US3485825A - Conessine derivatives - Google Patents

Conessine derivatives Download PDF

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Publication number
US3485825A
US3485825A US791805*A US3485825DA US3485825A US 3485825 A US3485825 A US 3485825A US 3485825D A US3485825D A US 3485825DA US 3485825 A US3485825 A US 3485825A
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US
United States
Prior art keywords
conessine
compounds
bis
bromide
dimethylamino
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
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US791805*A
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English (en)
Inventor
Arthur Friedrich Marx
Jacob Wieriks
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DSM Delft BV
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Koninklijke Nederlandsche Gist en Spiritusfabriek BV
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0036—Nitrogen-containing hetero ring
    • C07J71/0042—Nitrogen only

Definitions

  • Type I comprises substances with depolarizing properties, such as succinylcholine.
  • Cholinesterase inhibitors cannot antagonize their activity.
  • the effect of succinylcholine is prolonged on the other hand by cholinesterase inhibition. Its breakdown normally takes place in the plasma under the influence of pseudocholinesterase.
  • Products of type II are competitive antagonists of acetylcholine.
  • This type includes, inter alia, d-tubocurarine and gallamine. Their activity on the contrary can be antagonized by cholinesterase inhibitors.
  • Type III comprises non-competitively acting compounds, such as dioxahexadecanium bromide.
  • cholinesterase inhibitors are not antagonistically active.
  • Products of type IV inhibit the synthesis of acetylcholine, e.g., the hemicholinia. Cholinesterase inhibitors do have an antagonizing influence. Substances of type IV, however, can readily be distinguished from those of type II, inter alia through the difference in the rapidity with which the block sets in.
  • decamethonium which has properties of types I and III.
  • a peripherally acting muscular relaxing agent has to meet, inter alia, the following requirements.
  • the block should rapidly be complete. If the effect does not rapidly disappear spontaneously, an antagonist should be available, in this case, a cholinesterase inhibitor. If possible, there should be an ample margin between the dose which just paralyzes the respiratory muscles and the smallest dose required to paralyze the other striated muscles completely. Finally, any objectionable side actions, such as muscular pains and an undesirable fall in blood pressure, should be absent.
  • An object of the present invention is the obtention of a quaternary ammonium derivative of a compound of the formula having double bonds in the positions selected from the group consisting of the 5,6-position and the 4,5- and 6,7- positions; wherein R R and R are alkyl having from 1 to 5 carbon atoms; and R and R are members selected from the group consisting of two hydrogens, one a-hydroxyl and one hydrogen, one ,B-hydroxyl and one hydrogen; with the proviso that when said double bonds are in the 4,5- and 6,7-positions, R is one hydrogen; said quaternary ammonium derivative being selected from the group consisting of mono-quaternary compounds, bisquaternary compounds and strong mineral acid addition salts of mono-quaternary compounds; said quaternary ammonium derivative being derived from esters of strong mineral acids with an alcohol selected from the group consisting of lower alkanol, lower alkenol, phenyl-loweralkanol and cyclo
  • the compound defined above are all type II muscular relaxing agents. They are, therefore, competitive antagonists of acetylcholine and their activity can be antagonized with cholinesterase inhibitors.
  • the motor nerve end plate inhibition sets in very rapidly and the rate of its spontaneous disappearance varies, dependent upon the substituents. The latter is of particular importance, for thus, the anaesthetist can make his choice for each individual case from a series of compositions with a very brief to a prolonged effect. Moreover, he can, if necessary, rapidly eliminate the effect by administering an antagonist. Finally, the margin between the dose which paralyzes the respiratory muscles and the dose which paralyzes the other muscles is relatively wide, While an influence on the blood pressure is completely or substantially absent.
  • compositions of special importance are 11a-hydroxy 3,6-dimethylamino-n -conenine-bis-ethiodide, which has no undesirable influence on the blood pressure at dosages up to 5 times the therapeutic dosage and has an effect which sets in rapidly, while the rapidity with which the inhibition disappears is relatively low; 3fi-dimethylamino- A -conenine-mono-ethiodide, which causes an increase in blood pressure of short duration, the blocking effect setting in very rapidly and disappearing very rapidly; and 3B dimethylamino A conadienine mono 3N- ethoiodide which differs from the other compounds of the invention in that it has no undesirable influence the blood pressure and the electrocardiogram (ECG) at dosages up to times the therapeutic dosage, and hence is a very safe drug. At such dosages the compound causes only a slight and short-lasting rise of the blood pressure, but no dangerous lowering of the blood pressure occurs in this wide range of dosages.
  • ECG electrocardiogram
  • the invention relates to the above-defined compounds with the exception of bis-metho-compounds of conessine.
