  • some of the compounds of this invention when compared with the established ratio existing between antihypertensive and sedative efiects in the above-mentioned natural Rauwolfia alkaloids, some of the compounds of this invention have more predominant sedative eflects with negligible antihypertensive activity, whereas in others, the latter may be more pronounced than the sedative and tranquilizing component.
  • the compounds of the present invention may, therefore, be used as antihypertensive agents to relieve hypertensive conditions, such as, for example, benign or malignant hypertension, renal hypertension or hypertension associated with pregnancy, such as toxemia of pregnancy, and/or as sedative agents to relieve states of hyperactivity, tension and agitation, as, for example, associated with mental disturbances and the like.
  • hypertensive conditions such as, for example, benign or malignant hypertension, renal hypertension or hypertension associated with pregnancy, such as toxemia of pregnancy, and/or as sedative agents to relieve states of hyperactivity, tension and agitation, as, for example, associated with mental disturbances and the like.
  • R represents lower alkyl containing from one to four carbon atoms
  • R stands for 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, lower alkylsubstituted Z-cyclo-oxa-alkyl containing from five to seven atoms as ring members, or halogeno-substituted 2- cyclo-oxa-alkyl containing from five to seven atoms as ring members
  • each of the radicals R and R stands for hydrogen, lower alkyl containing from one to four car bon atoms, lower alkoxy containing from one to four carbon atoms, lower alkyl-mercapto containing from one to four carbon atoms, or halogeno, R attached to one of the positions 5 and 6, stands for hydrogen of lower alkyl
  • This group of compounds is represented, for example, by lower alkyl reserpate compounds of the formula:
  • R stands for lower alkyl containing from one to four carbon atoms, or the N-oxides thereof, whereby these compounds may be in different isomeric forms.
  • lower alkyl 18-0-(tetrahydro-Z-furanyl)-reserpates in which lower alkyl contains from one to four carbon atoms, e.g. methyl 18-0-(tetrahydro-Z-furanyl) -reserpate, ethyl 18-0-(tetrahydro-Z-furanyl)-reserpate, n-propyl l8-O-(tetrahydro-Z-fur-anyl)-rese1pate and the like
  • lower alkyl 18-0-(tetrahydro-Z-pyranyl)-reserpates in which lower alkyl contains from one to four carbon atoms, e.g.
  • R stands for lower alkyl containing from one to four carbon atoms, or their N-oxides, whereby these compounds may be in different isomeric forms.
  • the new compounds may also be represented by the 2- lower alkoxy-lower alkyl 18-O-R -11-R deserpidates, in which lower alkoxy contains from one to four carbon atoms, lower alkyl contains from two to three carbon atoms and separates alkoxy from the carboxy group by from two to three carbon atoms, R represents 2-cyclo-oxaalkyl containing from five to seven atoms as ring members, and R represents hydrogen or methoxy.
  • This group is represented by 2-l-ower alkoxy-ethyl IB-O-(tetrahydro- 2-furanyl)-reserpates, in which alkoxy contains from one to four carbon atoms, such as Z-methoxy-ethyl 18-O- (tetrahydro-Z-furanyl)-reserpate and the like, and the 2- lower alkoxy-ethyl 18-O-(tetrahydro-Z-furanyl)-deserpidates, in which lower alkoxy contains from one to four carbon atoms, such as Z-methoxyethyl IS-O-(tetrahydro- Z-furanyD-deserpidate and the like, 2-lowe-r alkoXy-cthyl 18-0-(tetrahydro-Z-pyranyl)-reserpates, in which alkoxy contains from one to four carbon atoms, such as 2- methoxy-ethyl l8-0-(-
  • An additional group of the new compounds is represented by the lower alkyl l0-methoXy-l8-O-R -deserpidates, in which R stands for 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, and lower alkyl contains from one to four carbon atoms; such compounds are, for example, lower alkyl lO-rnethoxy-lS-O-(tetrahydro-Z-furanyl)-deserpidate, in which lower alkyl contains from one to four carbon atoms, e.g.
  • a further group of highly active compounds are the lower alkyl 12-methoxy-18-O-R -deserpidates, in which R represents Z-cyclo-oxa-alkyl containing from five to seven atoms as ring members, and lower alkyl contains from one to four carbon atoms as ring members.
  • This group may be illustrated by lower alkyl l2-methoxy-l8-O- (tetrahydro-2-furanyl)-deserpidates, in which lower alkyl contains from one to four carbon atoms; methyl 12-methoxy-18-0-(tetrahydro-Z-furanyl)-deserpidate, ethyl 12- methoxy-l 8-0- (tetrahydro-Lfuranyl -deserpidate, n-propyl 12-methoxy-18-O-(tctrahydro-Z-furanyl)-deserpidate and the like, lower alkyl 12-methoXy-1S-O-(tetrahydro-Z- pyranyD-deserpidates, in which lower alkyl contains from one to four carbon atoms; methyl l2-methoxy-l8-O-(tctrahydro-Z-pyranyl)-deserpidate, ethyl 12-methoxy-18-O- tetrahydro
  • Lower alkyl 10-halogeno-l8-O-R -deserpidates in which R stands for 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, halogeno represents primarily chloro or bromo, as well as iodo, and lower alkyl contains from one to four carbon atoms, are an additional series of new compounds of this invention.
  • An additional group of compounds are the lower alkyl 6-methyl-l8-O-R -reserpates, in which R stands for 2- cyclo-oxa-alkyl containing from five to seven atoms as ring members, and lower alkyl contains from one to four carbon atoms.
  • the lower alkyl 6-methyl-18-O-(tetrahydro-Z-furanyl)-reserpates and the lower alkyl 6-methyll8-O-(tetrahydro-Z-pyranyl)-reserpates, in which lower alkyl contains from one to four carbon atoms, are more specific groups of these compounds, which may be illustrated, for example, by methyl 6-metl1yl-lS-O-(tetrahydro- Z-furanyD-reserpate, ethyl 6-methyl-IS-O-(tetrahydro-Z- furanyU-reserpate, n-propyl 6-methyl-l 8-O-(tetrahydro-2- furanyl)-reserpate and the like, methyl 6-methyl-l8-O- (tetrahydro-Z-pyranyl)-reserpate, ethyl 6 methyl-18-O- (tetrahydro-2-pyranyl)-reser
  • lower alkyl 18-O-R -deserpidate compounds in which R represents 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, and lower alkyl contains from one to four carbon atoms, are, for example, lower alkyl S-methyl-l8-O-R -deserpidates, lower alkyl 5- methyl-l8-O-R -reserpates, lower alkyl 6-methyl-1S-O-R deserpidates, lower alkyl 9-methyl-l8-O-R -deserpidates, lower alkyl ll-methyl-l8-O-R -deserpidates, lower alkyl 9-methoxy-l8-O-R -deserpidates, lower alkyl lO-methoxy- 18-OR -rese1 pates, lower alkyl ll-ethoxy-l8-O-R -deserpidates, lower alkyl 11-n-propyloxy-
  • the compounds of this invention may be 'used as medicaments in the form of pharmaceutical preparations, which contain the new compounds in admixture with a pahrmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration.
  • a pahrmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration.
  • substances which do not react with the new compounds such as water, gelatine, lactose, starches, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known carrier for medicaments.
  • Thte pharmaceutical preparations maybe in solid form, for example, as tablets, dragees, capsules and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents and the like, salts for varying the osmotic pressure, bulfers and the like. They may also contain, in combination, other therapeutically useful substances. The compounds of this invention may also be used in compositions for veterinary use by adding them to standard feed formulae.
  • R R R R and R have the previously given meaning, or an N-oxide thereof, with a reactive ester of a 2-hydroxy-cyclo-oxa-alkane, which contains at least five atoms as ring members, in the presence of a condensing reagent, and, if desired, separating a resulting mixture of isomeric compounds into the single isomers, and/ or, if desired, converting a resulting compound into a salt or an N-oxide thereof.
  • the reactive ester of a Z-hydroxy-cyclooxa-alkane, used as the reagent in the above reaction, is particularly an ester with a strong inorganic or organic acid, particularly a mineral acid, such as a hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like, as well as a monocyclic carbocyclic aryl sulfonic acid, eg p-toluene sulfonic acid and the like.
  • a strong inorganic or organic acid particularly a mineral acid, such as a hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like, as well as a monocyclic carbocyclic aryl sulfonic acid, eg p-toluene sulfonic acid and the like.
  • the reagent is represented primarily by a Z-halogeno-cyclo-oxa-alkane, which contains at least five atoms as ring members, particularly by a 2-chloro-cyclooxa-alkane, as well as by a 2 bromo-cyclo-oxa-alkane, which contain from five to seven atoms as ring members.
  • cyclo-oXa-alkane compounds may contain hydrocarbon radicals, such as, for example, lower alkyl, e.g. methyl and the like, or functional groups, such as additional halogen atoms, e.g.
  • substituted reagents are, for example, 2-chloro-S-methyl-tetrahydrofuran (2-chloro-5- methyl-cyclo-oxapentane), 2-chloro-4-methyl-tetrahydropyran (2-chloro-4-methyl-cyclo-oxahexane), 2-chloro-6- methyl-tetrahydropyran (2-chloro-6methyl-cyclo-oxahexane), 2,3-dichloro-tetrahydropyran (2,3-dichloro-cyclooxahexane) and the like.
  • a condensing reagent may be represented more particulady by N,N-dimethylformamide; any other suitable reagent may be used.
  • N,N-dimethylformamide may also serve as a solvent; other inert solvents may be used as diluents.
  • reaction mixture is allowed to stand, if necessary, while cooling and with protection from light, until the reaction is completed.
  • desired compound is isolated from the reaction mixture according to methods known per se, for example, by evaporating the solvent and isolating the reaction product from the residue, by diluting the reaction mixture and precipitating or extracting the product, and the like.
  • the reaction product may be purified by crystallization, adsorption and elution, recrystallization and the like.
  • deserpidate compounds used as the starting ma terials are known or, if new, may be prepared according to procedures used for known analogous compounds.
  • deserpidic acids may be esterified by treatment with a lower diazoalkane, a lower alkoxy-lower diazoalkane or a tertiary amino-lower diazoalkane, or
  • the deserpidic acid compound or a salt thereof may be added to a solution of the diazo reagent in an inert solvent, such as an ether, particularly diethylether, which is preferably kept in a suspension or a solution, for example, of a lower alkanol, e.g. methanol, ethanol and the like, a halogenated lower aliphatic hydrocarbon, e.g. chloroform, methylene chloride and the like, or any other suitable, inert solvent.
  • the diaz compound may be distilled out of a solution, such as a diethylether solution, into the suspension or solution of a deserpidic acid compound or a salt thereof.
  • An excess of the diazo derivative present in the reaction mixture may be destroyed, for example, by adding an additional carboxylic acid, e.g. acetic, benzoic acid and the like.
  • the esterification may be carried out under cooling or at room temperature, and, if desired, under the atmosphere of an inert gas, e.g. nitrogen.
  • the desired deserpidate compound may be obtained.
  • an alkali metal e.g. lithium, potassium, or particularly sodium
  • a lower alkanol, a lower alkoxy-loWer alkanol or a tertiary amino-lower alkanol and adding a deserpidic acid lactone to the resulting alkali metal derivative of the alcohol, the desired deserpidate compound may be obtained.
  • this reaction may proceed under cooling or at room temperature, the mixture is advantageously heated, if necessary, in the atmosphere of an inert gas, e.g. nitrogen.
  • N-oxides of the starting material may be prepared according to known N-oxidation methods; for example, a solution of the starting material may be treated with a per-acid, such as, for example, peracetic, perbenzoic, monoperphthalic, p-toluene persulfonic acid and the like, with hydrogen peroxide or with ozone.
  • a per-acid such as, for example, peracetic, perbenzoic, monoperphthalic, p-toluene persulfonic acid and the like, with hydrogen peroxide or with ozone.
  • R R R R and R have the above-given meaning, a salt or an N-oxide thereof, with a cyclo-oxaalk-Z-ene, which contains at least five atoms as ring members, and which is capable of introducing the desired radical R in the presence of an acid condensing reagent,
  • the cyclo-oxa-alk-Z-enes used as the reagents contain no further substituents, or, whenever substituents, such as halogen, lower alkyl and the like, are present, such substituents are attached to those carbon atoms, which do not involve the 2,3-double bond.
  • substituents such as halogen, lower alkyl and the like
  • Especially suitable reagents are cyclo-oxa-alk-Z-enes, which contain from five to six atoms as ring members, and which, when sub- These reagents are reacted with the deserpidate compound in the presence of an acid condensing reagent, represented by a strong Lewis acid.
  • Mineral acids e.g.
  • hydrochloric, hydro'bromic or sulfuric acid used in anhydrous form or as concentrated aqueous solutions
  • phosphoric acid for example, in the form of polyphosphoric acid
  • phosphorous oxychloride for example, in the form of polyphosphoric acid
  • fluoboric acid in the form of a highly concentrated aqueous solution
  • boron trifluoride in the form of its etherate, particularly with diethyl ether
  • a carbocyclic aryl sulfonic acid such as a monocyclic CEllbOCYCllC acid, especially p-toluene sulfonic acid, or similar reagents having Lewis acid properties, such as, for example, cation exchange resins in acid form, e.g. sulfonic acid resins, or any other suitable Lewis acid may serve as a condensing reagent.
  • Lewis acid properties such as, for example, cation exchange resins in acid form, e.g. sulfonic acid resin
  • the deserpidate compound may first form a salt with such acid and react in the form of an acid addition salt. Therefore, a salt of the deserpidate compound with an acid may also be used as the starting material.
  • the reaction may be carried out in the absence of a solvent, whereby an excess of a liquid cyclo-oxa-alk-Zene may also serve as the solvent, or in the presence of an inert solvent.
  • solvents are, for example, carbocyclic aryl hydrocarbons, such as monocyclic carbocyclic aryl hydrocarbons, e.g. benzene, toluene and the like, ethers, e.g. diethylether, tetrahydrofuran, p-dioxane and the like, lower alkanones, e.g. acetone, ethyl methyl 'ketone and the like, formamides, e.g. formamide, N,N-dimethylformamide and the like, acetonitrile or any other suitable solvent.
  • carbocyclic aryl hydrocarbons such as monocyclic carbocyclic aryl hydrocarbons, e.g. benzene, tolu
  • the reaction may be carried out by mixing the reagents or solutions thereof, whereupon the temperature may raise, and the mixture may then be allowed to stand or may be agitated under cooling, at room temperature or at an elevated temperature.
  • the desired product may be isolated according to standard procedures, e.g. extraction, adsorption and elution, crystallization, and the like, preferably after having neutralized the acidic reaction mixture with an alkaline reagent, for example, ammonia, e.g. aqueous ammonia, ammonia in a lower alkanol such as methanol, ethanol and the like, aqueous alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate and the like, aqueous alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, or any other suitable alkaline reagent.
  • an alkaline reagent for example, ammonia, e.g. aqueous ammonia, ammoni
  • the reaction may also be carried out in the atmosphere of an inert gas, e.g. nitrogen and/or, if necessary, with the exclusion of moisture by adding a dehydrating reagent, or under pressure in a closed vessel.
  • an inert gas e.g. nitrogen and/or, if necessary, with the exclusion of moisture by adding a dehydrating reagent, or under pressure in a closed vessel.
  • the compounds of the present invention may also be prepared by converting in compounds of the formula:
  • the l8-O-R deserpidic acid compounds in which R has the previously given meaning, may be treated with a diazo compound of the formula R N in which R has the previously given meaning, particularly a lower diazoalkane, e.g.
  • diazomethane diazoethane, l-diazopropane, l-diazo-n-butane, l-diazo-isobutane, l-diazo-n-pentane, 1- diazo-isopentane, 1-diazo-n-hexane and the like
  • a lower alkoxy-lower diazoalkane particularly a lower alkoxylower diazoalkane, in which lower alkoxy is separated from the diazo group by from two to three carbon atoms, and lower alkane contains from two to three carbon atoms, e.g.
  • Z-methoxy-diazoethane, Z-ethoxy-diazoethane, 2-npropyloxy-diazoethane, 3-methoxy-1-diazopropane, 3-ethoxy-l-diazopropane and the like, or a tertiary amino-lower diazoalkane, particularly an N,N-di-l0wer alkyl-.amino lower diazoalkane, in which the N,N-di-low er alkyl-amino group is separated from the diazo group by from two to three carbon atoms, and lower alkane contains from two to three carbon atoms, e.g.
  • reaction of the l8-O-R -deserpidic acid compounds with such diazo-reagents is carried out, for example, in the presence of a diluent, such as in a lower alkanol, e.g. methanol, ethanol, n-propanol, isopropanol and the like, a halogenated lower alkane, e.g.
  • the diazo-reagent is used in solution, for example, in an ether solution. Cooling of the reaction mixture and/or the presence of an atmosphere consisting of an inert gas, e.g. nitrogen, may be required.
  • an inert gas e.g. nitrogen
  • R represents lower alkyl containing from one to four carbon atoms
  • R stands for .2-cyclo-oxa-alkylcontaining from five to seven atoms as ring members, lower alkyl-substituted Z-cyclo-oxa-alkyl containing from five to seven atoms as ring members, or halogeno-substituted 2- cyclo-oxa-alkyl containing from five to seven atoms as ring members eachlof the groups
  • R and R stands for hydrogen, lower alkyl containing from one to four carbon atoms, lower alkoxy containing from one to four carbon atoms, lower alkylmercapto containing from one to four carbon atoms or halogeno
  • R attached to one of thepositions 5 and 6 stands for hydrogen or lower alkyl containing from one to four carbon atoms, salts or the N-oxides of these compounds, as well as their various isomeric forms.
  • these deserpidic acid compounds or salts thereof may be converted into the desired deserpidate compounds by treatment, for example, with lower diazoalkanes, lower alkoxy-lower diazoalkanes, in which lower alkoxy is separated from the diazo group by from two to three carbon atoms, and lower alkane contains from two to three carbon atoms, N,N-di-lower alkylamino-lower diazoalkanes, in which the N,N-di-lower alkyl-amino group is separated from the diazo group by from two to three carbon atoms, and lower alkane contains from two to three carbon atoms.
  • the deserpidic acid compounds used as the intermediates may be prepared, for example, by treating a deserpidic acid compound of the formula:
  • R R R and R have the previously given meaning, or an N-oxide thereof, with a reactive ester of a 2-hydroxy-cyclo-oxa-alkane, which contains at least five atoms as ring members, in the presence of a condensation reagent, and, if desired, separating a resulting mixture of isomeric compounds into the single isomers, and/or, if desired, converting a resulting salt into a free compound, and/or, if desired, converting a resulting compound into a salt or an N-oxide thereof.
  • 2-halogeno-cyclo-oxa-alkanes primarily 2-chloro-cyclooxa-alkanes, which contain from five to seven atoms as ring members, e.g. Z-chloro-tetrahydrofuran (2-chlorocyclo-oxapentane), 2-chloro-tetrahydropyran (2-chlorocyclo-oxahexane) and the like are used as the preferred reagents, and N,N-dimethylformamide is a very suitable condensing reagent, which may simultaneously serve as a solvent.
  • the starting materials may also be prepared by treating a deserpidic acid compound of the formula:
  • R R R R and R have the above-given meaning, a salt or an N-oxide thereof, with a cycle-oxaalk-2ene containing at least five atoms as ring members, in the presence of an acid condensing reagent, and, if desired, carrying out the optional steps.
  • a cyclo-oXa-alk-2-ene containing from five to six atoms as ring members such as the previously described 2,3-dihydrofurans (cyclo-oxapent-Z- enes), 2,3-dihydropyrans (cyclo-oxa-hex-Z-enes) and the like, are used as the preferred reagents, and an acid condensing reagent, such as a mineral acid, p-toluene sulfonic acid and the like, is used to promote the reaction.
  • an acid condensing reagent such as a mineral acid, p-toluene sulfonic acid and the like
  • the deserpidic acids used as starting materials may also be prepared, for example, by replacing in deserpidate l 3 compounds or N-oxides thereof, these compounds having the formula:
  • R R R R and R have the previously given meaning, and R represents lower alkyl, lower alkoxylower alkyl, tertiary amino-lower alkyl or the group of the formula Ph(Z) CH-, in which Ph represents monocyclic carbocyclic aryl and Z stands for hydrogen or lower alkyl, the esterified carboxyl group in 16-p0sition by a free carboxyl group, and, if desired, carrying out the optional steps.
  • Lower alkyl, lower alkoxy-lower alkyl and tertiary amino-lower alkyl, representing R are identical with the radicals standing for the previously defined R
  • the monocyclic carbocyclic .aryl radical Pb in the formula Ph(Z)CH stands primarily for phenyl; it may also be represented by substituted phenyl, whereby substituents may be lower alkyl, e.g. methyl and the like, lower alkoxy, e.g. methoxy and thelike, or halogen, e.g. chlorine, bromine aud the like, or any other substituents, which do not hinder the departure of the monocyclic carbocyclic arylmethyl radical.
  • Z may represent lower alkyl, e.g. methyl, ethyl, n-propyl and the like, it stands primarily for hydrogen.
  • the radical R in the above-depicted formula for the intermediate may be replaced by hydrogen by way of hydrolytic cleavage.
  • This reaction may be carried out according to known methods, for example, by treatment with an alkaline reagent, such as, for example, with a solution of an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, in an appropriate solvent such as a lower alkanol, e.g. methanol, ethanol and the like, water, an aqueous lower alkanol and the like.
  • an alkaline reagent such as, for example, with a solution of an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like
  • an appropriate solvent such as a lower alkanol, e.g. methanol, ethanol and the like, water, an aqueous lower alkanol and the like.
  • the group Ph(Z)CH- in which the Ph and Z have the previously given meaning, may also be removed by hydrogenolysis, i.e. by reacting the intermediate, preferably a solution thereof, for example, in a lower alkanol, e.g. methanol, ethanol and the like, with hydrogen in the presence of a catalyst.
  • a catalyst contains a metal of the eighth group of the periodic system, for example, palladium and the like, and may be represented by palladium black or any other suitable catalyst.
  • increased pressure and/or elevated temperature may be employed, although normally the reaction proceeds under atmospheric pressure and at room temperature.
  • the reaction vessel is agitated to expose the catalyst to the hydrogen.
  • R R R R R R Ph and Z have the previously given meaning, and salts thereof; they are new and are intended to be included within the scope of this invention.
  • Particularly useful as intermediates in the above'reaction are the compounds of the formula:
  • R represents lower alkyl containing from one to four carbon atoms
  • R stands for 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, lower alkyl-substituted 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, or halogeno-substituted 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members
  • each of the groups R, and R stands for hydrogen, lower alkyl containing from one to four carbon atoms, lower alkoxy containing from one to four carbon atoms, lower alkyl-mercapto containing from one to four carbon atoms or halogeno
  • R stands for hydrogen or lower alkyl containing from one to four carbon atoms, or the N-oxides of these compounds, as well as their various isomeric forms.
  • This group of compounds may be represented by benzyl 18O-(2-cyclo-oxa-alkyl)-reserpates or benzyl l8-O-(2-cyclo-oXa-alkyl)-deserpiclates, in which compounds 2-cyclo-oxa-a1kyl contains from five to seven atoms as ring members, e.g.
  • R R R and R have the previously given meaning, salts or N-oxides thereof, with analcohol of the formula Ph-(Z) CHOH, in which Ph and Z have the previously given meaning, preferably in the presence of an alcoholysis catalyst, such as an alkali metal, e.g. sodium and the like, compound of such alcohol, and reacting a resulting compound of the formula:
  • a cyclo-oxa-alk-Z-enc which contains at least five atoms as ring members, in the presence of an acid condensing reagent, and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting a resulting compound into a salt or an N-oxide thereof.
  • the alcoholysis of the (16 l8)-lactone of a deserpidic acid compound may be carried out according to known methods. For example, a small amount of an alkali metal, e.g. sodium, potassium and the like, is dissolved in an alcohol of the formula Ph(Z)CHOH, in which Ph and Z have the previously indicated meaning, or a solution thereof in an inert solvent; the resulting reagent is then reacted with the lactone or a solution thereof. The reaction may proceed under cooling or at room temperature, but may be more readily completed by heating, if necessary, in the atmosphere of an inert gas, e.g. nitrogen.
  • an inert gas e.g. nitrogen.
  • 2,3-dihydrofuran (cyclo-oxapent-Z- ene), 2,3-dihydropyr'an (cyclo-oxahex-Z-ene) and the like, in the presence of an acid condensing reagent, e.g. hydrogen chloride, p-toluene sulfonic acid and the like, is carried out according to previously described methods.
  • an acid condensing reagent e.g. hydrogen chloride, p-toluene sulfonic acid and the like
  • the compounds of the present invention may also be prepared by transesterifying in deserpidate compounds of the formula:
  • the transesterification reaction may be carried out, for example, by treating the starting material with an alcohol of the formula R OH, in which R has the above-given meaning, and stands primarily for lower alkyl, particularly lower alkyl containing from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, n-butyl, isobutyl and the like; alcohols of the formula R --OI-I are, therefore, primarily lower alkanols such as methanol, ethanol, n-propanol, nbutanol, isobutanol and the like.
