US3119819A - Intermediates for 18-o-alkyl-reserpic acid esters and related compounds - Google Patents

Intermediates for 18-o-alkyl-reserpic acid esters and related compounds Download PDF

Info

Publication number
US3119819A
US3119819A US37097A US3709760A US3119819A US 3119819 A US3119819 A US 3119819A US 37097 A US37097 A US 37097A US 3709760 A US3709760 A US 3709760A US 3119819 A US3119819 A US 3119819A
Authority
US
United States
Prior art keywords
methyl
lower alkyl
acid
ethyl
compounds
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
US37097A
Other languages
English (en)
Inventor
Robison Michael Mullen
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
Priority to US37097A priority Critical patent/US3119819A/en
Application filed by Ciba Geigy Corp filed Critical Ciba Geigy Corp
Priority to CH1551064A priority patent/CH414660A/de
Priority to CH796560A priority patent/CH387054A/de
Priority to CH1551164A priority patent/CH392539A/de
Priority to CH796660A priority patent/CH410967A/de
Priority to CH76365A priority patent/CH411918A/de
Priority to CH1551364A priority patent/CH388324A/de
Priority to CH1551464A priority patent/CH388325A/de
Priority to CH796860A priority patent/CH413850A/de
Priority to CH76265A priority patent/CH411917A/de
Priority to CH76465A priority patent/CH410971A/de
Priority to CH796760A priority patent/CH414656A/de
Priority to CH1551264A priority patent/CH392540A/de
Priority to ES0259870A priority patent/ES259870A1/es
Priority to DEC25721A priority patent/DE1197737B/de
Priority to ES0259869A priority patent/ES259869A1/es
Priority to AT138161A priority patent/AT241696B/de
Priority to AT579960A priority patent/AT241694B/de
Priority to AT138061A priority patent/AT241695B/de
Priority to AT137961A priority patent/AT248031B/de
Priority to NL254293A priority patent/NL126895C/xx
Priority to AT579760A priority patent/AT241693B/de
Priority to GB26593/60A priority patent/GB885981A/en
Application granted granted Critical
Publication of US3119819A publication Critical patent/US3119819A/en
Priority to SE454964A priority patent/SE314883B/xx
Priority to FI2236/64A priority patent/FI40249B/fi
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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • the compounds may contain additional substituents; such substituents are, for example, aliphatic hydrocarbon, such as lower alkyl and the like, etherified hydroxyl, such as lower alkoxy, cycloalkyloxy, cycloalkyL lower alkoxy, carbocyclic aryloxy, carbocyclic aryl-lower alkoxy, lower alkylenedioxy and the like, esterified hydroxyl, such as lower alkoxy-carbonyloxy, lower alkanoyloxy, halogeno and the like, etherified mercapto, such as lower alkylmercapto and the like, nitro, amino, such as N,N-disubstituted amino and the like, halogeuo-lower alkyl or any other suitable substituent.
  • substituents are, for example, aliphatic hydrocarbon, such as lower alkyl and the like, etherified hydroxyl, such as lower alkoxy, cycloalkyloxy, cycloalkyL
  • substituents are preferably attached to positions of the aromatic nucleus, i.e. ring A, of the molecule, which are available for substitution, i.e. positions 9, 10, 11 and/or 12; the substituents, particularly aliphatic hydrocarbon radicals, may also be attached to positions of other nuclei, particularly of the heterocyclic nucleus C.
  • R represents lower alkyl or substituted lower alkyl, such as, for example, etherified hydroxy-lower alkyl, e.g. lower alkoxy-lower alkyl and the like, as well as tertiary amino-lower alkyl, e.g. N,N-di-lower alkylamino-lower alkyl and the like
  • R stands for lower alkyl
  • R represents aliphatic hydrocarbon, particularly lower alkyl and the like, or substituted aliphatic hydrocarbon, such as, for example, etherified hydroxy-lower alkyl, e.g. lower alkoxy-lower alkyl and the like, tertiary aminolower alkyl, e.g. N,N-di-lower alkyl-amino and the like
  • R stands for lower alkyl
  • R represents aliphatic hydrocarbon, particularly lower alkyl and the like, or substituted aliphatic hydrocarbon, such as, for example, ether
  • each of the radicals R, and R stands for hydrogen, lower aliphatic hydrocarbon, especially lower alkyl, etherified hydroxyl, particularly lower alkoxy, halogeno, or etherified mercapto, particularly lower alkyl-mercapto, as well as other etherified hydroxyl groups, such as cycloalkyloxy, cycloalkyl-lower alkoxy, carbocyclic aryloxy, carbocyclic aryl-lower alkoxy and the like, esterifiecl hydroxyl, e.g. lower alkoxy-carbonyloxy, lower alkanoyloxy and the like, nitro, amino, e.g.
  • the radical of the alcohol portion of the ester grouping attached to the 16-position of the molecule which is also represented by the group R in the above formula, stands primarily for a lower alkyl group containing from one to seven, preferably from one to four, carbon atoms; such groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, as well as n-pentyl, isopentyl, n-hexyl, n-heptyl, and the like.
  • the esterifying group of the ester grouping attached to the l6-position of the molecule may also stand for a substituted lower alkyl radical, such as, for example, etherified hydroxy-lower alkyl, as well as tertiary amino-lower alkyl and the like.
  • An etherified hydrox'ylower alkyl radical represents primarily lower alkoxylower alkyl, in which lower alkoxy contains from one to four carbon atoms and represents, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like.
  • the amino group of a tertiary amino-lower alkyl radical is primarily an N,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-methylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-isopropylamino and the like, as well as a l-N,N-lower alkylene-irnino group, in which lower alkylene contains from four to six ring carbon atoms, e.g.
  • the lower alkyl portion in a substituted lower alkyl radical may be a lower alkylene radical containing from two to seven carbon atoms, which separates the substituent, such as the etherified hydroxyl group and the like, from the carbon atom of the carboxy group by at least two carbon atoms.
  • such lower alkylene radical contains from two to three carbon atoms and separates the substituent, such as the etherified hydroxyl group and the like, from the carboxy group by the same number of carbon atoms.
  • alkylene radicals are primarily 1,2-ethylene, l-methyl- 1,2-ethylene, Z-methyl-LZ-ethyleue or Lil-propylene; other lower alkylene radicals may be, for example, 1,4- butylene, l-methyl-Ll-propylene and the like.
  • the lower alkyl portion of the lower alkoxy group attached to the 17-position of the molecule and represented, for example, by R, in the previously given formula, contains from one to four carbon atoms, and stands for ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, but represents, above all, methyl.
  • the etherified hydroxyl group attached to the Ill-position of the yohimbane molecule and represented, for example, by the grouping R in the previously given formula is etherified by an aliphatic hydrocarbon radical.
  • Such radical representing, for example, the group R stands for lower alkyl, containing from one to seven, preferably from one to four, carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n'pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl and the like.
  • the ethcrifying group as represented, for example, by the radical R may also be a substituted aliphatic hydrocarbon radical, such as, for example, an etherified hydroxy-lower alkyl radical, such as lower alkoxy-lower alkyl, in which lower alkoxy contains from one to four carbon atoms and stands, for example, for methoxy, ethoxy, n-propyloxy, n-butyloxy and the like, or a tertiary amino-lower alkyl radical, in which tertiary amino repre sents, for example, N,N-di-lower alkyl-amino, e.g.
  • a substituted aliphatic hydrocarbon radical such as, for example, an etherified hydroxy-lower alkyl radical, such as lower alkoxy-lower alkyl, in which lower alkoxy contains from one to four carbon atoms and stands, for example, for methoxy, ethoxy, n-propyl
  • a functional group is separated from the oxygen atom, to which the radical R is attached, by from two to seven, advantageously by from two to three, carbon atoms.
  • Substituted aliphatic hydrocarbon radicals, particularly those representing R are, therefore, 2-lower alkoxy-ethyl, e.g. 2methoxyethyl, Z-cihoxyethyl and the like, 2-lower alkoxy-propyl, e.g. Z-methoxy-propyl, 2- ethoxy-propyl and the like, 3-lower alkoxy-propyl, e.g.
  • 2-N,N-dilower alkyl-amino-ethyl e.g. 2-N,N-dirnethylaminoethyl, 2-N,N-diethylaminoethyl and the like
  • 2-N,N-di-lower alkyl-amino-propyl e.g. 2-N,N-dimethylaminopropyl, 2- N,N-diethylam.inopropyl and the like
  • 3-N,N-di-lo'wer alkyl-amino-propyl e.g.
  • etherlfied hydroxyl groups contain as etherifying groups, represented, for example, by the radical R in the above-given formula, other aliphatic radicals, such as, for example, lower alkenyl, such as lower allylic alkenyl, containing preferably from three to five carbon atoms, e.g. allyl, Z-methyl-allyl, Z-butenyl, 3-rnethyl-2- butenyl, Z-pentenyl and the like, cycloalkyl containing from three to eight, preferably from five to six, ring carbon atoms, e.g.
  • cyclopcntyl or cyclohexyl as well as cyclopropyl, cycloheptyl, cyclo-octyl and the like, cycloalkenyl, containing preferably from five to six ring carbon atoms, e.g. 3-cyclopentenyl, 2-cyclohexenyl and the like, cycloalkyl-lower alkyl, in which cycloalkyl contains from three to eight, especially from five to six, ring carbon atoms, and lower alkyl contains from one to four carbon atoms, e.g.
  • carbocyclic aryl-aliphatic hydrocarbon radicals such as monocyclic carbocyclic aryllower alkyl, e.g. benzyl, diphenylmethyl, l-phenylethyl, 2-phenylethyl and the like and analogous radicals, in which the carbocyclic aryl nucleus is substituted, for example, by lower alkyl, e.g. methyl, ethyl and the like,
  • lower alkoxy e.g. methoxy, ethoxy and the like, lower alkenyloxy, e.g. allyloxy and the like, halogeno, e.g. chloro, bromo and the like, lower alkoxy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, halogeno-lower alkyl, e.g. trifiuoromcthyl and the like, nitro, amino, such as N,N-di-lower alkyl-amino, e.g.
  • Additional substituted aliphatic hydrocarbon radicals are particularly lower alkyl radicals substituted by functional groups, such as, for example, by acyl, particularly lower alkanoyl, e.g. acetyl, propionyl and the like, or carbo-lower alkoxy, e.g. carbomethoxy carbethoxy and the like, etherified mercapto, such as lower alkyl-mercapo, e.g. methylmercapto, ethylmercapto and the like, halogeno, e.g. chloro, bromo and the like, or any other substituent suitable for being attached to an aliphatic hydrocarbon, particularly a lower alkyl, radical.
  • functional groups such as, for example, by acyl, particularly lower alkanoyl, e.g. acetyl, propionyl and the like, or carbo-lower alkoxy, e.g. carbomethoxy carbethoxy and the like, etherified mer
  • substituted aliphatic radicals are, therefore, primarily lower alkanoyl-lower alkyl, e.g. acetylmethyl, propionylmethyl and the like, carbo-lower alkoxy-lower alkyl, e.g. carbornethoxymethyl, carbethoxymethyl and the like, lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, halogeno-lower alkyl, e.g. chloromethyl and the like, as well as other analogous substituents.
  • lower alkanoyl-lower alkyl e.g. acetylmethyl, propionylmethyl and the like
  • carbo-lower alkoxy-lower alkyl e.g. carbornethoxymethyl, carbethoxymethyl and the like
  • lower alkyl-mercapto e.g. methylmercapto, ethylmercapto and the like
  • Substituents attached to any of the positions available for substitution in ring A may be represented, for example, by lower aliphatic hydrocarbon, especially lower alkyl, containing preferably from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, or by functional groups, such as, for example, etherified hydroxyl, particularly lower alkoxy, containing preferably from one to four carbon atoms, e.g.
  • cycloalkyloxy e.g. cyclopentyloxy, cyclohexyloxy and the like
  • cycloalkyllower alkoxy e.g. cyclopentylmethoxy, 2-cyclopentylethoxy, cyclohexylmethoxy and the like
  • carbocyclic aryloxy such as monocyclic car-bocyclic aryloxy, e.g.
  • carbocyclic aryl-lower alkoxy such as monocyclic carbocyclic aryl-lower alkoxy, for example, phenyl-lower alkoxy, e.g. benzyloxy, diphenyloxy, IZ-phenylethoxy and the like, esterified hydroxyl, particularly lower alkoxy-carbonyloxy, e.g. methoxycarbonyloxy, ethoxycarbonyloxy and the like, or lower aikanoyloxy, e.g.
  • mercapto particularly lower alkyl-mercapto, containing preferably from one to four carbon atoms, e.g. methylmercapto, ethylmercapto and the like, nitro, amino, particularly N,N-disubstituted amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N- ethylN-methyl-amino, N,N'diethylamino and the like, halogeno, e.g.
  • a substituent may also be attached to two adjacent positions of ring A and form an additional ring; for example, the radicals R and R in the formula, when taken together and substituting two neighboring positions, may also form a cyclic substituent.
  • substituents may be represented, for example, by lower alkylene-dioxy, e.g. rnethylenedi oxy, or any other analogous grouping.
  • Substituents which may be attached to other positions in the molecule, particularly to the positions available for substitution in ring C are particularly aliphatic hydrocarbon, such as lower alkyl radicals, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl, isopropyl and the like.
  • the radical R in the previously given formula which stands primarily for hydrogen, may, therefore, also stand for lower alkyl, particularly for methyl.
  • Salts of the compounds of this invention are primarily therapeutically acceptable acid addition salts, particularly those with inorganic acids, particularly with mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, as well as with organic acids, e.g. acetic, tartaric, methane sulfonic acid and the like.
  • N-oxides of the above-mentioned compounds are included within the scope of the present invention.
  • therapeutically acceptable acid addition salts of such N-oxides for example, the addition salts with the above-mentioned inorganic, particularly mineral, and organic acids.
  • the latter may be obtained in the form of a mixture of racemates, racemates or optically pure compounds.
  • the compounds of the present invention have sedative and tranquilizing effects on the central nervous system, as well as antihypertensive properties.
  • qualitative differences can be observed within the group of the new compounds of this invention.
  • certain compounds of this invention when compared with the ratio existing between antihypertensive and sedative effects in naturally occuring Rauwolfia alkaloids, such as, for example, reserpine, deserpidine, rescinnamine and the like, certain compounds of this invention have more predominant sedative effects with negligible antihypertensive activity, whereas in others, the latter may be more pronounced than the sedative and tranquilizing component.
  • the compounds of this invention react quickly and the activity is of definite duration, i.e. the recovery after treatment is more complete and easily controllable.
  • the therapeutically acceptable salts particularly those with mineral acids, e.g. hydrochloric acid and the like, are to a high degree water-soluble, and are, therefore, extremely useful in the preparation of aqueous solutions for injection and in aqueous oral preparations, e.g. elixirs and the like.
  • the compounds of the present invention can, therefore, be used as sedative and tranquilizing agents to relieve states of hyperactivity tension and agitation, as, for example, associated with mental disturbances and the like. Furthermore, they can 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. They also can be used as intermediates for the formation of other useful compounds.