  • the last-mentioned compounds are excluded, as Heilbronn, Dictionary of Organic Compounds, vol. 2, p. 730, states the bis-metho-iodide and the bis-metho-sulfate of conessine, but without mention of any pharmacological activity.
  • the bis-metho-compounds of conessine show a smaller margin between the dose which paralyzes the respiratory muscles and the dose which paralyzes the other muscles, than the other compounds of the invention.
  • the invention further relates to a process for preparing the above-defined compound.
  • the compounds are prepared by reacting the corresponding non-quaternized compounds with a quaternizing agent.
  • Suitable quaternizing agents are the familiar esters of aliphatic and araliphatic alcohols derived from strong acids. Aliphatic and araliphatic esters of sulfuric acid, hydrohalogenic acids, such as hydrochloric acid, hydrobromic acid, or hydroiodic acid, may be mentioned as examples, in particular, the iodides and bromides. As alcohols, of particular importance are the lower alkanols, lower alkenols, phenyl-lower-alkanols and cycloalkyllower-alkanols.
  • the quaternizing esters are preferably ethyl iodide, methyl iodide, ethyl bromide, methyl bromide, methyl sulfate, allyl bromide, benzyl bromide, cyclohexylmethyl bromide, etc.
  • the quaternizing reaction is carried out in the conventional way, for instance, by boiling the starting material, such as conessine or a conessine derivative, in a suitable solvent, such as acetonitrile, alcohols, mixtures of alcohols and water, benzene, or acetone with an alkyl or aralkyl halide.
  • a suitable solvent such as acetonitrile, alcohols, mixtures of alcohols and water, benzene, or acetone with an alkyl or aralkyl halide.
  • the mono-quaternary compounds are preferably obtained by boiling in anhydrous or 90% ethanol. In most cases compounds with a quaternized 3-dialkylamino group are thus obtained. A quaternization of the nitrogen of the pyrrolidine ring alone, however, is not precluded.
  • the invention also relates to pharmaceutical compositions containing the compounds according to the inven tion, as well as to processes for preparing such compositions.
  • the pharmaceutical compositions can be prepared in a usual way.
  • the compounds in question are preferably dissolved in a physiological salt solution, may or may not be placed in particular doses in ampoules under an inert gas, and may subsequently be sterilized in the conventional way.
  • the compositions can be used for human as Well as veterinary practice.
  • the corresponding bis-methoiodide is prepared in an analogous manner. It melts at 296 to 297 C.
  • Conessine bis-ethiodide 5 gm. of conessine and 40 ml. of ethyl iodide (freshly distilled) are boiled in ml. of acetonitrile with reflux cooling.
  • Conessine monoethiodide hydroiodide 5 gm. of conessine and 12 ml. of ethyl iodide (freshly distilled) are boiled in m1. of anhydrous ethanol with reflux cooling.
  • the product is filtered off and washed with acetone.
  • the crude product is recrystallized several times more from methanolacetone. Yield 4.15 gm.; melting point :263 to 266 C.
  • Conessine bis-benzyl bromide 10 gm. of conessine and ml. of benzyl bromide are boiled in 100 ml. of acetonitrile for 3 /2 hours with reflux cooling, after Which the mixture is evaporated under reduced pressure. The residue is dissolved in dilute sulfuric acid (1 N) and the solution is shaken outwith heptane to remove the excess of benzyl bromide. The solution is subsequently basified and extracted with methyl isobutyl ketone, non-converted conessine and any conessine monobenzyl bromide that may have formed being extracted.
  • the aqueous layer is evaporated under reduced pressure and the residue (consisting of Na SO and conessine bis-benzyl bromide) is stirred with anhydrous ethanol.
  • the suspension thus obtained is filtered through a short aluminum oxide column.
  • the column is Washed with anhydrous ethanol until no more conessine bisbenzyl bromide is present in the filtrate.
  • the precipitate thus formed is subsequently filtered 01f and washed with acetonitrile.
  • This precipitate consists substantially of conessine dihydrobromide.
  • the corresponding 7a-hydroxy compound is prepared in an analogous manner (melting point approximately 230 C.).
  • I.R.-spectrum in chloroform: 2788, 1709, 1634, and 1600 cmi- N.M.R.-spectrum (in CDCl 0.98, 1.04 (doublet), 1.50 (triplet), 1.92 (doublet), 2.23, 3.07 (doublet), 3.30, 3.75 (quadruplet), 4.6 (multiplet), 5.55, 5.9, and 6.1 (AB-spectrum) p.p.m.
  • the liquids used had been prepared as follows:
  • the water was boiled and saturated with nitrogen gas during cooling.
  • EXAMPLE XII having double bonds in the positions selected from the group consisting of the 5,6-position and the 4,5- and 6,7- positions; wherein R R and R are alkyl having from 1 to 5 carbon atoms; and R and R are members selected from the group consisting of two hydrogens, one whydroxyl and one hydrogen, and one B-hydroxyl and one hydrogen, with the proviso that when said double bonds are in the 4,5- and 6,7-positions, R is one hydrogen; said quaternary ammonium derivative being selected from the group consisting of mono-quaternary compounds, bisquaternary compounds and strong mineral acid addition salts of mono-quaternary compounds; said quaternary ammonium derivative being derived from esters of strong mineral acids with an alcohol selected from the group consisting of lower alkanol, lower alkenol, phenyl-loweralkanol and cycloalkyl-loWer-alkanol, with the proviso that when the double bond is in the 5,6-position,