  • R -OH Other alcohols of the formula R -OH are those, in which R represents lower alkoxy-lower alkyl or tertiary amino-lower alkyl, whereby the lower alkoxy and tertiary amino groups are separated from the hydroxyl group by from two to seven, primarily by from two to three, carbon atoms; such alcohols are, for example, Z-methoxyethanol, 2-ethoxyethanol, 3- methoxypropanol, 2-N,N-dimethylaminoethanol, 2-N,N- diethylaminoethanol and the like.
  • transesterification catalyst particularly a basic transesterification catalyst.
  • catalysts are, for example, alkoxide ions, as, for example, furnished by alkali metal lower alkanolates, e.g. lithium, sodium or potassium methanolate, ethanolate, n-propanol-ate, n-butanolate or isobutanolate and the like, alkaline earth metal lower alkanolates, e.g. barium or strontium methanolate, ethanolate, n-propanolate, n-butanolate or isobutanolate and the like, or aluminum lower alkanolates, e.g. aluminum methanolate, ethanolate, n-propanolate, isopropanolate,
  • alkali metal lower alkanolates e.g. lithium, sodium or potassium methanolate, ethanolate, n-propanol-ate, n-butanolate or isobutanolate and the like
  • n-butanolate or isobutanolate and the like The individual alkanolate compounds are employed together with the corresponding lower alkanol used as the transesterification reagent.
  • Other alcohols of the formula R OH, in which R represents, for example, lower alkoxy-lower alkyl or tertiary amino-lower alkyl, may be used in the presence of the corresponding alkali metal, alkaline earth metal or aluminum alcoholates.
  • Other basic transesterification catalysts are, for example, alkali metal cyanides,
  • inert solvents may be used in the above-mentioned reactions; carbocyclic aryl hydrocarbons, e.g. benzene, toluene and the like, are examples of such inert solvents.
  • the reaction may be carried out at an elevated temperature, under increased pressure and/or in the atmosphere of an inert gas, e.g. nitrogen.
  • the compounds of the present invention may also be obtained by isomerizing in a compound of the formula:
  • R R R R R R and R have the above-given meaning, a salt or an N-oxide thereof, the hydrogen atom attached to the 3-position in the presence of an acid 17 reagent and isolating the desired compound of the formula:
  • R R R R R and R have the previously given meaning, a salt or an N-oxide thereof, and, if de sired. carrying out the optional steps.
  • Acid reagents used in the above isomerization procedure are more especially lower aliphatic carboxylic acids, such as lower alkanoic acids, e.g. acetic acid, propionic acid and the like, primarily glacial acetic acid, monocyclic carbocyclic aryl sulfonic acids, e.g. p-toluene sulfonic acid and the like or any other suitable acidic reagent or mixtures of acids.
  • aromatic sulfonic acids are advantageously used together with one of the lower aliphatic carboxylic acids mentioned above; a suitable mixture is, for example, p-toluene sulfonic acid in glacial acetic acid.
  • the reaction may be carried out in the absence or presence of an additional solvent; for example, p-toluene sulfonic acid may be used in the presence of an organic base, e.g. pyridine, collidine and the like, as well as in the presence of another acid, e.g. glacial acetic acid and the like.
  • Isomerization may be effected at room temperature or, if necessary, at an elevated temperature, in an open vessel or under pressure, preferably in the atmosphere of an inert gas, e.g. nitrogen.
  • Optimum yields in such isomerization reactions may be obtained by removing the desired product from the reaction medium, thus displacing the reaction equilibrium in favor of the product.
  • the removal may be accomplished by separating the product, a salt or an N-oxide thereof from the starting material by exploiting their relative solubilities in solvent systems.
  • the product, a salt or an N-oxide thereof may be separated from the starting material either by adsorption on a suitable material, such as alumina or paper, and subsequent fractional elution, or by fractional crystallization from a solvent.
  • the starting material separated from the desired product may then be recycled into the isomerization process, enhancing the over-all yield of the reaction.
  • R R R R R R and R have the previously given meaning, their salts or N-oXides, are new and are intended to be included within the scope of this invention.
  • R represents lower alkyl containing from one to four carbon atoms, lower alkoXy-lower alkyl, in which lower alkoXy contains from one to four carbon atoms and lower alkyl, containing from two to three carbon atoms, separates lower alkoxy from the carboxy group by from two to three carbon atoms, or N,N-di-lower alkyl-aminolower alkyl, in which lower alkyl of the N,N-di-lower alkyl amino portion contains from one to four carbon atoms and lower alkyl, separating N,N-di-lower alkylamino from the carboxy group by two to three carbon atoms, contains from two to three carbons, R represents lower alkyl containing from one to four carbon atoms, R stands for 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, lower alkyl-substituted 2-cyclo-oXa-alkyl containing from five
  • This group may be represented by lower alkyl l8-O-(2-cyclooXa-alkyl) -3-iso-reserpates, in which cyclo-oXa-alkyl contains from five to seven atoms as ring members, e.g. methyl 18-0-(tetrahydro-Z-furanyl)-3 iso-reserpate, ethyl 18O-(tetrahydro-Z-furanyl) -3-iso-reserpate,.
  • the 9-position, the l0-position, the ll-position and/or the ll-position may contain lower alkyl, e.g. methyl and the like, lower alkoxy, e.g. methoxy and the like, or halogen, e.g. chlorine, bromine and the like as substituents, and/ or in which the l7-position contains a lower alkoxy substituent other than methoXy, e.g. ethoxy and the like.
  • R R R R R R and R have the above-given meaning, a salt or an N-oxide thereof, with a reactive ester of a Z-hydroxy-oxa-alkane, which contains at least five atoms as ring members, in the presence of a condensing reagent, or with a cyclo-oxa-alk-Z-ene, which contains at least five atoms as ring members, in the presence of an acid condensing reagent, and, if desired, converting a resulting salt into a free base, and/ or, if desired, separating a resulting mixture of isomeric compounds into single isomers, and/ or, if desired, converting a resulting compound into a salt or an N-oxide thereof.
  • Reactive esters of 2-hydroxy-cyclo-oxa-alkanes are primarily 2-halogeno-cyclo-alkanes, especially 2-chloro-cycloalkanes, which contain from five to seven atoms as ring members, e.g. 2-chloro-tetrahydrofuran (2-chlorocyclo-oxapentane), 2-chloro-tetrahydropyran (Z-chlorocyclo-oxapentane) and the like; these reagents are used in the presence of a condensing reagent, particularly N,N- dimethylformamide and the like.
  • Cyclo-oxa-alk-Z-enes particularly those which contain from five to six atoms as ring members, e.g. 2,3-dihydrofuran (cyclo-oxapent- Z-ene), 2,3-dihydropyran (cyclo-oxahex-Z-ene) and the like, are used in the presence of a Lewis acid, particularly of hydrogen halide, e.g. hydrogen chloride and the like, p-toluene sulfonic acid, fluoboric acid and the like.
  • a Lewis acid particularly of hydrogen halide, e.g. hydrogen chloride and the like, p-toluene sulfonic acid, fluoboric acid and the like.
  • R R R D and R have the previously given meaning, and R stands for cyclo-dioxa-alkyl or cyclooxathia-alkyl, which radicals contain at least five atoms as ring members, and which are attached to the oxygen atoms of the l8-position through one of the carbon atoms adjacent to a ring oxygen atom, salts or N-oxides thereof, as Well as the various isomeric forms of these compounds, and process for the preparation of these compounds.
  • the radicals R contain primarily from five to seven atoms as ring members and, as mentioned hereinbefore, are attached to the oxygen atom of the 18-position through one of the carbon atoms adjacent to a ring oxygen atom.
  • the radicals are unsubstituted or may contain as additional substituents lower aliphatic hydrocarbons, particularly lower alkyl, e.g. methyl, ethyl and the like, or functional groups, particularly halogen atoms, e.g. chlorine, bromine and the like, or other suitable groups.
  • Specific radicals representing R are, for example, 1,3-
  • dioxalanyl cycle-1,3-dioxapentyl radicals, e.g. 2-(1,3- dioxalanyl) (or 2-cyclo-1,3-dioxapentyl), 4-('1,3-dioxalanyl) (or 4-cyclo-1,3-dioxapentyl), 2-methyl-4-(l,3- dioxalanyl) (or 2-methy1-4-cyclo-1,3-dioxapentyl) and the like, 1,3-dioxany1 (or cyclo-1,3-d.ioxahexyl) radicals, e.g.
  • 2-(1,4-dioxanyl) (or 2-cyclo-1,4-dioxahexyl), 5-methyl-2-(1,4-dioxanyl) (or S-methyl-Z-cyclo-1,4-dioxahexyl), 6-methyl-2-(1,4dioxanyl) (or 6-methyl-2-cyclo- 1,4-dioxahexyl) and the like
  • cyclo-1,4-dioxaheptyl radicals e.g. 2-cyclo-l,4-dioxaheptyl and the like
  • 1,3-oxathialanyl (or cyclo-1,3-oxathiapentyl) radicals, e.g.
  • R represents lower alkyl containing from one to four carbon atoms, lower alkoxy-lower alkyl, in which lower alkoxy contains from one to four carbon atoms and lower alkyl, containing from two to three carbon atoms, separates lower alkoxy from the carboxyl group by from two to three carbon atoms, or N,N-di-lower alkyl-amino lower alkyl, in which lower alkyl of the N,N-di-lower alkyl-amino portion contains from one to four carbon atoms and lower alkyl, separating N,N-dilower alkyl-amino from the carboxyl group by two to three carbon atoms, contains from two to three carbons, R represents lower alkyl containing from one to four carbon atoms, R stands for 2-(1,4-dioxanyl) (or 2- cyclo-1,4-diox-ahexyl), lower alkyl-substituted 2-( 1,4-di
  • R represents lower alkyl containing from one to four carbon atoms
  • X stands for oxygen or sulfur, or N-oxides of such compounds.
  • Members of this group are, for example, methyl 1 8O-[2-(l,4-dioxanyl)]-reserpate, ethyl 18-O[2-(l,4-dioxanyl) ]-reserpate, n-propyl 18-O-[2-(1,4-dioxanyl)J-reserpate, isopropyl 18-0-[2-(1, 4-dioxanyl)]-reserpate, n-outyl l8-O-[2-(1,4-oxathianyl)] reserpate, methyl 18-0-[2-(1,4-oXathianyl)]-reserpate, ethyl 18-O-[2-(1,4-oxathianyl)]-reserpate,
  • R represents lower alkyl containing from one to four carbon atoms
  • X stands for oxygen or sulfur, or N-oxides of such compounds.
  • This group may be illustrated, for example, by methyl 18-O-[2-( 1,4-dioxanyl) ]-deserpidate, ethyl 18-G-[2-( 1,4-dioxanyl) ]-deserpidate, n-propyl l8-O-[2-(l,4-dioxanyl)l-deserpidate, isopropyl 18-O-[2-(l,4-dioxanyl)]-deserpidate, n butyl l8- O[2-(l,4-dioxanyl)]-deserpidate, methyl 18-O-[2-(L4- oxathianyl) -deserpidate, ethyl 18-O-[2-(1,4-0xathianyl) desenpidate, n-
  • Additional compounds which illustrate the above group, are lower alkoxy-lower alkyl, in which lower alkoxy contains from one to four carbon atoms and lower alkyl, containing from two to three carbon atoms, separates lower alkoxy from the carboxy group by from two to three carbon atoms, e.g.
  • 18-O-R '-reserpate or 18-O-R -deserpidate in which R represents 2-(1,4-dioxanyl) or 2-(1,4-oxathianyl), or lower alkyl, erg.
  • R R R R and R have the previously given meaning, or an N-oxide thereof, with a reactive ester of a hydroxy-cyclo-dioxa-alkane or a hydroxy-cyclo-oxathia-alkane, which contains at least five atoms as ring members, and in which the hydroxyl group is attached to one of the carbon atoms adjacent to a ring oxygen atom, in the presence of a condensing reagent, or converting in a compound of the formula:
  • R R R R and R have the previously given meaning, and R represents lower alkyl, lower alkoxy-lower alkyl, tertiary amino-lower alkyl, or a group of the formula Ph(Z)CH, in which Ph and Z have the previously given meaning, or an N-oxide thereof, the radical R into the desired radical R by transesterification with an alcohol of the formula Bi -OH, in which R has the previously given meaning, in the presence of a transesterification reagent, or isomerizing in a compound of the formula:
  • R R R R R R and R have the previously given meaning, a salt or an N-oxide thereof, the hydrogen atom attached to the 3-position in the presence of an acid reagent, and isolating the desired compound having the previously given formula, and, if desired, converting a resulting salt into the free compound, and/or, if desired, separating a mixture of isomeric compounds into the single compounds, and/or, if desired, converting a resulting compound into a salt or into an N-oxide thereof.
  • a reactive ester of a hydroxy-cyclo-dioxaalkane or a hydroxy-cyclo-oxathia-alkane is an ester with one of the previously mentioned acids, particularly with a hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like;
  • specific reagents are, for example, halogeno- 1,3-dioxalanes (or halogeno-cyclo-1,3-dioxapentanes), in which halogen is attached to one of the carbon atoms adjacent to the ring oxygen atoms, e.g.
  • 2-chloro-1,3-dioxane (or Z-chloro-cyclo-1,3-dioxahexane), 4-chloro-1,3-dioxane (or 4-chloro-cyclo-1,3-dioxahexane) and the like, halogeno-l,4-dioxanes (or halogeno-cyclo- 1,4-dioxahexanes), in which halogen is attached to one of the carbon atoms adjacent to the ring oxygen atoms, e.g.
  • 2-chloro-1,4-oxathiane (or Z-chloro-cyclo-1,4-oxathiahexane), 2-chloro-5- methyl-1,4-oxathiane (or Z-chloro-S-methyl-cyclo-l,4 oxathiahexane) and the like.
  • a condensing reagent particularly N,N- dimethylformamide and the like.
  • the free carboxyl group in a deserpidic acid corn pound of the previously given structural formula may be converted into the desired esterified carboxyl group by treatment with a diazo compound of the formula R N in which R has the previously given meaning, particularly with a lower diazo-alkane, e.g. diazomethane, diazoethane, l-diazopropane and the like, with a lower alkoxydiazo-lower alkane, e.g.
  • R represents lower alkyl containing from one to four carbon atoms
  • R represents 2-cyclo-1,4-dioxahexyl or 2-cyclo-1,4-oxathiahexyl or the corresponding lower alkyl-substituted or halogeno-substituted radicals
  • each of the groups R; and R stands for hydrogen, lower alkyl containing from one to four carbon atoms, lower alkoxy containing from one to four carbon atoms, lower alkyl-mercapto containing from one to four carbon atoms or halogeno, and R attached to one of the positions 5 and 6, stands for hydrogen or lower allryl, or N-oxides of such compounds, as well as the various possible isomeric forms thereof.
  • Specific compounds of this group are 18-O-[2-(l,4-dioxanyl)]-reserpic acid, 18-O-[2-(l,4- oxathianyl)]-reserpic acid, l8-O-[2-(1,4-dioxanyl)]-deserpidic acid, 18-O-[2-(l,4-oxathianyl)]-deserpidic acid,
  • a trans-esterification catalyst such as, for example, an alkali metal compound of the alcohol R OH
  • Alcohols of the above-given formula are particularly lower alkanols, e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol and the like, lower alkoxy-lower alkanols, e.g. Z-methoxyethanol, 2-ethoxyethanol, 3-methoxypropanol and the like, or N,N-di-lower alkyl-amino-lower alkanols, e.g. 2-N,N-dimethylaminoethanol and the like; transesterification catalysts may be, for example, the alkali metal, e.g.
  • R represents lower alkyl containing from one to four carbon atoms
  • R stands for 2-(l,4-dioxany1) (or 2-cyclo-1,4-dioxahexyl), lower alkyl-substituted 2-(1, 4-dioxanyl) (or lower alkyl-substituted 2-cyclo-1,4- dioxahexyl), halogeno-substituted 2-(1,4-dioXanyl) (or halogeno-substituted 2-cyclo-l,4-dioxahexyl), 2-(1,4-oxathianyl) (or 2-cyclo-1,4-oxathiahexyl), lower a1kyl-substituted 2-(1,4-oxathianyl) (or lower alkyl-substituted 2- cyclo l, l oxathiahexyl), or halogeno-substituted 2-( 1,
  • This group of compounds may be represented by benzyl l8-O-R '-resperate and benzyl l8-O-R -desperpidate, in which R stands for 2-(l,4-dioxanyl) or 2-(1,,4-0X- athianyl), or N-oxides thereof; specific compounds are, for example, benzyl 18-O-[2-(l,4-dioxany1)]-resperate, benzyl 18-O-[2-(1,4 xathianyl)]-resperate, benzyl 18-O- [2-(l,4-dioxanyl)]-desperidate, benzyl 18-O-[2-(1,4-oxathianyl)]-deserpidate and the like.
  • R R R and R have the previously given meaning, salts or N-oxides thereof, with an alcohol of the formula Ph(Z) CHOH, in which Ph and Z have the previously given meaning, preferably in the presence of an alcoholysis catalyst, such as an alkali metal, e.g.
  • R R R R Ph and Z have the previously given meaning, with the reactive ester of a hydroxy-cyclodioxa-alkane or of a hydroxy-cyclooxathia alkane, which contain at least five atoms as ring members, and in which the hydroxyl group is attached to one of the carbon atoms adjacent to a ring oxygen, in the presence of a condensing reagent, and, if desired, converting a resulting compound into a salt or an N-oxide thereof.
  • the alcoholysis of the lactone can be performed as previously shown; a deserpidate compound reacts with the reactive ester of a hydroXy-cyclo-dioXa-alkane or a hydroxy-cyclo-oxathia-alkane according to the above-described method, particularly in the presence of N,N-dimethylformamide as a condensing reagent.
  • Isomerization of 3-iso-deserpidate compounds having the previously shown structural formula may be carried out as previously shown; acids, such as glacial acetic acid, p-toulene sulfonic acid or a mixture of such acids, are suitable isomerization reagents.
  • R represents lower alkyl containing from one to four carbon atoms
  • lower alkoXy-lower alkyl in which lower alkoxy contains from one to four carbon atoms and lower alkyl, containing from two to three carbon atoms, separates lower alkoiry from the carboXy group by from two to three carbon atoms
  • N,N-di-lower alkyl-amino-lower alkyl in which lower alkyl of the N, N-di-lower alkyl amino portion contains from one to four carbon atoms and lower alkyl, separating N-N-dilower alkyl-amino from the carboxy group by two to three carbon atoms, contains from two to three carbons
  • R represents lower alkyl containing from.
  • R stands for 2-(1,4-dioxanyl) (or 2- cyclo-l,4-dioxahexyl), lower alkyl-substituted 2-(1,4- dioxanyl) (or lower alkyl substituted 2.
  • This group of compounds may be represented by lower alkyl 18-O-R -3-iso-reserpate or lower alkyl 18-O-R '-iso deserpidate, in which R stands for 2-(1,4-dioxanyl) or 2-(1,4-oxathianyl)', or N-oxides thereof.
  • Specific compounds are, for example, methyl 18-O-[2(1,4-dioxanyl) 3-iso-reserpate, ethyl l8-O-[2-(1,4-dioxanyl)]-3-iso-reserpate, n-propyl 18-O-[2-(1,4-dioxanyl)]-3-iso-reserpate, methyl 18-0-[2-(1,4-oxathianyl)]-3-iso-reserpate, methyl 18-O'-[2-(1,4-dioxanyl)]-3-iso-deserpidate, methyl l8- O-[2-(1,4-oxathianyl)]-3-iso-deserpidate and the like.
  • R R R R and R have the above-given meaning, or an N-oxide thereof, with the reactive ester of a hydroxy-cyclo-dioxa-alkane or of a hydroxy-cyclooxathia-alkane, which contain at least five atoms as ring members, and in which the hydroxyl group is attached to one of the carbon atoms adjacent to a ring oxygen atom, in the presence of a condensing reagent, and, if desired, converting a resulting compound into a salt or an N-oxide thereof.
  • reaction of the deserpidate compound with the ester of a hydroxy-cyclo-dioxa-alkane or a hydroxy-cyclooxathia-alkane can be carried out according to the previously described method, particularly in the presence of N,N-dimethylformamide as a condensing reagent.
  • the compounds prepared according to the process of this invention may be obtained in the form of the free bases or the salts thereof.
  • a salt may be converted into the free base by reacting the former with an alkaline reagent, such as, for example, aqueous silver oxide, aqueous ammonia, or any other suitable alkaline reagent.
  • a free base may be converted into its therapeutically useful acid addition salts by reaction with one of the acids mentioned hereinbefore; such reaction may be carried out, for example, by treating a solution of the base in a solvent, such as a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol and the like, with the appropriate acid or a solution thereof, and isolating the formed salt.
  • N-oxides of the compounds of the present invention may be formed according to known methods; for example, .the resulting deserpidate compound, preferably a solution thereof in an inert solvent, may be reacted with an N-oxidizing reagent, such as, for example, hydrogen peroxide, ozone, persulfuric acid, or more especially, organic peracids, such as organic percarboxylic acids, e.g. peracetic, perbenzoic, monoperphthalic acid and the like, or per-sulfonic acids, e.g. p-toluene persulfonic acid and the like.
  • Inert solvents are, for example, monocyclic carboxylic aryl hydrocarbons, e.g.
  • benzene, toluene and the like halogenated lower alkanes, e.g. chloroform, ethylene chloride and the like, lower alkanols, e.g. methanol, ethanol and the like, or any other suitable solvent.
  • halogenated lower alkanes e.g. chloroform, ethylene chloride and the like
  • lower alkanols e.g. methanol, ethanol and the like
  • racemic or optically active deserpidic acid derivatives may be used as starting materials whereby the latter is preferably used in the optically active form, particularly when derived from natural sources.
  • Resulting racemates may be resolved into the optically active forms, the laevo-rotatory l-form and the dextro-rotatory d-form. Resolution procedures may be carried out according to known methods suitable for the separation of racemates. For example, to a solution of the free base of a racemate (a d, l-compound) in a solvent, such as a lower alkanol, e.g.
  • a lower alkanone e.g. acetone, ethyl methyl ketone and the like, or any other suitable solvent, or a mixture of solvents
  • a lower alkanone e.g. acetone, ethyl methyl ketone and the like, or any other suitable solvent, or a mixture of solvents
  • optically active forms of saltforming acids having an asymmetric carbon atom are, for example, the d-tartaric acid (L-tartaric acid) and the l-tartaric acid (D-tartaric acid), as well as the optically active forms of dibenzoyl tartaric, di-p-toluyl-tartaric, malic, mandelic, IO-camphor sulfonic acid, quinic acid and the like.
  • T he free and optically active base may be obtained from a resulting sal-t according to methods known for the conversion of a salt into a base as, for example, is outlined hereinbefore.
  • An optically active base may be converted into a therapeutically useful acid addition salt with one of the acids mentioned hereinbefore, or may be converted into an N-oxide described hereinbefore.
  • the optically active forms may also be isolated by biochemical methods.
  • two isomeric compounds may be formed, which may be separated on the basis of differences of physico-chemical properties, e.g. solubility, adsorbability and the like.
  • the invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out. It also includes any new intermediates, which may be formed in one of the procedures outline hereinbefore.
  • Example 1 1 g. of methyl reserpate is suspended in 25 ml. of 2,3- dihydropyran and 7 drops of concentrated aqueous hydrochloric acid (37 percent) is added, while agitating. The flask is closed with a glass stopper, shaken and then allowed to stand for three days at room temperature. 10 ml. of aqueous ammonia (28 percent) is added while stirring, and an excess of benzene is then given to the reaction rnixture to form two layers. The organic layer is separated, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in acetone, the solvent is evaporated and the residue is again taken up in acetone, whereupon crystals are formed which are filtered off.
  • the mother liquor is diluted with ether and a second crop of crystals are obtained which are 29 combined with the first crystallization product.
  • the methyl 18-0-(tetrahydro-Z-pyranyl)-reserpate melts at 262-265" (decomposition); yield: 0.29 g.
  • Example 2 To a mixture of 1 g. of methyl reserpate and 15 ml. of 2,3-dihydropyran is added 35 ml. of benzene, which has been saturated at room temperature with gaseous hydrogen chloride. The reaction vessel is then closed, thoroughly shaken and allowed to stand for two hours at room temperature to form a complete solution. 20 ml. of 10 percent aqueous sodium hydroxide is added while shaking, the benzene layer is separated, washed once with water and dried over sodium sulfate. The solvent is evaporated under reduced pressure and ether is added to the residue. The crystalline material is filtered oil and washed with ether to yield the methyl 18-O-(tetrahydro- 2-pyranyl)-reserpate, M.P. 265-267"; yield: 0.55 g.
  • Example 3 To 5 g. of n-propyl reserpate in 100 ml. of 2,3-dihydropyran is added 100 ml. of benzene, which has been saturated with hydrogen chloride at room temperature; the reaction mixture is placed in a flask and the closed flask is allowed to stand at room temperature for about thirty minutes. 80 ml. of a cold 10 percent aqueous solution of sodium hydroxide, containing a small amount of ammonia, is added while shaking. The benzene layer is separated, washed twice with ice water, containing a small amount of ammonia, dried over sodium sulfate, filtered and evaporated under reduced pressure.
  • the oily residue is dissolved in petroleum ether and crystallizes after cooling.
  • the crystalline material is filtered oli, and dissolved in methylene chloride; the solution is filtered through a column containing magnesia-silica gel, the solvent is evaporated, and the residue is crystallized from a mixture of petroleum ether and ether to yield 3.49 g. of n-propyl 18-0-(tetrahydro-2-pyrauyl)-reserpate, M.P. 190-192.
  • the starting material may be prepared as follows: The gaseous n-diazopropane is distilled from its ether solution into a suspension of 20 g. of reserpic acid in a 1:1 mixture of chloroform and ethanol. Any excess of n-diazopropane is decomposed with acetic acid, the solvents are evaporated under reduced pressure and the residue is poured into 8 ml. of water containing 20 ml. of concentrated aqueous ammonia. A white crystalline precipitate is obtained, which is washed with water to yield the n-propyl reserpate, M.P. 164-166".
  • Example 4 To 1 g. of Z-methoxyethyl reserpate in 25 ml. of 2,3- dihydropyran is added 25 ml. of benzene, which has been saturated at room temperature with hydrogen chloride; the mixture is allowed to stand at room temperature for two hours. To the homogeneous solution is then added 20 ml. of 10 percent aqueous sodium hydroxide while shaking. The organic layer is separated, washed twice with water containing a few drops of concentrated aqueous ammonia and then dried over sodium sulfate. A yellow oil is obtained after evaporating the solvent under reduced pressure.