  • each of the groups R and R represents lower atoms, especially methyl, as well as ethyl, npropyl, isopropyl, n-butyl, isobutyl, secondary butyl and the like, and R, represents lower alkoxy containing from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R is "preferably attached to the l0-position or the ll-position, the therapeutically acceptable acid addition salts, the N-oxides and the therapeutically acceptable acid addition salts of such N-oxides.
  • lower alkyl l8-0-lower alkyl-9-methoxydeserpidates e.g. methyl 9-methoxy-lS-O-methyl-deserpidate, methyl 18-O-ethyl-9-methoxy-deserpidate, methyl 9-methoxy-IS-O-n-propyl-deserpidate, ethyl 9-methoxy- IS-O-methyl-deserpidatc and the like
  • lower alkyl 18-O- lower alkyl-lll-methoxy-deserpidate e.g.
  • IO-methoxy-lS-O-methyl-deserpidate methyl 18-O-ethyl-10-meth oxy-deserpidate, methyl IO-methoxy-lS-O-n-propyl-deserpidate, ethyl IO-methoxy-l8-0-methyl-deserpidate, n-propyl lfi-methoxy-l 8-O-methyl-deserpidate, isopropyl 10- methoxy-l-methyl-deserpidate and the like, lower alkyl ll-ethoxy-l8-O-lower alkyl-deserpidate, e.g.
  • methyl llethoxy-l8-0-methyl-deserpidate methyl ll-ethoxy-l 8-0- ethyl-deserpidate and the like
  • lower alkyl l8-O-lower al-kyl-l1-n-propyloxy-deserpidate e.g. methyl 18-O-methyll l-n-propyloxy-deserpidate, methyl l8-O-ethyl-11-n-propyloxy-deserpidate and the like
  • lower alkyl ll-isopropyloxy-lS-O-lower alkyl-deserpidate e.g.
  • methyl ll-isopropyloxy-18-O-methyl-deserpidate ethyl ll-isopropyloxy- IB O-methyI-deserpidate and the like
  • lower alkyl ll-nbutyloxy-lS-Odower alkyl-deserpidate e.g. methyl ll-nbutyloxy-lS-O-methyl-deserpidate, methyl l1n-butyloxy- IS-O-ethyI-descrpidate and the like
  • lower alkyl 18-O-lower alkyl-IZ-methoxy-deserpidates e.g. methyl IZ-methoxy- ISO-methyl-deserpidate, ethyl 12-methoxy-l8-0-methyldeserpidate and the like.
  • An additional preferred group of compounds are the lower alkyl 18-0-lower alkyl-deserpidates, in which lower alkyl contains preferably from one to four carbon atoms,
  • alkyl containing preferably from one to four carbon 7 and is represented primarily by methyl, as well as ethyl,
  • Specific members of this group are, for example, methyl IB-O-methyl-deserpidate, methyl IB-O-ethyl-deserpidate, methyl l8-O-n-propyldeserpidate, methyl 18-O-isopropyl-deserpidate, methyl IB-O-n-butyl-deserpidate, methyl l8-O-secondary butyldeserpidate, ethyl IB-O-methyl-deserpidate, ethyl 180- ethyl-deserpidate, ethyl l8-O-n-propyl-deserpidate, n-propyl 18-O-methyl-deserpidate, n-propyl l8-O-ethyl-deserpidate, isopropyl l8-O-methyl-deserpidate, isopropyl 18- O-n-butyl-deserpidate, n-butyl l
  • lower alkyl 18-O-lower alkyl--methyl-reserpates e.g. methyl 5- methyl-lS-O-methyl-reserpate, methyl IS-O-ethyl-S-methyl-reserpate, ethyl S-methyl-l8-Omethyl-reserpate and the like
  • lower alkyl l8-O-lower alkyl-G-methyl-reserpates e.g.
  • methyl 6-methyl-18-O-rnethyl-reserpate methyl 18-O- n-butyl-6-methyl-reserpate, ethyl 6-methyl-l8-O-methylreserpate and the like
  • lower alkyl 18-O-lower alkyl-6- methyl-deserpidate e.g. methyl G-methyl-lS-O-methyldeserpidate, methyl fi-methyl-18-0-n-propyl-deserpidate, ethyl G-methyl-IS-O-methyl-deserpidate and the like
  • lower alkyl 18O-lower alkyl-9-methyl-deserpidate e.g.
  • lower alkyl 17a.- desmethoxy-lB-O-lower alkyl-17a-n-propyloxy-reserpate e.g. methyl 17a-desmethoxy4S-O-methyl-lh-n-propyloxy-reserpate, ethyl l7a-desmethoxy-18-O-methyl-l7a-npropyloxy-reserpate and the like
  • lower alkyl l7a-desmethoxy 17u-isopropyloxy-l8-0-lower alkyl-reserpate e.g.
  • methyl 17a desmethoxy-17a-isopropyloxy-IS-O-methylreserpate, methyl l7e-desmethoxy-l8-0-ethyll7u-isopropyloxy-reserpate and the like, lower alkyl l7a-desmethoxy- 17a-ethoxy-l8-O-lower alkyl-deserpid'ate, e.g.
  • lower alkoxy-lower alkyl 18-O-lower alkylreserpates and lower alkoxy-lower alkyl l8-O-lower alkyldeserpidates in which lower alkyl of the lower alkoxylower alkyl portion represents a lower alkylene radical which contains from two to three carbon atoms and separates the lower alkoxy group from the carbon atom of the carboxyl group by the same number of carbon atoms, and lower alkoxy has from one to four carbon atoms, whereas the lower alkyl group attached to the oxygen atom of the Iii-position contains from one to four carbon atoms; lower alkoxy-lower alkyl represents, for example, Z-methoxyethyl, 2-ethoxyethyl, 2-methoxypropyl, 3-methoxyethyl and the like, and lower alkyl may stand for methyl, ethyl, n-propyl, is
  • Specific compounds of this group are, for example, Z-methoxyethyl IS-O-methyl-reserpate, Z-methoxyethyl IS-O-ethyl-reserpate, Z-ethoxyethyl 18-O methyl-reserpate, Z-ethoxyethyl IS-O-n-propyl-reserpate, 2-rnethoxypropyl IS-O-methyl-reserpate, 3-methoxypropyl IS-O-methyl-reserpate, Z-methoxyethyl IB-O-methyl-deserpidate, 2-rnethoxyethyl IS-O-ethyl-deserpidate, Z-ethoxyethyl l8-O-methyl-deserpidate and the like.
  • Specific compounds of this group are, for example, 2-N,N-dimethylarninoethyl 18-O- methyl-rcserpate, 2-N,N-dimethylaminoethyl l8-O-ethylreserpate, 2vN,N-diethylaminoethyl 18-0- methyl-reserpate, 3-N,Ndimethylaminopropyl l8-O-methyl-reserpate, 2-N,N-dimethylaminoethyl 18 O methyl-deserpidate, 2- N,N-dirnethylaminoethyl l8-O-ethyl-deserpidate, 2-N,N- dimethylaminopropyl IS-O-methyl-deserpidate and the like.
  • the compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contain the new compounds or derivatives thereof, such as therapeutically acceptable acid addition salts thereof, N-oxides thereof or therapeutically acceptable acid addition salts of N-oxides thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration.
  • inert substances which are compatible with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes,-propylene glycol, polyalkylene glyools or any other known inert carrier used in medicaments.
  • the pharmaceutical preparation may be in solid form, for example, as tablets, capsules, dragees and the like, or in liquid form, for example, as solutions, suspension, emulsions and the like.
  • they may contain additional substances such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers or any other auxiliary substances. They may also contain, in combination, other therapeutically useful substances.
  • Compounds of this invention can be formed by etherifying in an l8-hydroxy-l7-lower alkoxy-3-epi-allo-yohimbane lo carboxylic acid ester, particularly in a compound of the formula:
  • R R R R, and K have the previously given meaning, a salt thereof, an N-oxide thereof or a salt of an N-oxide thereof, the free hydroxyl group attached to the IS-position by treatment with a diazo-compound in the presence of a strong inorganic Lewis acid, and, if desired, converting a resulting salt into the free base, and/or, if desired, converting a resulting compound into a salt, an N-oxide or a salt of an N-oxide thereof, and/ or, if desired, converting a resulting mixture of isomers into the single isomers.
  • Salts of the starting materials or of an N-oxide thereof are addition saltswith acids, primarily those with inorganic, such as mineral, acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acid and the like. Acid addition salts may also be those with the strong inorganic Lewis acid catalyzing the etherification reaction, e.g. fiuo' boric acid and the like; these salts may be formed during the reaction. a
  • the starting materials, the salts, the N-ox-ides or the salts of N-oxides thereof are reacted with the aliphatic diam-hydrocarbon, for example, a lower diazo-alkane, particularly diazomethane and the like, as well as with a substituted aliphatic diazo-hydrocarbon, such as an etherified hydroxy-lower diazo-alkane, particularly a lower alkoxy-lower diazoalkane, a tertiary amino-lower diazo-alkane, particularly an N,N-di-lower alkyl-aminolower diazo-alkane and the like, or any other suitable reagent, in the presence of a strong inorganic Lewis acid.
  • a substituted aliphatic diazo-hydrocarbon such as an etherified hydroxy-lower diazo-alkane, particularly a lower alkoxy-lower diazoalkane, a tertiary amino-lower diazo-alkan
  • Fluoboric acid which may be employed in the form of a concentrated aqueous solution (for example, an about l2 N to an about 16 N aqueous solution), represents the preferred reagent.
  • Other Lewis acid reagents may be, for example, perchloric acid (preferably in anhydrous form) and the like. Due to the salt-forming properties of the free starting material, the Lewis acid, catalyzing the etherification of the 18-hydroxyl group, is used in excess of one mol, whenever the free base is present; an about one to an about two hundred, preferably an about ten to an about fifty, percent excess appears to be suflicient to promote the etherification reaction.
  • solvents which are inert towards the starting materials and the reaction reagents;
  • solvents are, for example, halogenated lower aliphatic hydrocarbons, e.g. methylene chloride, chloroform, ethylene chloride, trichloroethane, tetrachloroethane and the like, others, e.g. diethylether, tetrahydrofuran and the like, lower alkyl lower alkanoates, e.g. ethyl acetate and the like, acetonitrile or any other useful solvents, as well as mixtures of such solvents.
  • solvents are, for example, halogenated lower aliphatic hydrocarbons, e.g. methylene chloride, chloroform, ethylene chloride, trichloroethane, tetrachloroethane and the like, others, e.g. diethylether, tetrahydrofuran and the like, lower alkyl lower
  • a solution of the cliazo reagent in an inert solvent such as an ether, e.g. diethylether and the like, or a halogenated hydrocarbon, e.g. methylene chloride and the like, or a mixture of solvents, may be added to the mixture of the starting material and the Lewis acid, preferably kept in solution.
  • the diazo compound may also be distilled out of its solution into the solution of the mixture of the starting material and the Lewis acid. Furthermore, the latter mixture may also be given to a solution of the diazo reagent.
  • the reaction may be carried out at room temperature; however, cooling of the reaction mixture to below room temperature, for example, to from about 10 to about -20", especially to from about 0 to about l5, may be advantageous. If necessary, the reaction may be carried out in the atmosphere of an inert gas, e.g. nitrogen.
  • an inert gas e.g. nitrogen.
  • An excess of the diazo reagent present at the end of the reaction may be destroyed, for example, by adding an acid, preferably an easily esterifiable carboxylic acid, e.g. acetic, benzoic acid and the like.
  • the desired product may be isolated and separated from any by-products according to standard procedures, e.g. extraction, adsorption and elution, crystallization, etc. and purified, for example, by recrystallization, if necessary, after treatment of a solution thereof with an adsorbent, e.g. aluminum oxide, charcoal, diatomaceous earth and the like.
  • an adsorbent e.g. aluminum oxide, charcoal, diatomaceous earth and the like.
  • R R R and R have the previously given meaning, salts thereof, N-oxides thereof or salts of N- oxides thereof, may be esterified, for example, by treatment with a lower diazo-alkane, or a substituted lower diazo-alkane, such as an etherified hydroxy-lower diazoalkane, a tertiary amino-lower diazo-alkane and the like.
  • an inert solvent such as an ether, particularly diethylether
  • an acid of the above formula a salt, an N-oxide or a salt of an N-oxide 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.
  • the diazo compound may be distilled out of a solution, such as a diethylether solution, into the suspension or solution of the free acid used as the starting material.
  • An excess of the diazo reagent 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 starting materials may also be prepared by sub- 1 l jecting (16-) l8)-lactones of 18-hydroxy-17-lower alkoxy- 3-epi-alloyohimbane lfi-carboxylic acids, such as, for example, compounds of the formula:
  • alcoholysis a salt, an N-oxide or a salt of an N-oxide thereof, to alcoholysis with lower alkanols or substituted lower alkanols, such as etherified hydroxy-lower alkanols, tertiary amino-lower alkanols and the like, in the presence of an alcoholysis catalyst.
  • the alcoholyzing reaction may be carried out, for example, by treating the lactone compound used as the starting material with a lower alkanol, or a substituted lower alkanol, such as an etherified hydroxy-lower alkanol, a tertiary amino-lower alkanol and the like, in the presence of an alcoholysis catalyst, for example, an alkali metal, e.g.
  • N-oxides of the starting material may be prepared according to known N-oxidation methods; for example, a solution of the starting material in an inert solvent may be treated with a per-acid, such as, for example, peracetic, perbenzoic, mono-perphthalic, p-toluene persulfonic acid and the like, with hydrogen peroxide or with ozone and the like.
  • a per-acid such as, for example, peracetic, perbenzoic, mono-perphthalic, p-toluene persulfonic acid and the like, with hydrogen peroxide or with ozone and the like.
  • Salts or salts of N-oxides of the above-mentioned starting material may be prepared by treating the latter or an N-oxide thereof with an acid, particularly an inorganic acid, such as a mineral acid, e.g. hydrochloric, sulfuric, phosphoric acid and the like, preferably in the presence of a suitable solvent.
  • an acid particularly an inorganic acid, such as a mineral acid, e.g. hydrochloric, sulfuric, phosphoric acid and the like, preferably in the presence of a suitable solvent.
  • R R R R R R and R have the previously given meaning, with the proviso that the radical R has the same meaning as the radical R salts, N-oxidesor salts of N-oxides thereof, comprises reacting an 18-hydr0xy-17-lower alkoxy-3-epi-a1lo-yohambane 1 6-carboxylic acid, particularly a compound of the formula:
  • R,,, R R and R have the above-given meaning, a salt, an N-oxide or a salt of an N-oxide thereof, with a lower diazo-alkane or with a substituted lower diazo-alkane, such as an etherified hydroxy-lower diazoalkane, a tertiary amino-lower diazo-alkane and the like, in the presence of a strong Lewis acid and isolating the desired compound, and, if desired, carrying out the optional steps.
  • This reaction may be carried out according to the previously given method and is catalyzed by the necessary amount of a strong Lewis acid. It may also be carried out in such manner that first the reactive carboxyl group in the lfi-position is esterified. This may be done by adding part (one mol or an excess) of the diazo-reagent to the free acid compound, using appropriate solvents, and, after the addition of the Lewis acid to catalyze the etherification, giving to the reaction mixture the additional amount (one moi or an excess) of the diazo-reagent.
  • the above reaction may be illustrated by thetreatment of reserpic acid with an excess of diazomethane in the presence of a strong Lewis acid, such as fluoboric acid and the like, and isolation of the desired methyl 1 8-O-methyl-reserpate.
  • a strong Lewis acid such as fluoboric acid and the like
  • a further method for preparing the compounds of this invention comprises esterifying in iii-etherified hydroxyl7-lower alkoxy-3-epi-allo-yohimbane l6-carboxylic acid compounds, particularly in compounds of the formula:
  • R R R,, R and R have the above-given meaning, salts, N-oxides or salts of N-oxides thereof, the free carboxyl group attached to the l6'position, and, if desired, carrying out the optional steps.
  • the carboxyl group may be esterified according to known methods; for example, the starting material, preferably a solution thereof, may be treated with a diazoreagent, such as, for example, an aliphatic diazo-hydrocarbon or a substituted aliphatic diam-hydrocarbon.
