Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/40—Oxygen atoms
  • C07D211/44—Oxygen atoms attached in position 4
  • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps

Definitions

• This invention relates to compounds useful as neuromuscular blocking ("NMB”) muscle relaxants. More specifically, the invention relates to a series of acyloxy-substituted aralkyl bis-quaternary ammonium derivatives of cyclic alkanol diesters.
• NMB neuromuscular blocking
• NMB agents neuromuscular blocking agents
• NMB agents features: one or usually two quaternary nitrogen atoms incorporated into onium heads. While many "non-depolarizing" NMB agents contain alkoxy groups in bulky onium head substituents, none include an acyloxy substituted aralkyl or aralkenyl moiety as part of their molecular structure. The incorporation of alkoxy, but not acyloxy , groups is based on a traditionally deep-rooted belief in the development of NMB relaxants. For example, metocurine was an improvement over tubocurarine because it contains additional methoxy substituents.
• NMB agents atracurium (and cis-atracurium), mivacurium and doxacurium, still contain 4, 5 or 6 methoxy groups, in that order. Each of the additional methoxy groups has improved the potency and reduced certain side effects of those compound. There was no hint that mono-acyloxylation of the aralkyl ring alone, without additional groups, would yield superior NMB agents.
• Quaternary ammonium derivatives of aliphatic (like succinic acid) and aromatic (like phthalic acid) dicarboxylic acids esters of tropine (a bicyclic aminoalkanol) were described by Nador, K. and Gyermek, L. (Acta Chim. Acad. Sci. Hung. 2, 369-374, 1952) as compounds having curare-like effects. All these compounds were symmetrically substituted at the nitrogen atoms, some of them with an unsubstituted or mono-substituted (methyl, bromo) benzyl group (see also Hungarian Patent No. 142, 597 issued on September 15, 1955).
• the present invention is therefore based on a new concept that could not have been predicted, considering the deep-rooted belief of others and our own, and actual examples observed in the past, that increasing the number of substitutions (usually on the benzyl quaternizing group) would improve the NMB agents.
• This invention discloses a series of acyloxy substituted aralkyl and aralkenyl bis- quaternary ammonium derivatives of various cyclic aminoalkanol esters of dicarboxylic acids as neuromuscular relaxants, methods of making them and using them, and pharmaceutical compositions containing them.
• the first aspect of this invention is a group of compounds 1/a, having the general formula illustrated below:
• a second aspect of this invention is a group of compounds 1/b, having the general formula illustrated below:
• R! and Ri' are mono-acyloxy substituted aralkyl or aralkenyl;
• R 2 and R 2 ' are alkyl, alkenyl or alkynyl;
• A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedi- carbonyl, bicycloalkenedicarbonyl, polycycloalkanedicarbonyl, polycycloalkenedicarbonyl or aromatic dicarbonyl;
• n is 0, 1, or 2;
• m is 0, 1, or 2;
• p is 0, 1, or 2;
• R and R 3 ' are H, CH 3 , or lower alkyl;
• R-t and KT are H, CH 3 , or lower alkyl;
• Y is CH 2( O or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; wherein R ⁇ and R ⁇ , R and R ', R 3 and R 3 ', and R ⁇ and R-i' can be the same or different; X is a pharmaceutically acceptable anion.
• a third aspect of this invention is the method of use of the compounds of the general formulae 1/a-l/b as neuromuscular relaxants.
• the fourth aspect of this invention is a pharmaceutical composition, including the compounds of general formulae a and b and a pharmaceutically acceptable excipient.
• alkyl means a hydrocarbon radical having from 1 to 20 carbon atoms.
• alkyl can be substituted or non-substituted, for example, methyl, butyl, octyl, and dodecyl.
• a preferred alkyl group is methyl.
• alkenyl means any hydrocarbon radicals having from 1 to 20 carbon atoms that include at least one carbon-carbon double bond at any position. Examples include ethylenyl, buta-2-enyl, octa-5-enyl, and dodecyl-2, 10-dienyl.
• alkynyl means any hydrocarbon radicals having from 1 to 20 carbon atoms that include at least one carbon-carbon triple bond at any position. Examples include acetylenyl, 2-butynyl, 5-octynyl and 1,7-decanedynyl.
• aryl refers to aromatic hydrocarbon radicals.
• Examples include phenyl, naphthyl, and anthracyl.
• aralkyl refers to aryl hydrocarbon radicals including an alkyl portion as defined above. Examples include benzyl, phenylethyl, and 6- napthylhexyl.
• aralkenyl refers to aryl hydrocarbon radicals including an alkenyl portion, as defined above, and an aryl portion, as defined above. Examples include styryl, 3 -(benzyl) prop-2-enyl, and 6-napthylhex-2-enyl.