  • the starting material may be prepared as follows: To a mixture of 226 g. of a 33 percent aqueous solution of 2-methoxyethylamine and 150 ml. of diethyl ether, kept at to in an ice bath, is added dropwise 54 g. of ethyl chloroformate. 100 g. of a cold 40% aqueous solution of sodium hydroxide and a second portion of 54 g. of ethyl chloroformate are given to the mixture, which is stirred for one hour. The ether layer is separated, the aqueous phase is extracted with ml. of diethyl ether, and the two ether solutions are combined and dried over potassium carbonate. The solvent is evaporated under reduced pressure and the ethyl N(2-methoxyethyl)-car bamate is distilled at 106/ 17-20 mm.
  • a gently refluxing solution of 5 g. of potassium hydroxide in 15 g. of methanol and 150 ml. of diethyl ether is treated with a solution of 15.5 g. of ethyl N-(2-methoxyethyl)-N-nitroso-carbamate in 50 ml. of diethylether, which is added dropwise over a period of one hour. After refluxing for 5 minutes, 100 ml. of water is added and the yellow ether solution, containing the 2-methoxydiazoethane, is separated.
  • deserpidates which may be prepared according to the previously given procedure by replacing the starting material by other intermediates are, for example, 2-ethoxyethyl 18-O-(tetrahydro-2-pyranyl)-reserpate, 2-n-propyloxyethyl 18-O-(tetrahydro-2-pyranyl)-reserpate, 2-isopropyloxyethyl 18-O-(tetrahydro-Z-pyranyl)- reserpate, 3-methoxypropyl l8-O-(tetrahydro-2-pyranyD-reserpate, 2-rnethoxyethyl 18-O-(tetrahydro-2-pyranyll-deserpidate, 2-ethoxyethyl 18-O-(tetrahydro-2-pyranyD-deserpidate, Z-methoxyethyl 5 -methyl- 1 S-O-(tetrahydro-Z-pyranyl)- re
  • Example 5 To a solution of 4.3 g. of crude methyl deserpidate and 4.6 ml. of 2,3-dihydropyran in 40 ml. of acetone is grad ually added 2.82 g. of p-toluene sulfonic acid in 12 ml. of acetone while stirring. The solution is agitated for an additional thirty minutes, ethyl acetate is added and the resulting solution is washed twice with 10 percent aqueous sodium hydroxide and then with water. The organic layer is dried over sodium sulfate, the solvent is removed under reduced pressure and the residue is crystallized from a mixture of ethyl acetate and petroleum ether. The resulting methyl 18-O-(tetrahydro-2-pyranyl)-deserpidate is recrystallized from ethyl acetate, M.P. 255-257"; yield: 0.57 g.
  • Methyl deserpidate may be replaced by other lower alkyl deserpidates in the above example, and compounds, such as ethyl 18-O-(tetrahydro 2 pyranyl) deserpidate, n-propyl 18-O-(tetrahydro-2-pyranyl)-deserpidate, isopropyl-l8-O-(tetrahydro-2-pyranyl)-deserpidate, n-butyl 18-O- (tetrahydro-2-pyranyl)-deserpidate, isobutyl 18O-(tetrahydro-2-pyranyl)-deserpidate and the like, are formed upon treatment with 2,3-dihydropyran according to the above procedure.
  • compounds such as ethyl 18-O-(tetrahydro 2 pyranyl) deserpidate, n-propyl 18-O-(tetrahydro-2-pyranyl)-deserpidate, isopropy
  • Example 6 A mixture of 1.0 g. of Z-dimethylaminoethyl reserpate and 25 ml. of 2,3-dihydropyran, When treated with 25 m1. of benzene, which has been saturated with hydrogen chloride, according to the procedure outlined in Example 2, yields the desired Z-dirnethylaminoethyl 18-O-(tetrahydro- 2-pyranyl)-reserpate.
  • the starting material used in the above reaction may be prepared as follows: A m xture of 88 g. of a 33% aqueous N,N-dimethylethylenediamine solution and 150 ml. of ether is cooled to 5 and a total of 108.5 of ethyl chloroformate is added in portions. A solution of 40 g. of sodium hydroxide in 60 ml. of water is given to the reaction mixture simultaneously with the second half of the ethyl chloroformate; stirring is continued for an additional hour. The ether layer is separated, the aqueous portion is extracted with ether and the ether extracts are combined and dried over anhydrous potassium carbonate. The ether is evaporated, the residue is distilled, B.P. 118- 122 at 17-20 mm., to yield the ethyl N-(Z-dimethylaminoethyD-carbamate.
  • a solution of 40 g. of ethyl N-(2-dimethylaminoethyl) carbamate in 125 ml. of methylene chloride is cooled to and 19.5 g. of nitrosyl chloride in 300 ml. of methylene chloride is added over a period of approximately one hour while stirring and keeping the temperature between 0 to Stirring is continued for an additional two hours, the precipitate is filtered ofi and recrystallized from 32 ethyl acetate to yield ethyl N-(Z-dimethylaminoethyD-N- nitroso-carbamate hydrochloride, MP. 133-135".
  • a suspension of 11.3 g. of ethyl N(2-dimethylaminoethyD-N-nitroso-carbamate hydrochloride in ml. of ether is added to a mixture of 40 g. of a 25 percent methanol solution of potassium hydroxide and 300 ml. of ether while gently refluxing. After fifteen minutes of additional heating the ether layer, containing the 2dimethyl amino-diazoethane, is decanted and immediately used.
  • deserpidates may be prepared according to the previously given procedure by replacing the starting material by other deserpidates; such compounds are, for example,
  • Example 7 To 1 g. of ethyl reserpate in 25 ml. of 2,3-dihydropyran is given 25 ml. of benzene, which has been freshly saturated with hydrogen chloride. The mixture is allowed to stand at room temperature for 45 minutes. After cooling in ice-water 20 ml. of cold 10 percent aqueous sodium hydroxide containing a small amount of ammonia is added to the mixture while shaking. Two layers separate quickly; the organic portion in washed twice with ice-water containing a small amount of ammonia and then dried over sodium sulfate while cooling. The solution is filtered and evaporated under reduced pressure at less than 55.
  • Example 8 A mixture of 1 g. of nbutyl reserpate (M.P. ll6ll8, prepared by treating reserpic acid with an ether solution of n-diazobutane) in 25 ml. of 2,3-dihydropyran, to which is added 25 ml. of benzene, which has been freshly saturated With hydrogen chloride, is allowed to stand for 30 minutes and is then worked up as shown in Example 7. 0.08 g. of n-butyl 18-O-(tetrahydro-2-pyranyl)-reserpate, M.P. 190l92, is obtained.
  • Example 9 To a solution of 2 g. of n-hexyl reserpate in 15 ml. of acetone and 2 ml. of 2,3-dihydropyran is added dropwise, at room temperature and while stirring a solution of 1.2 g. of p-toluene-sulfonic acid in ml. of acetone. The mixture is allowed to stand at room temperature for thirty minutes, and is then diluted with an excess of ethyl acetate.
  • the organic solution is washed with 10 percent aqueous ammonia to remove all traces of the acid, the ethyl acetate solution is dried, evaporated to dryness, and the oily residue is crystallized from a mixture of ether and petro' leum ether.
  • the crystalline material is filtered 01f and Washed with a small amount of petroleum ether to yield the desired n-hexyl l8-O-(tetrahydro-2-pyranyl)-reserpate, M.P. l67-170. An additional amount can be recovered from the filtrate; total yield: 0.70 g.
  • n-hexyl reserpate M.P. 1l7l18
  • M.P. 1l7l18 may be prepared by treating reserpic acid with an ether solution of n-diazohexane.
  • the latter can be obtained by reacting n-hexylamine with ethyl chloroformate, nitrosating the resulting ethyl N-n-hexyl-carbamate with sodium nitrite in the presence of nitric acid, treating the ethyl N-n-hexyl- N-nitroso-carbamate with a 25 percent solution of potassium hydroxide in methanol in the presence of ether and separating the ether solution of n-diazohexane; these reactions are carried out as previously shown.
  • Example 10 To a suspension of 20.0 g. of methyl reserpate in 150 ml. of acetone containing 20 ml. of 2,3-dihydropyran is added dropwise while vigorously stirring a solution of 12.0 g. of p-toluene-sulfonic acid in 50 ml. of acetone. The temperature is kept below 3550 by external cooling. A clear amber solution forms during the addition of the p-toluene sulfonic acid. The reaction mixture is allowed to stand at room temperature for thirty minutes and is then diluted with 250 ml. of ethyl acetate; the mixture is repeatedly washed with 10 percent aqueous ammonia to completely remove any remaining acid.
  • fluoboric acid may be used as the Lewis acid in the previously described procedures.
  • Example 1 A mixture of 1.0 g. of methyl S-methyl-reserpate and 2 ml. of 2,3dihydropyran, when reacted according to the procedure of Example 10, i.e. in the presence of 0.6 g. of p-toluene sulfonic acid and 20 ml. of acetone, yields the methyl S-methyll 8-O-(tetrohydro-2-pyranyl)-reserpate.
  • Example 12 Treatment of an acetone solution of 0.5 g. of methyl 6-methyl-deserpidate with 0.8 ml. of 2,3-dihydropyran in the presence of 0.4 g. of p-toluene sulfonic acid according to the procedure of Example 10, yields the methyl 6- methyl-l 8-O-(tetrahydro-2pyranyl)-deserpidate.
  • Methyl 6-methyl-18-O-(tetrahydro-2-pyranyl)-reserpate can be formed by reacting an acetone solution of 1.0 g. of methyl o-methyl-reserpate with 2 ml. of 2,3-dihydropyran in the presence of 0.5 g. of p-toluene sulfonic acid accord ing to the procedure described in Example 10.
  • Example 14 0.5 g. of n-propyl 6-methyl-reserpate, when treated with 1 ml. of 2,3-dihydropyran in the presence of 0.3 g. of p-toluene sulfonic acid and acetone according to the procedure of Example 10, yields the desired n-propyl 6- methyl- 1 8-O-(t trohydro-2-pyranyl)-reserpate.
  • Example 15 A mixture of 1.0 g. of methyl 9-methyl-dcserpidate, 1 ml. of 2,3-dihydropyran and 0.6 g. of p-toluene sulfonic acid in acetone, when treated according to the procedure of Example 10, yields the methyl 9-methyl-l8-O-(tet1'ahydro-Z-pyranyl) -deserpidate.
  • Example 16 By reacting 1.0 g. of methyl l0-methoxy-deserpidate with 2 ml. of 2,3-dihydropyran according to the method described in Example 10, i.e. in an acetone solution and in the presence of 0.6 g. of p-toluene sulfonic acid, the methyl IO-methoxy- 1 8-0- (tetrahydro-2-pyranyl) -deserpidate can be prepared.
  • Analogous compounds such as, for example, methyl 9-methoxy- 1 8-0- tetrahydro-Z-pyranyl -deserpid-ate, ethyl 10 meth0xy-18-O- (tetrahydro-Z-pyranyl) -deserpidate, npropyl 10 methoxy-18-O-( tetrahydro-Z-pyranyl) -deserpidate, methyl l0 -methoxy-l8-O-(tetrahydro-Z-pyranyl)- reserpate, n-propyl lO-methoxy-l8-O-(tetrahydro-2-pyranyD-reserpate and the like, may be prepared accordingly by using appropriate starting materials.
  • Example 17 The methyl 12-methoxy-l8-O-(tetrahydro-Z-pyranyl)- deserpidate may be prepared by reacting an acetone solution of 0.5 g. of methyl l2-methoxy-deserpidate with 1 ml. of 2,3-dihydropyran in the presence of 0.3 g. of ptoluene sulfonic acid according to the procedure of Example 10.
  • Ethyl IZ-methoxy-l 8-O-(tetrahydro-Z-pyranyl) -de:serpidate, n-propyl 12-methoxy-18-O-(tetrahydro-2-pyranyl)- deserpidate and the like may be prepared according to the previously described procedure by treating the appropriate starting materials with 2,3-dihydropyran in the presence of an acidic condensing catalyst, for example, p-toluene sulfonic acid as described in Example 10.
  • an acidic condensing catalyst for example, p-toluene sulfonic acid as described in Example 10.
  • Example 18 A mixture of 1.0 g. of methyl ll-ethoxy-deserpidate, 2 ml. of 2,3-dihydropyran and 0.6 g. of p-toluene sulfonic acid in acetone, when reacted as described in Example 10, yields the desired methyl ll-ethoxy-lS-O-(tetrahydro- Z-pyranyl) -deserpidate.
  • Methyl 10,11 methylenedi-oxy-l8-O-(tetrahydro-2-pyranyl)-deserpidate may be prepared by reacting 0.5 g. of methyl 10,11methylenedioxy-deserpidate with 0.8 ml. of 2,3-dihydropyran in the presence of 0.3 g. of p-toluene sulfonic acid according to the procedure of Example 10.
  • the ethyl 10,1l-methylenedioxy-l8-O-(tetrahydro-2- pyranyl)-deserpidate, n-propyl 10,1l-methylenedioxy-l8- O-(tetrahydro-Z-pyranyl)-deserpidate and the like may be prepared by substituting in the previous example ethyl 10,11-methylenedioxy-deserpidate, n-propyl 10,11-methylenedioxy-deserpidate and the like for the methyl 10,11- rnethylenedioxy-deserpidate and reacting the former with 2,3-dihydropyran according to the procedure described in Example 10.
  • Example 20 Upon treatment of methyl 1.0 g. of -benzyloxydeserpidate with 1.5 ml. of 2,3-dihydropyran in the presence of 0.6 g. of p-toluene sulfonic acid according to the procedure of Example 10, the methyl lO-benzyloxy-lS-O- (tetrahydro-Z-pyranyl)-deserpidate can be obtained.
  • the ethyl 10-benzyloxy-l8-O-(tetrahydro-2-pyranyl)- deserpidate, methyl 11 benzyloxy 18-O-(tetrahydro-2- pyranyl)-deserpidate and the like may be prepared by reacting the appropriate starting materials with 2,3-dihydropyran according to the procedure of Example 10.
  • Example 21 0.5 g. of methyl 11-methylmercapto-deserpidate, when treated with 0.9 ml. of 2,3-dihydropyran in the presence of 0.3 g. of p-toluene sulfonic acid according to the procedure of Example 10, yields methyl ll-methylmercapto- 1 8-O-(tetrahydro-2-pyranyl -deserpidate.
  • Ethyl 11-methylmercapto-deserpidate or methyl l1- ethylmercapto-deserpidate when reacted with 2,3-dihydropyran according to the procedure of Example 10, yield the ethyl 11 methylmercapto l8-O-(tetrahydro-2-pyranyl)- deserpidate and the methyl 11-ethy1mercapto-l8-O-(tetrahydro-2-pyranyl) -deserpidate, respectively.
  • Example 22 The reaction of 0.6 g. of methyl 10-chlor0-deserpidate with 1 ml, of 2,3-dihydropyran in the presence of 0.4
  • Analogous compounds which may be prepared according to the procedure of Example 10 by selecting the appropriate starting materials, are, for example, ethyl l0- chloro-18-O-(tetrahydro-Z-pyranyl)-deserpidate, n-propyl 10 chloro 18 O (tetrahydro-Z-pyranyl)-deserpidate, methyl l0-fiuoro-18-O-(tetrahydro-2-pyranyl)-deserpidate, methyl 11 chloro 18-O-(tetrahydro-Z-pyranyl)-deserpidate, methyl 10 bromo 18 O-(tetrahydro-2-pyranyl)- reserpate, methyl lO-bromo-IS-O-(tetrahydro-Z-pyranyl)- deserpidate and the like.
  • Example 23 Methyl 17-desmethoxy-17-ethoxy-reserpate (0.5 g.), when reacted with 1 ml. of 2,3-dihydropyran in the presence of 0.3 g. of p-toluene sulfonic acid according to the procedure of Example 10, yields the methyl l7-desmethoxy-17-ethoxy-l 8-O-(tetrahydro-Z-pyranyl) -reserpate.
  • Example 10 Other compounds which may be prepared according to the procedure of Example 10 by selecting the appropriate starting materials, are, for example, ethyl 17-desmethoxyl7-ethoxy- 1 8-O- tetrahydro-Z-pyranyl -reserpate, methyl 17 desmethoxy l7-n-propyloxy-18-O-(tetrahydro-2-pyranyl)-reserpate, methyl 17-desmethoxy-17-isopropyloxy- 18-0-(tetrahydro-Z-pyranyl)-reserpate, methyl 17-desmethoxy 17 -ethoxy-1 8-O- (tetrahydro-Z-pyranyl) -deserpidate and the like.
  • Example 24 To 2.0 g. of methyl reserpate and 2 ml. of 2,3-dihydrofuran in 15 ml. of acetone is added slowly a solution of 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone at room temperature while stirring. After the addition is completed, the solution is allowed to stand at room temperature for 25 minutes, ml. of ethyl acetate is added, the solution is washed with 10 percent aqueous ammonia, then with water and dried over sodium sulfate. The solution is concentrated under reduced pressure until crystals appear. The crystalline material is filtered oh? and washed with ether to yield 0.7 g. of methyl 18-0-(tetrahydro-Z-furanyl)-reserpate, M.P. 256- 258 (decomposition).
  • lower alkyl 18-O-(tetrahydro-Z-furanyl)-deserpidate compounds which may be prepared according to the above-described procedure by selecting the appropriate starting materials are, for example, ethyl 18-O- (tetrahydro-Z-furanyl)-reserpate, n-propyl 18-O-(tetrahydro-Z-furanyl)-reserpate, isopropyl 18-O-(tetrahydro- Z-furanyD-reserpate, n-butyl l8-O-(tetrahydro-2-furanyl)-reserpate, isobutyl 18-O-(tetrahydro-Z-furanyl)-reserpate, methyl l8-O-(tetrahydro-Z-furanyl)-desirpidate, ethyl 18-O-(tetrahydro-Z-furanyl)-desirpidate,
  • Example 25 A mixture of 2.0 g. of methyl reserpate and 2 ml. of 4-methyl-2,3-dihydropyran in 15 ml. of acetone is stirred, while a solution of 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone is added slowly. The reaction mixture is allowed to stand at room temperature for 1 /2 hours, 100 ml. of ethyl acetate is added and the diluted mixture is washed with 10 percent aqueous ammonia and then with water. The organic layer is dried over sodium sulfate and concentrated to dryness under reduced pressure; the oily residue crystallizes when stirred with diethyl ether.
  • Analogous deserpidate compounds such as, for example, ethyl 18-O-(4-methyl-tetrahydro-Z-pyranyl)-reserpate, n-propyl 18-O-(4-methyl-tetrahydro-2-pyranyl)-reserpate, methyl l8-O-(4-methyl-tetrahydro 2-pyranyl)-deserpidate, methyl 10-methoxy-18-O-(4-methyl-tetrahydro- 2 pyranyl) deserpidate, methyl 12 methoxy 18 O- (4-methyl-tetrahydro-Z-pyranyl)-deserpidate and the like, may be prepared by reacting the appropriate starting materials with 4-methyl-2,3-dihydropyranyl
  • Example 26 To a solution of 2.0 g. of isopropyl reserpate and 5 ml. of 2,3-dihydropyran in 15 ml. of acetone is added dropwise and at room temperature while stirring a solution of 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone. The solution warms up towards the end of the addition of the acid and darkens in color;.it is stirred for an additional thirty minutes. To the reaction mixture is added an excess of ethyl acetate, the solution is washed with 10 percent aqueous sodium hydroxide and water and then dried over anhydrous sodium sulfate.
  • the starting material used in the above reaction may be prepared as follows: A mixture of 10 g. of methyl reserpate, 500 ml. of isopropanol and 20 drops of benzyl trimethyl ammonium hydroxide is refluxed for 2 /2 hours. After standing at room temperature for several hours, a white precipitate (needles) is formed, which is removed by filtration. The filtrate is evaporated to dryness, the foamy residue is taken up in 500 ml. of water containing 5 ml. of concentrated aqueous ammonia. The aqueous mixture is extracted with methylene chloride, the organic solvent is passed through a column containing a diatomaceous earth preparation and is then evaporated to dryness under reduced pressure. The residue is crystallized by the addition of diethyl ether, the crystalline material is filtered otf, dried and identified as isopropyl reserpate, M.P. 214216.
  • Example 27 A solution of 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone is added dropwise to 2 g. of isobutyl reserpate and 2 ml. of 2,3-dihydropyran in 15 ml. of acetone. The reaction mixture is stirred and kept at room temperature during the addition and is then allowed to stand at the same temperature for an additional thirty minutes. An excess of ethyl acetate is added, the organic portion is washed with 10 percent aqueous ammonia to neutralize the acid and is then dried and evaporated to dryness.
  • the isobutyl reserpate may be prepared as follows: To a stirred solution of 34 g. of ethyl N-isobutyl-carbamate in 120 ml. of methylene chloride, kept at 0, is added dropwise 15 g. of nitrosyl chloride, whereby the temperature is not allowed to raise to more than 5. The mixture is stirred for an additional hour, the solvent is evaporated under reduced pressure and the resulting ethyl N-isobutyl-N-nitroso-carbamate is used in the following step without any further purification.
  • a mixture of 30 g. of ethyl N-isobutyl-N-nitrosocarbamate and 75 ml. of ether is added dropwise to a refluxing mixture of 50 g. of a percent solution of 33 potassium hydroxide in methanol, and 300 m1. of ether.
  • the mixture is refluxed for an additional thirty minutes, an excess of water is added and the organic phase is separated, washed with water and dried over anhydrous sodium sulfate.
  • the ether solution of the resulting diazoisobutane is used in the next step.
  • Example 28 To a mixture of 2.0 g. of isopentyl reserpate and 2 m1. of 2,3-dihydropyran in 25 ml. of acetone is added gradually 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone. After standing at room temperature for thirty minutes an excess of ethyl acetate is added; the resulting mixture is then washed twice with 10 percent aqueous sodium hydroxide. The organic layer is dried over sodium sulfate and evaporated under reduced pressure; the oily residue is heated in a distillation apparatus to about under reduced pressure.
  • Ethyl acetate is added to the nondistillable residue, a crystalline material precipitates, which is filtered off and dissolved in methylene chloride.
  • the solution is passed through a column containing a synthetic magnesium silicate adsorbent preparation; the residue obtained after evaporating the solvent from the eluate is crystallized from ethyl acetate to yield isopentyl 18-0-(tetrahydro-Z-pyranyl)-reserpate, M.P. 135; yield: 0.12 g.
  • the starting material may be prepared as follows: To a solution of 60 g. of ethyl N-isopentyl-carbamate, B.P. 107108/17-20 mm. (prepared by reacting isopenthylamine with ethyl chloroformate in the presence of sodium hydroxide and in a mixture of water and ether) in 150 m1. of ether is added 50 g. of ice and then 163 g. of sodium nitrite in 250 ml. of water. A solution of 1.50 g. of concentrated nitric acid and 150 g. of ice is gradually given to the reaction mixture over a period of 1 /2 hours, keeping the temperature below 15 by adding more ice.
  • the separated ether layer is Washed twice with water and cold aqueous potassium carbonate, and is then dried over potassium carbonate.
  • the solvent is removed on the steam bath, leaving ethyl N-isopentyl-N-nitroso-carbamate, yield: 78 g.
  • a mixture of 40.0 g. of ethyl N-isopentyl-N-nitrosocarbamate in 75 ml. of ether is added dropwise to 80.0 g. of a 25 percent solution of potassium hydroxide in methanol and 400 ml. of ether while refluxing. Boiling is continued for an additional twenty minutes. An excess of Water is added, the ether layer is separated, washed with water and dried over sodium sulfate.
  • Example 29 1.0 g. of 18-O-(tetrahydro-2-pyranyl)-reserpic acid is added in small amounts to an ether solution of diazoethane until evolution of nitrogen ceases. The reaction mixture is allowed to stand at room temperature, an excess of benzoic acid in ether is added and the solvent is evaporated. Dilute aqueous ammonia is given to the residue, and the aqueous mixture is extracted with methylene chloride. The organic solvent is evaporated after drying and the residue is worked up to yield the desired ethyl 18-0-(tetrahydro-Z-pyranyl)-reserpate, M.P. 210- 218.
  • the 18-0-(tetrahydro-2-pyranyl)-reserpic acid may also be prepared as follows: To 0.5 g. of reserpic acid hydrochloride in 10 ml. of N,N-dimethylforma1nide and 5 m1. of 2,3-dihydropyran is added dropwise 0.3 g. of ptoluene sulfonic acid in 5 ml. of N,N-dimethylformamide while stirring at room temperature. The solution is stirred for an additional thirty minutes, and is then poured into water; the mixture is extracted with methylene chloride, the organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure.
  • 18-0-(tetrahydro-Z-pyranyl) -deserpidic acid compounds such as for example, 18-O-(tetrahydro-Z-pyranyl)-deserpidic acid, S-methyl-lS-O-(tetrahydro-Z-pyranyl)-reserpic acid, 5-methyl-18-O-(tetrahydro-2-pyranyl)- deserpidic acid, 6-methyl-18-O (tetrahydro-2-pyranyl)- reserpic acid, 9-methyl-18-O-(tetrahydro-Z-pyranyl)-deserpidic acid, 1l-methyl-l8-O-(tetrahydro-2-pyranyl)-de serpidic acid, 9-methoxy-18-O-(tetrahydro-Z-pyranyl)-deserpidic acid, 10-methoxy-18-O-(tetrahydro-Z-pyranyl)- deserpidic acid, 10-meth0xy-18-
  • 2,3-dihydropyran may be replaced by a 2-halogenotetrahydropyran, such as 2-chloro-tetrahydropyran, which upon reaction with a deserpidic acid compound, e.g. reserpic, deserpidic acid and the like, in the presence of N,N-dimethylformamide as shown in Example 33, yields the desired 18-O-(tetrahydro-Z-pyranyl)-deserpidic acid compound, e.g. 18-O-(tetrahydro-Z-pyranyl)-reserpic acid, 18-0-(tetrahydro-Z-pyranyl)-deserpidic acid and the like can be formed.
  • a deserpidic acid compound e.g. reserpic, deserpidic acid and the like
  • '18-O-(tetrahydro 2 furanyl)-deserpidic acid compounds such as for example, 18-0-(tetrahydro-2-furanyl)- reserpic acid, 18-O-(tetrahydro-2-furanyl) -deserpidic acid, 1*0-methoxy-18-O-(tetrahydro-Z-furanyl)-deserpidic acid, 12-methoxy-18-O-(tetrahydro-Z-furanyl)-deserpidic acid and the like, can be obtained by hydrolyzing a corresponding lower alkyl 18-O-(tetrahydro-Z-furanyl)-deserpidate compound or by reacting a mixture of the corresponding 18-unsubstituted deserpidic acid compound and 2,3-dihydrofuran in an N,N-dimethylformamide solution with p-toluene sulfonic acid as shown in the above example.
  • Example 30 A solution of 0.5 g. of methyl 18-O-(tetrahydro-2- pyranyl)-reserpate, prepared, for example, according to the procedure of Example 10, in ethanol containing sodium ethanolate, when heated to reflux over a short period of time, yields the desired ethyl 18-O-(tertahydro- Z-pyranyD-resperpate, M.P. 210218.
  • Example 31 To a solution of 1.29 g. of methyl reserpate N-oxide and 1.25 ml. of 2,3dihydropyran in 10 ml. of acetone is gradually added, while stirring, 0.76 g. of p-toluene sulfonic acid in 3.2 ml. of acetone. Stirring is continued for an additional thirty minutes and ethyl acetate is added; the organic layer is washed twice with 10 percent aqueous sodium hydroxide and with water. The organic solution is dried over sodium sulfate, the solvent is removed under reduced pressure, and the residue is precipitated from a mixture of acetone and diethyl ether and crystallized from ethyl acetate. The resulting methyl 18-0- (tetrahydro-Z-pyranyl)-reserpate N-oxide melts at 226- 227; yield: 0.11 g.
  • N-oxides such as, for example, ethyl 18-O-(tetrahydro-Z-pyranyl)-reserpate N-oxide, n-propyl 18-O-(tetrahydro-Z-pyranyl)-reserpate N-oxide, methyl 18-O-(tetrahydro-Z-pyranyl)-deserpidate N-oxide, methyl IO-methoxy-18-0-(tetrahydro-2-pyranyl) deserpidate N oxide, methoxyethyl 18-0-(tetrahydro-Z-pyranyl)-reserpate N- oxide, methyl l8-O-(4-methyl-tetrahydro-Z-pyranyl)-reserpate N-oxide, methyl 18-0-(tetrahydro-Z-furanyl)-reserpate N-oxide and the like, may be obtained by reacting the appropriate lower alkyl or lower al
  • Example 32 A suspension of 249.3 g. of methyl reserpate in 1870 ml. of acetone and 250 ml. of 2,3-dihydropyran is stirred at room temperature; a solution of 129.3 g. of p-toluene sulfonic acid monohydrate in 620 ml. of acetone is added over a period of nine minutes. The resulting solution is stirred for thirty minutes, the acetone is removed by distillation and the residue is suspended in 2500 ml. of ethyl acetate. The organic solution is washed with a mixture of 602 ml. of 10 percent aqueous sodium carbonate and 780 ml.