  • a diazoreagent such as, for example, an aliphatic diazo-hydrocarbon or a substituted aliphatic diam-hydrocarbon.
  • reagents are primarily lower diazo-alkanes, e.g. diazomethane, diazoethane, n-diazopropane, diazo-isopropane, n-diazobutane, diazo-isobutene and the like.
  • reagents are, for example, etherified hydroxy-lower diazoalkanes, such as lower alkoxy-lower diazo-alkanes, in which lower alkoxy is separated from the diazo group by at least two, preferably by from two to three carbon atoms, e.g.
  • diazo reagents are advantageously used in solution with an inert diluent, such as, for example, an ether, e.g. diethylether and the like, or they may be distilled out of their solution into a solution of the starting material. An excess of the diam-compound present after the completion of the reaction may be destroyed, for example, by adding an additional carboxylic acid, such as acetic, benzoic acid and the like.
  • the diazo-reagent may be given to the starting material or a solution thereof; suitable solvents are, for example, ethers, e.g. diethylether, detrahydrofuran and the like, lower alkanols, e.g. methanol, ethanol and the like, halogenated hydrocarbons, e.g. chloroform, methylenechloride and the like, or any other appropriate solvents.
  • suitable solvents are, for example, ethers, e.g. diethylether, detrahydrofuran and the like, lower alkanols, e.g. methanol, ethanol and the like, halogenated hydrocarbons, e.g. chloroform, methylenechloride and the like, or any other appropriate solvents.
  • the above procedure may be illustrated by the treatment of IB-O-methyl-reserpic acid with diazomethane to form the desired methyl l8-0-methyl-deserpidate.
  • the starting materials used in the above procedure may be prepared, for example, by converting in an IS-etherified hydroxyl-l7-lower alkoxy-3-epiallo-yohirnlbane l6-carboxylic acid ester, particularly in compounds of the formula:
  • R,, R R R R and R have the above-given meaning, or a salt, an N-oxide or a salt of an N-oxide thereof, the esterified carboxyl group attached to the Iii-position into a free carboxyl group, and, if desired, converting a resulting compound into a salt, an Noxide or a salt of an N-oxide thereof.
  • Hydrolysis may be carried out according to known methods; for example, the esterified carboxyl group may be cleaved by treatment with an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, in a lower alkanol, e.g. methanol, ethanol and the like, or, preferably, in an aqueous solution of a lower alkanol.
  • an alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide and the like
  • a lower alkanol e.g. methanol, ethanol and the like
  • This procedure including the preparation of the starting material may be illustrated, for example, by the hydrolysis of ethyl l8-O-methyl-reserpate furnishing the IS-O-methyI-reserpic acid, which may then be esterificd with a diam-compound other than diazoethane, for example, diazomethane and the like.
  • R represents lower alkyl, particularly methyl and the like, and R, stands for lower alkoxy, particularly methoxy, whereby the latter is preferably attached to the IO-position or the ll-position, salts, N-oxides or salts of N-oxides.
  • This group of compounds may be represented by 18-O-lower alkyl-reserpic acids, e.g. 18-O- methyl-reserpic acid, 1'8-0-ethyl-reserpic acid, 18-0-npropyl-deserpidic acid, l8-0-n-butyl-reserpic acid and the like, 18-O-lower alkyl-IG-methOxy-deserpidic acids, e.g.
  • Another preferred group of compounds are the 18-0- lower alkyl-deserpidic acids, e.g., l8-O-methyl-desenpidic acid, IB-O-ethyl-deserpidic acid and the like, as well as, for example, S-methyl l8-0-methyl-reserpic acid, 6-methyl-lS-O-methyl-deserpidic acid, 9-methyl-l8-O-methyldeserpidic acid, l0-methoxy-l8-O-methyl-reserpic acid, 10-chloro-18-O-methyl-deserpidic acid, l0-bromo-18-O- methyl-reserpic acid, IS-O-methyl-ll-methylmercaptodeserpidic acid, l0,ll-methylenedioxy-lS-O-n-propyl-deserpidic acid, l7-desmethoxy-l7-ethoxy-18-O-methyl-reserpic acid and the like.
  • the above starting materials may also be prepared, for example, by alcoholysis of a (16 18)-lactone of 18- hydro ry-l'i-lowe'r alkoxy-3-epi-allo-yohimbane l6-carboxylic acid, particularly a lactone of the formula:
  • R,, R R and K have the previously given meaning, a salt, an N-oxide or a salt of an N-oxide thereof, with an alcohol of the formula rnn-o-c ll 2 in which R R R and R have the previously given meaning, Ph represents monocyclic carbocyclic aryl and Z stands for hydrogen or lower alkyl, a salt, an N-oxide or a salt of an N-oxide thereof, the free hydroxyl group by treatment with a diam-reagent, such as a diazo-com pound of the formula R N in which R, has the previously given meaning, in the presence of a strong inorganic Lewis acid, and converting in a resulting IB-etherified hydroxyl-I7-lower alkoxy-3-epi-allo-yohimbane 16-carboxylic acid ester, particularly in a resulting compound of the formula:
  • the alcoholysis of the lactone is carried out according to known methods; for example, an alcohol of the formula Ph(Z)CHOI-l, in which Ph and Z have the previously indicated meaning, or a solution thereof in an inert solvent, is reacted with an alkali metal, e.g. sodium, potassium and the like, and the resulting reagent is treated with the lactone or a solution thereof.
  • the reaction may prooeed 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.
  • the monocyclic carbocyclic aryl radical Pb in the above alcohol stands primarily for phenyl; it may also represent substituted phenyl, whereby substituents may be lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, or halogeno, e.g. chloro, bromo and the like or any other substituent, which does not hinder the alcoholysis or the subsequent cleavage 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.
  • Etherification of the free hydroxyl group in l8-position may be carried out as previously shown, i.e. by treatment with an appropriate diazo-reagent in the presence of a strong Lewis acid, e.g. fiuoboric acid and the like.
  • a strong Lewis acid e.g. fiuoboric acid and the like.
  • the esterified carboxyl group may be converted to the free carboxyl group, for example, by hydrogenolysis, which may be carried out by treatment of the ester, preferably in solution, for example, in a lower alkanol, e.g. methanol, ethanol and the like, with hydrogen in the presence of a catalyst, which contains a metal of the eighth group of the periodic system, for example, palladium, e.g. palladium black, or any other suitable catalyst. If necessary, an increased pressure, and/or an 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.
  • hydrogenolysis which may be carried out by treatment of the ester, preferably in solution, for example, in a lower alkanol, e.g. methanol, ethanol and the like, with hydrogen in the presence of a catalyst, which contains a metal of the eighth group of the periodic system, for example, palladium,
  • the resulting reaction mixture is freed from the catalyst, for example, by filtration, and the desired product may be isolated according to standard methods, for example, by extraction, crystallization, adsorption and elution, and the like and is purified, for example, by recrystallization and the like.
  • the ester group may also be cleaved by hydrolysis, for example, by the previously described alkaline hydrolysis or by acid hydrolysis, for example, by treatment with a 16 hydrohalic acid, e.g. hydrogen bromide and the like, in a lower alkanoic acid, e.g. glacial acetic acid and the like.
  • a 16 hydrohalic acid e.g. hydrogen bromide and the like
  • a lower alkanoic acid e.g. glacial acetic acid and the like.
  • R represents lower alkyl, particularly methyl and the like, and R stands for lower alkoxy, especially methoxy and the like, whereby the group R is preferably attached to the Ill-position or the ll-position salts, N- oxides or salts of N-oxides thereof.
  • Such compounds are, for example, benzyl l8-O-lower alkyl-reserpates, e.g. benzyl lS-O-methyl-reserpate, benzyl 18-O-ethyl-reserpate and the like, benzyl l8-O-lower alkyl-l0-methoxydeserpidates, e.g.
  • benzyl IO-methoxy-lS-O-methyl-deserpidate benzyl lO-methoxy-lB-O-n-propyl-deserpidate and the like.
  • Other highly useful intermediates are, for example, the benzyl 18-O-lower alkyl-deserpidates, e.g. benzyl 18-O-methyl-deserpidate, benzyl 18-O-ethyl-deserpidate and the like, or analogous compounds.
  • Compounds of the present invention may also be ob tained by transesterifying in l8-etherified hydroxy-l7- lower alkoxy-3-epi-allo-yohimbane 16-carboxylic acid ester, particularly in compounds of the formula:
  • Alcohols of the formula R -OH are, therefore, primarily lower alkanols such as methanol, ethanol, propanol, butanol or isobutanol and the like.
  • Other alcohols, particularly alcohols of the formula R OH are those, in which R represents substituted lower alkyl, such as etherified hydroxy-lower alkyl, e.g.
  • alcohols are, for example, Z-methoxyethanol, 2-ethoxyethanol, 3-methoxypropanol, 2-N,N-dimethyl-ethanol, 2-N,N-diethylaminoethanol and the like.
  • Transesterification is carried out in the presence of a transesterification catalyst, particularly a basic transesterification catalyst.
  • a transesterification catalyst particularly a basic transesterification catalyst.
  • Such catalysts are, for example, alkoio ide ions, as, for example, furnished by alkali metal lower alkanolates, e.g. lithium, sodium or potassium methanolate, ethanolate, n-propanolate, n butanolate, or isobutanolate and the like, alkaline earth metal lower alkanolates, e.g. barium or strontium methanolate, ethanolate, n-propa-nolate, n-butanolate, or isobutanolate and the like, or aluminum lower alkanolates, e.g.
  • alkanolate compounds are employed together with the corresponding lower alkanol used as the transesterification reagent.
  • Other alcohols such as those of the formula il -OH, in which R represents, for example, substituted lower alkyl, such as etherified hydroxy-lower alkyl, e.g. lower al-koxy-lower alkyl and the like, tertiary aminolower alkyl and the like, may be used in the presence of the corresponding alkali metal, alkaline earth metal or aluminum alcoholates.
  • Other basic tra-nsesterification 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.
  • the transesterification reaction may also be catalyzed by acidic reagents; inorganic acids, such as tungstic acid and the like, or organic acids, such as ptoluene sulfonic acids and the like, may be used.
  • esterifying alcohols which may simultaneously serve as diluents
  • inert solvents may be used in the above-mentioned transesterification reaction
  • carbocyclic aryl hydrocarbons e.g. benzene, toluene and the like
  • 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.
  • alower alkyl'l B-Ornethyl-reserpate in which lower alkyl contains more than one carbon atom, may be treated with methanol in the presence of a transesterfying reagent, such as, for example, sodium methanolate to form the desired methyl l8-O-methylreserpate.
  • a transesterfying reagent such as, for example, sodium methanolate
  • the compounds of the present invention may also be prepared, for example, by removing in IS-etherified hydroxy-l7-lower alkoxy-B-epi-allo-yohimbane 16-carboxylic acid ester salts, which contain attached to the nitrogen atom representing the d position a substituent, particularly in compounds of the formula:
  • R represents a group capable of being removed
  • A11 stands for an union, the substituent attached to the nitrogen atom of the 4-position, for example, the group R, and, if desired, carrying out the optional steps.
  • the substituent attached to the nitrogen atom may be an altiphatic hydrocarbon radical, such as, for example, lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl, isopropyl, n-butyl and the like, lower alkenyl, such as allylic lower alkenyl, containing preferably from three to five carbon atoms, e.g. ally], Z-methylollyl, Z-butenyl and the like, or any other suitable aliphatic radical.
  • an altiphatic hydrocarbon radical such as, for example, lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl, isopropyl, n-butyl and the like
  • lower alkenyl such as allylic lower alkenyl, containing preferably from three to five carbon atoms, e.g. ally], Z
  • the group attached to the nitrogen atom of the 4-position may also stand for a substituted aliphatic hydrocarbon radical; substituting groups may be, for example, carbocyclic aryl, such as monocyclic or bicyclic carbocyclic aryl, e.g. phenyl, 1- naphthyl, Z-naphthyl and the like, or analogous radicals substituted by additional groups, such as lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, halogeno, e.g.
  • aliphatic hydrocarbon radical may be functional groups, such as, for example, etherified hydroxyl, particularly lower alkoxy, containing preferably from one to tour carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy and the like, carbocyclic aryloxy, particularly monocyclic or bicyclic carbocyclic aryloxy, e.g.
  • phenyloxy and phenyloxy in which phenyl is substituted by.
  • additional substituents such as those previously mentioned, earbocyclic aryl-lower aliphatic hydrocarbonoxy, such as monocyclic or bicyclic carbocyclic aryl-lower al-koxy, e.g. benzyloxy, diphenylmethyloxy and the like and analogous groups, in which the carbocyclic aryl nucleus contains additional substituents, such as those mentioned hereinbefore.
  • Other functional groups attached to an aliphatic hydrocarbon radical substituting the nitrogen atom of the 4-position are, for example, etherifiecl mercapto, such as, for example, lower alkylmercapto, e.g.
  • carbocyclic aryl-mercapto such as monocyclic or bicyclic oarbocyclicmercapto, e.g. phenylmercapto and the like and phenylmercapto, in which phenyl is sub stituted by the aforementioned substituents
  • carbocyclic aryl-lower aliphatic hydrocarbon-mercapto such as monocyclic or bicyclic oarbocyclic aryl-lower alkyl-mercapto, e.g.
  • the aliphatic hydt ocmbon group to which the abovementioned substi-tuents are added, are primarily represented by lower alkylene radicals, above all by the methylene radical, as well as by 1,1-ethylene, LZ-ethylene, 1,1- propylene and the like.
  • Preferred substituted aliphatic hydrocarbon radicals attached to the nitrogen atom of the 4-position are, for example, monocyclic carbocyclic aryl-lower alkyl, particularly monocycl-ic carbocyclic aryl-methyl, e.g.
  • lower alkyl-mercapto-lower alkyl particularly lower alkyl-meroaptome-thyl, e.g. methylmercaptomethyl, ethylmercaptomethyl and the like
  • monocyclic carbccyclic aryl-lower alkyl-mer capto-lower alkyl especially monocyclic carbocyclic andlower alkyl-mercaptomcthyl, e.g. benzylmercapbomethyl and the like
  • halogeno-lower alkyl primarily halogenomethyl, e.g.
  • chloromethyl bromomethyl and the like, carbo-lowelr alkoxy-lower alkyl, particularly carbodower alkoxy-methyl, eg carbomethoxyrnet hyl, carbethoxymethy] and the like.
  • the anion of the salts used as the starting materials stands primarily for the anion of a strong inorganic, especially mineral, acid, e.g. hydrochloric, hydnobromic, hydriodic, sulfuric, fiuoboric acid and the like, or of a strong organic, particularly a strong organic sulfonic, acid, e.g. p-tolnene sul-fonic acid and the like.
  • the group attached to the nitrogen atom of the 4 position may be removed according to methods, the selection of which depends primarily on the nature of this group.
  • the substituent may be cleaved off by pyrolysis at an elevated temperature, preferably under reduced pressure, and, if desired, in a high-boiling solvent and/or in the atmosphere of an inert gas, e.g. nitrogen.
  • an inert gas e.g. nitrogen.
  • Specifically substituted groups may be removed by other procedures.