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US791805*A 1965-02-26 1969-01-16 Conessine derivatives Expired - Lifetime US3485825A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
NL6502483A NL6502483A (en, 2012) 1965-02-26 1965-02-26

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US3485825A true US3485825A (en) 1969-12-23

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Country Status (6)

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US (1) US3485825A (en, 2012)
BE (1) BE676980A (en, 2012)
CH (1) CH498823A (en, 2012)
FR (1) FR5242M (en, 2012)
GB (1) GB1104731A (en, 2012)
NL (2) NL6502483A (en, 2012)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050227953A1 (en) * 2004-04-07 2005-10-13 Chen Zhao Azacyclosteroid histamine-3 receptor ligands
WO2005100377A1 (en) * 2004-04-07 2005-10-27 Abbott Laboratories Azacyclosteroid histamine-3 receptor ligands
US20100040568A1 (en) * 2008-04-30 2010-02-18 Skinmedica, Inc. Steroidal compounds as melanogenesis modifiers and uses thereof
US9295664B2 (en) 2011-06-06 2016-03-29 University Of Iowa Research Foundation Methods for lowering blood glucose
US9856204B2 (en) 2010-05-20 2018-01-02 University Of Iowa Research Foundation Methods for inhibiting muscle atrophy
US11090313B2 (en) 2010-05-20 2021-08-17 University Of Iowa Research Foundation Methods for inhibiting muscle atrophy

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL6908367A (en, 2012) * 1969-01-16 1970-07-20 Koninklijke Gist Spiritus

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2912432A (en) * 1958-11-28 1959-11-10 Searle & Co 3-oxo and 3-hydroxy derivatives of 18-dimethyl-aminopregn-20-enes and intermediates
US2913455A (en) * 1958-05-22 1959-11-17 Searle & Co 18-dimethylamino steroids and intermediates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2913455A (en) * 1958-05-22 1959-11-17 Searle & Co 18-dimethylamino steroids and intermediates
US2912432A (en) * 1958-11-28 1959-11-10 Searle & Co 3-oxo and 3-hydroxy derivatives of 18-dimethyl-aminopregn-20-enes and intermediates

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050227953A1 (en) * 2004-04-07 2005-10-13 Chen Zhao Azacyclosteroid histamine-3 receptor ligands
WO2005100377A1 (en) * 2004-04-07 2005-10-27 Abbott Laboratories Azacyclosteroid histamine-3 receptor ligands
US7345034B2 (en) 2004-04-07 2008-03-18 Abbott Laboratories Azacyclosteroid histamine-3 receptor ligands
US20080113982A1 (en) * 2004-04-07 2008-05-15 Chen Zhao Azacyclosteroid histamine-3 receptor ligands
US20100040568A1 (en) * 2008-04-30 2010-02-18 Skinmedica, Inc. Steroidal compounds as melanogenesis modifiers and uses thereof
US9856204B2 (en) 2010-05-20 2018-01-02 University Of Iowa Research Foundation Methods for inhibiting muscle atrophy
US11090313B2 (en) 2010-05-20 2021-08-17 University Of Iowa Research Foundation Methods for inhibiting muscle atrophy
US9295664B2 (en) 2011-06-06 2016-03-29 University Of Iowa Research Foundation Methods for lowering blood glucose
US10137136B2 (en) 2011-06-06 2018-11-27 University Of Iowa Research Foundation Methods for inhibiting muscle atrophy
US10668087B2 (en) 2011-06-06 2020-06-02 University Of Iowa Research Foundation Methods for inhibiting muscle atrophy

Also Published As

Publication number Publication date
BE676980A (en, 2012) 1966-08-24
NL6502483A (en, 2012) 1966-08-29
CH498823A (de) 1970-11-15
FR5242M (en, 2012) 1967-07-17
NL124636C (en, 2012)
GB1104731A (en) 1968-02-28

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