Description

United States Patent U 3,048,591 18-0-HETERO-RESERPATES Robert Armistead Lucas, Mendham, N.J., assignor to Ciha Qorporatioma corporation of Delaware No Drawing. Filed Jan. 7, 1960, Ser. No. 931 15 Claims. (Cl. 260287) The present invention concerns compounds derived from deserpidic acids. More particularly, it relates to compounds of the formula:
in which R represents lower alkyl, lower alkoxy-lower alkyl or tertiary amino-lower alkyl, R stands for lower alkyl, R represents cyclo-oxa-alkyl, particularly 2-cyclooXa-alkyl, which contains at least five atoms as ring members, each of the radicals R and R stands for hydrogen, lower aliphatic hydrocarbon, or a functional group, such as, for example, etherified hydroxyl, esterified hydroxyl, etherified mercapto, nit-ro, amino, halogeno or halogen-olower alkyl, or, when attached to adjacent positions and taken together, for lower :alkylene-dioxy, and R attached to either one of the positions 5 or 6, stands for hydrogen or lower alkyl, salts or N-oxides thereof, as well as process for the preparation of such compounds.
A lower alkyl group R containing from one to seven, preferably from one to four, carbon atoms, stands, for example, for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl as Well as n-pentyl, isopentyl, n-hexyl and the like.
In a lower alkoxy-lower alkyl group R the lower alkoxy portion contains from one to {our carbon atoms and represents, for example, methoxy, ethoxy, n-pr-opyloxy, isopropyloxy, n-butyloxy and the like. The amino group of a tertiary amino-lower alkyl radical R is primarily an IJ,N-di-lower alkyl-amino group, in which lower alkyl contains from one to four carbon atoms, e.g. N,N- dimethylamino, N-ethyl-N-methyl-amino, N,N-diethyl amino, N,N-di-n-propylamino, N,N- di-isopropylamino and the like, an N,N-lower alkylene-irnino group, in which lower alkylene contains from four to six carbon atoms, e. g. l-pyrrolidino, l-piperidino, l-hexamethyleneimino and the like, an N,N-lower oxa-alkylene-imino group, in which lower oxa-alkylene contains preferably four carbon atoms, e.g. l-morpholino and the like, or an N,N-lower azaalkylene-irnino group, in which lower aza-alkylene contains preferably four carbon atoms, e.g. 4-methyl-1-piperazino and the like.
The lower alkyl portion of a lower alkoxy-lower alkyl or a tertiary amino-lower alkyl radical R is represented by a lower alkylene radical containing from two to seven carbon atoms, which separates the lower alkoxy group or the amino group from the carbon atom of the carboxy group by at least two carbon atoms. Preferably, the lower alkylene radical contains from two to three carbon atoms and separates the lower alkoxy and the amino group from the carboxy group by the same number of carbon atoms. Such radicals are primarily 1,2-ethylene, l-methyl-1,2- ethylene, 2-methyl-l,2-ethylene or 1,3-propylene; other lower alkylene radicals may be, for example, 1,4-butylene or 1-methyl-1,3-propylene and the like.
The lower alkyl group R containing from one to four carbon atoms, stands for ethyl, n-propyl, isopropyl, n-
3,048,591 Patented Aug. 7 1962 butyl, isobutyl and the like, but represents above all methyl.
The 2-cyclo-oxa-alkyl radical R attached to the oxygen atom of the position 18 of the deserpidate portion is more especially represented by a 2-cyclo-oxa-alkyl radical containing from five to seven atoms as ring members, such as a tetrahydro-Z-furanyl (Z-cyclo-oxapentyl), a tetrahydroe2- pyranyl (Z-cyclo-oxahexyl), a 2-cyclo-oxaheptyl radical and the like.
The carbon atoms of the cyclo-oxa-alkyl, particularly a 2-cyclo-oxa-alkyl, nucleus may be unsubstituted or substituted by lower aliphatic hydrocarbon, particularly lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, as well as, for example, lower cycloalkyl, e.g. cyclopentyl, cyclohexyl and the like, or carbocyclic aryl, such as monocyclic or bicyclic carbocyclic aryl, e.g. phenyl, naphthyl and the like, or carbocyclic aryllower aliphatic hydrocarbon, such as monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the like. Two of the carbon atoms of the cyclo-oxa-alkyl nucleus may also be part of a second, especially of a carbocyclic, ring system fused onto the cyclo-oxa-alkyl nucleus; carbocyclic rings, which may be fused onto the :cyclo-oxa-alkyl nucleus, may be represented, for example, by cycloalkyl containing from five to seven carbon atoms, e.g. cyclopentyl, cyclohexyl, cycloheptyl and the like, or carbocyclic aryl, such as monocyclic or bicyclic carbocyclic aryl, e.g. phenyl, naphthyl and the like.
Other substituents attached to any of the available carbon atoms of the cyclo-oxa-alkyl, particularly the Z-cyclooxa-alkyl, radical are, for example, halogen atoms, e.g. fluorine, chlorine, bromine and the like, as well as other functional groups.
The group R may, therefore, be represented by tetrahydrofuranyl (cyclo-oxapentyl) radicals, particularly tetrahydro-Z-furanyl (Z-cyclo-oxapentyl) radicals, e.g. tetrahydro-Z-furanyl (Lcyclo-oxapentyl), 4-methyl-tetrahydro-2- furanyl (4-methyl-2-cyclo-oxapentyl), S-methyl-tetrahydro- Z-furanyl (S-methyl-Z-cyclo-oxapentyl), 3-chloro-tetrahydro-Z-furanyl (3-chloro-2-cyclo-oxapentyl) and the like, tetrahydropyranyl (cyclo-oxahexyl) radicals, particularly tetrahydro-Z-pyranyl (2-cyclo-oxahexyl) radicals, e. g. tetrahydro-Z-pyranyl (Z-cyclo-oxahexyl), 4-methyl-tetrahydro- 2-pyranyl (4-methyl-2-cyclo-oxahexyl), 6-methyl-tetrahy dro-Z-pyranyl (6-methyl-2-cyclo-oxahexyl), fi-phenyl-tetrahydro-Z-pyranyl (6-phenyl-2-cyclo-oxahexyl), hexahydrobenz[e]tetrahydro 2 pyranyl (bicyclo[4,4,0]-2-oxa-3- decyl), benZ[e]dihydro-2-pyranyl (2-benz[e]cyclo-oxahexyl), 3-chloro-tetrahydro-2-pyranyl (3-chloro-2-cyclooxahexyl), 3-bromo-tetrahydro-2-pyranyl (3-bromo-2- cyclooxahexyl) and the like, or cyclo-oxaheptyl radicals, particularly 2-cyclo-oxaheptyl radicals, e.g. Z-cyclo-oxaheptyl and the like.
The substituents R and R may represent hydrogen or any of the groups mentioned hereinabove. Such groups are, for example, lower aliphatic hydrocarbon, primarily lower alkyl containing from one to four carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl and the like, or functional groups, such as, for example, etherified hydroxy, particularly lower alkoxy containing from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, i-butyloxy, and the like, as well as cycloalkyloxy, e.g. cyclohexyloxy andthe like, carbocyclic aryloxy, such as monocyclic carbocyclic aryloxy, e.g. phenyloxy and the like, carbocyclic aryl-lower alkoxy, such as monocyclic carbocyclic aryl-lower alkoxy, for example, phenyl-lower alkoxy, e.g. benzyloxy and the like, esterified hydroxyl, particularly lower alkoxy-carbonyloxy, e.g. methoxycarbonyloxy, ethoxycarbonyloxy and the like, or lower alkanoyloxy, e.g. acetoxy, propionyloxy and the like, etherified mercapto, particularly lowfunctional group. Whenever attached to two adjacent positions, the radicals R and R when taken together, may also form a cyclic substituent; such substituent may be represented, for example, by lower alkylene-dioxy, e.g. methylenedioxy, or any other analogous substituent.
The radical R stands preferably for hydrogen; when representing lower alkyl, such radical may stand for 'methyl, as well as ethyl and the like.
Salts of the compounds of this invention are primarily therapeutically acceptable acid addition salts with inorganic or organic acids, particularly with mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like.
Due to the presence of a tertiary amino group in the molecule, the compounds may also be present in the form of their N-oxides.
In view of the fact that several asymmetric carbon atoms are present in the compounds of this invention, the latter may :be obtained in the form of a mixture of racemates, racemates or optically pure compounds.
The new compounds of this invention have antihypertensive properties, as well as sedative and tranquilizing eflects on the central nervous system. They are characterized by a quick onset of the physiological action. Furthermore, tests show that animals, treated with the compounds of the present invention, recover faster and more completely from the pharmacological effects than those treated with known, naturally occurring Rauwolfia alkaloids, for example, with reserpine, deserpidine or rescinnamine. In addition, certain quantitative difierentiations may be observed within the group of the new compounds of this invention. For example, when compared with the established ratio existing between antihypertensive and sedative efiects in the above-mentioned natural Rauwolfia alkaloids, some of the compounds of this invention have more predominant sedative eflects with negligible antihypertensive activity, whereas in others, the latter may be more pronounced than the sedative and tranquilizing component.
The compounds of the present invention may, therefore, be used as antihypertensive agents to relieve hypertensive conditions, such as, for example, benign or malignant hypertension, renal hypertension or hypertension associated with pregnancy, such as toxemia of pregnancy, and/or as sedative agents to relieve states of hyperactivity, tension and agitation, as, for example, associated with mental disturbances and the like.
Very pronounced antihypertensive and/or sedative effects are exhibited by compounds of the formula:
carbon atoms, and lower alkyl, separating N,N-di-lower alkyl-amino from the carboxy group by two to three carbon atoms, contains from two to three carbon atoms, R represents lower alkyl containing from one to four carbon atoms, R stands for 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, lower alkylsubstituted Z-cyclo-oxa-alkyl containing from five to seven atoms as ring members, or halogeno-substituted 2- cyclo-oxa-alkyl containing from five to seven atoms as ring members, each of the radicals R and R stands for hydrogen, lower alkyl containing from one to four car bon atoms, lower alkoxy containing from one to four carbon atoms, lower alkyl-mercapto containing from one to four carbon atoms, or halogeno, R attached to one of the positions 5 and 6, stands for hydrogen of lower alkyl containing from one to four carbon atoms, the therapeutically useful mineral acid addition salts or the N-oxides of these compounds, as well as their various isomeric forms.
This group of compounds is represented, for example, by lower alkyl reserpate compounds of the formula:
in which R stands for lower alkyl containing from one to four carbon atoms, or the N-oxides thereof, whereby these compounds may be in different isomeric forms.
. Specific members illustrating this group of compounds are lower alkyl 18-0-(tetrahydro-Z-furanyl)-reserpates, in which lower alkyl contains from one to four carbon atoms, e.g. methyl 18-0-(tetrahydro-Z-furanyl) -reserpate, ethyl 18-0-(tetrahydro-Z-furanyl)-reserpate, n-propyl l8-O-(tetrahydro-Z-fur-anyl)-rese1pate and the like, lower alkyl 18-0-(tetrahydro-Z-pyranyl)-reserpates, in which lower alkyl contains from one to four carbon atoms, e.g. methyl 18-0-(tetrahydro-Z-pyranyl)-reserpate, ethyl l8-O-(tetrahydro-2-pyranyl)- reserpate, n-propyl IS-O-(tetrahydro- Z-pyranyD-reserpate, isopropyl 18-O-(tetral1ydro-2-py ranyl)-reserpate, n-butyl 18-O-(tetrahydro-2-pyranyl) reserpate, isobu-tyl 18-O-(tetrahydro-Z-pyranyl)-reserpate, n-pentyl l8-0-(tetrahydro-2-pyranyl)-reserpate and the like, or the lower alkyl l8-O-(2-cyclo-oxaheptyl)- reserpates, in which lower alkyl contains from one to four carbon atoms, e.g. methyl 18-O-(2-cyclo'oxaheptyl)-reserpate, ethyl 18-0-(2cyclo-oxaheptyl)-reserpate, n-propyl 18-O- (Z-cyclo-oxaheptyl)-reserpate and the like, and the N- oxides of such compounds, which compounds may be present in difierent isomeric forms.
The above group of compounds may also be represented by those of the formula:
in which R, stands for lower alkyl containing from one to four carbon atoms, or their N-oxides, whereby these compounds may be in different isomeric forms. Lower alkyl l8-0-(tetrahydro-Z-furanyl)-deserpidates, in which lower alkyl contains from one to four carbon atoms, e.g. methyl 18-O-(tetrahydro-Z-furanyl)-deserpidate, ethyl l8- O-(tetrahydro-Z-furanyl)-deserpidate and the like, lower alkyl 18-O-(2-cyclo-oxaheptyl)-deserpidates, in, which lower alkyl contains from one to four carbon atoms, e.g. methyl 18-0-(tetrahydro-Z-pyranyl)-deserpidate, ethyl 18- O-(tetrahydro-Z-p-yranyl)-deserpidate, n-propyl 18-0- (tetrahydro-Z-pyranyl)-deserpidate and the like, or lower alkyl 18-0-(2-cyclo=oxaheptyl)-deserpidates, in which lower alkyl contains from one to four carbon atoms, e.g. methyl 18-0-(2-cyclo-2-oxaheptyl)-deserpidate, ethyl l8-O-(2-cyclo-oxaheptyl)-descrpidate and the like, and the N-oxides of such compounds, which compounds may be present in different isomeric forms, represent this group.
The new compounds may also be represented by the 2- lower alkoxy-lower alkyl 18-O-R -11-R deserpidates, in which lower alkoxy contains from one to four carbon atoms, lower alkyl contains from two to three carbon atoms and separates alkoxy from the carboxy group by from two to three carbon atoms, R represents 2-cyclo-oxaalkyl containing from five to seven atoms as ring members, and R represents hydrogen or methoxy. This group is represented by 2-l-ower alkoxy-ethyl IB-O-(tetrahydro- 2-furanyl)-reserpates, in which alkoxy contains from one to four carbon atoms, such as Z-methoxy-ethyl 18-O- (tetrahydro-Z-furanyl)-reserpate and the like, and the 2- lower alkoxy-ethyl 18-O-(tetrahydro-Z-furanyl)-deserpidates, in which lower alkoxy contains from one to four carbon atoms, such as Z-methoxyethyl IS-O-(tetrahydro- Z-furanyD-deserpidate and the like, 2-lowe-r alkoXy-cthyl 18-0-(tetrahydro-Z-pyranyl)-reserpates, in which alkoxy contains from one to four carbon atoms, such as 2- methoxy-ethyl l8-0-(-tetrahydro-Z-pyranyl)-reserpate and the like, and the 2-lower ialkoxy-ethyl 18-O-(tetrahydro-2- pyranyD-deserpidates, in which lower alkoxy contains from one to four carbon atoms, such as 2-methoxyethyl 1S-O-(tetrahydro-Z-pyranyl)-deserpidate and the like.
An additional group of the new compounds is represented by the lower alkyl l0-methoXy-l8-O-R -deserpidates, in which R stands for 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, and lower alkyl contains from one to four carbon atoms; such compounds are, for example, lower alkyl lO-rnethoxy-lS-O-(tetrahydro-Z-furanyl)-deserpidate, in which lower alkyl contains from one to four carbon atoms, e.g. methyl lO-methoxyl8-0-(tetrahydro-Z-furanyl)-deserpidate, ethyl lO-methoxy-lS-O-(tetrahydro-Z-furanyl)-deserpidate, n-propyl 10- methoxy-l8-0-(tetrahydro-Z-furanyl)-deserpidate and the like, lower alkyl IO-methoxy-l8-O-(tetrahydro-2-pyranly)-deserpidate, in which lower alkyl contains from one to four carbon atoms, e.g. methyl 10-methoxy-18-O- (tctrahydro-2-pyranyl)-deserpidate, ethyl lO-methoxy-IS- O-(tetrahydro-Z-pyranyl)-deserpidate, n-propyl IO-methoxy-18-0-( tetrahydrO-Z-pyranyl)-deserpidate and the like.
A further group of highly active compounds are the lower alkyl 12-methoxy-18-O-R -deserpidates, in which R represents Z-cyclo-oxa-alkyl containing from five to seven atoms as ring members, and lower alkyl contains from one to four carbon atoms as ring members. This group may be illustrated by lower alkyl l2-methoxy-l8-O- (tetrahydro-2-furanyl)-deserpidates, in which lower alkyl contains from one to four carbon atoms; methyl 12-methoxy-18-0-(tetrahydro-Z-furanyl)-deserpidate, ethyl 12- methoxy-l 8-0- (tetrahydro-Lfuranyl -deserpidate, n-propyl 12-methoxy-18-O-(tctrahydro-Z-furanyl)-deserpidate and the like, lower alkyl 12-methoXy-1S-O-(tetrahydro-Z- pyranyD-deserpidates, in which lower alkyl contains from one to four carbon atoms; methyl l2-methoxy-l8-O-(tctrahydro-Z-pyranyl)-deserpidate, ethyl 12-methoxy-18-O- tetrahydro-Z-pyranyl)-deserpidate, n-propyl IZ-methoxyl8-0-(tetrahydro-2-pyranyl)-deserpidate and the like, are specific examples of such compounds.
Lower alkyl 10-halogeno-l8-O-R -deserpidates, in which R stands for 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, halogeno represents primarily chloro or bromo, as well as iodo, and lower alkyl contains from one to four carbon atoms, are an additional series of new compounds of this invention.
Lower alkyl l0-chloro-l8-O-(tetrahydro-Z-furanyl)-reserpates, lower alkyl 10-bromol8-O-(tetrahydro-Z-furanyl)- reserpates, lower alkyl 10-chloro-18-O-(tetrahydro-Z-pyranyl)-deserpidates and lower alkyl 10-bromo-18-O-(tetrahydro-2-pyranyl)-deserpidates, in which lower alkyl contains from one to four carbon atoms, illustrate this group; methyl 1O chloro-18-0(tetrahydro-Z-furanyl)-deserpidate, ethyl lO-chloro-l8-O- (tetrahydro-Z-furanyl)-deserpidate, n-propyl 10'chloro-l8-O-(tetrahydro-2-furanyl)- deserpidate, methyl lO-bromo-lS-O-(tetrahydro-Z-furanyD-deserpidate, ethyl 10-bromo-l8-O-(tetrahydro-2-fur anyl)-deserpidate, n-propyl 10-bromo-18-O-(tetrahydro-2- furanyD-deserpidate and the like, methyl lfl-chloro-lS-O- (tetrahydro-Z-pyranyl)-deserpidate, ethyl 10-chloro-18-O- (tetrahydro-Z-pyranyl)-deserpidate, n-propyl l0-chloro- 18-O-(tetrahydro-2-pyranyl) -deserpidate, methyl 10 bromo-lS-O-(tetrahydro-Z-pyranyl)-deserpidate, ethyl l0- hromo-l8-O-(tetrahydro-Z-pyranyl)-deserpidate, n-propyl l0 bromo-l8-O-(tetrahydro-Z-pyranyl)-d-eserpidate and the like, are specific members of such compounds.
An additional group of compounds are the lower alkyl 6-methyl-l8-O-R -reserpates, in which R stands for 2- cyclo-oxa-alkyl containing from five to seven atoms as ring members, and lower alkyl contains from one to four carbon atoms. The lower alkyl 6-methyl-18-O-(tetrahydro-Z-furanyl)-reserpates and the lower alkyl 6-methyll8-O-(tetrahydro-Z-pyranyl)-reserpates, in which lower alkyl contains from one to four carbon atoms, are more specific groups of these compounds, which may be illustrated, for example, by methyl 6-metl1yl-lS-O-(tetrahydro- Z-furanyD-reserpate, ethyl 6-methyl-IS-O-(tetrahydro-Z- furanyU-reserpate, n-propyl 6-methyl-l 8-O-(tetrahydro-2- furanyl)-reserpate and the like, methyl 6-methyl-l8-O- (tetrahydro-Z-pyranyl)-reserpate, ethyl 6 methyl-18-O- (tetrahydro-2-pyranyl)-reserpate, n-propyl ,6-methyl-l8- O-(tetrahydro-Z-pyranyl)-reserpate and the like.
Other lower alkyl 18-O-R -deserpidate compounds, in which R represents 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, and lower alkyl contains from one to four carbon atoms, are, for example, lower alkyl S-methyl-l8-O-R -deserpidates, lower alkyl 5- methyl-l8-O-R -reserpates, lower alkyl 6-methyl-1S-O-R deserpidates, lower alkyl 9-methyl-l8-O-R -deserpidates, lower alkyl ll-methyl-l8-O-R -deserpidates, lower alkyl 9-methoxy-l8-O-R -deserpidates, lower alkyl lO-methoxy- 18-OR -rese1 pates, lower alkyl ll-ethoxy-l8-O-R -deserpidates, lower alkyl 11-n-propyloxy-l8-O-R -deserpidates, lower alkyl 1l-isopropyloxy-l8-O-R -deserpidates, lower alkyl ll-n butyloxy-l8-O-R deserpidates, lower alkyl 10, 1l-methylenedioxy-18-OR -dcscrpidates, lower alkyl 10- benzyloxy-l8-O-R -deserpidates, lower alkyl ll-benzyl- 0xyl8-O-R -deserpidates, lower alkyl ll-methylmercaptol8-O-R -deserpidates, lower alkyl ll-ethylmercapto-lS-O- R -deserpidates, lower alkyl l7-desmethoxy-l7-ethoxy-18- o-R -deserpidates, lower alkyl l7-desmethoxy-l7-ethoxyl8-O-R -reserpates, lower alkyl l7-desmethoxy-17-n-propyloxy-l8 O-R -reserpates, lower alkyl l7-desmethoxyl7-isopropyloxy-l8-O-R -reserpates and the like, in which R represents cyclo-oxa-alkyl containing from five to seven atoms as ring members, represented primarily by tetrahydro-Z-furanyl or tetrahydro-Z-pyranyl, and in which lower alkyl contains from one to four carbon atoms.
The compounds of this invention may be 'used as medicaments in the form of pharmaceutical preparations, which contain the new compounds in admixture with a pahrmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known carrier for medicaments. Thte pharmaceutical preparations maybe in solid form, for example, as tablets, dragees, capsules and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents and the like, salts for varying the osmotic pressure, bulfers and the like. They may also contain, in combination, other therapeutically useful substances. The compounds of this invention may also be used in compositions for veterinary use by adding them to standard feed formulae.
Compounds of the present invention may be prepared by reacting a deserpidate compound of the formula:
in which R R R R and R have the previously given meaning, or an N-oxide thereof, with a reactive ester of a 2-hydroxy-cyclo-oxa-alkane, which contains at least five atoms as ring members, in the presence of a condensing reagent, and, if desired, separating a resulting mixture of isomeric compounds into the single isomers, and/ or, if desired, converting a resulting compound into a salt or an N-oxide thereof.
The reactive ester of a Z-hydroxy-cyclooxa-alkane, used as the reagent in the above reaction, is particularly an ester with a strong inorganic or organic acid, particularly a mineral acid, such as a hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like, as well as a monocyclic carbocyclic aryl sulfonic acid, eg p-toluene sulfonic acid and the like. The reagent is represented primarily by a Z-halogeno-cyclo-oxa-alkane, which contains at least five atoms as ring members, particularly by a 2-chloro-cyclooxa-alkane, as well as by a 2 bromo-cyclo-oxa-alkane, which contain from five to seven atoms as ring members. Specific reagents are, for example, 2-chloro-tetra-hydro furan (2-chloro-cyclo-oxapentane), Z-chloro-tetrahydropyran (2-chloro-cyclo-oxahexane), 2-chloro-cyclo-oxaheptane, as Well as the corresponding bromo derivatives. The above cyclo-oXa-alkane compounds may contain hydrocarbon radicals, such as, for example, lower alkyl, e.g. methyl and the like, or functional groups, such as additional halogen atoms, e.g. chlorine and the like, or any other suitable sustituent; substituted reagents are, for example, 2-chloro-S-methyl-tetrahydrofuran (2-chloro-5- methyl-cyclo-oxapentane), 2-chloro-4-methyl-tetrahydropyran (2-chloro-4-methyl-cyclo-oxahexane), 2-chloro-6- methyl-tetrahydropyran (2-chloro-6methyl-cyclo-oxahexane), 2,3-dichloro-tetrahydropyran (2,3-dichloro-cyclooxahexane) and the like.
A condensing reagent may be represented more particulady by N,N-dimethylformamide; any other suitable reagent may be used. N,N-dimethylformamide may also serve as a solvent; other inert solvents may be used as diluents.
Ordinarily, the reaction mixture is allowed to stand, if necessary, while cooling and with protection from light, until the reaction is completed. The desired compound is isolated from the reaction mixture according to methods known per se, for example, by evaporating the solvent and isolating the reaction product from the residue, by diluting the reaction mixture and precipitating or extracting the product, and the like. The reaction product may be purified by crystallization, adsorption and elution, recrystallization and the like.
The deserpidate compounds used as the starting ma terials are known or, if new, may be prepared according to procedures used for known analogous compounds. For example, deserpidic acids may be esterified by treatment with a lower diazoalkane, a lower alkoxy-lower diazoalkane or a tertiary amino-lower diazoalkane, or
by alcoholysis of deserpidic acid (l6 18)-lactones with alkali metal compounds of lower alkanols, lower alkoxylower alkanols or tertiary amino-lower alkanols.
For example, to a solution of the diazo reagent in an inert solvent, such as an ether, particularly diethylether, may be added the deserpidic acid compound or a salt thereof, which is preferably kept in a suspension or a solution, for example, of a lower alkanol, e.g. methanol, ethanol and the like, a halogenated lower aliphatic hydrocarbon, e.g. chloroform, methylene chloride and the like, or any other suitable, inert solvent. Or, the diaz compound may be distilled out of a solution, such as a diethylether solution, into the suspension or solution of a deserpidic acid compound or a salt thereof. An excess of the diazo derivative present in the reaction mixture may be destroyed, for example, by adding an additional carboxylic acid, e.g. acetic, benzoic acid and the like. The esterification may be carried out under cooling or at room temperature, and, if desired, under the atmosphere of an inert gas, e.g. nitrogen.
Or, by treating the necessary amount of an alkali metal, e.g. lithium, potassium, or particularly sodium, with a lower alkanol, a lower alkoxy-loWer alkanol or a tertiary amino-lower alkanol and adding a deserpidic acid lactone to the resulting alkali metal derivative of the alcohol, the desired deserpidate compound may be obtained. Although this reaction may proceed under cooling or at room temperature, the mixture is advantageously heated, if necessary, in the atmosphere of an inert gas, e.g. nitrogen.
N-oxides of the starting material may be prepared according to known N-oxidation methods; for example, a solution of the starting material may be treated with a per-acid, such as, for example, peracetic, perbenzoic, monoperphthalic, p-toluene persulfonic acid and the like, with hydrogen peroxide or with ozone.
Compounds of the present invention may also be prepared by reacting a deserpidate of the formula:
in which R R R R and R have the above-given meaning, a salt or an N-oxide thereof, with a cyclo-oxaalk-Z-ene, which contains at least five atoms as ring members, and which is capable of introducing the desired radical R in the presence of an acid condensing reagent,
and, if desired, converting a resulting salt into the free base, and/or, if desired, separating a resulting mixture of isomeric compounds into the single isomers, and/or, if desired, converting a resulting compound into a salt or an N-oxide thereof.
The cyclo-oxa-alk-Z-enes used as the reagents, contain no further substituents, or, whenever substituents, such as halogen, lower alkyl and the like, are present, such substituents are attached to those carbon atoms, which do not involve the 2,3-double bond. Especially suitable reagents are cyclo-oxa-alk-Z-enes, which contain from five to six atoms as ring members, and which, when sub- These reagents are reacted with the deserpidate compound in the presence of an acid condensing reagent, represented by a strong Lewis acid. Mineral acids, e.g. hydrochloric, hydro'bromic or sulfuric acid (used in anhydrous form or as concentrated aqueous solutions), phosphoric acid (for example, in the form of polyphosphoric acid), phosphorous oxychloride, fluoboric acid (in the form of a highly concentrated aqueous solution), boron trifluoride (in the form of its etherate, particularly with diethyl ether), or a carbocyclic aryl sulfonic acid, such as a monocyclic CEllbOCYCllC acid, especially p-toluene sulfonic acid, or similar reagents having Lewis acid properties, such as, for example, cation exchange resins in acid form, e.g. sulfonic acid resins, or any other suitable Lewis acid may serve as a condensing reagent.
In the presence of the strong Lewis acid the deserpidate compound may first form a salt with such acid and react in the form of an acid addition salt. Therefore, a salt of the deserpidate compound with an acid may also be used as the starting material.
The reaction may be carried out in the absence of a solvent, whereby an excess of a liquid cyclo-oxa-alk-Zene may also serve as the solvent, or in the presence of an inert solvent. Such solvents are, for example, carbocyclic aryl hydrocarbons, such as monocyclic carbocyclic aryl hydrocarbons, e.g. benzene, toluene and the like, ethers, e.g. diethylether, tetrahydrofuran, p-dioxane and the like, lower alkanones, e.g. acetone, ethyl methyl 'ketone and the like, formamides, e.g. formamide, N,N-dimethylformamide and the like, acetonitrile or any other suitable solvent.
The reaction may be carried out by mixing the reagents or solutions thereof, whereupon the temperature may raise, and the mixture may then be allowed to stand or may be agitated under cooling, at room temperature or at an elevated temperature. The desired product may be isolated according to standard procedures, e.g. extraction, adsorption and elution, crystallization, and the like, preferably after having neutralized the acidic reaction mixture with an alkaline reagent, for example, ammonia, e.g. aqueous ammonia, ammonia in a lower alkanol such as methanol, ethanol and the like, aqueous alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate and the like, aqueous alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, or any other suitable alkaline reagent.
The reaction may also be carried out in the atmosphere of an inert gas, e.g. nitrogen and/or, if necessary, with the exclusion of moisture by adding a dehydrating reagent, or under pressure in a closed vessel.
The compounds of the present invention may also be prepared by converting in compounds of the formula:
I! on used for the preparation of analogous compounds. For
example, the l8-O-R deserpidic acid compounds, in which R has the previously given meaning, may be treated with a diazo compound of the formula R N in which R has the previously given meaning, particularly a lower diazoalkane, e.g. diazomethane, diazoethane, l-diazopropane, l-diazo-n-butane, l-diazo-isobutane, l-diazo-n-pentane, 1- diazo-isopentane, 1-diazo-n-hexane and the like, a lower alkoxy-lower diazoalkane, particularly a lower alkoxylower diazoalkane, in which lower alkoxy is separated from the diazo group by from two to three carbon atoms, and lower alkane contains from two to three carbon atoms, e.g. Z-methoxy-diazoethane, Z-ethoxy-diazoethane, 2-npropyloxy-diazoethane, 3-methoxy-1-diazopropane, 3-ethoxy-l-diazopropane and the like, or a tertiary amino-lower diazoalkane, particularly an N,N-di-l0wer alkyl-.amino lower diazoalkane, in which the N,N-di-low=er alkyl-amino group is separated from the diazo group by from two to three carbon atoms, and lower alkane contains from two to three carbon atoms, e.g. 2-N,N-dimethylamino diazoethane, 2-N,N-diethylamino-diazoethane, 3-N,N-dimethylaminol-diazopropane and the like. The reaction of the l8-O-R -deserpidic acid compounds with such diazo-reagents is carried out, for example, in the presence of a diluent, such as in a lower alkanol, e.g. methanol, ethanol, n-propanol, isopropanol and the like, a halogenated lower alkane, e.g. chloroform, methylene chloride and the like, or any other suitable solvent; preferably, the diazo-reagent is used in solution, for example, in an ether solution. Cooling of the reaction mixture and/or the presence of an atmosphere consisting of an inert gas, e.g. nitrogen, may be required.
The starting materials used in the above process for the preparation of the compounds of this invention are new and are intended to be included Within the scope of the invention. They may be depicted by the formula:
in which the radicals R R R R and R have thepreviously given meaning, salts and N-oxides of such com pounds. Particularly useful are the compounds of the formula:
in which R represents lower alkyl containing from one to four carbon atoms, R stands for .2-cyclo-oxa-alkylcontaining from five to seven atoms as ring members, lower alkyl-substituted Z-cyclo-oxa-alkyl containing from five to seven atoms as ring members, or halogeno-substituted 2- cyclo-oxa-alkyl containing from five to seven atoms as ring members eachlof the groups R and R stands for hydrogen, lower alkyl containing from one to four carbon atoms, lower alkoxy containing from one to four carbon atoms, lower alkylmercapto containing from one to four carbon atoms or halogeno, and R attached to one of thepositions 5 and 6, stands for hydrogen or lower alkyl containing from one to four carbon atoms, salts or the N-oxides of these compounds, as well as their various isomeric forms.
V This group of compounds may be represented by re serpic acid compounds of the formula:
salts or N-oxides thereof. Specific compounds of this type are, for example, l8-O-(tetrahydro-2-furanyl)-reserpic acid, 18-0-(tetrahydro-Z-pyranyl)-reserpic acid and the like. Another group of these compounds may be represented by the formula:
salts or N-oxides thereof. Specific compounds of this type are, for example, l8-O-(tetrahydro-2-furanyl) deserpidic acid, 18-0-(tetrahydro-Z-pyranyl)-deserpidic acid and the like. Apart from the above-mentioned reserpic acids and deserpidic acids, other deserpidic acid-type compounds of the previously given formula, are, for example,
S-methyl-18-O(tetrahydro-2-furanyl)-deserpidic acid, S-methyl-l8-0-(tetrahydro-2-furanyl)-reserpic acid, 6-methyl-1 8-O- (tetrahydro-Z-furanyl) -deserpidic acid, 6-methyl-l 8-0- (tetrahydro-Z-furanyl) -reserpic acid, 9-methyl18-0-(tetrahydro-Z-furanyl) -deserpidic acid, lO-methoxy-l 8-0- (tetrahydro-Z-furanyl) -deserpidic acid, lO-methoxy-l 8-O-(tetrahydro-2-furanyl) reserpic acid, 1 l-ethoxy-l 8-0- (tetrahydro-Z-furanyl) -deserpidic acid, l2-methoxy-1 8-0- (tetrahydro-2-furanyl) -deserpidic acid, 10-chloro-l 8-0-(tetrahydro-Z-furanyl) -deserpidic acid, 10-bromo-l 8-O(tetrahydro-2-furanyl) -deserpidic acid, 10-bromo-l 8-0- (tetrahydro-Z-furanyl) -reserpic acid, 17 desmethoxy 17 ethoxy 18 O (tetrahydro 2- furanyl) -reserpic acid, 5 -methyl-1 8-O-(tetrahydro-2-pyranyl) -deserpidic acid, S-methyl-1S-O-(tetrahydro-Z-pyranyl) -reserpic acid, 6-methyl-18-O-(tetrahydro2-pyranyl) -reserpic acid, 6-methy1-1 8-O-(tetrahydro-2-pyranyl) -deserpidic acid, 9-metl1yl-18-O-(tetrahydro-Z-pyranyl)-deserpidic acid, 1 1-methy1-18-O-(tetrahydro-Z-pyranyl)-deserpidic acid, 9-methoxy-18-0-(tetrahydro-Lpyranyl) -deserpidic acid, 10-methoxy-18-O-(tetrahydro-2-pyranyl)deserpidic acid, l0-methoxy-18-O-(tetrahydro-2-pyranyl)-reserpic acid, 1 l-ethoxy-1S-O-(tetrahydro-Z-pyranyl) -deserpidic acid, 11 n propyloxy 18 O (tetrahydro 2 pyrany1)- deserpidic acid, 12-methoxy-18-0-(tetrahydro-2-pyranyl) -deserpidic acid, 11 methyl mercapto 18 O (tetrahydro 2 pyrany1)-deserpidic acid, 1.1 ethyl mercapto 18 O (tetrahydro 2 pyranyl)- deser pidic acid, 10,11 methylenedioxy 18 O (tetrahydro 2 pyranyl) -deser-pidic acid, 10-chloro-l8-0-(tetrahydro-Z-pyranyl)-deserpidic acid, 10-bromo- 1 8-0- (tetrahydro-Z-pyranyl -deserpidic acid, 10-bromo-18-0-(tetrahydro-Z-pyranyl)-reserpic acid, 17 desrnethoxy 17 ethoxy 18 O (tetrahydro 2- pyranyl)-reserpic acid and the like, as well as salts or N-oxides thereof. As
,- shown hereinabove, these deserpidic acid compounds or salts thereof may be converted into the desired deserpidate compounds by treatment, for example, with lower diazoalkanes, lower alkoxy-lower diazoalkanes, in which lower alkoxy is separated from the diazo group by from two to three carbon atoms, and lower alkane contains from two to three carbon atoms, N,N-di-lower alkylamino-lower diazoalkanes, in which the N,N-di-lower alkyl-amino group is separated from the diazo group by from two to three carbon atoms, and lower alkane contains from two to three carbon atoms.
The deserpidic acid compounds used as the intermediates may be prepared, for example, by treating a deserpidic acid compound of the formula:
in which R R R and R have the previously given meaning, or an N-oxide thereof, with a reactive ester of a 2-hydroxy-cyclo-oxa-alkane, which contains at least five atoms as ring members, in the presence of a condensation reagent, and, if desired, separating a resulting mixture of isomeric compounds into the single isomers, and/or, if desired, converting a resulting salt into a free compound, and/or, if desired, converting a resulting compound into a salt or an N-oxide thereof.
This reaction may be carried out as shown hereinabove. 2-halogeno-cyclo-oxa-alkanes, primarily 2-chloro-cyclooxa-alkanes, which contain from five to seven atoms as ring members, e.g. Z-chloro-tetrahydrofuran (2-chlorocyclo-oxapentane), 2-chloro-tetrahydropyran (2-chlorocyclo-oxahexane) and the like are used as the preferred reagents, and N,N-dimethylformamide is a very suitable condensing reagent, which may simultaneously serve as a solvent.
The starting materials may also be prepared by treating a deserpidic acid compound of the formula:
in which R R R R and R have the above-given meaning, a salt or an N-oxide thereof, with a cycle-oxaalk-2ene containing at least five atoms as ring members, in the presence of an acid condensing reagent, and, if desired, carrying out the optional steps.
The above reaction is carried out according to the previously shown procedure; a cyclo-oXa-alk-2-ene containing from five to six atoms as ring members, such as the previously described 2,3-dihydrofurans (cyclo-oxapent-Z- enes), 2,3-dihydropyrans (cyclo-oxa-hex-Z-enes) and the like, are used as the preferred reagents, and an acid condensing reagent, such as a mineral acid, p-toluene sulfonic acid and the like, is used to promote the reaction.
The deserpidic acids used as starting materials may also be prepared, for example, by replacing in deserpidate l 3 compounds or N-oxides thereof, these compounds having the formula:
in which R R R R and R have the previously given meaning, and R represents lower alkyl, lower alkoxylower alkyl, tertiary amino-lower alkyl or the group of the formula Ph(Z) CH-, in which Ph represents monocyclic carbocyclic aryl and Z stands for hydrogen or lower alkyl, the esterified carboxyl group in 16-p0sition by a free carboxyl group, and, if desired, carrying out the optional steps.
Lower alkyl, lower alkoxy-lower alkyl and tertiary amino-lower alkyl, representing R are identical with the radicals standing for the previously defined R The monocyclic carbocyclic .aryl radical Pb in the formula Ph(Z)CH stands primarily for phenyl; it may also be represented by substituted phenyl, whereby substituents may be lower alkyl, e.g. methyl and the like, lower alkoxy, e.g. methoxy and thelike, or halogen, e.g. chlorine, bromine aud the like, or any other substituents, which do not hinder the departure of the monocyclic carbocyclic arylmethyl radical. Although Z may represent lower alkyl, e.g. methyl, ethyl, n-propyl and the like, it stands primarily for hydrogen.
The radical R in the above-depicted formula for the intermediate may be replaced by hydrogen by way of hydrolytic cleavage. This reaction may be carried out according to known methods, for example, by treatment with an alkaline reagent, such as, for example, with a solution of an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, in an appropriate solvent such as a lower alkanol, e.g. methanol, ethanol and the like, water, an aqueous lower alkanol and the like.
The group Ph(Z)CH-, in which the Ph and Z have the previously given meaning, may also be removed by hydrogenolysis, i.e. by reacting the intermediate, preferably a solution thereof, for example, in a lower alkanol, e.g. methanol, ethanol and the like, with hydrogen in the presence of a catalyst. Such catalyst contains a metal of the eighth group of the periodic system, for example, palladium and the like, and may be represented by palladium black or any other suitable catalyst. If necessary, increased pressure and/or elevated temperature may be employed, although normally the reaction proceeds under atmospheric pressure and at room temperature. In order to secure a complete hydrogenolysis, the reaction vessel is agitated to expose the catalyst to the hydrogen.
The intermediates, which are used in the above reaction and in which R represents lower alkyl, lower alkoxylower alkyl or tertiary amino-lower alkyl, are identical with the previously described products, in which R is replaced by the radical R those compounds may be used as intermediates in the preparation of final products, in which R, and R have different meanings.
Other intermediates useful in the above preparation of starting materials are the compounds of the formula:
in which R R R R R Ph and Z have the previously given meaning, and salts thereof; they are new and are intended to be included within the scope of this invention. Particularly useful as intermediates in the above'reaction are the compounds of the formula:
in which R represents lower alkyl containing from one to four carbon atoms, R stands for 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, lower alkyl-substituted 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, or halogeno-substituted 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, each of the groups R, and R stands for hydrogen, lower alkyl containing from one to four carbon atoms, lower alkoxy containing from one to four carbon atoms, lower alkyl-mercapto containing from one to four carbon atoms or halogeno, R stands for hydrogen or lower alkyl containing from one to four carbon atoms, or the N-oxides of these compounds, as well as their various isomeric forms. This group of compounds may be represented by benzyl 18O-(2-cyclo-oxa-alkyl)-reserpates or benzyl l8-O-(2-cyclo-oXa-alkyl)-deserpiclates, in which compounds 2-cyclo-oxa-a1kyl contains from five to seven atoms as ring members, e.g. benzyl IS-O-(tetrahydro-Z- furanyl) -reserpate, benzyl l8-O-( tetrahydro-Z-furanyl deserpidate, benzyl 18-0- (tetrahydro-Z-pyranyl)-reserpate, benzyl 18-0-(tetrahydro-Z-pyranyl)-deserpidate and the like.
These compounds may be prepared, for example, by alcoholyzing a lactone of the formula:
in which R R R and R have the previously given meaning, salts or N-oxides thereof, with analcohol of the formula Ph-(Z) CHOH, in which Ph and Z have the previously given meaning, preferably in the presence of an alcoholysis catalyst, such as an alkali metal, e.g. sodium and the like, compound of such alcohol, and reacting a resulting compound of the formula:
'With a cyclo-oxa-alk-Z-enc, which contains at least five atoms as ring members, in the presence of an acid condensing reagent, and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting a resulting compound into a salt or an N-oxide thereof.
The alcoholysis of the (16 l8)-lactone of a deserpidic acid compound may be carried out according to known methods. For example, a small amount of an alkali metal, e.g. sodium, potassium and the like, is dissolved in an alcohol of the formula Ph(Z)CHOH, in which Ph and Z have the previously indicated meaning, or a solution thereof in an inert solvent; the resulting reagent is then reacted with the lactone or a solution thereof. The reaction may proceed under cooling or at room temperature, but may be more readily completed by heating, if necessary, in the atmosphere of an inert gas, e.g. nitrogen.
Treatment of the resulting deserpidic acid ester compound with a reactive ester of a Z-hydroxy-cyclo-oxaalkane, which contains from five to seven atoms as ring members, particularly a corresponding 2-halogeno-cyclooxa alkane, e.g. Z-chloro-tetrahydrofuran (2-chloro-cyclooxapentane), 2-chloro-tetrahydropyran (2-chloro-cyclooxahexane) and the like, in the presence of a condensing reagent, especially N,N-dimethylforma-mide, or with a cyclo-oxa-alk-2-ene, which contains from five to six atom-s as ring members, e.g. 2,3-dihydrofuran (cyclo-oxapent-Z- ene), 2,3-dihydropyr'an (cyclo-oxahex-Z-ene) and the like, in the presence of an acid condensing reagent, e.g. hydrogen chloride, p-toluene sulfonic acid and the like, is carried out according to previously described methods.
The compounds of the present invention may also be prepared by transesterifying in deserpidate compounds of the formula:
.fication agent, and, if desired, carrying out the optional steps.
The transesterification reaction may be carried out, for example, by treating the starting material with an alcohol of the formula R OH, in which R has the above-given meaning, and stands primarily for lower alkyl, particularly lower alkyl containing from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, n-butyl, isobutyl and the like; alcohols of the formula R --OI-I are, therefore, primarily lower alkanols such as methanol, ethanol, n-propanol, nbutanol, isobutanol and the like. Other alcohols of the formula R -OH are those, in which R represents lower alkoxy-lower alkyl or tertiary amino-lower alkyl, whereby the lower alkoxy and tertiary amino groups are separated from the hydroxyl group by from two to seven, primarily by from two to three, carbon atoms; such alcohols are, for example, Z-methoxyethanol, 2-ethoxyethanol, 3- methoxypropanol, 2-N,N-dimethylaminoethanol, 2-N,N- diethylaminoethanol and the like.
The reaction is carried out in the presence of a transesterification catalyst, particularly a basic transesterification catalyst. Such catalysts are, for example, alkoxide ions, as, for example, furnished by alkali metal lower alkanolates, e.g. lithium, sodium or potassium methanolate, ethanolate, n-propanol-ate, n-butanolate or isobutanolate and the like, alkaline earth metal lower alkanolates, e.g. barium or strontium methanolate, ethanolate, n-propanolate, n-butanolate or isobutanolate and the like, or aluminum lower alkanolates, e.g. aluminum methanolate, ethanolate, n-propanolate, isopropanolate,
n-butanolate or isobutanolate and the like. The individual alkanolate compounds are employed together with the corresponding lower alkanol used as the transesterification reagent. Other alcohols of the formula R OH, in which R represents, for example, lower alkoxy-lower alkyl or tertiary amino-lower alkyl, may be used in the presence of the corresponding alkali metal, alkaline earth metal or aluminum alcoholates. Other basic transesterification catalysts are, for example, alkali metal cyanides,
e.g. potassium cyanide and the like, or strong quaternary ammonium hydroxides, e.g. benzyl-trimethyl-ammonium hydroxide and the like.
Apart from the alcohols of the formula R OH, which may simultaneously serve as diluents, other inert solvents may be used in the above-mentioned reactions; carbocyclic aryl hydrocarbons, e.g. benzene, toluene and the like, are examples of such inert solvents. If necessary, the reaction may be carried out at an elevated temperature, under increased pressure and/or in the atmosphere of an inert gas, e.g. nitrogen.
This method is, therefore, suitable for preparing from compounds of this invention other compounds which are embraced by the generic formula given for the compounds of this invention, and which may not be readily accessible by the other procedures.
The compounds of the present invention may also be obtained by isomerizing in a compound of the formula:
in which R R R R R and R have the above-given meaning, a salt or an N-oxide thereof, the hydrogen atom attached to the 3-position in the presence of an acid 17 reagent and isolating the desired compound of the formula:
in which R R R R R and R have the previously given meaning, a salt or an N-oxide thereof, and, if de sired. carrying out the optional steps.
Acid reagents used in the above isomerization procedure are more especially lower aliphatic carboxylic acids, such as lower alkanoic acids, e.g. acetic acid, propionic acid and the like, primarily glacial acetic acid, monocyclic carbocyclic aryl sulfonic acids, e.g. p-toluene sulfonic acid and the like or any other suitable acidic reagent or mixtures of acids. Thus, aromatic sulfonic acids are advantageously used together with one of the lower aliphatic carboxylic acids mentioned above; a suitable mixture is, for example, p-toluene sulfonic acid in glacial acetic acid. The reaction may be carried out in the absence or presence of an additional solvent; for example, p-toluene sulfonic acid may be used in the presence of an organic base, e.g. pyridine, collidine and the like, as well as in the presence of another acid, e.g. glacial acetic acid and the like. Isomerization may be effected at room temperature or, if necessary, at an elevated temperature, in an open vessel or under pressure, preferably in the atmosphere of an inert gas, e.g. nitrogen.
Optimum yields in such isomerization reactions may be obtained by removing the desired product from the reaction medium, thus displacing the reaction equilibrium in favor of the product. The removal may be accomplished by separating the product, a salt or an N-oxide thereof from the starting material by exploiting their relative solubilities in solvent systems. For example, the product, a salt or an N-oxide thereof, may be separated from the starting material either by adsorption on a suitable material, such as alumina or paper, and subsequent fractional elution, or by fractional crystallization from a solvent. The starting material separated from the desired product may then be recycled into the isomerization process, enhancing the over-all yield of the reaction.
The intermediates used in the above procedure and having the formula:
in which R R R R R and R have the previously given meaning, their salts or N-oXides, are new and are intended to be included within the scope of this invention.
Particularly useful are the intermediates of the formula:
in which R represents lower alkyl containing from one to four carbon atoms, lower alkoXy-lower alkyl, in which lower alkoXy contains from one to four carbon atoms and lower alkyl, containing from two to three carbon atoms, separates lower alkoxy from the carboxy group by from two to three carbon atoms, or N,N-di-lower alkyl-aminolower alkyl, in which lower alkyl of the N,N-di-lower alkyl amino portion contains from one to four carbon atoms and lower alkyl, separating N,N-di-lower alkylamino from the carboxy group by two to three carbon atoms, contains from two to three carbons, R represents lower alkyl containing from one to four carbon atoms, R stands for 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, lower alkyl-substituted 2-cyclo-oXa-alkyl containing from five to seven atoms as ring members, or halogeno-substituted 2-cyclo-oxa-alkyl containing from five to seven atoms as ring members, each of the groups R, and R stands for hydrogen, lower alkyl containing from one to four carbon atoms, lower alkoxy containing from one to four carbon atoms or halogeno, and R attached to one of the positions 5 and 6, stands for hydrogen or lower alkyl containing from one to four carbon atoms, or the N-oxides of these compounds, as well as their various isomeric forms. This group may be represented by lower alkyl l8-O-(2-cyclooXa-alkyl) -3-iso-reserpates, in which cyclo-oXa-alkyl contains from five to seven atoms as ring members, e.g. methyl 18-0-(tetrahydro-Z-furanyl)-3 iso-reserpate, ethyl 18O-(tetrahydro-Z-furanyl) -3-iso-reserpate,. methyl 18-O- (tetrahydro-Z-pyranyl)-3-iso-reserpate, ethyl IS-O-(tetrahydro-Z-pyranyl)-3-iso-reserpate, n-propyl 18-O-(tetrahydro-2-pyrany1)-3-iso-reserpate, isopropyl 18-O-(tetrahydro-Z-pyranyl)-3-iso-reserpate, methyl 18-O-(2-cyclo-oxaheptyl)-3-iso-reserpate and the like, and by lower alkyl 18-O-(2-cyclo-oXa-alkyl)-3-iso-deserpidates, in which cyclo-oXa-alkyl contains from five to seven atoms as ring members, e.g. methyl 1S-O-(tetrahydro-Z-furanyl)-3-isodeserpidate, ethyl 18-O-(tetrahydro-Z-furanyl)-3-iso-deserpidate, methyl l8-O-(tetrahydro-Z-pyranyl)-3-iso-deserpidate, ethyl 18-O-(tetrahydro-2-pyranyl)-3-iso-deserpidate, n-propyl 1S-O-(tetrahydro-Z-pyranyl)-3-iso-deserpidate, isopropyl 18-O-(tetrahydro-Z-pyranyl)-3-iso-deserpidate, methyl 18-O-(Z-cyclo-oxaheptyl)-3-iso-deserpidat and the like, as well as by analogous compounds, particularly lower alkyl 18-O-(2-cyclo-oxa-alkyl)-deserpidate compounds, in which cyclo-oXa-alkyl contains from five to seven atoms as ring members, and in which the 5position and/or the 6-position may be substituted by lower alkyl, e.g. methyl and the like, or in which the 9-position, the l0-position, the ll-position and/or the ll-position may contain lower alkyl, e.g. methyl and the like, lower alkoxy, e.g. methoxy and the like, or halogen, e.g. chlorine, bromine and the like as substituents, and/ or in which the l7-position contains a lower alkoxy substituent other than methoXy, e.g. ethoxy and the like.
19 The above-mentioned starting material may be prepared by reacting compounds of the formula:
in which R R R R R and R have the above-given meaning, a salt or an N-oxide thereof, with a reactive ester of a Z-hydroxy-oxa-alkane, which contains at least five atoms as ring members, in the presence of a condensing reagent, or with a cyclo-oxa-alk-Z-ene, which contains at least five atoms as ring members, in the presence of an acid condensing reagent, and, if desired, converting a resulting salt into a free base, and/ or, if desired, separating a resulting mixture of isomeric compounds into single isomers, and/ or, if desired, converting a resulting compound into a salt or an N-oxide thereof.
The reaction of the 3-iso-deserpidate compounds with the above reagents is carried out as previously shown. Reactive esters of 2-hydroxy-cyclo-oxa-alkanes are primarily 2-halogeno-cyclo-alkanes, especially 2-chloro-cycloalkanes, which contain from five to seven atoms as ring members, e.g. 2-chloro-tetrahydrofuran (2-chlorocyclo-oxapentane), 2-chloro-tetrahydropyran (Z-chlorocyclo-oxapentane) and the like; these reagents are used in the presence of a condensing reagent, particularly N,N- dimethylformamide and the like. Cyclo-oxa-alk-Z-enes, particularly those which contain from five to six atoms as ring members, e.g. 2,3-dihydrofuran (cyclo-oxapent- Z-ene), 2,3-dihydropyran (cyclo-oxahex-Z-ene) and the like, are used in the presence of a Lewis acid, particularly of hydrogen halide, e.g. hydrogen chloride and the like, p-toluene sulfonic acid, fluoboric acid and the like.
The intermediates used in the preparation of the starting materials are known, or, if new, may be prepared according to procedures used for analogous compounds.
Also included within the scope of the invention are compounds of the formula:
in which R R R D and R have the previously given meaning, and R stands for cyclo-dioxa-alkyl or cyclooxathia-alkyl, which radicals contain at least five atoms as ring members, and which are attached to the oxygen atoms of the l8-position through one of the carbon atoms adjacent to a ring oxygen atom, salts or N-oxides thereof, as Well as the various isomeric forms of these compounds, and process for the preparation of these compounds.
The radicals R contain primarily from five to seven atoms as ring members and, as mentioned hereinbefore, are attached to the oxygen atom of the 18-position through one of the carbon atoms adjacent to a ring oxygen atom. The radicals are unsubstituted or may contain as additional substituents lower aliphatic hydrocarbons, particularly lower alkyl, e.g. methyl, ethyl and the like, or functional groups, particularly halogen atoms, e.g. chlorine, bromine and the like, or other suitable groups. Specific radicals representing R are, for example, 1,3-
dioxalanyl (cycle-1,3-dioxapentyl) radicals, e.g. 2-(1,3- dioxalanyl) (or 2-cyclo-1,3-dioxapentyl), 4-('1,3-dioxalanyl) (or 4-cyclo-1,3-dioxapentyl), 2-methyl-4-(l,3- dioxalanyl) (or 2-methy1-4-cyclo-1,3-dioxapentyl) and the like, 1,3-dioxany1 (or cyclo-1,3-d.ioxahexyl) radicals, e.g. 2-(1,3-dioxanyl) (or 2-cyclo-1,3-dioxahexyl), 4- (1,3-dioxanyl) (or 4-cyclo-l,3-dioxahexyl), 2-methyl-4- (1,3-dioxanyl) (or 2-methyl-4-cyclo-1,3-dioxahexyl), 5- chloro-4-(1,3-dioxanyl) (or 5-chlor0-4-cyclo-1,3-dioxahexyl) and the like, 1,4-dioxanyl (or cyc1o-1,4-dioxahexyl) radicals, e.g. 2-(1,4-dioxanyl) (or 2-cyclo-1,4-dioxahexyl), 5-methyl-2-(1,4-dioxanyl) (or S-methyl-Z-cyclo-1,4-dioxahexyl), 6-methyl-2-(1,4dioxanyl) (or 6-methyl-2-cyclo- 1,4-dioxahexyl) and the like, cyclo-1,4-dioxaheptyl radicals, e.g. 2-cyclo-l,4-dioxaheptyl and the like, 1,3-oxathialanyl (or cyclo-1,3-oxathiapentyl) radicals, e.g. 2- (1,3-oxathialanyl) (or 2-cyclo-1,3-oxathiapentyl), 5-(1,3.- oxathianyl) (or S-cyclo-1,3-oxathiapentyl) and the like, 1,3-oxathianyl (or 2-cyclo-1,3-oxathiahexyl) radicals, e.g. 2-(1,3-oxathianyl) (or 2-cyclo-l,3-oxathiahexyl), 6- (1,3-oxathianyl) (or 6-cyclo-1,3-oxathiahexyl), Z-methyl- 6-(1,3-oxathianyl) (or 2-methyl-6-cyclo-1,3-oxathiahexyl) and the like, 1,4-oxathianyl (or cyclo-1,4-oxathiahexyl) radicals, e.g. 2-(1,4-oxathianyl) (or 2-cyclo-1,4-oxathiahexyl), 5-methyl-2-(1,4-oxathianyl) (or S-methyl-Z-cyclo- 1,4-oxathiahexyl) and the like.
These compounds, as Well as their salts and N-oxides, show antihypertensive and/or sedative and tranquilizing eifects, and can, therefore, be used to relieve hypertensive conditions and/or states of overactiveness, nervousness and tensions, such as the conditions mentioned hereinabove.
The above compounds may be illustrated by the deserpidate compounds of the formula:
in which R represents lower alkyl containing from one to four carbon atoms, lower alkoxy-lower alkyl, in which lower alkoxy contains from one to four carbon atoms and lower alkyl, containing from two to three carbon atoms, separates lower alkoxy from the carboxyl group by from two to three carbon atoms, or N,N-di-lower alkyl-amino lower alkyl, in which lower alkyl of the N,N-di-lower alkyl-amino portion contains from one to four carbon atoms and lower alkyl, separating N,N-dilower alkyl-amino from the carboxyl group by two to three carbon atoms, contains from two to three carbons, R represents lower alkyl containing from one to four carbon atoms, R stands for 2-(1,4-dioxanyl) (or 2- cyclo-1,4-diox-ahexyl), lower alkyl-substituted 2-( 1,4-dioxanyl) (or lower alkyl-substituted 2-cyclo-1,4-dioxahexyl), halogeno-substituted 2-(1,4-dioxanyl) (or halogeno-substituted 2-cyclo-1,4-dioxahexyl), 2-(1,4-0xathianyl) (or 2-cyclo-l,4-oxathiahexyl), lower alkyl-substituted 2-(1,4-oxathianyl) (or lower alkyl substituted 2-cyclo- 1,4-oxathiahexyl), or halogeno-substituted 2-(1,4-oxathianyl) (or halogeno-substituted 2-cyclo-1,4-oxathiahexyl), each of the groups R, and R stands for hydrogen, lower alkyl containing from one to four carbon atoms, lower alkoxy containing from one to 'four carbon atoms or halogeno, and R attached to one of the positions 5 and 6, stands for hydrogen or lower alkyl containing from one to four carbon atoms, therapeutically acceptable mineral acid addition salts or the N-oxides of these compounds, as Well as their various isomeric forms. I
This group may be illustrated by the reserpate compounds of the formula:
in which R represents lower alkyl containing from one to four carbon atoms, and X stands for oxygen or sulfur, or N-oxides of such compounds. Members of this group are, for example, methyl 1 8O-[2-(l,4-dioxanyl)]-reserpate, ethyl 18-O[2-(l,4-dioxanyl) ]-reserpate, n-propyl 18-O-[2-(1,4-dioxanyl)J-reserpate, isopropyl 18-0-[2-(1, 4-dioxanyl)]-reserpate, n-outyl l8-O-[2-(1,4-oxathianyl)] reserpate, methyl 18-0-[2-(1,4-oXathianyl)]-reserpate, ethyl 18-O-[2-(1,4-oxathianyl)]-reserpate, n-propyl 18-0-[2- (1,4-oxathianyl)]-reserpate, isopropyl 18-O-[2-(l,4-oxathianyl)]-reserpate and the like, as well as N-oxides of such compounds, whereby these compounds may be present in various isomeric forms.
Another outstanding group of compounds are the deserpidate compounds of the formula:
in which R represents lower alkyl containing from one to four carbon atoms, and X stands for oxygen or sulfur, or N-oxides of such compounds. This group may be illustrated, for example, by methyl 18-O-[2-( 1,4-dioxanyl) ]-deserpidate, ethyl 18-G-[2-( 1,4-dioxanyl) ]-deserpidate, n-propyl l8-O-[2-(l,4-dioxanyl)l-deserpidate, isopropyl 18-O-[2-(l,4-dioxanyl)]-deserpidate, n butyl l8- O[2-(l,4-dioxanyl)]-deserpidate, methyl 18-O-[2-(L4- oxathianyl) -deserpidate, ethyl 18-O-[2-(1,4-0xathianyl) desenpidate, n-propyl l8-O-[2-(1,4-oxathianyl)]-deserpidate, isopropyl l8-O-[2-(1,4-oxathianyl)]-deserpidate and the like, as well as N-oxides of such compounds, and the various isomeric forms of these compounds.
Additional compounds, which illustrate the above group, are lower alkoxy-lower alkyl, in which lower alkoxy contains from one to four carbon atoms and lower alkyl, containing from two to three carbon atoms, separates lower alkoxy from the carboxy group by from two to three carbon atoms, e.g. Z-methoxyethyl, Z-ethoxyethyl, 3- methoxypropyl and the like, 18-O-R -reserpate or 18- O-R -deserpidate, in which R represents 2-(1,4-dioxanyl) or 2-(l,4-oxathianyl), N,N-di-lower alkyl-aminolower alkyl, in which lower alkyl of the N,N-di-lower alkyl-amino group contains from one to four carbon atoms, and lower alkyl, separating the amino group from the carboxy group by from two to three carbon atoms, contains from two to three carbon atoms, eg. 2 N,N dimethylaminoethyl, 2 N,N diethylarninoethyl, 3 N,N dimethylaminopropyl and the like, 18-O-R '-reserpate or 18-O-R -deserpidate, in which R represents 2-(1,4-dioxanyl) or 2-(1,4-oxathianyl), or lower alkyl, erg. methyl, ethyl, n-propyl and the like, 5- methyl-l8-O-R '-reserpate, lower alkyl 5-methyl-l8-O- R -deserpidate, lower alkyl 6-methyl-18-O-R -reserpate, lower alkyl 6-n1ethyl-18-O-R '-deserpidate, lower alkyl 9-rnethyl-l8O-R -deserpidate, lower alkyl ll-rnethyll8-O-R '-deserpidate, lower. alkyl 9-methoxy-18-O-R deserpidate, lower alkyl ltl-methoxy-l8-O-R -deserpidate,
in which R R R R and R have the previously given meaning, or an N-oxide thereof, with a reactive ester of a hydroxy-cyclo-dioxa-alkane or a hydroxy-cyclo-oxathia-alkane, which contains at least five atoms as ring members, and in which the hydroxyl group is attached to one of the carbon atoms adjacent to a ring oxygen atom, in the presence of a condensing reagent, or converting in a compound of the formula:
in which R R R R and R have the previously given meaning, a salt or an N-oxide thereof, the free carboxyl group of the formula HO-(O=)C into an esterified carboxyl group of the formula R O(O =)C-, in which R has the previously given meaning, or converting in a compound of the formula:
in which R R R R and R have the previously given meaning, and R represents lower alkyl, lower alkoxy-lower alkyl, tertiary amino-lower alkyl, or a group of the formula Ph(Z)CH, in which Ph and Z have the previously given meaning, or an N-oxide thereof, the radical R into the desired radical R by transesterification with an alcohol of the formula Bi -OH, in which R has the previously given meaning, in the presence of a transesterification reagent, or isomerizing in a compound of the formula:
in which R R R R R and R have the previously given meaning, a salt or an N-oxide thereof, the hydrogen atom attached to the 3-position in the presence of an acid reagent, and isolating the desired compound having the previously given formula, and, if desired, converting a resulting salt into the free compound, and/or, if desired, separating a mixture of isomeric compounds into the single compounds, and/or, if desired, converting a resulting compound into a salt or into an N-oxide thereof.
The reactions in the above procedures are carried out according to the general methods given hereinbefore. For example, a reactive ester of a hydroxy-cyclo-dioxaalkane or a hydroxy-cyclo-oxathia-alkane is an ester with one of the previously mentioned acids, particularly with a hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like; specific reagents are, for example, halogeno- 1,3-dioxalanes (or halogeno-cyclo-1,3-dioxapentanes), in which halogen is attached to one of the carbon atoms adjacent to the ring oxygen atoms, e.g. 2-chloro-1,3- dioxalane (or 2-chloro-cyclo-1,3-dioxapentane), 4-chloro- 1,3-dioxalane (or 4-chloro-cyclo-1,3-dioxapentane) and the like, halogeno-l,3-dioxanes (or halogeno-cyclo-l,3- dioxahexanes), in which halogen is attached to one of the carbon atoms adjacent tothe ring oxygen atoms, e.g. 2-chloro-1,3-dioxane (or Z-chloro-cyclo-1,3-dioxahexane), 4-chloro-1,3-dioxane (or 4-chloro-cyclo-1,3-dioxahexane) and the like, halogeno-l,4-dioxanes (or halogeno-cyclo- 1,4-dioxahexanes), in which halogen is attached to one of the carbon atoms adjacent to the ring oxygen atoms, e.g. 2-chloro-l,4-dioxane (or 2-chloro-cyclo-1,4-dioxahexane), 2-c'nloro-5-rnethyl-1,4-dioxane (or 2-chloro-5- methyl-cyclo-1,4-dioxahexane) and the like, halogeno-1,3- oxathialanes (or halogenowyclo-1,3-oxathiapentanes), in which the halogen atom is attached to a carbon atom adjacent to the ring oxygen atom, e.g. 2-chloro-1,3-oxathialane (or 2-chloro-cyclo-1,3-oxathiapentane), S-chloro- 1,3-oxathialane (or S-chloro-cyclo-1,3-oxathiapentane) and the like, halogeno-1,3-oxathiahexanes (or halogenocyclo-l,3-oxathiahexane), in which the halogen atom is attached to a carbon atom adjacent to the ring oxygen atom, e.g. 2-chloro-1,3-oxathiane (or 2-chloro-cyclo-l,3- oxathiahexane), 6-chloro-l,3-oxathiane (or 6-chloro cyclo-1,3-oxathiahexane) and the like, or halogeno-1,4 oxathianes (or halogeno-cyclo-l,3-oxathiahexanes), in which the halogen atom is attached to a carbon atom adjacent to the ring oxygen atom, e.g. 2-chloro-1,4-oxathiane (or Z-chloro-cyclo-1,4-oxathiahexane), 2-chloro-5- methyl-1,4-oxathiane (or Z-chloro-S-methyl-cyclo-l,4 oxathiahexane) and the like. These reagents are used in the presence of a condensing reagent, particularly N,N- dimethylformamide and the like.
Or, the free carboxyl group in a deserpidic acid corn pound of the previously given structural formula may be converted into the desired esterified carboxyl group by treatment with a diazo compound of the formula R N in which R has the previously given meaning, particularly with a lower diazo-alkane, e.g. diazomethane, diazoethane, l-diazopropane and the like, with a lower alkoxydiazo-lower alkane, e.g. Z-methoxy-diazoethane, 2-ethoxydiazoethane, 3-methoxy-1-diazopropane and the like, or with an N,N-di-lower alkyl-amino-lower diazoalkane, e.g.
24 2-N,N-dirnethylamino-diazoethane and the like. reagents may be used as previously shown.
The starting materials used in this modification of the procedure having the formula:
These F in which R R R R and R have the previously given meaning, salts or N-oxides thereof, are new and are intended to be included within the scope of the invention. Particularly useful are the deserpidic acid compounds of the formula:
in which R represents lower alkyl containing from one to four carbon atoms, R represents 2-cyclo-1,4-dioxahexyl or 2-cyclo-1,4-oxathiahexyl or the corresponding lower alkyl-substituted or halogeno-substituted radicals,
each of the groups R; and R stands for hydrogen, lower alkyl containing from one to four carbon atoms, lower alkoxy containing from one to four carbon atoms, lower alkyl-mercapto containing from one to four carbon atoms or halogeno, and R attached to one of the positions 5 and 6, stands for hydrogen or lower allryl, or N-oxides of such compounds, as well as the various possible isomeric forms thereof. Specific compounds of this group are 18-O-[2-(l,4-dioxanyl)]-reserpic acid, 18-O-[2-(l,4- oxathianyl)]-reserpic acid, l8-O-[2-(1,4-dioxanyl)]-deserpidic acid, 18-O-[2-(l,4-oxathianyl)]-deserpidic acid,
6-methyl-l8-O- [2-( 1,4-dioxanyl) ]-reserpic acid, IQ-methoxy-l8-O-[2-( 1,4-dioxanyl) ]-deserpidic acid, l2-methoxyl 8-O- [2-( 1,4-dioxanyl) -deserpidic acid, l0-chlorol8-O-[2-(L4-dioxan31l) l-deserpidic acid, lO-bromo-18-O- [2-(1,4-dioxanyl)]-deserpidic acid, 17-aesmeth xy ethoxy-l8-O-[2-(l,4-dioxanyl)]-reserpic acid and the like.
These starting materials may be obtained according to the methods previously outlined for the preparation of analogous deserpidic acid compounds.
Transesterification of the esterified carboxyl group of the formula R -O(O=)C, in which R has the previously given meaning, into the desired esterified carboxyl group of the formula R -O(O=)C-, in which R has the previously given meaning, may be carried out as previously shown; for example, the compound previously shown by way of the above-depicted structural formula, when reacted with an alcohol of the formula R OH, in which R has the previously given meaning, in the presence of a trans-esterification catalyst, such as, for example, an alkali metal compound of the alcohol R OH, yields an ester compound, in which the esterified carboxyl group has the formula R -O(O=)C-, in which R has the previously given meaning. Alcohols of the above-given formula are particularly lower alkanols, e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol and the like, lower alkoxy-lower alkanols, e.g. Z-methoxyethanol, 2-ethoxyethanol, 3-methoxypropanol and the like, or N,N-di-lower alkyl-amino-lower alkanols, e.g. 2-N,N-dimethylaminoethanol and the like; transesterification catalysts may be, for example, the alkali metal, e.g. lithium, sodium, potassium and the like, compounds of these alcohols, or other suitable basic catalysts, such as those mentioned hereinbefore, e.g. potassium cyanide, benzyl trimethyl ammonium hydroxide and the like. The reaction is carried out as previously shown.
Starting materials, which are used in the above procedures and have the previously given structural formula, in which R R R R and R have the aforementioned meaning, and R stands for the group of the formula Ph-(Z)CH--, in which Ph and Z have the above-given meaning, are new and are intended to be included within the scope of the invention. Particularly useful are the compounds of the formula:
in which R represents lower alkyl containing from one to four carbon atoms, R stands for 2-(l,4-dioxany1) (or 2-cyclo-1,4-dioxahexyl), lower alkyl-substituted 2-(1, 4-dioxanyl) (or lower alkyl-substituted 2-cyclo-1,4- dioxahexyl), halogeno-substituted 2-(1,4-dioXanyl) (or halogeno-substituted 2-cyclo-l,4-dioxahexyl), 2-(1,4-oxathianyl) (or 2-cyclo-1,4-oxathiahexyl), lower a1kyl-substituted 2-(1,4-oxathianyl) (or lower alkyl-substituted 2- cyclo l, l oxathiahexyl), or halogeno-substituted 2-( 1,4- oxathianyl) (or halogeno-substituted 2 cyclo 1,4 oxathiahexyl), each of the groups R, and R stands for hydrogen, lower alkyl containing from one to four carbon atoms, lower alkoxy containing from one to four carbon atoms or halogeno, and R attached to one of the positions 5 and 6, stands for hydrogen or lower alkyl containing from one to four carbon atoms, acid addition salts or the N-oxides of these compounds, as well as their various isomeric forms.
This group of compounds may be represented by benzyl l8-O-R '-resperate and benzyl l8-O-R -desperpidate, in which R stands for 2-(l,4-dioxanyl) or 2-(1,,4-0X- athianyl), or N-oxides thereof; specific compounds are, for example, benzyl 18-O-[2-(l,4-dioxany1)]-resperate, benzyl 18-O-[2-(1,4 xathianyl)]-resperate, benzyl 18-O- [2-(l,4-dioxanyl)]-desperidate, benzyl 18-O-[2-(1,4-oxathianyl)]-deserpidate and the like.
These compounds may be prepared, for example, by alcoholyzing a lactone of the formula:
in which R R R and R have the previously given meaning, salts or N-oxides thereof, with an alcohol of the formula Ph(Z) CHOH, in which Ph and Z have the previously given meaning, preferably in the presence of an alcoholysis catalyst, such as an alkali metal, e.g.
in which R R R R Ph and Z have the previously given meaning, with the reactive ester of a hydroxy-cyclodioxa-alkane or of a hydroxy-cyclooxathia alkane, which contain at least five atoms as ring members, and in which the hydroxyl group is attached to one of the carbon atoms adjacent to a ring oxygen, in the presence of a condensing reagent, and, if desired, converting a resulting compound into a salt or an N-oxide thereof.
The alcoholysis of the lactone can be performed as previously shown; a deserpidate compound reacts with the reactive ester of a hydroXy-cyclo-dioXa-alkane or a hydroxy-cyclo-oxathia-alkane according to the above-described method, particularly in the presence of N,N-dimethylformamide as a condensing reagent.
Isomerization of 3-iso-deserpidate compounds having the previously shown structural formula may be carried out as previously shown; acids, such as glacial acetic acid, p-toulene sulfonic acid or a mixture of such acids, are suitable isomerization reagents.
The starting materials used in the latter modification, which has the previously given structural formula, are new and are intended to be included within the scope of the invention. Especially valuable starting materials are the compounds of the formula:
in which R represents lower alkyl containing from one to four carbon atoms, lower alkoXy-lower alkyl, in which lower alkoxy contains from one to four carbon atoms and lower alkyl, containing from two to three carbon atoms, separates lower alkoiry from the carboXy group by from two to three carbon atoms, or N,N-di-lower alkyl-amino-lower alkyl, in which lower alkyl of the N, N-di-lower alkyl amino portion contains from one to four carbon atoms and lower alkyl, separating N-N-dilower alkyl-amino from the carboxy group by two to three carbon atoms, contains from two to three carbons, R represents lower alkyl containing from. one to four carbon atoms, R stands for 2-(1,4-dioxanyl) (or 2- cyclo-l,4-dioxahexyl), lower alkyl-substituted 2-(1,4- dioxanyl) (or lower alkyl substituted 2. cyclo 1,4 di oxahexyl), halogeno-substituted 2-(1,4-dioxanyl) (or halogeno-substituted 2-cyclo-l,4-dioxahexyl), 2-(1,4-oxathianyl) (or 2-cyclo-1,4-oxathiahexyl), lower alkyl-substituted 2-(l,4-oxathianyl) (or lower alkyl-substituted 2- cyclo-1,4-oxathiahexyl), or halogeno-su-bstituted 2-(1,4 oxathianyl) (or halogeno-substituted 2.-cyclo-l,4-oX- athiahexyl), each of the groups R; and R stands for hydrogen, lower alkyl containing from one to four carbon atoms, lower al'koxy containing from one to four carbon atoms or halogeno, and R attached to one of the positions 5 and 6, stands for hydrogen or lower alkyl containing from one to four carbon atoms, acid addition 27 salts or the N-ox-ides of these compounds, as well as their various isomeric forms.
This group of compounds may be represented by lower alkyl 18-O-R -3-iso-reserpate or lower alkyl 18-O-R '-iso deserpidate, in which R stands for 2-(1,4-dioxanyl) or 2-(1,4-oxathianyl)', or N-oxides thereof. Specific compounds are, for example, methyl 18-O-[2(1,4-dioxanyl) 3-iso-reserpate, ethyl l8-O-[2-(1,4-dioxanyl)]-3-iso-reserpate, n-propyl 18-O-[2-(1,4-dioxanyl)]-3-iso-reserpate, methyl 18-0-[2-(1,4-oxathianyl)]-3-iso-reserpate, methyl 18-O'-[2-(1,4-dioxanyl)]-3-iso-deserpidate, methyl l8- O-[2-(1,4-oxathianyl)]-3-iso-deserpidate and the like.
These compounds may be prepared, for example, by reacting a compound of the formula:
in which R R R R and R have the above-given meaning, or an N-oxide thereof, with the reactive ester of a hydroxy-cyclo-dioxa-alkane or of a hydroxy-cyclooxathia-alkane, which contain at least five atoms as ring members, and in which the hydroxyl group is attached to one of the carbon atoms adjacent to a ring oxygen atom, in the presence of a condensing reagent, and, if desired, converting a resulting compound into a salt or an N-oxide thereof.
The reaction of the deserpidate compound with the ester of a hydroxy-cyclo-dioxa-alkane or a hydroxy-cyclooxathia-alkane can be carried out according to the previously described method, particularly in the presence of N,N-dimethylformamide as a condensing reagent.
The compounds prepared according to the process of this invention may be obtained in the form of the free bases or the salts thereof. A salt may be converted into the free base by reacting the former with an alkaline reagent, such as, for example, aqueous silver oxide, aqueous ammonia, or any other suitable alkaline reagent. A free base may be converted into its therapeutically useful acid addition salts by reaction with one of the acids mentioned hereinbefore; such reaction may be carried out, for example, by treating a solution of the base in a solvent, such as a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol and the like, with the appropriate acid or a solution thereof, and isolating the formed salt.
N-oxides of the compounds of the present invention may be formed according to known methods; for example, .the resulting deserpidate compound, preferably a solution thereof in an inert solvent, may be reacted with an N-oxidizing reagent, such as, for example, hydrogen peroxide, ozone, persulfuric acid, or more especially, organic peracids, such as organic percarboxylic acids, e.g. peracetic, perbenzoic, monoperphthalic acid and the like, or per-sulfonic acids, e.g. p-toluene persulfonic acid and the like. Inert solvents are, for example, monocyclic carboxylic aryl hydrocarbons, e.g. benzene, toluene and the like, halogenated lower alkanes, e.g. chloroform, ethylene chloride and the like, lower alkanols, e.g. methanol, ethanol and the like, or any other suitable solvent. In the N-oxidation reaction an excess of the oxidation reagent and/ or an increase in temperature should be avoided in order to prevent oxidative degradation.
Depending on the form of starting materials used in the formation of the compounds of the present invention, the latter may be obtained in the form of different isomers. Thus, racemic or optically active deserpidic acid derivatives may be used as starting materials whereby the latter is preferably used in the optically active form, particularly when derived from natural sources. Resulting racemates may be resolved into the optically active forms, the laevo-rotatory l-form and the dextro-rotatory d-form. Resolution procedures may be carried out according to known methods suitable for the separation of racemates. For example, to a solution of the free base of a racemate (a d, l-compound) in a solvent, such as a lower alkanol, e.g. methanol, ethanol, isopropanol and the like, a lower alkanone, e.g. acetone, ethyl methyl ketone and the like, or any other suitable solvent, or a mixture of solvents, is added one of the optically active forms of an acid containing an asymmetric carbon atom, or a solution thereof, for example, in the same lower alkanol, lower alkanone, other solvent, or solvent mixture mentioned hereinabove. Salts, which are formed by the optically active forms of the base With the optically active form of the acid may then be isolated, primarily on the basis of their different solubilities. Useful as optically active forms of saltforming acids having an asymmetric carbon atom, are, for example, the d-tartaric acid (L-tartaric acid) and the l-tartaric acid (D-tartaric acid), as well as the optically active forms of dibenzoyl tartaric, di-p-toluyl-tartaric, malic, mandelic, IO-camphor sulfonic acid, quinic acid and the like. T he free and optically active base may be obtained from a resulting sal-t according to methods known for the conversion of a salt into a base as, for example, is outlined hereinbefore. An optically active base may be converted into a therapeutically useful acid addition salt with one of the acids mentioned hereinbefore, or may be converted into an N-oxide described hereinbefore. The optically active forms may also be isolated by biochemical methods.
Or, by reacting a deserpidate compound with a cycloalk-Z-ene as mentioned hereinbefore, two isomeric compounds may be formed, which may be separated on the basis of differences of physico-chemical properties, e.g. solubility, adsorbability and the like.
The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out. It also includes any new intermediates, which may be formed in one of the procedures outline hereinbefore.
In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.
The present application is a continuation-in-part application of my applications Serial No. 837,351, filed September l, 1959, and Serial No, 837,352, filed September 1, 1959, each of which in turn is a continuation-in-part application of my application Serial No. 818,511, filed June 8, 1959, which in turn is a continuation-in-part of my application Serial No. 803,360, filed April 1, 1959, which in turn is a continuation-impart of my application Serial No. 793,959, filed February 18, 1959, all now abandoned.
The following examples illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.
Example 1 1 g. of methyl reserpate is suspended in 25 ml. of 2,3- dihydropyran and 7 drops of concentrated aqueous hydrochloric acid (37 percent) is added, while agitating. The flask is closed with a glass stopper, shaken and then allowed to stand for three days at room temperature. 10 ml. of aqueous ammonia (28 percent) is added while stirring, and an excess of benzene is then given to the reaction rnixture to form two layers. The organic layer is separated, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in acetone, the solvent is evaporated and the residue is again taken up in acetone, whereupon crystals are formed which are filtered off. The mother liquor is diluted with ether and a second crop of crystals are obtained which are 29 combined with the first crystallization product. The methyl 18-0-(tetrahydro-Z-pyranyl)-reserpate melts at 262-265" (decomposition); yield: 0.29 g.
Example 2 To a mixture of 1 g. of methyl reserpate and 15 ml. of 2,3-dihydropyran is added 35 ml. of benzene, which has been saturated at room temperature with gaseous hydrogen chloride. The reaction vessel is then closed, thoroughly shaken and allowed to stand for two hours at room temperature to form a complete solution. 20 ml. of 10 percent aqueous sodium hydroxide is added while shaking, the benzene layer is separated, washed once with water and dried over sodium sulfate. The solvent is evaporated under reduced pressure and ether is added to the residue. The crystalline material is filtered oil and washed with ether to yield the methyl 18-O-(tetrahydro- 2-pyranyl)-reserpate, M.P. 265-267"; yield: 0.55 g.
The resulting product is identical in every respect with the compound obtained according to the procedure of Example 1.
Example 3 To 5 g. of n-propyl reserpate in 100 ml. of 2,3-dihydropyran is added 100 ml. of benzene, which has been saturated with hydrogen chloride at room temperature; the reaction mixture is placed in a flask and the closed flask is allowed to stand at room temperature for about thirty minutes. 80 ml. of a cold 10 percent aqueous solution of sodium hydroxide, containing a small amount of ammonia, is added while shaking. The benzene layer is separated, washed twice with ice water, containing a small amount of ammonia, dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue is dissolved in petroleum ether and crystallizes after cooling. The crystalline material is filtered oli, and dissolved in methylene chloride; the solution is filtered through a column containing magnesia-silica gel, the solvent is evaporated, and the residue is crystallized from a mixture of petroleum ether and ether to yield 3.49 g. of n-propyl 18-0-(tetrahydro-2-pyrauyl)-reserpate, M.P. 190-192.
The starting material may be prepared as follows: The gaseous n-diazopropane is distilled from its ether solution into a suspension of 20 g. of reserpic acid in a 1:1 mixture of chloroform and ethanol. Any excess of n-diazopropane is decomposed with acetic acid, the solvents are evaporated under reduced pressure and the residue is poured into 8 ml. of water containing 20 ml. of concentrated aqueous ammonia. A white crystalline precipitate is obtained, which is washed with water to yield the n-propyl reserpate, M.P. 164-166".
Example 4 To 1 g. of Z-methoxyethyl reserpate in 25 ml. of 2,3- dihydropyran is added 25 ml. of benzene, which has been saturated at room temperature with hydrogen chloride; the mixture is allowed to stand at room temperature for two hours. To the homogeneous solution is then added 20 ml. of 10 percent aqueous sodium hydroxide while shaking. The organic layer is separated, washed twice with water containing a few drops of concentrated aqueous ammonia and then dried over sodium sulfate. A yellow oil is obtained after evaporating the solvent under reduced pressure. It is dissolved in acetone; petroleum ether is added to this solution, the supernatant liquid is decanted from the gummy precipitate, which is allowed to stand overnight in the refrigerator. The gel-like solid is dried on a filter to yield a tan powder, representing 2-methoxyethyl 18 O (tetrahydro-Z-pyranyl)-reserpate, Ml. 7885.
The starting material may be prepared as follows: To a mixture of 226 g. of a 33 percent aqueous solution of 2-methoxyethylamine and 150 ml. of diethyl ether, kept at to in an ice bath, is added dropwise 54 g. of ethyl chloroformate. 100 g. of a cold 40% aqueous solution of sodium hydroxide and a second portion of 54 g. of ethyl chloroformate are given to the mixture, which is stirred for one hour. The ether layer is separated, the aqueous phase is extracted with ml. of diethyl ether, and the two ether solutions are combined and dried over potassium carbonate. The solvent is evaporated under reduced pressure and the ethyl N(2-methoxyethyl)-car bamate is distilled at 106/ 17-20 mm.
To a solution of 33 g. of ethyl N-(2-methoxyethyl)- carbamate in 200 ml. of diethyl ether are added 25 g. of cracked ice and a solution of 81 g. of sodium. nitrite in ml. of water. While keeping the temperature below 15 g. of 35% aqueous nitric acid is added carefully over a period of one hour. The ether layer is separated, washed with water and aqueous potassium carbonate and then dried over potassium carbonate. The residue, obtained after evaporation of the solvent under reduced pressure, represents the ethyl N-(2-methoxyethyl)-N-nitroso-carbamate, which is used without further purification.
A gently refluxing solution of 5 g. of potassium hydroxide in 15 g. of methanol and 150 ml. of diethyl ether is treated with a solution of 15.5 g. of ethyl N-(2-methoxyethyl)-N-nitroso-carbamate in 50 ml. of diethylether, which is added dropwise over a period of one hour. After refluxing for 5 minutes, 100 ml. of water is added and the yellow ether solution, containing the 2-methoxydiazoethane, is separated.
The above ether solution of Z-methoxy-diazoethane is reacted with small portions of a slurry of reserpic acid in methanol until no further reaction can be observed. A few drops of acetic acid are added, the solution is evaporated under reduced pressure and the residual oil is dissolved in ethyl acetate. Upon addition of petroleum ether a precipitate is formed, which is filtered off, dissolved in methylene chloride, which solution is washed with aqueous ammonia and filtered through a small column containing a diatomaceous earth. The residue, obtained after evaporation of the solvent, is crystallized from ethyl acetate to yield the 2-methoxyethyl reser-pate, M.P. 183-185".
Other deserpidates which may be prepared according to the previously given procedure by replacing the starting material by other intermediates are, for example, 2-ethoxyethyl 18-O-(tetrahydro-2-pyranyl)-reserpate, 2-n-propyloxyethyl 18-O-(tetrahydro-2-pyranyl)-reserpate, 2-isopropyloxyethyl 18-O-(tetrahydro-Z-pyranyl)- reserpate, 3-methoxypropyl l8-O-(tetrahydro-2-pyranyD-reserpate, 2-rnethoxyethyl 18-O-(tetrahydro-2-pyranyll-deserpidate, 2-ethoxyethyl 18-O-(tetrahydro-2-pyranyD-deserpidate, Z-methoxyethyl 5 -methyl- 1 S-O-(tetrahydro-Z-pyranyl)- reserpate,
2-methoxyethyl S-methyl-l8-O-(tetrahydro-2pyranyl)- deserpidate,
2-meth0xyethyl 6-methyl-18-O(tetrahydro2-pyranyl)- reserpate,
Z-methoxyethyl 9-methyl'18-O-(tetrahydro-Z-pyranyl)- deserpidate,
2-methoxyethyl 1 l-methyl- 1 S-O-(tetrahydro-Z-pyranyl)- deserpidate,
Z-methoxyethyl 9-methoxy-18-O-(tetrahydro-Z-pyranyD- deserpidate,
Z-methoxyethyl IO-methoxy-l8-O-(tetrahydro-Z-pyranyhdeserpidate,
Z-methoxyethyl 10-methoxy-18O-(tetrahydro-2-pyranyl) reserpate,
Z-methoxyethyl 12-methoxy-18-O-(tetrahydro-2-pyranyl)- deserpidate,
Z-methoxyethyl 11-ethoxy-18-O-(tetrahydro-Z-pyranyl) deserpidate,
Z-methoxyethyl 1 l-n-propyloxy-l 8-O-(tetrahydro-2- pyranyl)-deserpidate,
Z-ethoxyethyl 1l-isopropyloxy-18-O-(tetrahydro-2- pyranyD-deserpidate,
spa-8,591
2-methoxyethyl 1 1-n-buty1oxy-18-O-(tetrahydro-2- pyranyl)-deserpidate,
Z-methoxyethyl 10,1 l-methylenedioxy-18-O-(tetrahydro- 2pyranyl)-deserpidate,
Z-methoxyethyl 1 O-benzyloxy-l 8-O-(tetrahydro-2- pyranyl)-deserpidate,
2-ethoxyethyl 1 l-benzyloxy- 1 8-O-(tetrahydro-2-pyranyl)- deserpidate,
Z-methoxyethyl 1 l-methylmercaptol 8-O-(tetrahydro-2- pyranyl)-deserpidate,
3-methoxypropyl 1 l-ethylmercapto-l8-O-(tetrahydro-2- pyranyl)-deserpidate,
2-methoxyethyl 10-chloro-1 8-O-(tetrahydro-2-pyranyl)- deserpidate,
2-methoxyethyl 10-bromo-l 8-O-(tetrahydro-Z-pyranyl)- deserpidate,
Z-methoxyethyl 17-desmethoxy-17-ethoxy-18-O-(tetrahydro-2-pyranyl)-reserpate,
2-methoxyethyl 17-desmethoxy-17-11-propyloxy-18-O- (tetrahydro-2-pyranyl)-reserpate,
2-methoxyethyl 17-desmethoxy-17-isopropyloxy-18 O- tetrahydro-2-pyranyl)-reserpate and the like.
Example 5 To a solution of 4.3 g. of crude methyl deserpidate and 4.6 ml. of 2,3-dihydropyran in 40 ml. of acetone is grad ually added 2.82 g. of p-toluene sulfonic acid in 12 ml. of acetone while stirring. The solution is agitated for an additional thirty minutes, ethyl acetate is added and the resulting solution is washed twice with 10 percent aqueous sodium hydroxide and then with water. The organic layer is dried over sodium sulfate, the solvent is removed under reduced pressure and the residue is crystallized from a mixture of ethyl acetate and petroleum ether. The resulting methyl 18-O-(tetrahydro-2-pyranyl)-deserpidate is recrystallized from ethyl acetate, M.P. 255-257"; yield: 0.57 g.
Methyl deserpidate may be replaced by other lower alkyl deserpidates in the above example, and compounds, such as ethyl 18-O-(tetrahydro 2 pyranyl) deserpidate, n-propyl 18-O-(tetrahydro-2-pyranyl)-deserpidate, isopropyl-l8-O-(tetrahydro-2-pyranyl)-deserpidate, n-butyl 18-O- (tetrahydro-2-pyranyl)-deserpidate, isobutyl 18O-(tetrahydro-2-pyranyl)-deserpidate and the like, are formed upon treatment with 2,3-dihydropyran according to the above procedure.
Example 6 A mixture of 1.0 g. of Z-dimethylaminoethyl reserpate and 25 ml. of 2,3-dihydropyran, When treated with 25 m1. of benzene, which has been saturated with hydrogen chloride, according to the procedure outlined in Example 2, yields the desired Z-dirnethylaminoethyl 18-O-(tetrahydro- 2-pyranyl)-reserpate.
The starting material used in the above reaction may be prepared as follows: A m xture of 88 g. of a 33% aqueous N,N-dimethylethylenediamine solution and 150 ml. of ether is cooled to 5 and a total of 108.5 of ethyl chloroformate is added in portions. A solution of 40 g. of sodium hydroxide in 60 ml. of water is given to the reaction mixture simultaneously with the second half of the ethyl chloroformate; stirring is continued for an additional hour. The ether layer is separated, the aqueous portion is extracted with ether and the ether extracts are combined and dried over anhydrous potassium carbonate. The ether is evaporated, the residue is distilled, B.P. 118- 122 at 17-20 mm., to yield the ethyl N-(Z-dimethylaminoethyD-carbamate.
A solution of 40 g. of ethyl N-(2-dimethylaminoethyl) carbamate in 125 ml. of methylene chloride is cooled to and 19.5 g. of nitrosyl chloride in 300 ml. of methylene chloride is added over a period of approximately one hour while stirring and keeping the temperature between 0 to Stirring is continued for an additional two hours, the precipitate is filtered ofi and recrystallized from 32 ethyl acetate to yield ethyl N-(Z-dimethylaminoethyD-N- nitroso-carbamate hydrochloride, MP. 133-135".
A suspension of 11.3 g. of ethyl N(2-dimethylaminoethyD-N-nitroso-carbamate hydrochloride in ml. of ether is added to a mixture of 40 g. of a 25 percent methanol solution of potassium hydroxide and 300 ml. of ether while gently refluxing. After fifteen minutes of additional heating the ether layer, containing the 2dimethyl amino-diazoethane, is decanted and immediately used.
To the above described ether solution is added portionwise 12.0 g. of reserpic acid in methylene chloride and methanol. The mixture is allowed to stand overnight at room temperature, the solvents are evaporated under reduced pressure, and the residue is added to 400 ml. of water containing 20 ml. of ammonium hydroxide. The water solution is extracted with methylene chloride, the organic solution is filtered through a column containing a diatomaceous earth and evaporated. The Z-dimethyl-i aniinoethyl reserpate is recrystallized from a mixture of ethyl acetate and petroleum ether, MP. -114.
Other deserpidates may be prepared according to the previously given procedure by replacing the starting material by other deserpidates; such compounds are, for example,
2-N,N-diethylaminoethyl 18-O-(tetrahydro-Z-pyranyD- reserpate,
2-(1-piperidino)-ethyl 18-O-(tetrahydro-2-pyranyD- reserpate,
2-(4-methyl-1-piperazino)-ethyl 1 S-O-(tetrahydro-Z- pyranyl)-reserpate,
3-N,N-dmethylaminopropyl 18-0-(tetrahydro-2-pyranyl)- reserpate,
2-N,N-dimethylaminoethyl 18-O(tetrahydro-2-pyranyl)- deserpidate,
3-N,N-diethylaminopropyl 18-O-(tetrahydro-2-pyranyl)- deserpidate,
2-N,N-dimethylaminoethyl S-methyl- 1 8-O-(tetrahydro-2- pyranyl)-reserpate,
2N,N-dimethylaminoethyl 5-methyl-1 8-O-(tetrahydro-2- pyranyl)-deserpidate,