  • monocyclic carbocyclic arylmethyl or l-monocyclic carbocyclic arylcthyl groups such as benzyl, diphenylmethyl, trityl, l-phenylethyl and the like, as well as monocyclic carbocyclic aryl-lower alkoxymethyl, e.g. benzoyl-oxymethyl, diphenylmothoxymethyl and the like, or any other analogous substitnenlt
  • hydrogenolysis for example, by treatment with hydrogen in the presence of a catalyst containing a metal of the eighthgroup of the periodic system, e.g. nickel, palladium and the like.
  • etherified hydroxy'mcthyl such as lower alkoxymethyl, e.g. methoxymethyl and the like, or any other ethe-rified hydroxymethyl group, e.g. benzyloxymethyl and the like, h-alogenomethyl, e.g. chloromethyl and the like, carbo-lower alkoxy-methyl, e.g. car-bornethoxyrnethyl, carbeflio xymemyl and the like, my be re moved by hydrolysis, for example, by treatment with a dilute inorganic acid, such as, for example, hydrochloric, sulfuric acid and the like.
  • a dilute inorganic acid such as, for example, hydrochloric, sulfuric acid and the like.
  • Still other groups represenh ing, for example, the substituent R in the above formula, particularly etherified mercaptomethyl, such as lower alkyl-mercaptomethyl, e.g. methylmercaptcmcthyl, ethylmercaptomethyl and the like, earbocyclic aryl-memapto methyl, particularly monocyclic aryl-mercaptlomethyl, e.g. phenylmercaptomethyl and the like, or carbocyclic a-ryllower aliphatic lrydrocarbommercaptomethyl, such as mono-cyclic carbocyclic aryl-lower alkyl mercaptomethyl, e.g. benzylmercaptomethyl and the like, may be removed by desulfurization in the presence of a hydrogenation catalyst, particularly a catalyst a metal of the eighth group of the periodic system, e.g. Raney nickel, palladium black and the like.
  • a hydrogenation catalyst particularly a
  • the starting materials used in the above procedure may 20 be obtained according to dilferent methods.
  • an 18-hydroxy-17-lower alkoxy-3-epi-allo-yohimb ane l6-carboxylic acid ester, particularly a compound of the formula:
  • R R R R and R have the previously given meaning, or a salt thereof, may be treated with a reactive ester of an aliphatic hydroxy-hydrocar-bon compound or a reactive ester of a substituted aliphatic hydroxy'hydiocarbon compound, which contains as a substituent one of the above-mentioned groups, represented, for example, by the compound of the formula R-OH, in which R has the previously given meaning, and, if necessary, the 18-hydroxyl group in a resulting 18-hydroxy-17-lower alkoxy-3-epi-alloyohimbane IG-carboxylic acid ester salt, which contains an aliphatic hydrocarbon or a substituted aliphatic hydrocarbon attached to the nitrogen atom of the 4-posi-tion, particularly in a resulting compound of the formula:
  • R R R R R R R and An have the previously given meaning, may be etherificd and the desired star-ting materials may be isolated.
  • Reactive esters of aliphatic hydroxy-hydrocarbon and substituted aliphatic hydroxy-hydrocarbon compounds are particularly those with strong inorganic acids, particularly strong mineral acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like, or with strong organic acids, such as organic sulfonic acids, e.g. p-toluene sulfonic acid and the like.
  • the reaction is carried out in the absence or presence of an inert solvent, under cooling, at room temperature or at an elevated temperature, and, if necessary, under pressure or in the atmosphere of an inert gas, e.g. nitrogen.
  • etherification of the free hydroxyl group in the 18- position may occur simultantously with the introduction of a removable group into the 4-position.
  • a free 18- hydroxyl group in a resulting compound may then be etherified as previously shown, for example, by treatment with an aliphatic diam-hydrocarbon, particularly a lower diazo-alkane, such as diazomethane and the like, or a substituted aliphatic diam-hydrocarbon, such as an etherified hydroxy-lower diazo-alkane and the like, if necessary, in the presence of a strong Lewis acid, such as fluoboric acid and the like.
  • each of the radicals R and R stands for lower alkyl, particularly methyl and the like R represents lower alkoxy, especially methoxy and the like, whereby R is preferably attached to the IO-position or the ll-position, R stands for lower alkyl, especially methyl and the like, monocyclic carbocyclic aryl-lower alkyl, particularly monocyclic carbocyclic aryl-methyl, e.g. benzyl and the like, or l-monocyclic oarbocyclic aryl-methyl, e.g.
  • etherified hydroxy-lower alkyl such as lower alkoxy-lower alkyl, particularly lower alkoxymethy l, e.g. methoxymethyl and the like, monocyclic carbocyclic aryl-lower alkoxy'lower alkyl, particularly monocyclic carbocyclic aryilower alkoxy-methyl, e.g. benzyloxymethyl, diphenyloxymethyl and the like, lower alkyl-mercapto-lower alkyl, particularly lower alkyl-mercaptomethyl, e.g. methylmercaptomethyl and the like, halogeno-lower alkyl, particularly halogenomethyl, e.g.
  • A11 represents the anion of a strong acid, primarily a strong inorganic acid.
  • Another preferred group of starting materials may be represented by the compounds of the formula:
  • R R R R R R R R and A11 have the previously given meaning, with the proviso that the groups R R and R have the same meaning, may also be obtained, for example, by treating a (16 18)-lactone of an l8-hydroxy-l7-lower alkoxy-3-epi-allo-yohimbane 16-carboxylic acid, particularly a compound of the formula:
  • R R R and R have the previously given meaning, or a salt thereof, with a tri-substituted oxonium fluoborate and recovering the desired compound.
  • the above-mentioned tri-substituted oxonium fluoborate reagent may be represented, for example, by tri-lower alkyl-oxonium fluoborate, especially by trimethyl-oxonium fluoborate, as well as triethyl oxonium fluoborate and the like.
  • the reaction with this reagent is preferably carried ,out in the presence of an inert solvent, if necessary, at an elevated temperature, and, if necessary, under presure or in the atmosphere of an inert gas, e.g. nitrogen,
  • the above reaction i.e. treatment of a (16+ 18)-lactone of 18-hydroxy-17-lower alkoxy-3-epi-allo-yohimhane 16- carboxylic acid with a tIi-substituted oxonium fluoborate, may also yield the desired IS-etherified hydroxyl7- lower alkoxy-3-api-allo-yohimbane lfi-earboxylic acid esters directly as a by-product, particularly the 17,18-di-lower alkoxy-S-epi-allo-yohimbane l6-carboxylic acid lower alkyl esters, such as those of the formula:
  • R R R and R have the previously given meaning, and the radicals R and R representing lower alkyl, have the same meaning, whenever the lactone, used as the starting material, is reacted with a tri-lower alkyl-oxonium fluoborate.
  • the formation of the compounds of this invention according to the above procedure is, therefore, also included within the scope of the invention; it may be illustrated by the reaction of the (l6- l8)-lactone of reserpic acid with trimethyl oxonium fluoborate, preferably in the presence of a diluent, and isolation of the desired methyl 18-0-methyl-reserpate.
  • An additional procedure useful for the preparation of compounds of the present invention comprises removing in IS-etherified hydroxyl-l7-lower alkoxy-B-epi-allo-yohimbane l6-carboxylic acid N-oxides, particularly in compounds of the formula:
  • R,, R R R R and R or salts thereof the oxygen atom ataehed to the nitrogen atom in the 4-position, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting compound into a salt thereof.
  • the oxygen atom may be removed by treatment with a reducing reagent, for example, with hydrogen in the presence of a catalyst, which contains a metal of the eighth group of the periodic system, such as nickel, platinum, palladium and the like, e.g. Raney nickel, platinum oxide and the like, or with nascent hydrogen, as generated, for example, by heavy metals, e.g. iron, zinc, tin and the like, in the presence of acids, e.g. acetic acid and the like, or with any other appropriate reducing reagent or method.
  • a reducing reagent for example, with hydrogen in the presence of a catalyst, which contains a metal of the eighth group of the periodic system, such as nickel, platinum, palladium and the like, e.g. Raney nickel, platinum oxide and the like, or with nascent hydrogen, as generated, for example, by heavy metals, e.g. iron, zinc, tin and the like, in the presence of acids, e.g. ace
  • the starting materials used in the above reaction may be prepared, for example, by etherifying in an l8-hydroxy-l7- lower alkoxy-3-epi-allo-yohimbane l6-carboxylic acid ester N-oxide, particularly in a compound of the formula:
  • R R R R and R have the previously given meaning, or a salt thereof, the 18-hydroxyl group.
  • This etherification may be carried out by treatment with an aliphatic diazo-hydrocarbon, such as lower diazo-alkane, particularly diazomethane and the like, or a substituted ali phatic diam-hydrocarbon, preferably in the presence of a strong Lewis acid, e.g. fluoboric acid and the like, in the presence of a suitable solvent according to the previously outlined method, or by treatment with any other etherification reagent suitable for the etherification of a secondary hydroxyl group.
  • an aliphatic diazo-hydrocarbon such as lower diazo-alkane, particularly diazomethane and the like
  • a substituted ali phatic diam-hydrocarbon preferably in the presence of a strong Lewis acid, e.g. fluoboric acid and the like, in the presence of a suitable solvent according to the previously outlined method, or by treatment with any other
  • N-oxides used as intermediates for the preparation of the starting materials are known, or, if new, may be prepared according to methods used for the preparation of known compounds.
  • the compounds of the present invention may also be prepared by removing in IS-etherified hydroxy-l7-lower alkoxy-allo-yohimbane l6-carboxlic acid esters, in which a double bond extends from the 3-position or salts of such compounds, par-ticularly in compounds of the formula:
  • R R R R R R and R have the previously given meaning, and in which a double bond extends from the 3-position, or salts thereof, the double bond extending from the 3-position by reduction and, if desired, carrying out the optional steps.
  • the double bond extends probably from the 3-position to the l4-position, or, in the salts thereof, from the 3-position to the 4-position.
  • the anion in the above-mentioned salts stands primarily for the anion of a strong inorganic acid, particularly a mineral acid, such as a hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like, or phosphoric acid, a halogenophosphoric acid, e.g. chlorophosphoric acid and the like, or perchloric acid or any other suitable acid. It may also represent the anion of an organic acid; a salt with an organic acid may be present whenever a solution of the starting material in an organic acid, e.g. acetic acid and the like, is used in the above-described removal procedure.
  • the removal of the double bond may be carried out with the help of a reduction procedure, particularly by treating a solution of the starting material in an acid, such as, for example, acetic acid (preferably in the form of aqueous acetic acid), perchloric acid and the like, with a metal. Together with the acid the metal furnishes the reducing reagent capable of reducing the double bond; zinc, in the presence of an acid, e.g. acetic, percbloric acid and the like, yields a very useful reducing reagent.
  • Zinc in the presence of perchloric acid which may be used in an aqueous mixture or in admixture with another acid, e.g.
  • acetic acid represents the preferred reagent; this reagent is particularly suitable because the rate of reduction is fast and any contact of the starting material, as well as the reduction product with the acidic medium can be kept to a minimum.
  • Organic diluents such as ethers, e.g. tetrahydrofuran, p-dioxan and the like, lower alkanones, e.g. acetone and the like, or any other suitable solvent may be present as additional diluents, if desired, together with water.
  • the reduction may he carried out at room temperature, or, if necessary, under cooling or at an elevated temperature.
  • the product of the reduction procedure may be isolated, for example, by neutralizing the reaction mixture with an alkaline reagent, e.g. ammonia and the like, if desired, after removing the solvent or part of it, and extracting the organic material with a solvent, e.g. methylene chloride and the like, or by any other suitable isolation method.
  • an alkaline reagent e.g. ammonia and the like
  • a solvent e.g. methylene chloride and the like
  • the above procedure may be illustrated, for example, by the treatment of methyl n -clehydro-ltl-O methyl-reserpate, in which the double bond probably extends from the 3-position to the l4-position, or a methyl A -dehydro- IS-O -methyI-reserpate salt, in which the double bond extends from the 3-position to the 4-position, with zinc in the presence of an acid, e.g. acetic, perchloric acid and the like, and the isolation of the desired methyl 18-0- methyl-reserpate.
  • an acid e.g. acetic, perchloric acid and the like
  • the starting material which is used in the above procedure and has the previously given formula, is new and is intended to be included within the scope of the present invention.
  • a preferred group of starting materials has the previously given formula and is particularly represented by the compounds of the formula:
  • each ofthe groups R and R stands for lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl, isopropyl, n-butyl and the like, and R stands for lower alkoxy, containing preferably from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, n-butyloxy and the like, whereby R is preferably attached to the l-position or the ll-position, and in which a double bond extends from the 3-position to the 14-position, and salts of such compounds, in which a double bond extends from the 3-position to the 4- position, especially salts containing as the anion portion an anion derived from an inorganic, particularly a mineral, acid, such as one of those mentioned hereinabove.
  • this group of starting materials are, for example, lower alkyl A -dehydro-l8-O-lower alkyl-re serpa'tes, e.g. methyl d -dchydro-lS-O-rnethyl-reserpate, methyl A -dehydro-1B-O'ethyl-reserpate, methyl A dehydro-l80-n-propy-l-reserpate, methyl M-dehydro-liS-O-m butyl-reser-pate, ethyl A -dehydro-I8-O-methyl-reserpate, ethyl .M-dehydro-d8-O-ethyl-reserpate, n-propyl A -dehydro-lB-O-methyl-rescrpate, isopropyl M-dehydro-lE-O- methyhreserpatc,
  • Another group of very usefiul intermediates are, for example, lower alkyl n -dehydro-l 8-0-lower alkyl-deserpidates, e.g. methyl M-dehydro-lS-O-methyl-deserpidate, methyl M-dehydro-l8-0-ethyl-deserpidate, methyl A -dehydro-18-O-n-butyl-deserpidate, ethyl A -del1ydro-18-O- methyl-desenpidate, ethyl M-dehydro-lS-O-n-propyl deserpidate, n-propyl A -dehydrod8-0-methyl-deserpidate, isopropyl n -dehydro-l S-O-methyl-deserpidate, n-butyl A -de- 26 hydro-18-0-methyl-deserpidate and the like, in which the double bond probably extends from the 3-position to the 14
  • Salts of the above-mentioned compounds contain as anions those of inorganic, particularly mineral, acids, such as hydrohalic acids, e.-g. hydrochloric, hydrobromic acid and the like, phosphoric acid, halogenophosphoric acids, e.g. chlorophosphoric acid and the like, or perchloric acid or any other suitable inorganic acid, as well as organic acids, e.g. acetic acid and the like.
  • acids such as hydrohalic acids, e.-g. hydrochloric, hydrobromic acid and the like, phosphoric acid, halogenophosphoric acids, e.g. chlorophosphoric acid and the like, or perchloric acid or any other suitable inorganic acid, as well as organic acids, e.g. acetic acid and the like.