• cycloalkyl refers to an alkyl group that has its carbon atoms arranged into a ring. Examples include cyclohexyl, cyclobutyl, and cyclododecyl.
• cycloalkenyl refers to an alkenyl that has its carbon atoms arranged into a ring. Examples include cyclohexenyl and 1,5-cyclododecadienyl.
• bicycloalkyl refers to an alkyl that has its carbon atoms arranged into two rings. Examples include decahydronaphthyl, norbornyl, and bicyclo [2.2.2]octyl.
• bicycloalkenyl refers to an alkenyl that has its carbon atoms arranged into two rings. Examples include norbornenyl and 1,2,3,4,5,6,7,8- octahydro-naphthyl.
• polycycloalkyl refers to an alkyl that has its carbon atoms arranged into three or more rings.
• polycycloalkenyl refers to an alkenyl that has its carbon atoms arranged into three or more rings.
• substituted refers to a hydrocarbon radical selected from the groups alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, polycycloalkyl, polycycloalkenyl, and all as defined above, where one or more hydrogens have been replaced with alkyl, fluoride, chloride, bromide, iodide, hydroxy, mercapto, alkoxy, acyloxy, alkylthio, arylthio, acetamido, amino, or nitro group(s).
• Substituted refers to a hydrocarbon radical selected from the groups alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, polycycloalkyl, polycycloalkenyl, and all as defined above, where one or more carbons have been replaced with oxygen, sulfur, nitrogen, or silicon atom(s).
• mono-acyloxy substituted refers to one acyloxy group, which replaces a hydrogen atom of the aromatic group of the aralkyl or aralkenyl moiety.
• alkyl-cycloalkyl refers to a hydrocarbon radical including an alkyl and a cycloalkyl group. Examples include 3-methylcyclohexyl and 4- hexylcycloheptyl.
• alkanedicarbonyl refers to a radical that includes an alkyl as defined above and two carbonyl groups. Examples include succinyl, glutaryl, sebacyl, 9 methyl- 1,11- dicarboxyundecanyl, and the like.
• alkenedicarbonyl refers to a radical that includes at least one carbon-carbon double bond and two carbonyl groups. Examples include fumaryl, chlorofumaryl, 1,3-dicarboxypropenyl, l,6-dicarboxy-3-hexenyl, and traumatyl (1, 10-dicarboxy-2-decenyl).
• alkynedicarbonyl refers to a radical that includes at least one carbon-carbon triple bond and two carbonyl groups. Examples include 1,2- dicarboxypropynyl, l,6-dicarboxy-2-hexynyl, and the like.
• bicycloalkanedicarbonyl refers to a radical that includes bicycloalkenyl as defined above and two carbonyl groups. Examples include 5- norbornane- 2,3-dicarbonyl, dihydronaphthalene-l,5-dicarbonyl, and 9,10-dihydro-9,10- ethanoanthracene-11, 12-dicarbonyl.
• bicycloalkenedicarbonyl refers to a radical that includes bicycloalkenyl as defined above and two carbonyl groups. Examples include 3,6-endomethylene-l,2,3,6-tetrahydrophthaloyl and 1,2,3,4,5,6,7,8-octahydronaphthal- ene- 1 ,5-dicarbonyl.
• aromatic dicarbonyl refers to a radical that includes an aromatic group substituted with two carbonyl groups. Examples include phthalyl, terephthalyl, 1,4-dicarboxynaphthyl, and the like.
• acyloxy refers to RC(O)O- in which R is hydrogen or a normal or substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, or bicycloalkenyl. Examples include acetoxy, propionyloxy, 2,3-difluoro- butyryloxy, benzoyloxy, cyclopropylacetoxy and chloroacetoxy.
• tropine refers to tropine (8-methyl-8-azabicyclo- [3.2.1]octan-3 ⁇ -ol, also known as alpha- or endo-tropine), and pseudotropine (8- methyl-8-azabicyclo[3.2.1]octan-3 ⁇ -ol, also known as beta- or exo-tropine), dependent on the configuration of the hydroxy group attached to the C3 atom of tropine.
• the term "granatanol” refers to 9-methyl-9- azabicyclo[3.3.1]nonan-3 ⁇ -ol or 9-methyl-9-azabicyclo[3.3.1]nonan-3 ⁇ -ol
• the term "granatanine” refers to 9-methyl-9-azabicyclo[3.3.1]nonane. It will of course be realized that the nitrogen atom of tropine and of granatanol is already methyl substituted. Therefore, when the tropine or granatanol nitrogen is referred to as substituted, as in N-methyltropinium iodide, it will be understood that the nitrogen is quaternary nitrogen and the halide is present for charge balance.