2-N,N-dimethylaminoethyl 6-methyl-l 8-O-(tetrahydro-2- pyranyl)-reserpate,
2-N,N-dimethylaminoethyl 9-methyl-18-O-(tetrahydro-2- pyranyl)-deserpidate,
2-N,N-dimethylaminoethyl 1 l-methyl-18-O-(tetrahydro- 2-pyranyl)-deserpidate,
2-N,N-dimethylaminoethyl 9-methoxy-1S-O-(tetrahydro- Z-pyranyD-deserpidate,
2-N,N-dimethylaminoethyl 10-methoxy- 1 8-O-(tetrahydro- 2-pyranyD-deserpidate,
2-N,N-dimethylaminoethyl 10-methoxy-l S-O-(tetrahydro- 2-pyranyl)-reserpate,
2-N,N-dimethylaminoethyl 12-methoxy-1 S-O-(tetrahydro- 2-pyranyl)-deserpidate,
2-N,N-dimethylarninoethyl 1 l-ethoxy-18-O-(tetrahydro-2- pyranyl)-deserpidate,
2-N,N-dimethylaminoethyl 1 1-n-propyloxy-18-O-(tetrahydro-Z-pyranyl)-deserpidate,
2-N,N-diethylaminoethyl 1 1-isopropyloxy-18-O(tetrahydro-Z-pyranyD-deserpidate,
2-N,N-dimethylaminoethyl 1 l-n-butyloxy- 1 S-O-(tetrahydro-2-pyranyl)-deserpidate,
2N,Ndimethylaminoethyl 10,1 1-methylenedioXy-18-O- (tetrahydro-Z-pyranyl)-deserpidate,
2-N,N-dimethylaminoethyl 10-benzyloxy-1B-O-(tetrahydro-Z-pyranyD-deserpidate,
2-N,N-dimethylaminoethyl 1 1-benzyloxy-18-O-(tetrahydro-2-pyranyl)-deserpidate,
2-N,N-dirnethylaminoethyl 1 1-methylmercapto-18-O- (tetrahydro-2-pyranyD-deserpidate,
3-N,N-dimethylaminopropyl 1 l-ethylmercapto-18-O- (tetrahydro-2-pyranyl)-deserpidate,
2-N,N-dimethylaminoethyl lO-chloro- 1 8-O-(tetrahydro-2- pyranyl)-deserpidate,
33 2-N,N-dirnethylaminoethyl 10-bromo-18-0-(tetrahydro-2- pyranyD-deserpidate, 2-N,N-dimethylaminoethyl I l desmethoxy-l7-ethoxy-18- O-(tetrahydro-2-pyranyl)-reserpate, 2-N,Ndimethylaminoethyl l7-desmethoxy-l7-n-propyloxy-l8-0-(tetrahydro-Z-pyranyD-reserpate, 2-N,N-dimethylamiuoethyl l7-desmethoxy-l7-isopropyloxyl 8-O-(tetrahydro-Z-pyranyl)-reserpate and the like.
Example 7 To 1 g. of ethyl reserpate in 25 ml. of 2,3-dihydropyran is given 25 ml. of benzene, which has been freshly saturated with hydrogen chloride. The mixture is allowed to stand at room temperature for 45 minutes. After cooling in ice-water 20 ml. of cold 10 percent aqueous sodium hydroxide containing a small amount of ammonia is added to the mixture while shaking. Two layers separate quickly; the organic portion in washed twice with ice-water containing a small amount of ammonia and then dried over sodium sulfate while cooling. The solution is filtered and evaporated under reduced pressure at less than 55. An amber oil is recovered, petroleum ether is added and evaporated again and the resulting residue is dissolved in fresh petroleum ether. After cooling the solution overnight in the refrigerator, 1 g. of solid material is filtered oil, washed with petroleum ether and dissolved in 25 ml. of methylene chloride containing two drops of aqueous ammonia. The solution is filtered through a synthetic magnesia-silica gel preparation, which is washed with an additional amount of methylene chloride, until a total of 100 ml. is collected. The solvent is evaporated under reduced pressure; the resulting foam crystallizes upon adding a small amount of diethyl ether. The ethyl 18-O- (tetrahydro-Z-pyranyl)-reserpate is filtered and washed with diethyl ether, then with petroleum ether, M.P. 210- 218; yield: 0.6 g.
Example 8 A mixture of 1 g. of nbutyl reserpate (M.P. ll6ll8, prepared by treating reserpic acid with an ether solution of n-diazobutane) in 25 ml. of 2,3-dihydropyran, to which is added 25 ml. of benzene, which has been freshly saturated With hydrogen chloride, is allowed to stand for 30 minutes and is then worked up as shown in Example 7. 0.08 g. of n-butyl 18-O-(tetrahydro-2-pyranyl)-reserpate, M.P. 190l92, is obtained.
Example 9 To a solution of 2 g. of n-hexyl reserpate in 15 ml. of acetone and 2 ml. of 2,3-dihydropyran is added dropwise, at room temperature and while stirring a solution of 1.2 g. of p-toluene-sulfonic acid in ml. of acetone. The mixture is allowed to stand at room temperature for thirty minutes, and is then diluted with an excess of ethyl acetate. The organic solution is washed with 10 percent aqueous ammonia to remove all traces of the acid, the ethyl acetate solution is dried, evaporated to dryness, and the oily residue is crystallized from a mixture of ether and petro' leum ether. The crystalline material is filtered 01f and Washed with a small amount of petroleum ether to yield the desired n-hexyl l8-O-(tetrahydro-2-pyranyl)-reserpate, M.P. l67-170. An additional amount can be recovered from the filtrate; total yield: 0.70 g.
The n-hexyl reserpate, M.P. 1l7l18, may be prepared by treating reserpic acid with an ether solution of n-diazohexane. The latter can be obtained by reacting n-hexylamine with ethyl chloroformate, nitrosating the resulting ethyl N-n-hexyl-carbamate with sodium nitrite in the presence of nitric acid, treating the ethyl N-n-hexyl- N-nitroso-carbamate with a 25 percent solution of potassium hydroxide in methanol in the presence of ether and separating the ether solution of n-diazohexane; these reactions are carried out as previously shown.
Example 10 To a suspension of 20.0 g. of methyl reserpate in 150 ml. of acetone containing 20 ml. of 2,3-dihydropyran is added dropwise while vigorously stirring a solution of 12.0 g. of p-toluene-sulfonic acid in 50 ml. of acetone. The temperature is kept below 3550 by external cooling. A clear amber solution forms during the addition of the p-toluene sulfonic acid. The reaction mixture is allowed to stand at room temperature for thirty minutes and is then diluted with 250 ml. of ethyl acetate; the mixture is repeatedly washed with 10 percent aqueous ammonia to completely remove any remaining acid. The ethyl acetate solution is washed with water, dried over anhydrous sodium sulfate and concentrated to the small volume, when crystallization occurs. The crystalline material is filtered oil and washed with ether to yield the desired methyl l8-O-(tetrahydro-Z-pyranyl)-reserpate, M.P. 262- 264. The product is identical in every respect with the compound obtained according to the procedure of Example 1.
Instead of hydrogen chloride or p-toluenesulfonic acid, fluoboric acid may be used as the Lewis acid in the previously described procedures.
Example 1] A mixture of 1.0 g. of methyl S-methyl-reserpate and 2 ml. of 2,3dihydropyran, when reacted according to the procedure of Example 10, i.e. in the presence of 0.6 g. of p-toluene sulfonic acid and 20 ml. of acetone, yields the methyl S-methyll 8-O-(tetrohydro-2-pyranyl)-reserpate.
Example 12 Treatment of an acetone solution of 0.5 g. of methyl 6-methyl-deserpidate with 0.8 ml. of 2,3-dihydropyran in the presence of 0.4 g. of p-toluene sulfonic acid according to the procedure of Example 10, yields the methyl 6- methyl-l 8-O-(tetrahydro-2pyranyl)-deserpidate.
Example 13 Methyl 6-methyl-18-O-(tetrahydro-2-pyranyl)-reserpate can be formed by reacting an acetone solution of 1.0 g. of methyl o-methyl-reserpate with 2 ml. of 2,3-dihydropyran in the presence of 0.5 g. of p-toluene sulfonic acid accord ing to the procedure described in Example 10.
Example 14 0.5 g. of n-propyl 6-methyl-reserpate, when treated with 1 ml. of 2,3-dihydropyran in the presence of 0.3 g. of p-toluene sulfonic acid and acetone according to the procedure of Example 10, yields the desired n-propyl 6- methyl- 1 8-O-(t trohydro-2-pyranyl)-reserpate.
Example 15 A mixture of 1.0 g. of methyl 9-methyl-dcserpidate, 1 ml. of 2,3-dihydropyran and 0.6 g. of p-toluene sulfonic acid in acetone, when treated according to the procedure of Example 10, yields the methyl 9-methyl-l8-O-(tet1'ahydro-Z-pyranyl) -deserpidate.
Other compounds, which may be prepared according to the previously described method by selecting the appropriate starting materials are, for example, ethyl 9- methyl l8-O-(tetrahydroQ-pyranyl)-deserpidate, methyl ll methyl l8-0-(tetrahydro-Z-pyranyl)-dcserpidate, npropyl 1 1-methyl-18-O-(tetrahydro-2-pyranyl) -deserpidate and the like.
Example 16 By reacting 1.0 g. of methyl l0-methoxy-deserpidate with 2 ml. of 2,3-dihydropyran according to the method described in Example 10, i.e. in an acetone solution and in the presence of 0.6 g. of p-toluene sulfonic acid, the methyl IO-methoxy- 1 8-0- (tetrahydro-2-pyranyl) -deserpidate can be prepared.
Analogous compounds, such as, for example, methyl 9-methoxy- 1 8-0- tetrahydro-Z-pyranyl -deserpid-ate, ethyl 10 meth0xy-18-O- (tetrahydro-Z-pyranyl) -deserpidate, npropyl 10 methoxy-18-O-( tetrahydro-Z-pyranyl) -deserpidate, methyl l0 -methoxy-l8-O-(tetrahydro-Z-pyranyl)- reserpate, n-propyl lO-methoxy-l8-O-(tetrahydro-2-pyranyD-reserpate and the like, may be prepared accordingly by using appropriate starting materials.
Example 17 The methyl 12-methoxy-l8-O-(tetrahydro-Z-pyranyl)- deserpidate may be prepared by reacting an acetone solution of 0.5 g. of methyl l2-methoxy-deserpidate with 1 ml. of 2,3-dihydropyran in the presence of 0.3 g. of ptoluene sulfonic acid according to the procedure of Example 10.
Ethyl IZ-methoxy-l 8-O-(tetrahydro-Z-pyranyl) -de:serpidate, n-propyl 12-methoxy-18-O-(tetrahydro-2-pyranyl)- deserpidate and the like may be prepared according to the previously described procedure by treating the appropriate starting materials with 2,3-dihydropyran in the presence of an acidic condensing catalyst, for example, p-toluene sulfonic acid as described in Example 10.
Example 18 A mixture of 1.0 g. of methyl ll-ethoxy-deserpidate, 2 ml. of 2,3-dihydropyran and 0.6 g. of p-toluene sulfonic acid in acetone, when reacted as described in Example 10, yields the desired methyl ll-ethoxy-lS-O-(tetrahydro- Z-pyranyl) -deserpidate.
Other compounds, which may be prepared according to the procedure of the above example by selecting the appropriate starting materials are, for example, ethyl 11- ethoxy-18-0-(tetrahydro-Z-pyranyl) -deserpidate, n-propyl 11 ethoxy 18 O (tetrahydro-2-pyranyl)-deserpidate, methyl 11 n propyloxy 18 O-(tetrahydro-Z-pyranyl)- deserpidate, methyl ll-isopropyloxy-18-0-(tetrahydro-2- pyranyl)-deserpidate, methyl 1ln-butyloxy-lS-O-(tetrahydro-Z-pyranyl)-deserpidate and the like.
Example 19 Methyl 10,11 methylenedi-oxy-l8-O-(tetrahydro-2-pyranyl)-deserpidate may be prepared by reacting 0.5 g. of methyl 10,11methylenedioxy-deserpidate with 0.8 ml. of 2,3-dihydropyran in the presence of 0.3 g. of p-toluene sulfonic acid according to the procedure of Example 10.
The ethyl 10,1l-methylenedioxy-l8-O-(tetrahydro-2- pyranyl)-deserpidate, n-propyl 10,1l-methylenedioxy-l8- O-(tetrahydro-Z-pyranyl)-deserpidate and the like may be prepared by substituting in the previous example ethyl 10,11-methylenedioxy-deserpidate, n-propyl 10,11-methylenedioxy-deserpidate and the like for the methyl 10,11- rnethylenedioxy-deserpidate and reacting the former with 2,3-dihydropyran according to the procedure described in Example 10.
Example 20 Upon treatment of methyl 1.0 g. of -benzyloxydeserpidate with 1.5 ml. of 2,3-dihydropyran in the presence of 0.6 g. of p-toluene sulfonic acid according to the procedure of Example 10, the methyl lO-benzyloxy-lS-O- (tetrahydro-Z-pyranyl)-deserpidate can be obtained.
The ethyl 10-benzyloxy-l8-O-(tetrahydro-2-pyranyl)- deserpidate, methyl 11 benzyloxy 18-O-(tetrahydro-2- pyranyl)-deserpidate and the like may be prepared by reacting the appropriate starting materials with 2,3-dihydropyran according to the procedure of Example 10.
Example 21 0.5 g. of methyl 11-methylmercapto-deserpidate, when treated with 0.9 ml. of 2,3-dihydropyran in the presence of 0.3 g. of p-toluene sulfonic acid according to the procedure of Example 10, yields methyl ll-methylmercapto- 1 8-O-(tetrahydro-2-pyranyl -deserpidate.
Ethyl 11-methylmercapto-deserpidate or methyl l1- ethylmercapto-deserpidate, when reacted with 2,3-dihydropyran according to the procedure of Example 10, yield the ethyl 11 methylmercapto l8-O-(tetrahydro-2-pyranyl)- deserpidate and the methyl 11-ethy1mercapto-l8-O-(tetrahydro-2-pyranyl) -deserpidate, respectively.
Example 22 The reaction of 0.6 g. of methyl 10-chlor0-deserpidate with 1 ml, of 2,3-dihydropyran in the presence of 0.4
36 g. of p-toluene sulfonic acid and in an acetone solution according to the procedure described in Example 10, yields the desired methyl l0-chl-oro18-O-(tetrahydro-2- pyranyl) -deserpidate.
Analogous compounds, which may be prepared according to the procedure of Example 10 by selecting the appropriate starting materials, are, for example, ethyl l0- chloro-18-O-(tetrahydro-Z-pyranyl)-deserpidate, n-propyl 10 chloro 18 O (tetrahydro-Z-pyranyl)-deserpidate, methyl l0-fiuoro-18-O-(tetrahydro-2-pyranyl)-deserpidate, methyl 11 chloro 18-O-(tetrahydro-Z-pyranyl)-deserpidate, methyl 10 bromo 18 O-(tetrahydro-2-pyranyl)- reserpate, methyl lO-bromo-IS-O-(tetrahydro-Z-pyranyl)- deserpidate and the like.
Example 23 Methyl 17-desmethoxy-17-ethoxy-reserpate (0.5 g.), when reacted with 1 ml. of 2,3-dihydropyran in the presence of 0.3 g. of p-toluene sulfonic acid according to the procedure of Example 10, yields the methyl l7-desmethoxy-17-ethoxy-l 8-O-(tetrahydro-Z-pyranyl) -reserpate.
Other compounds which may be prepared according to the procedure of Example 10 by selecting the appropriate starting materials, are, for example, ethyl 17-desmethoxyl7-ethoxy- 1 8-O- tetrahydro-Z-pyranyl -reserpate, methyl 17 desmethoxy l7-n-propyloxy-18-O-(tetrahydro-2-pyranyl)-reserpate, methyl 17-desmethoxy-17-isopropyloxy- 18-0-(tetrahydro-Z-pyranyl)-reserpate, methyl 17-desmethoxy 17 -ethoxy-1 8-O- (tetrahydro-Z-pyranyl) -deserpidate and the like.
Example 24 To 2.0 g. of methyl reserpate and 2 ml. of 2,3-dihydrofuran in 15 ml. of acetone is added slowly a solution of 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone at room temperature while stirring. After the addition is completed, the solution is allowed to stand at room temperature for 25 minutes, ml. of ethyl acetate is added, the solution is washed with 10 percent aqueous ammonia, then with water and dried over sodium sulfate. The solution is concentrated under reduced pressure until crystals appear. The crystalline material is filtered oh? and washed with ether to yield 0.7 g. of methyl 18-0-(tetrahydro-Z-furanyl)-reserpate, M.P. 256- 258 (decomposition).
Other lower alkyl 18-O-(tetrahydro-Z-furanyl)-deserpidate compounds, which may be prepared according to the above-described procedure by selecting the appropriate starting materials are, for example, ethyl 18-O- (tetrahydro-Z-furanyl)-reserpate, n-propyl 18-O-(tetrahydro-Z-furanyl)-reserpate, isopropyl 18-O-(tetrahydro- Z-furanyD-reserpate, n-butyl l8-O-(tetrahydro-2-furanyl)-reserpate, isobutyl 18-O-(tetrahydro-Z-furanyl)-reserpate, methyl l8-O-(tetrahydro-Z-furanyl)-desirpidate, ethyl 18-O-(tetrahydro-Z-furanyl)-desirpidate, methyl 6- methyl-l8-O-(tetrahydro-2-furanyD-reserpate, methyl 9- methyl 18 O (tetrahydro 2 furanyl) desirpid'ate, methyl 10-methoxy-18O-(tetrahydro-Z-furanyl)-deserpidate, methyl 11-ethoxy-l8-O-(tetrahydro-Z-furanyl-deserpidate, methyl 12-methoxy-18-O-(tetrahydro-Z-furanyl -deserpidate, methyl 10-bromol 8-O- (tetrahydro-Z-furanyl)-deserpidate, methyl lO-methylmercapto-lS-O-(tetrahydro-Z-furanyl)-deserpidate, methyl 17-desmethoxy- 17-ethoxy-l8-O-(tetrahydro-2-furanyl)-reserpate and the like.
Example 25 A mixture of 2.0 g. of methyl reserpate and 2 ml. of 4-methyl-2,3-dihydropyran in 15 ml. of acetone is stirred, while a solution of 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone is added slowly. The reaction mixture is allowed to stand at room temperature for 1 /2 hours, 100 ml. of ethyl acetate is added and the diluted mixture is washed with 10 percent aqueous ammonia and then with water. The organic layer is dried over sodium sulfate and concentrated to dryness under reduced pressure; the oily residue crystallizes when stirred with diethyl ether. The solid material is recrystallized from ethanol to yield the desired methyl 18-O-(4-methyl-tetrahydro-2-pyranyl)-reserpate, M.P. 250-252 (with decomposition) Analogous deserpidate compounds, such as, for example, ethyl 18-O-(4-methyl-tetrahydro-Z-pyranyl)-reserpate, n-propyl 18-O-(4-methyl-tetrahydro-2-pyranyl)-reserpate, methyl l8-O-(4-methyl-tetrahydro 2-pyranyl)-deserpidate, methyl 10-methoxy-18-O-(4-methyl-tetrahydro- 2 pyranyl) deserpidate, methyl 12 methoxy 18 O- (4-methyl-tetrahydro-Z-pyranyl)-deserpidate and the like, may be prepared by reacting the appropriate starting materials with 4-methyl-2,3-dihydropyran as shown in the above example.
Example 26 To a solution of 2.0 g. of isopropyl reserpate and 5 ml. of 2,3-dihydropyran in 15 ml. of acetone is added dropwise and at room temperature while stirring a solution of 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone. The solution warms up towards the end of the addition of the acid and darkens in color;.it is stirred for an additional thirty minutes. To the reaction mixture is added an excess of ethyl acetate, the solution is washed with 10 percent aqueous sodium hydroxide and water and then dried over anhydrous sodium sulfate. The solvent is evaporated to yield an oil, which crystallizes upon adding diethyl ether to yield the desired isopropyl 18-0-(tetrahydro-Z-pyranyl)-reserpate, M.P. 250- 253; yield: 0.475 g.
The starting material used in the above reaction may be prepared as follows: A mixture of 10 g. of methyl reserpate, 500 ml. of isopropanol and 20 drops of benzyl trimethyl ammonium hydroxide is refluxed for 2 /2 hours. After standing at room temperature for several hours, a white precipitate (needles) is formed, which is removed by filtration. The filtrate is evaporated to dryness, the foamy residue is taken up in 500 ml. of water containing 5 ml. of concentrated aqueous ammonia. The aqueous mixture is extracted with methylene chloride, the organic solvent is passed through a column containing a diatomaceous earth preparation and is then evaporated to dryness under reduced pressure. The residue is crystallized by the addition of diethyl ether, the crystalline material is filtered otf, dried and identified as isopropyl reserpate, M.P. 214216.
Example 27 A solution of 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone is added dropwise to 2 g. of isobutyl reserpate and 2 ml. of 2,3-dihydropyran in 15 ml. of acetone. The reaction mixture is stirred and kept at room temperature during the addition and is then allowed to stand at the same temperature for an additional thirty minutes. An excess of ethyl acetate is added, the organic portion is washed with 10 percent aqueous ammonia to neutralize the acid and is then dried and evaporated to dryness. The residue is crystallized from a mixture of ether and petroleum ether to yield the desired isobutyl 18-O-(tetrahydro-2-pyranyl)-reserpate, which, after washing with a small amount of petroleum ether, melts at 206-208"; yield: 0.75 g.
The isobutyl reserpate may be prepared as follows: To a stirred solution of 34 g. of ethyl N-isobutyl-carbamate in 120 ml. of methylene chloride, kept at 0, is added dropwise 15 g. of nitrosyl chloride, whereby the temperature is not allowed to raise to more than 5. The mixture is stirred for an additional hour, the solvent is evaporated under reduced pressure and the resulting ethyl N-isobutyl-N-nitroso-carbamate is used in the following step without any further purification.
A mixture of 30 g. of ethyl N-isobutyl-N-nitrosocarbamate and 75 ml. of ether is added dropwise to a refluxing mixture of 50 g. of a percent solution of 33 potassium hydroxide in methanol, and 300 m1. of ether. The mixture is refluxed for an additional thirty minutes, an excess of water is added and the organic phase is separated, washed with water and dried over anhydrous sodium sulfate. The ether solution of the resulting diazoisobutane is used in the next step.
A total of 6 g. of reserpic acid is added in small amounts to the ether solution of diazoisobutane over a period of four hours. The ether is then evaporated under reduced pressure, the residue is added to a solution of 20 ml. of concentrated aqueous ammonia in 600 ml. of water. The aqueous solution is extracted with methylene chloride, the organic layer is separated, passed through a short column containing a synthetic magnesium silicate adsorbent preparation and then evaporated. The residue is distilled under reduced pressure to remove unreacted ethyl Nisobutyl-carbamate (B.P. 93 94/ 15 mm.), and the non-distillable material is recrystallized from ether to yield isobutyl reserpate, M.P. 145-148"; yield: 3.0 g.
Example 28 To a mixture of 2.0 g. of isopentyl reserpate and 2 m1. of 2,3-dihydropyran in 25 ml. of acetone is added gradually 1.2 g. of p-toluene sulfonic acid in 5 ml. of acetone. After standing at room temperature for thirty minutes an excess of ethyl acetate is added; the resulting mixture is then washed twice with 10 percent aqueous sodium hydroxide. The organic layer is dried over sodium sulfate and evaporated under reduced pressure; the oily residue is heated in a distillation apparatus to about under reduced pressure. Ethyl acetate is added to the nondistillable residue, a crystalline material precipitates, which is filtered off and dissolved in methylene chloride. The solution is passed through a column containing a synthetic magnesium silicate adsorbent preparation; the residue obtained after evaporating the solvent from the eluate is crystallized from ethyl acetate to yield isopentyl 18-0-(tetrahydro-Z-pyranyl)-reserpate, M.P. 135; yield: 0.12 g.
The starting material may be prepared as follows: To a solution of 60 g. of ethyl N-isopentyl-carbamate, B.P. 107108/17-20 mm. (prepared by reacting isopenthylamine with ethyl chloroformate in the presence of sodium hydroxide and in a mixture of water and ether) in 150 m1. of ether is added 50 g. of ice and then 163 g. of sodium nitrite in 250 ml. of water. A solution of 1.50 g. of concentrated nitric acid and 150 g. of ice is gradually given to the reaction mixture over a period of 1 /2 hours, keeping the temperature below 15 by adding more ice. The separated ether layer is Washed twice with water and cold aqueous potassium carbonate, and is then dried over potassium carbonate. The solvent is removed on the steam bath, leaving ethyl N-isopentyl-N-nitroso-carbamate, yield: 78 g.
A mixture of 40.0 g. of ethyl N-isopentyl-N-nitrosocarbamate in 75 ml. of ether is added dropwise to 80.0 g. of a 25 percent solution of potassium hydroxide in methanol and 400 ml. of ether while refluxing. Boiling is continued for an additional twenty minutes. An excess of Water is added, the ether layer is separated, washed with water and dried over sodium sulfate.
To the ether solution, containing the diazoisopentane, is added reserpic acid hydrochloride portionwise until no further liberation of gas is observed. The reaction mixture is stirred overnight at room temperature, the ether is removed under reduced pressure, the residue is dissolved in methylene chloride, the organic phase is washed with water containing ammonium hydroxide and then passed through a short column containing a synthetic magnesium silicate adsorbent preparation. The residue, obtained after evaporating the solvent of the eluate, crystallizes from a mixture of ethyl acetate and petroleum ether after an initially precipitating gum has been removed. The crystalline isopentyl reserpate melts at 138; yield: 4.13 g.
39 Example 29 1.0 g. of 18-O-(tetrahydro-2-pyranyl)-reserpic acid is added in small amounts to an ether solution of diazoethane until evolution of nitrogen ceases. The reaction mixture is allowed to stand at room temperature, an excess of benzoic acid in ether is added and the solvent is evaporated. Dilute aqueous ammonia is given to the residue, and the aqueous mixture is extracted with methylene chloride. The organic solvent is evaporated after drying and the residue is worked up to yield the desired ethyl 18-0-(tetrahydro-Z-pyranyl)-reserpate, M.P. 210- 218.
The starting material may be prepared as follows: A solution of 3.6 g. of methyl 18-O-(tetrahydro-2-pyranyl)- reserpate in 45 ml. of 1 N aqueous sodium hydroxide is refluxed for 2% hours. The resulting solution is concentrated under reduced pressure, and the residue is diluted with Water. The solution is adjusted to pH=7 with acetic acid and then extracted with methylene chloride. The organic solution is dried over sodium sulfate, the solvent is evaporated under reduced pressure and the residue is crystallized from a mixture of ethyl acetate and ethylene chloride to yield 1.5 g. of 18-O-(tetrahydro-2-pyranyl)- reserpic acid, M.P. 215-218 (with decomposition).
The 18-0-(tetrahydro-2-pyranyl)-reserpic acid may also be prepared as follows: To 0.5 g. of reserpic acid hydrochloride in 10 ml. of N,N-dimethylforma1nide and 5 m1. of 2,3-dihydropyran is added dropwise 0.3 g. of ptoluene sulfonic acid in 5 ml. of N,N-dimethylformamide while stirring at room temperature. The solution is stirred for an additional thirty minutes, and is then poured into water; the mixture is extracted with methylene chloride, the organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is crystallized by adding diethyl ether and stirring until crystals appear. The solid material is filtered off, washed with ether, dried and recrystallized from a mixture of ethyl acetate and methylene chloride, M.P. 200 205; yield: 0.3 g.
Other 18-0-(tetrahydro-Z-pyranyl) -deserpidic acid compounds, such as for example, 18-O-(tetrahydro-Z-pyranyl)-deserpidic acid, S-methyl-lS-O-(tetrahydro-Z-pyranyl)-reserpic acid, 5-methyl-18-O-(tetrahydro-2-pyranyl)- deserpidic acid, 6-methyl-18-O (tetrahydro-2-pyranyl)- reserpic acid, 9-methyl-18-O-(tetrahydro-Z-pyranyl)-deserpidic acid, 1l-methyl-l8-O-(tetrahydro-2-pyranyl)-de serpidic acid, 9-methoxy-18-O-(tetrahydro-Z-pyranyl)-deserpidic acid, 10-methoxy-18-O-(tetrahydro-Z-pyranyl)- deserpidic acid, 10-meth0xy-18-O-(tetrahydro-2-pyranyl) reserpic acid, 12-methoxy-(tetrahydroQ-pyranyl)-deserpidic acid, 1l-ethoxy-l8-O-(tetrahydro-Z-pyranyl)-deserpidic acid, 11-n-propy1oxy-18-O (tetrahydro-2-pyranyl)- deserpidic acid, 1l-isopropyloxy-lS-O-(tetrahydro-Z-pyranyl) -deserpidic acid, 1l-n-butyloxy-18-O-(tetrahydro-2- pyranyl) -deserpidic acid, 10,1l-methylenedioxy-18-O-(tetrahydro-Z-pyranyl)-deserpidic acid, 10-benzyloxy-18-O- (tetrahydro-Z-pyranyl)-deserpidic acid, 11-benzyloxy-18- O-(tetrahydro-Z-pyranyl)-deserpidic acid, 11-methylmercapto-l8-0-(tetrahydro-2-pyranyl)-deserpidic acid, 11- ethylmercapto 18 O (tetrathydro 2 pyranyl)-deserpidic acid, 10-chloro-18-O-(tetrahydro-Z-pyranyl)-deserpidic acid, 10-bromo-18-O-(tetrahydro-Z-pyranyl)-deserpidic acid, 17desmethoxy-17-ethoxy-1S-O-(tetrahydrd- 2-pyranyl)-reserpic acid, 17-desmethoxy-17-n-propyloxy- 18-O-(tetrahydro-2-pyranyl)-reserpic acid, 17-desmethoxy-17-isopropyloxy-18-0-(tetrahydro-2-pyranyl) -reserpic acid and the like, may either be prepared by hydrolysis, for example, of the corresponding lower alkyl IS-O-(tetrahydro-2-pyranyl)-deserpidate compounds, or by treatment of the corresponding deserpidic acid compounds with 2,3- dihydropyran as shown hereinabove.
2,3-dihydropyran may be replaced by a 2-halogenotetrahydropyran, such as 2-chloro-tetrahydropyran, which upon reaction with a deserpidic acid compound, e.g. reserpic, deserpidic acid and the like, in the presence of N,N-dimethylformamide as shown in Example 33, yields the desired 18-O-(tetrahydro-Z-pyranyl)-deserpidic acid compound, e.g. 18-O-(tetrahydro-Z-pyranyl)-reserpic acid, 18-0-(tetrahydro-Z-pyranyl)-deserpidic acid and the like can be formed.
'18-O-(tetrahydro 2 furanyl)-deserpidic acid compounds, such as for example, 18-0-(tetrahydro-2-furanyl)- reserpic acid, 18-O-(tetrahydro-2-furanyl) -deserpidic acid, 1*0-methoxy-18-O-(tetrahydro-Z-furanyl)-deserpidic acid, 12-methoxy-18-O-(tetrahydro-Z-furanyl)-deserpidic acid and the like, can be obtained by hydrolyzing a corresponding lower alkyl 18-O-(tetrahydro-Z-furanyl)-deserpidate compound or by reacting a mixture of the corresponding 18-unsubstituted deserpidic acid compound and 2,3-dihydrofuran in an N,N-dimethylformamide solution with p-toluene sulfonic acid as shown in the above example.
Example 30 A solution of 0.5 g. of methyl 18-O-(tetrahydro-2- pyranyl)-reserpate, prepared, for example, according to the procedure of Example 10, in ethanol containing sodium ethanolate, when heated to reflux over a short period of time, yields the desired ethyl 18-O-(tertahydro- Z-pyranyD-resperpate, M.P. 210218.
Example 31 To a solution of 1.29 g. of methyl reserpate N-oxide and 1.25 ml. of 2,3dihydropyran in 10 ml. of acetone is gradually added, while stirring, 0.76 g. of p-toluene sulfonic acid in 3.2 ml. of acetone. Stirring is continued for an additional thirty minutes and ethyl acetate is added; the organic layer is washed twice with 10 percent aqueous sodium hydroxide and with water. The organic solution is dried over sodium sulfate, the solvent is removed under reduced pressure, and the residue is precipitated from a mixture of acetone and diethyl ether and crystallized from ethyl acetate. The resulting methyl 18-0- (tetrahydro-Z-pyranyl)-reserpate N-oxide melts at 226- 227; yield: 0.11 g.
Other N-oxides, such as, for example, ethyl 18-O-(tetrahydro-Z-pyranyl)-reserpate N-oxide, n-propyl 18-O-(tetrahydro-Z-pyranyl)-reserpate N-oxide, methyl 18-O-(tetrahydro-Z-pyranyl)-deserpidate N-oxide, methyl IO-methoxy-18-0-(tetrahydro-2-pyranyl) deserpidate N oxide, methoxyethyl 18-0-(tetrahydro-Z-pyranyl)-reserpate N- oxide, methyl l8-O-(4-methyl-tetrahydro-Z-pyranyl)-reserpate N-oxide, methyl 18-0-(tetrahydro-Z-furanyl)-reserpate N-oxide and the like, may be obtained by reacting the appropriate lower alkyl or lower alkoxy-lower alkyl deserpidate N-oxide compounds with 2,3-dihydropyran, 4-me'thyl-2,3-dihydrcpyran, 2,3-dihydrofuran and the like according to the above procedure.
Example 32 A suspension of 249.3 g. of methyl reserpate in 1870 ml. of acetone and 250 ml. of 2,3-dihydropyran is stirred at room temperature; a solution of 129.3 g. of p-toluene sulfonic acid monohydrate in 620 ml. of acetone is added over a period of nine minutes. The resulting solution is stirred for thirty minutes, the acetone is removed by distillation and the residue is suspended in 2500 ml. of ethyl acetate. The organic solution is washed with a mixture of 602 ml. of 10 percent aqueous sodium carbonate and 780 ml. of water, and then three times with 300 ml. of water. 1000 ml. of chloroform is added, the remaining water is distilled azeotropically and the solution is cooled. A precipitate is formed, is filtered off and washed with ethyl acetate and then with ether. The isolated product is identical in every respect with the methyl IS-O-(tetrahydro-2-pyranyl) -reserpate obtained according to the procedure of Example 10; its rotation is [a] =l48.75 (in chloroform); yield: 107.6 g.
The filtrate, obtained after separating the solid material, is concentrated to 400 ml. and the oily residue is dissolved in 500 ml. of isopropanol. On cooling at 5 overnight, a precipitate is formed, which is filtered off, washed