  • the above-mentioned starting materials may be prepared, for example, by etherifying in an l8-hydroxy-l7- lower alkoxy-3-oxo-2,Zl-seco-allo-yohimbane 16-carbox.
  • ylicl acid ester particularly in a compound of the formu a:
  • R,, R R R and R have the previously given meaning, the free hydroxyl group in the 18-position, and converting the resulting l8-etherified hydroxy-17-lower alkoxy-3-oxo-2,3-seco-allo-yohimbane 16-carboxylic acid ester, particularly the resulting compound of the formula:
  • R R R R R and R have the previously given meaning, into the desired starting material by ring closure, and, if desired, converting a resulting salt into the free base.
  • the etherification of the free hydroxyl group of the 18- position in the 2,3-seco-compound can be carried out according to known etherification procedures.
  • an aliphatic diam-hydrocarbon such as a lower diazo-alkane, particularly diazornethane and the like or a substituted aliphatic diam-hydrocarbon, for example, as in the previously described procedure in the presence of a Lewis acid, such as, for example, fluoboric acid and the like, alfords the desired etherification.
  • a Lewis acid such as, for example, fluoboric acid and the like
  • the latter may also be carried out by treatment with other reagents suitable for the etherification of a secondary hydroxyl group.
  • Such reagents are, for example, reactive esters formed by aliphatic hydroxy-hydrocarbon compounds, such as lower alkanols, particularly methanol, as well as ethanol and the like, or by substituted aliphatic hydroxy-hydrocarbon compounds with strong acids, such as inorganic acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like, or with organic acids, particularly strong organic sulfonic acids, eg, p-toluene sulfonic acid and the like, which reagents are preferably used in the presence of reagents facilitating the etherification procedure.
  • strong acids such as inorganic acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like
  • organic acids particularly strong organic sulfonic acids, eg, p-toluene sulfonic acid and the like
  • reagents are preferably used in the presence of reagent
  • reagents are preferably used in the presence of a base, such as an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, lower alkyl halides, especially methyl chloride, methyl bromide, methyl iodide and the like, as well as ethyl, n-propyl or n-butyl chloride, bromide or iodide and the like, which reagents are preferably used in the presence of a basic reagent, such as, for example, silver oxide and the like, or any other suitable etherification procedure.
  • a base such as an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, lower alkyl halides, especially methyl chloride, methyl bromide, methyl iodide and the like, as well as ethyl, n-propyl or n-butyl chloride, bromide or iodide
  • Ring closure of the resulting ether compound can be achieved, for example, by treatment with an acidic ring closing reagent, for example, phosphoric acids, e.g. polyphosphoric acid and the like, phosphorus halides, e.g. phosphorus trichloride, phosphorus pentachloride, or advantageously phosphorus oxyhalides, e.g. phosphorus oxychloride and the like.
  • an acidic ring closing reagent for example, phosphoric acids, e.g. polyphosphoric acid and the like, phosphorus halides, e.g. phosphorus trichloride, phosphorus pentachloride, or advantageously phosphorus oxyhalides, e.g. phosphorus oxychloride and the like.
  • R has the previously given meaning
  • An represents an anion, derived, for example, from the acidic ring closing reagent, into the free base, in which the double bond extends probably from the 3-position to the l t-position, particularly into a compound having probably the partial formula:
  • R has the previously given meaning
  • a base particularly ammonia, as well as an alkali metal carbonate, e.g. sodium, potassium carbonate or hydrogen carbonate and the like.
  • an alkali metal carbonate e.g. sodium, potassium carbonate or hydrogen carbonate and the like.
  • the free base forms a salt, in which the double bond extends from the 3-position to the 4-position.
  • R R R R R R and R have the previously 28 given meaning, are new and are intended to be included within the scope of the present invention.
  • Particularly useful as intermediates are the compounds of the formula:
  • each of the radicals R and R represents lower alkyl, preferably containing from one to four carbon atoms, especially methyl, as well as ethyl, n-proply, isopropyl, n-butyl, secondary butyl and the like, and R represents lower alkoxy, especially lower alkoxy containing from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby such lower alkoxy group R is preferably attached to the 10-position or the ll-position.
  • Specific compounds of this group are, for example, lower alkyl l8-O-lower alkyl-3-oxo-2,B-seco-reserpates, e.g. methyl l8-O-methyl-3oxo-2,3-seco-reserpate, methyl 18- O-ethyl-3-oxo-2,3-seco-reserpate, methyl l8-O-n-propyl-3- oxo-2,3-seoo-reserpate, methyl l8-O-n-butyl-3-oxo-2,3- seco-reserpate, methyl 18-O-isobutyl-3-oxo-2,3-seco-reserpate, ethyl l8-O-methyl-3-oxo-2,3-seco-reserpate, ethyl l8-O-n-propyl-3-oxo-2,3-seco-
  • methyl ll-ethoxy-lS-O- methyl-3-oxo-2,3-seco-deserpidate methyl l1-ethoxy-18- 0-n-propyl-3-oxo-2,3-seco-deserpidate and the like
  • lower alkyl l8-O-lower alkyl-12-methoxy-3-oxo-2,3-seco-deserpidates e.g. methyl l2-methoxy-l8-0-metl1yl-3-oxo- 2,3-seco-deserpidate, ethyl 12-methoxy-18-O-methyl-3- oxo-2,3-seco-deserpidate and the like.
  • Another group of highly useful intermediates are the lower alkyl l8-0-lower alkyl-3-oxo-2,3-seco-deserpidates, e.g. methyl 18-0- methyl-3-oxo-2,3-seco-deserpidate, methyl l8-O-ethyl-3- oxo-2,3-seco-deserpidate, methyl 18-O-n-propyl-3-oxm 2,3-seco-deserpidate, methyl l8-0-n-butyl-3-oxo-2,3-secodeserpidate, ethyl 18-O-methyl-3-oxo-2,3-seco-deserpidate, ethyl 18-O-ethyl-3-oxo 2,3-seco-deserpidate, n-propyl l8-0-methyl-3-oxo-2,3-seco-deserpidate, n-propyl 18-0-11- propyl
  • the intermediates used for the preparation of the starting materials of the described procedure may also be obtained, for example, by etherifying in an ester of 3p-hy- 29 droxy-2a-lower alkoxy-7-oxo-la,2p,3a,4,7,8,9a,loot-octahydronaphthalene-lfl-carboxylic acid of the formula:
  • R represents particularly lower alkyl, particularly methyl, as well as ethyl, n-propyl, isopropyl, n-butyl and the like, the hydroxyl group in the Sfl-position according to known methods used for the etherification of a secondary hydroxyl group, for example, by treatment with a diazo compound, such as a lower diazo-alkane, particularly diazomethane and the like, in the presence of an etherification catalyst, particularly 'fluoboric acid and the like, as previously described.
  • a diazo compound such as a lower diazo-alkane, particularly diazomethane and the like
  • a,fiketone is then oxidized, for example, with osmium tetroxide, in an aqueous solution, followed by treatment with sodium chlorate, to form an ester of smfia-dihydroxy-Sfl-etherified hydroxy-Za-lower alkoxy-7-oxo-la,2fl, 3u,4,5fi,6fl,7,8,9,10u decahydronaphthalene 1p earboxylic acid having the formula:
  • R R and R have the above-given meaning, which diol is then oxidatively split, for example, by treatment with periodic acid hydrate in an aqueous medium, to a monoester of the Sfl-aldehydo'Bp-etherified hydroxy- 6p carboxyrnethyl 2n: lower alkxy-la,2fl,3m,4,5ot,6ahexahydrobenzene-lfl-carboxylic acid of the formula:
  • R R, and R halve the previously given meaning, and R
  • R represents, for example, hUWGl alkyl, particularly methyl, as well as ethyl and the like.
  • This com- 30 pound is then reacted with a trylptamine, particularly a tryptamine compound of the formula:
  • R R R R R R R and R have the previouslygivonmisfiormedflnwhichflmeesterified carboxyl groups may be partially or totally hydrolized.
  • Hydmlized earboxyl groups may subsequently be re-esterified (for example, with a lower aliphatic du'azohydrocarbou, such as a lower diazoallnane, particularly diazomethamaswellasdiazoethaneandthelikeormyoflier suitable dnt).
  • a dehydrating agent such as, for example, a OBIbOXYliC acid anhydride, eg.
  • Import-ant intermediates are, for example, compounds of the formula:
  • R R, and R have the above-given meaning.
  • Particularly useful intermediates are the lower alkyl Zamethoxy-7-oxo-3fllower al-koxy-la,25,3m,4,7,8,9a,IOu-octahydronaphthnlene-lflmrboxylates, in which lower alkyl, containing from one to ⁇ our carbon atoms, represents primarily methyl, as well as ethyl, n-pnopyl and the like, and lower alkoxsy, containing from one to four carbon atorns, stands primarily for methoxy, as well as ethoxy, nn-propylox-y and the like, particularly methyl 2,3;8-dimeuhoxyJ-oxo-la,2fl,3a,4,7,8,9a,l0a ootahydronaphthalene-lfl-carboxylate and the like.
  • R R and R have the previously given meaning.
  • These intermediates are illustrated by the lower alkyl 50:,6a-djhYdl0XY-2a-In6th0XY-17-0XO-3B-[OW6I' alkoxy 1a,2fi,3a,4,5fl,6fi,7,8,9a,10a deoahydronaphthalenelfi-carboxylate's, in which lower alkyl, containing from one to four carbon atoms, represents primarily methyl, as well asethyl, n-propyl and the like, and lower alkoxy, containing from one to four carbon atoms, stands particularly for methoxy, as well as ethoxry, n-propylbxy and the like, especially by methyl $a,6a-dihYdlOXY-2u,3fldi lower alkoxy 7 oxo 1a,2,8,3m,4,5fl,6fl,7,8,9a,
  • R R and K have the perv'iously given meaning.
  • This group of intermediates may be represented by lower alkyl Sfi-aldehydoB-carboxymethyl-h-methoxy- 3fl-lower alkoxy-la,2fl,3a,4,5a,6u-helrahydrobenzene-lflcarbomylates, in which lower alkyl, containing from one to four carbon atoms, represents primarily methyl, as well as ethyl, n'propyl and the like, and lower alkoxy, containing from one to four carbon atoms, stands particularly for methoxy, as well as ethoxy, n-propyloxy and 32 the like, [primarily by methyl Sp-aldehydotSp-carboxymethyl 201,3,9 d imet'hoxy 1a,2fl,3nt,4,5at,6a. hexahydrobenzene-lfl-carboxylate land
  • R R R and R have the previously given meaning.
  • This group of intermediates is represented by lower alkyl 5fi-aldehydo-6fl-carbo-lower alkoxy-methyl- 2a-methoxy-3fl-lower alkoxy-1a,2B,3a,4,5a,6a,-hexahydrobenzene-lficarboxylate, in which lower alkyl, contairnnlg from one to four carbon atoms, represents primarily methyl, as well as ethyl, n-propyl and the like, and lower alkoxy, containing from one to four carbon atoms, stands particularly for methoxy, as well as ethoxy, n-propyloxy and the like, and especially by methyl 5paldehydo 6p carbomethoxy methyl 2a,3p dimethoxy la,2fl,3a,4,5nt,6a hexahydrobenzene lfl carboxylate and the like.
  • R1, R1,, R2, R3, R4, R5 and R6 have the PI'CViously given meaning, or salts thereof.
  • Each of the rad- :icals R R and R represents primarily lower alkyl, containing from one to four carbon atoms, especially methyl, as well as ethyl, n-propyl and the like. This group of intenmediates may be represented by compounds of the formula:
  • alkoxy group is preferably attached to the S-position or the 6-position of the indole portion of the molecule, or salts thereof.
  • This group of intermediates may be represented by the lower alkyl A )-dehydro-3-lower alkoxy- IS-O-lower alkyl-3-oxo-2,3;3,4-bis-seoo-resenpates, particularly by the methyl M -dehydro-il-methyblS-O-methy-l-3-oxo-2,3;3,4-bis-seco-reserpate, as well as analogous compounds, and acid addition salts thereof.
  • each of the radicals R R and R represents lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl and the like, or salts thereof.
  • a further group of important intermediates are the 18- etherified hydmxy-3,17-bis-lower alkoxy-3-oxo-2,3;3,4- bis-seco-al'lmyohimbane lG-carboxylic acid esters, particularly the compounds of the formula:
  • R R1 R R R R and R have the previously given meaning, or salts thereof.
  • R R and R represents primarily lower alkyl, containing from one to four carbon atoms, particularly methyl, as well as ethyl and the like. These compounds may be represented by the compounds of the formula:
  • R and R have the same meaning and stand for lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as Well as ethyl and the like, R represents lower alkyl, containing preferably from one to four carbon atoms,
  • R represents lower alkoxy, containing preferably from one to four carbon atoms, especially methoxy as well as ethoxy and the like, or salts thereof.
  • This group of intermediates is represented by the lower alkyl 3-lower a1k0xy-l8-O-l0wer alkyl-3-oxo-2,3;3,4-bis-secoreserpates, particularly by methyl 3-methoxy-l8-O-methyl-3-oxo-2,3; 3,4-bis-seco-reserpate, or salts thereof.
  • each of the radicals R R and R represents lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl and the like, or salts thereof.
  • a further method for the preparation of the compounds of this invention comprises isomerizing IS-etherified hydroxy-l'Z-lower alkoxy-allo-yohimbane lfi-carboxylic acid esters, particularly compounds of the formula:
  • R R R R R R and R have the abovegiven meaning, salts, N-oxides or salts of N-oxides thereof, by treatment with an acid and isolating the desired IS-etherified hydroxy-17-lower -alkoxy-3-epi-allo-yohimbane
  • ItS-carboxylic acid esters particularly the desired compounds of the formula:
  • R R R R R R and R have the above given meaning, salts, N-oxides or salts of N-oxides thereof, and, if desired, carrying out the optional steps.
  • Acids used in the above isomerization procedure are, for example, organic carboxylic acids, particularly aliphatic hydrocarbon carboxylic acids, such as lower alkanoic acids, eg acetic, propionic acid and the like, primarily glacial acetic acid, organic sulfonic acids, particularly carbocyclic aryl sulfonic acids, e.g. p-toluene sulfonic acid and the like, or lower alkane sulfonic acids, e.g. methane sulfonic acid and the like, or strong mineral acids such as hydrohalic acids, e.g. hydrogen chloride and the like, or mixtures of acids.
  • organic carboxylic acids particularly aliphatic hydrocarbon carboxylic acids, such as lower alkanoic acids, eg acetic, propionic acid and the like, primarily glacial acetic acid, organic sulfonic acids, particularly carbocyclic aryl sulfonic acids, e.g. p
  • carbocyclic aryl sulfonic acids are advantageously used together with one of the aliphatic hydrocarbon carboxylic acids mentioned above, 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 also be used in the presence of an organic base, e.g. collidine and the like, whereas hydrogen chloride may be used in an anhydrous lower alkanol, e.g. methanol, ethanol and the like.
  • Isomerization may occur at room temperature or preferably at an elevated temperature, in an open vessel or under pressure, preferably in an atmosphere of nitrogen.
  • Optimum yields in the isomerization reaction may be obtained by removing the desired product from the reaction milieu, thus displacing the reaction equilibrium in favor of the product.
  • the removal may be accomplished by separating the product, if desired, in the form of a salt thereof, from the starting material by exploiting the different relative solubilities in diiferent solvent systems.
  • the product or a salt thereof may be separated from the starting material or a salt thereof either by adsorption on a suitable material, such as alumina, paper and the like, and subsequent fractional elution, or by fractional crystallization from a solvent or a mixture of solvents.
  • the starting material separated from the desired product may then be recycled into the isomerization process, to enhance the overall yield of the reaction.