• the term "pharmaceutically acceptable anion” refers to an anion that has little or no toxic effect and does not significantly influence the pharmacological action of a pharmaceutically administered dose. Examples include chloride, bromide, iodide, nitrate, sulfate, phosphate, sulfonate, mesylate, besylate, tosylate, and the like.
• optical isomers, enantiomeric pairs, and diastereomeric pairs exist for many of the compounds within the scope of the present invention. All such compounds are intended as are all mixtures of optical isomers, enantoimeric pairs and diastereomeric pairs for each structural variation, including all pure compounds and racemic mixtures. Both s and trans geometrical isomers and mixtures are intended.
• one equivalent of the purified diester (III) is taken up in a moderately polar aprotic solvent, such as acetone or acetonitrile.
• a moderately polar aprotic solvent such as acetone or acetonitrile.
• Two and a half equivalent of the appropriate mono-acyloxy substituted aralkyl or aralkenyl halide, RX (IV) are added.
• the resulting solution is heated at between 50°C and 70°C for 6 to 12 h depending on the reactants.
• the resulting quaternary salts are filtered, and purified by recrystallization.
• one equivalent of the appropriate tropine (I) and one to one and a quarter equivalents of the desired mono-acyloxy substituted aralkyl halide (IV) are heated together in a moderately polar aprotic solvent, such as acetone or acetonitrile, for between 6 and 12 hours at between 60°C to 70°C.
• the resulting quaternary ammonium salt (V) is filtered, and purified by recrystallization.
• two equivalents of the quaternary salt (V) are reacted with one equivalent of the appropriate diacid dihalide (II) in dry methylene chloride in a sealed vessel.
• the ingredients are heated in a closed vessel at 80-100°C. After the solvent is removed, the residue is purified by recrystallization, and pure compound of Formula a or b are obtained.
• the compounds according to Formula a and Formula b of this invention can also be asymmetrical diammoniumesters. These compounds are made by following method: -l ino more than one equivalent of a first mono-acyloxy substituted aralkyl or aralkenyl halid, RX (IV) and one equivalent of diester (III) in acetone or acetonitrile are heated at 60°C for 12 hours. To the reaction mixture is added the second mono-acyloxy substituted aralkyl or aralkenyl halid, RX (IV). Then the reaction mixture is heated again at 90-100°C for 12 hours. The resulting precipitate is purified by recrystallization.
• Synthetic Pathway C An alternative to synthetic pathway A is illustrated in Synthetic Pathway C.
• Suitable cyclic aminoalkanol hydrochlorides such as tropine hydrochloride or granatanol hydrochloride, can be used as well.
• UTILITY Compounds of Formula a and b show marked activity as neuromuscular blocking agents. Such agents are typically administered intravenously.
• the form of administration can be a single injection, a series of injections, or given as a component of an intravenous infusion.
• the compounds of this invention are characterized by rapid onset of action and short duration of action in animals to the extent that they are clearly superior to any existing known and/or marketed muscle relaxants.
• the compounds of this invention have practically none of the objectionable cardiovascular side effects associated with succinylcholine, tubocurarine or gallamine, the earlier prototypes of clinically used muscle relaxants.
• their side-effect profiles are comparable to that of the present state of the art, clinically utilized agents.
• the bolus dosage may vary markedly between each individual patient as it does with other muscle relaxants, but generally, as estimated on the basis of animal experiments, the dose will be between 0.1 and 1.0 mg/kg of body weight. The precise dose must be arrived at after having considered each individual case, including age, sex, weight and general condition of the patient and the degree of muscle relaxation desired.
• the form of dosage may be liquid solution, either for direct injection or for addition to an intervenous fluid, or it can be a solid powder or granular material to be made into a solution prior to use.
• the liquid or solid may be formulated by any conventional means.
• One or more pharmaceutically acceptable excipients and adjuvants may be included in a clinical formulation, including pH modifiers, stabilizers, preservatives, biologically necessary salts, sugars, and the like.
• the activity of these compounds can be tested by any of several methods.
• the utility of the compounds of Formulae a and b has been tested by using anesthetized rats, rabbits, monkeys and/or pigs.
• a leg tendon is attached to a transducer.
• An appropriate motor nerve e.g. the sciatic or common peroneal nerve is stimulated.
• the resultant muscle twitches are transduced and recorded.
• the neuromuscular blocking agents of this invention are administered into a vein, the muscle twitch response to the stimulation decreases. This dose-dependent decrease is measured.
• the onset and duration of this action can be determined, and compared with those of known, clinically used agents. Electromyographic and mechanomyographic methods of measurements are both acceptable.