Claims (1)

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA:
US931A 1960-01-07 1960-01-07 18-o-hetero-reserpates Expired - Lifetime US3048591A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US931A US3048591A (en) 1960-01-07 1960-01-07 18-o-hetero-reserpates

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US931A US3048591A (en) 1960-01-07 1960-01-07 18-o-hetero-reserpates

Publications (1)

Publication Number Publication Date
US3048591A true US3048591A (en) 1962-08-07

Family

ID=21693609

Family Applications (1)

Application Number Title Priority Date Filing Date
US931A Expired - Lifetime US3048591A (en) 1960-01-07 1960-01-07 18-o-hetero-reserpates

Country Status (1)

Country Link
US (1) US3048591A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3311633A (en) * 1967-03-28 Behydro-emehnes
WO2014100354A1 (en) * 2012-12-21 2014-06-26 Map Pharmaceuticals, Inc. Novel methysergide derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2824874A (en) * 1958-02-25 Reserpic acid and derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2824874A (en) * 1958-02-25 Reserpic acid and derivatives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3311633A (en) * 1967-03-28 Behydro-emehnes
WO2014100354A1 (en) * 2012-12-21 2014-06-26 Map Pharmaceuticals, Inc. Novel methysergide derivatives
US8895743B2 (en) * 2012-12-21 2014-11-25 Map Pharmaceuticals, Inc. Methysergide derivatives

Similar Documents

Publication Publication Date Title
US5525607A (en) Xanthine compounds
US2857385A (en) Preparation op pentacyclic lactones
US3480626A (en) Certain azoniaspironortropine derivatives
US2824874A (en) Reserpic acid and derivatives
US3314966A (en) Substituted benzo[a]quinolizines
US3637755A (en) Pyranocyclopentenedione ketal
US3048591A (en) 18-o-hetero-reserpates
US3976641A (en) Cephalosporin intermediates and process therefor
US2995556A (en) David l
US3126387A (en) Analogs thereof
SE461653B (en) PROCEDURES FOR THE PREPARATION OF AMINOEBURNAND DERIVATIVES
DE2601473A1 (en) 2,3-DIHYDROERGOLINE AND METHOD FOR MANUFACTURING IT
US3264303A (en) Process for the manufacture of yohimbane-18-omicron-ethers
US2986562A (en) Reserpic and deserpidic acid lactone dienes
US3151117A (en) Process for the preparation of ethers
US3126388A (en) Ib-o-alkyl-deserkdates and related
US3138601A (en) Alkyl-ib-o-trialkoxyacetylreserpates
US2901483A (en) Process for the preparation of lactones in the yohimbane series
US2813871A (en) O-syringoyl reserpic acid esters
DE2029099B2 (en) Process for the preparation of acetidino [3,2-dJ thiazoles
US3119819A (en) Intermediates for 18-o-alkyl-reserpic acid esters and related compounds
US3126390A (en) Ib-epi-deserpidates and derivatives
US3126391A (en) Alkoxyalkyl ib-o-alkoxyalkyl -
US2802006A (en) Esters of the yohimbe alkaloids
US3901890A (en) Process for production of diketopiperazine dihydroxamates and intermediates therefor