  • each of the radicals R and R represents lowor alkyl, containing preferably from one to four carbon atoms, especially methyl, as well as ethyl, n-propyl, isopropyl and the like, and the radical R stands for lower alkoxy, containing preferably from one to four carbon atoms, especially for methoxy, as well as ethoxy, n-propyloxy and the like, whereby R is preferably attached to the l-position or the ll-position, acid addition salts, N-oxides or acid addition salts of N-oxides thereof.
  • This group of compounds is represented by lower alkyl 18-O- lower alkyl-S-iso-reserpates, e.g.
  • methyl ll-ethoxy-lB-O-methyl-3-iso-deserpidate ethyl ll-ethoxy-lS-O-n-propyl-B-isodeserpidate and the like
  • lower alkyl 18-0-lower alkyl- 1Z-methoxy-3-isodeserpidate e.g. methyl 12-methoxy- 18-O-methyl-3 iso deserpidate, methyl 18-0-ethyl-l2- 36 methoxy-3-iso-deserpida'te and the like, or acid addition salts of such and analogous compounds.
  • Another group of important starting materials useful in the above isomerization procedure are the lower alkyl 18-O-lower alkyl-B-iso-deserpidates, e.g. methyl 18-0- methyl-B-isodeserpidate, methyl l8-O-ethyl-3-iso-deserpidate, methyl l8-O-n-propyl-3-iso-deserpidate, ethyl 18-0- methyl-3-iso-deserpidate, ethyl l8-O-ethyl-3iso-deserpi date and the like, or salts of such compounds.
  • methyl 18-0- methyl-B-isodeserpidate methyl l8-O-ethyl-3-iso-deserpidate
  • methyl l8-O-n-propyl-3-iso-deserpidate ethyl 18-0- methyl-3-iso-deserpidate
  • the l8-etherified hydroxy-l7-lower alkoxy-allo-yohimbane l6-carboxylic acid esters used as the starting materials in the isomerization procedure may be prepared, for example, by removing in IB-etherified hydroxy-l7- lower alkoxy-allo-yohimbane l6-carboxylic acid esters, in which a double bond extends from the 3-position to the l4-position, or salts thereof, in which a double bond extends from the 3-position to the 4-position, particularly in compounds of the formula:
  • R R R R R R and R have the previously given meaning, in which a double bond extends from the 3-position to the l4-position, or salts thereof, in which a double bond extends from the 3-position to the 4-p0sition, the double bond extending from the 3-positi0tl t either the 4-position or the l4-position, and, if desired,- converting a resulting salt into the free compound, and, if desired, converting a resulting compound into a salt, an N-oxide or a salt of an N-oxide thereof.
  • the above-mentioned removal may be carried out by catalytic hydrogenation, for example, by treatment with hydrogen in the presence of a catalyst containing a metal of the eighth group of the Periodic System, e.g. nickel and the like, such as Raney nickel and the like, preferably in the presence of a solvent, such as a lower alkanol, e.g. methanol, ethanol and the like, or any other suitable diluent.
  • the reduction may be carried out at normal or under an increased pressure, and/or under cooling, at room temperature or at an elevated temperature.
  • the removal of the double bond may also be accomplished by treatment with a light metal hydride, particularly a borohydride, such as an alkali metal borohydride, etg.
  • lithium borohydride, sodium borohydride, potassium borohydridc and the like an alkaline earth metal borohydride, e.g. calcium borohydride, barium borohydride, strontium borohydride and the like, or an alkali metal lower a1- koxy-borohydn'de, e.g. sodium trimethoxy-borohydride and the like.
  • a solvent such as, for example, a lower alkanol, e.g. methanol, ethanol and the like, or a formamide, e.g. formamide, N,N-dimethylformamide and the like or any other suitable diluent.
  • the temperature may, if necessary, be elevated, and the reaction may be can ried out under the atmosphere of an inert gas, e.g. nitrogen.
  • the reduction of the double bond extending from the 3-position may also be carried out by treatment with a. metal amalgam in the presence of a moist solvent, such as an alkali metal amalgam, e.g. sodium amalgam and, the like, or aluminum amalgam in the presence of moist ether or any other suitable moist solvent.
  • a moist solvent such as an alkali metal amalgam, e.g. sodium amalgam and, the like, or aluminum amalgam in the presence of moist ether or any other suitable moist solvent.
  • the starting materials used in the isomerization procedure may also be produced, for example, by etherifyin'g: in 18-hydroxy-l7-l0wer alkoxy-allo-yohimbane l.6-car-- ammo boxylic acid esters, particularly in compounds of the formula:
  • R,, R R R R and R have the above-given meaning, a salt, an N-oxide or a salt of an N-oxide thereof, the free hydroxyl group attached to the Ill-position, and, if desired, carrying out the optional steps.
  • the above etherification of the secondary hydroxyl group attached to the l8-position may be carried out as previously shown, for example, by treatment with a diazo-reagent, such as an aliphatic diam-hydrocarbon, such as a lower diazo-alkane, particularly diazomethane, as Well as diazoethane, diazo-n-propane and the like, or a substituted aliphatic diam-hydrocarbon, such as, for example, an etherified hydroxy-lower diazo-alkane and the like, in the presence of a strong Lewis acid, such as fluoboric acid and the like.
  • a diazo-reagent such as an aliphatic diam-hydrocarbon, such as a lower diazo-alkane, particularly diazomethane, as Well as diazoethane, diazo-n-propane and the like
  • a substituted aliphatic diam-hydrocarbon such as, for example, an etherified hydroxy-lower diazo-
  • the compounds of this invention may also be prepared, for example, by replacing in an Ill-reactive esterified hydroxy-17-lower alkoxy-3-epi-allo-yohimbane 16car boxylic acid ester, particularly in a compound of the formula:
  • R,, R R R and R have the previously given meaning
  • E represents a reactive esterified hydroxyl group, a salt, an N-oxide or a salt of an N-oxide thereof, the reactive esterified hydroxyl group attached to the 18- position by an etherified hydroxyl group, and, if desired, carrying out the optional steps.
  • the hydroxyl group attached to the 18-position which is reactively esterified, and is represented, for example, by the group B in the above formula, is preferably esterified by an organic sulfonic acid, such as an aliphatic hydrocarbon sulfonic acid, particularly lower alkane sulfonic acid, especially methane sulfonic acid and the like, or a monocyclic carbocyclic aryl sulfonic acid, especially p-nitro-benzene sulfonic acid and the like.
  • an organic sulfonic acid such as an aliphatic hydrocarbon sulfonic acid, particularly lower alkane sulfonic acid, especially methane sulfonic acid and the like, or a monocyclic carbocyclic aryl sulfonic acid, especially p-nitro-benzene sulfonic acid and the like.
  • the reactively esten'fied hydroxyl group may, therefore, be represented by methane sulfonyloxy, p-nitro-benzene sulfonyloxy or analogous reactive esterified hydroxyl groups.
  • Replacement of the esterified hydroxyl group by an etherified hydroxyl group may be carried out by solvolysis, for example, by treatment with an alcohol of the formula R -0H, in which R, has the previously given meaning.
  • Solvolysis reagents are, therefore, aliphatic hydroxy-hydrocarbon compounds, such as lower alkanols, particularly methanol, as well as ethanol, n-propanol, isopropanol, nbutanol and the like, or substituted aliphatic hydroxyhydrocarbon, such as etherified hydroxy-lower alkanols and the like.
  • the reaction may be carried out in the presence of a diluent, such as an excess amount of the solvolysis reagent, particularly a lower alkanol, such as methanol and the like, or another solvent, for example,
  • solvolysis occurs at an elevated temperature, for example, under reflux, if necessary, under increased pressure or in the atmosphere of an inert gas, e.g. nitrogen.
  • the replacement of the above-described reactive esterified hydroxyl group by an etherified hydroxyl group may also occur by treatment with a metal compound of an alcohol of the formula R3-0H, in which R; has the previously given meaning.
  • Particularly useful as reagents are the alkali metal, e.g. lithium, sodium, potassium and the like, compounds of aliphatic hydroxy-hydrocarbons, such as lower alkanols, especially methanol, as well as ethanol, n-propanol and the like, or of substituted aliphatic hydroxy-hydrocarbons.
  • the treatment of the starting materials with these metal reagents is preferably carried out in the presence of a solvent, such as, for example, N,N-dimethyl-formamide, aoetonitrile and the like, if desired, in the presence of the alcohol forming the metal compound, such as a lower alkanol, particularly methanol, as well as ethanol and the like, and, if necessary, at an elevated temperature, under increased pressure and/or in the atmosphere of an inert gas, e.g. nitrogen and the like.
  • a solvent such as, for example, N,N-dimethyl-formamide, aoetonitrile and the like
  • the alcohol forming the metal compound such as a lower alkanol, particularly methanol, as well as ethanol and the like
  • the starting materials used in the above procedure may be prepared according to methods used for the manufacture of analogous compounds.
  • the free hydroxyl group in an l8-hydroxy-l7-lower alkoxy-Il-epiallo-yohimbane l6-carboxylic acid ester may be esterified by treatment of the mono-ester with a reactive derivative of an acid, particularly a halide, e.g. chloride and the like, thereof, in the presence of a tertiary base, e.g. pyridine and the like.
  • R,, R R R and R have the previously given meaning, and the grouping R "O represents an etherified hydroxyl group capable of being converted into another etherified hydroxyl group, particularly into a methoxy group, or a salt thereof, the etherified hydroxyl group into another etherified hydroxyl, particularly into a methoxy, group, and, if desired, carrying out the optional steps.
  • the etherified hydroxyl group attached to the ls-position is primarily represented by a methoxy group, which contains as a substituent a functional group capable of being replaced by a hydrogen atom.
  • functional groups are, for example, etherified mercapto, such as lower alkylmercapto, e.g. methylmercapto, ethylmercapto and the like, carboxyl, halogeno, e.g. chloro, bromo and the like, or any other group, which can be replaced by hydrogen.
  • substituents are replaced by hydrogen according to methods, the selection of which depends primarily on the nature of the different functional groups representing these substituents.
  • etherified mercapto groups may be removed by treatment with a hydrogenation catalyst, containing preferably a metal of the eighth group of the periodic system, e.g. nickel and the like, such as Raney nickel or analogous hydrogenation catalysts.
  • a halogen atom may be replaced by hydrogen, for example, by treating the starting material with catalytically activated hydrogen, for example, hydrogen in the presence of a palladium-containing catalyst, or any other suitable hydrogenation procedure.
  • a carboxyl group may be removed by decarboxylation, preferably at an elevated temperature.
  • Other substituents may be replaced by hydrogen while using appropriate methods.
  • the starting materials used in the above procedure may be prepared, for example, by removing in IS-etherified hydroxyl-l7-lower alkoxy-3-epi-allo-yohimbane l6-carboxylic acid ester salts, in which the etherified hydroxyl group is capable of being converted into another etherified hydroxyl group, and in which the nitrogen atom representing the 4-position carries a substituent capable of being removed, the substituent attached to the nitro gen atom of the 4-position.
  • the removal of the latter may be carried out according to previously shown meth- Ods.
  • the removal of the substituent attached to the 4- position to form the starting materials may occur simultaneously with the conversion of the etherified hydroxyl group of the Iii-position into another etherified hydroxyl group, and the desired formation of the desired final products.
  • the above-described intermediates used for the preparation of the starting materials may be obtained, for example, by etherifying in an l8-hydroxy-l7-lower alkoxy- 3-epi-allo-yohimbane lfi-carboxylic acid ester salt, which carries a removable substituent attached to the 4-position, the free hydroxyl group in the IS-position into an etherified hydroxyl group, which in the process of the invention is then capable of undergoing the transformation into the desired etherified hydroxyl group.
  • This etherification may be performed according to previously described methods.
  • the compounds of the present invention may be present in the form of mixtures of racemates, single racemates or antipodes. Racemates of intermediates and final products may be resolved into antipodes. Racematcs of final products or intermediates, which form acid addition salts, may be resolved, for example, by treating a solution of the free racemic base in a solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol and the like, a halogenated lower aliphatic hydrocarbon, e.g.
  • a solvent such as, for example, a lower alkanol, e.g. methanol, ethanol and the like, a halogenated lower aliphatic hydrocarbon, e.g.
  • optically active forms of an acid containing an asymmetric carbon atoms which may be employed in solution, for example, in one of the above-mentioned solvents.
  • a salt may then be isolated, which is formed by the optically active acid with one of the optically active forms of the base.
  • optically active forms of salt-forming acids having an asymmetric carbon atom are D- and L- tartaric acid, as well as the optically active forms of di-o- '40 toluyl-tartaric, malic, rnandelic, camphor-lO-sulfonic. quinic acid and the like.
  • Compounds, containing functional groups forming salts with bases may be resolved by reacting the free acid with the optically active form of a base containing an asymmetric carbon atom and thus forming a salt of such base with one of the optically active forms of the acid compound.
  • Suitable, optically active bases are, for example, the optically active forms of brucine, strychnine, quinine, cinchonine, cinchonidine and the like.
  • optically active forms may also be obtained by resolution with biochemical methods.
  • the free and optically active compounds may be obtained according to known methods used for the conversion of a salt into a free compound, for example, as outlined hereinbelow; a resulting optically active base may be converted into an acid addition salt with one of the acids mentioned hereinbefore.
  • the compounds of this invention or the N-oxides thereof may be obtained in the form of the free bases or as the salts thereof.
  • a salt including the salt of an N-oxide may be converted into the free base, for example, by reacting the former with an alkaline reagent, such as, for example, aqueous ammonia and the like.
  • a free base or the free N-oxide thereof may be converted into its therapeutically useful acid addition salts with one of the inorganic or organic acids outlined hereinbefore; the reaction may be carried out, for example, by treating a solution of the free base in a suitable solvent, such as a lower alkanol, e.g.
  • the salts may also be obtained as the hemihydrates, monohydrates, sesquihydrates or polyhydrates depending on the conditions used in the formation of the salts.
  • N-oxides of the compounds of the present invention may be formed according to known methods; for example, a resulting 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 persulfonic acids, e.g. p-toluene persulfonic acid and the like.
  • Inert solvents are, for example, halogenated lower alkanes, e.g.
  • 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 outlined hereinbefore.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Zoology (AREA)
  • Animal Husbandry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Fodder In General (AREA)
US37097A 1959-07-29 1960-06-20 Intermediates for 18-o-alkyl-reserpic acid esters and related compounds Expired - Lifetime US3119819A (en)