• Example 1 Preparation of Bis(gr-u ⁇ atan-3-yl) glutarate To a solution of glutaryl chloride (5.5 g, 32.6 mmol) in 50 rtiL of methylene chloride is added dropwise granatan-3-ol (10.1 g, 65.3 mmol) in 20 mL of methylene chloride at -20°C. After being stirred at 0°C for 1 h, the mixture is poured into 100 mL of 2 N NaOH aqueous solution and extracted with CHC1 3 . The combined organic layer is dried over MgSO 4 and concentrated.
• N-(4-acetoxybenzyl) tropinium chloride N-(2-butyryloxybenzyl) tropinium chloride N-(3-(3-acetoxyphenyl)propyl) tropinium bromide N-(4-(diphenylacetoxy)benzyl) tropinium bromide
• N-(4-propionyloxybenzyl) tropinium chloride 13.0 g, 38.3 mmol
• 3.17 g (17.5 mmol) of cyclobutane-l,2-dicarbonyl dichloride in 100 mL of dry methylene chloride are heated 100°C for 12 h in a sealed tube. After 5 mL of methanol is added to the cooled reaction mixture, solvent is removed on a rotary evaporator.
• the product is purified by recrystallization from methanol-methylene chloride; yielding 16.9 g (50%) of bis[N-(4-propionyloxybenzyl) tropanium-3-yl] cyclobutane-l,2-dicarboxylate dichloride.
• N-(4-(diphenylacetoxy)benzyl) tropinium bromide one can prepare: bis[N-(4-acetoxybenzyl)tropanium-3-yl] cyclobutane-l,2-dicarboxylate dichloride bis[N-(2-butyryloxybenzyl)tropanium-3-yl] cyclobutane-l,2-dicarboxylate dichloride bis[N-(3 -(3 -acetoxyphenyl)propyl)tropanium-3 -yl] cyclobutane- 1 ,2- dicarboxylate dibromide bis[N-(4-(diphenylacetoxy)tropanium-3-yl] cyclobutane- 1,2-dicarboxylate dibromide.
• the heterogeneous mixture is heated to 80°C overnight. After it cooled, the mixture is poured into 100 mL of 2 N NaOH aqueous solution, and extracted with CHC1 3 . The combined organic layer is dried over MgSO and concentrated. The resulting oil is purified by column chromatography (silica gel, 10% MeOH in CHC1 3 ) to yield 6.7 g (80%) of bis[quinuclidin-3-yl] sebacate as a thick oil.
• Example 8 In vivo animal testing of the Biological Activity of Neuromuscular Blocking Agents.
• neuromuscular blocking activity main pharmacological action
• other effects e.g. cardiovascular side effects
• Justification for this approach lies in the commonly known fact that the pharmacodynamic and pharmacokinetic properties of these agents are markedly variable from species to species. Therefore, the most important aspects of the projected therapeutic utility of these agents, e.g., neuromuscular blocking potency, onset and duration of action and side effects, cannot be ascertained in "in vitro" preparations or by using only one species of animals.
• Neuromuscular function was monitored by electromyography, recording evoked responses from the anterior tibial muscle as a result of supramaximal nerve stimuli consisting of single or "train-of-four" rectangular pulses of 0.1-0.2 msec duration every 10-12 seconds, delivered to the sciatic or common peroneal nerve by a laboratory nerve stimulator. Another mode of stimulation included repeated single stimuli delivered at 0.1 Hz or 1 Hz.
• Cardiac vagal block a side effect of several muscle relaxant agents, was assessed by stimulating the cervical vagus nerve peripherally and determining the possible blocking effect against the vagally induced bradycardia. The agents were dissolved in physiologic saline and injected intravenously at appropriate time intervals.
• standard neuromuscular blocking compounds e.g. succinylcholine, pancuronium, mivacurium, or rocuronium.
• ED 50 intravenous dose, ⁇ g/kg, causing 50% neuromuscular block.
• Onset time in minute to 80-85% neuromuscular block.
• RI recovery index, minute, spontaneous recovery, 25-15% neuromuscular response.
• NB vagal block, %, at 80-85% neuromuscular blocking dose.
• ⁇ BP change in arterial blood pressure, % at 80-85% neuromuscular blocking dose.
• ⁇ HR change in heart rate, %, at 80-85% neuromuscular blocking dose.
• Figure 1 illustrates the neuromuscular blocking effect of bis[N-(4-acetoxybenzyl) granatanium-3-yl] glutarate dibromide and bis[N-(4-acetoxybenzyl) tropanium-3 ⁇ -yl] glutarate dibromide, as compared with rocuronium, mivacurium and bis[N-(4- methoxybenzyl)tropanium-3 ⁇ -yl] glutarate dibromide in the rat. Shown are the response for muscle relaxation and the blood pressure response against time in minutes.

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