Priority Applications (25)

Application Number Priority Date Filing Date Title
US37097A US3119819A (en) 1959-07-29 1960-06-20 Intermediates for 18-o-alkyl-reserpic acid esters and related compounds
CH796760A CH414656A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung eines neuen Reserpsäurederivats
CH1551164A CH392539A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung eines neuen Reserpsäurederivats
CH796660A CH410967A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung neuer Reserpsäurederivate
CH76365A CH411918A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung neuer Reserpsäurederivate
CH1551364A CH388324A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung eines neuen Reserpsäurederivats
CH1551464A CH388325A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung eines neuen Reserpsäurederivats
CH796860A CH413850A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung neuer Reserpsäurederivate
CH76265A CH411917A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung neuer Reserpsäurederivate
CH76465A CH410971A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung neuer Reserpsäurederivate
CH796560A CH387054A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung eines neuen Reserpsäurederivats
CH1551264A CH392540A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung eines neuen Reserpsäurederivats
CH1551064A CH414660A (de) 1959-07-29 1960-07-14 Verfahren zur Herstellung eines neuen Reserpsäurederivats
DEC25721A DE1197737B (de) 1959-07-29 1960-07-26 Tierfuttermittel, Tierfutterzusatzmittel, Gefluegel-futtermittel oder Gefluegelfutterzusatzmittel
ES0259869A ES259869A1 (es) 1959-07-29 1960-07-26 Procedimiento para la obtenciën de un nuevo ester
ES0259870A ES259870A1 (es) 1959-07-29 1960-07-26 Procedimiento para la obtenciën de un nuevo ester
AT579960A AT241694B (de) 1959-09-01 1960-07-28 Verfahren zur Herstellung der neuen in 18-Stellung verätherten 17-Niederalkoxy-18-hydroxy-3-epi-alloyohimban-16-carbonsäureester, deren N-Oxyden und Salzen dieser Verbindungen
AT138061A AT241695B (de) 1959-09-01 1960-07-28 Verfahren zur Herstellung der neuen, in 18-Stellung verätherten 17-Niederalkoxy-18-hydroxy-3-epi-alloyohimban-16-carbonsäureester, deren N-Oxyden und Salzen dieser Verbindungen
AT137961A AT248031B (de) 1960-06-20 1960-07-28 Verfahren zur Herstellung der neuen, in 18-Stellung verätherten 17-Niederalkoxy-18-hydroxy-3-epi-alloyohimban-16-carbonsäureester, deren N-Oxyden und Salzen dieser Verbindungen
AT138161A AT241696B (de) 1959-09-01 1960-07-28 Verfahren zur Herstellung der neuen, in 18-Stellung verätherten 17-Niederalkoxy-18-hydroxy-3-epi-alloyohimban-16-carbonsäureester, deren N-Oxyden und Salzen dieser Verbindungen
NL254293A NL126895C (nl) 1959-09-01 1960-07-28 werkwijze ter bereiding van 18-alkoxyalloyohimbanderivaten met farmacologische werking
AT579760A AT241693B (de) 1959-07-29 1960-07-28 Verfahren zur Herstellung der neuen, in 18-Stellung verätherten 17-Niederalkoxy-18-hydroxy-3-epialloyohimban-16-carbonsäureester, deren N-Oxyden und Salzen dieser Verbindungen
GB26593/60A GB885981A (en) 1959-07-29 1960-07-29 New reserpine analogues and process for their manufacture
SE454964A SE314883B (de) 1959-07-29 1964-04-13
FI2236/64A FI40249B (de) 1959-07-29 1964-10-23

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US83018759A 1959-07-29 1959-07-29
US83735759A 1959-09-01 1959-09-01
US37097A US3119819A (en) 1959-07-29 1960-06-20 Intermediates for 18-o-alkyl-reserpic acid esters and related compounds

Publications (1)

Publication Number Publication Date
US3119819A true US3119819A (en) 1964-01-28

Family

ID=27365147

Family Applications (1)

Application Number Title Priority Date Filing Date
US37097A Expired - Lifetime US3119819A (en) 1959-07-29 1960-06-20 Intermediates for 18-o-alkyl-reserpic acid esters and related compounds

Country Status (8)

Country Link
US (1) US3119819A (de)
AT (1) AT241693B (de)
CH (12) CH414660A (de)
DE (1) DE1197737B (de)
ES (2) ES259869A1 (de)
FI (1) FI40249B (de)
GB (1) GB885981A (de)
SE (1) SE314883B (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5612356A (en) * 1992-12-28 1997-03-18 Eisai Co., Ltd. Heterocycle-containing carbonic acid derivatives
EP2386565A3 (de) * 1999-01-12 2013-11-20 Cambridge Enterprise Ltd. Verbindungen und Verfahren zur Hemmung oder Verstärkung einer Entzündungsreaktion

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1045772B (de) * 1956-04-24 1958-12-04 Ciba Geigy Wachstumsbeschleunigendes Beifuttermittel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5612356A (en) * 1992-12-28 1997-03-18 Eisai Co., Ltd. Heterocycle-containing carbonic acid derivatives
EP2386565A3 (de) * 1999-01-12 2013-11-20 Cambridge Enterprise Ltd. Verbindungen und Verfahren zur Hemmung oder Verstärkung einer Entzündungsreaktion

Also Published As

Publication number Publication date
CH411918A (de) 1966-04-30
CH387054A (de) 1965-01-31
CH411917A (de) 1966-04-30
CH410967A (de) 1966-04-15
CH388325A (de) 1965-02-28
SE314883B (de) 1969-09-15
DE1197737B (de) 1965-07-29
AT241693B (de) 1965-08-10
ES259870A1 (es) 1961-03-16
CH413850A (de) 1966-05-31
ES259869A1 (es) 1961-03-16
CH392540A (de) 1965-05-31
CH414660A (de) 1966-06-15
CH388324A (de) 1965-02-28
CH414656A (de) 1966-06-15
FI40249B (de) 1968-07-31
CH410971A (de) 1966-04-15
CH392539A (de) 1965-05-31
GB885981A (en) 1962-01-03

Similar Documents

Publication Publication Date Title
US3228943A (en) Lumilysergol derivatives
NO136851B (no) Roterende trommelcellefilter.
US2857385A (en) Preparation op pentacyclic lactones
US3119819A (en) Intermediates for 18-o-alkyl-reserpic acid esters and related compounds
US3532694A (en) Cephemoic acids and process for preparing same
US3209005A (en) Hexahydro-llbh-benzo[a] quinolizines and processes therefor
US2824874A (en) Reserpic acid and derivatives
US2877225A (en) Preparation of normal-alkyl reserpates and alkyl deserpidates
US3142682A (en) Tertiary amino derivatives of chromans and homo-chromans
US2789113A (en) N-oxides of reserpic acid compounds
Toke et al. Synthesis of yohimbines. I. Total synthesis of alloyohimbine and. alpha.-yohimbine and their epimers. Revised structure of natural alloyohimbine
KR880001236B1 (ko) 프리마이신 염의 제조방법
US2957867A (en) 1, 5-benzodiazepin-4-ones and process of producing same
US3048591A (en) 18-o-hetero-reserpates
US3126387A (en) Analogs thereof
US3126391A (en) Alkoxyalkyl ib-o-alkoxyalkyl -
US3374245A (en) Unsaturated oxacycles
US3184383A (en) New derivative of gitoxin, the use and preparation thereof
US3138601A (en) Alkyl-ib-o-trialkoxyacetylreserpates
US3821241A (en) 1-imidazolyl-2-substituted hydroxy propyl amines
US3151117A (en) Process for the preparation of ethers
US3126388A (en) Ib-o-alkyl-deserkdates and related
US3036079A (en) Methyl reserpate-18-desoxy-18-phosphates and related compounds
US3337561A (en) Process for obtaining alkaloids
US3093648A (en) -desoxy-