WO2000044377A1

WO2000044377A1 - Mono-acyloxy aralkyl neuromuscular relaxants

Info

Publication number: WO2000044377A1
Application number: PCT/US2000/002228
Authority: WO
Inventors: Chingmuh Lee; Laszlo Gyermek; Young-Moon Cho
Original assignee: Newlaxant, L.L.C.
Priority date: 1999-02-01
Filing date: 2000-01-31
Publication date: 2000-08-03
Also published as: AU2634900A; PE20001593A1; NO20013741L; PL349099A1; CZ20012780A3; HUP0200413A2; NO20013741D0; JP2002535366A; HUP0200413A3; CO5170470A1; ZA200105882B; EP1150673A4; AR022472A1; KR20010108125A; HK1039455A1; CN1338934A; MXPA01007783A; TR200102196T2; BR0007863A; CA2360790A1

Abstract

Mono-acyloxy substituted aralkyl and aralkenyl bis-quaternary ammonium derivatives of cyclic alkanol diesters according to general Formula (a) or (b), where R1 and R1' are mono-acyloxy subst ituted aralkyl or aralkenyl; R2 and R2' are alkyl or alkenyl; A is normal or substituted alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkenedicarbonyl, polycycloalkanedicarbonyl, polycycloalkenedicarbonyl or aromatic dicarbonyl; n is 0, 1, or 2; m is 0, 1, or 2; p is 0, 1, or 2; R3 and R3' are H, CH3, or lower alkyl; R4 and R4' are H, CH3, or lower alkyl; R3 and R4 together can also be -CH=CH-, -(CH2)h-Y-(CH2)k-, or (1), where Y is CH2, O or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; and R3' and R4' together can also be -CH=CH-, -(CH2)h-Y-(CH2)k-, or (1), where Y is CH2, O or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; wherein R1 and R1', R2 and R2', R3 and R3', and R4 and R4' can be the same or different; and X is a pharmaceutically acceptable anion; have advantageous neuromuscular relaxant properties.

Description

MONO-ACYLOXY ARALKYL NEUROMUSCULAR

RELAXANTS

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.

BACKGROUND OF THE INVENTION

During surgery, and certain non-surgical procedures especially those related to respiratory support and resuscitation of the patients in need of intensive or emergent care, it is common practice to have the muscles of the patient relaxed profoundly. Although general anesthesia renders the patient unconscious, it only rarely provides sufficient skeletal muscle relaxation. Besides, emergency and intensive care patients in need of relaxation are often not fully anesthetized. A variety of compounds, collectively called neuromuscular blocking agents (NMB agents), are commonly used for muscle relaxation. Two of the most desirable features of the NMB agents are rapid onset and short duration of action. Rapid onset provides the desirable relaxation before hypoxia and other complications occur. Rapid recovery allows the patient to regain muscle power, and therefore ability to breathe, at the end of surgery or procedure. Even for procedures requiring considerable length of time, NMB agents of short duration of action is still desirable; for the agents can be infused continuously to satisfy the need without sacrificing the desirable feature of rapid recovery once its infusion is discontinued.

One muscle relaxant used frequently in the past was succinylcholine, which has a very rapid onset and short duration of action. However, succinylcholine elicits muscle membrane "depolarization", which often causes serious side effects and makes the drug less desirable or contraindicated. Several other so-called "non-depolarizing" muscle relaxants are known and used widely in anesthesia and surgery. These chemically diverse agents, among others, include: tubocurarine, metocurine, pancuronium, atracurium, cisatracurium, vecuronium, mivacurium, and rocuronium. Although not completely satisfactory, they are clinically accepted because there is a need for them and because they produce only mild or no side effects. However, either their onset of action is too slow and/or their duration of action is too long. Consequentially, numerous therapeutic maneuvers, with their own complications and side effects, are practiced to compensate for these deficiencies. Thus, these agents, without exception, fall short of the requirements of an "ideal" surgical muscle relaxant.

The common structures of 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. Modern 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). Some other neuromuscular blocking compounds have been reported in the literature that include pairs of quaternary nitrogens as part of a tropane ring system. For example: Arch. Exper. Path. Pharmakol. 215. 283-298. 0952, and Brit. J. Pharmacol. 15. 71. (I960). However, with these quoted compounds the tropinyl moieties are joined by bridging the two quaternary nitrogens. US Patent #2,746.964 (1953) discloses dicarboxylic acid esters of piperidine-3-ol and their alkyl quaternary derivatives. None of the referenced publications have dealt with mono-acyloxy substituted aralkyl bisquaternary diester compounds.

In our research for the "ideal" muscle relaxant we have now discovered that mono- acyloxylation of aralkyl and aralkenyl quaternary ammonium derivatives of cyclic aminoalkanol diesters results in high potency, very rapid onset, very short duration of action, and minimal or no side effects in animals. Some of these mono-acyloxy substituted aralkyl and aralkenyl quaternary derivatives have much more rapid onset and shorter duration of action in animals than any muscle relaxant compounds hitherto known to the public. 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.

SUMMARY OF THE INVENTION

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:

Formula a

A second aspect of this invention is a group of compounds 1/b, having the general formula illustrated below:

Formula b where R! and Ri' are mono-acyloxy substituted aralkyl or aralkenyl; R₂ and R₂' 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 R₃' are H, CH₃, or lower alkyl; R-t and KT are H, CH₃, or lower alkyl; R₃ and R_t together can also be -CH=CH-, -(CH₂)_h-Y-(CH₂)_k-, Y

/ \ or -CH-CH-, where Y is CH_2; O or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; or R₃' and --C' together can also be -CH=CH-, -(CH₂)_h-Y-(CH₂)_k-,

Y or -CH-CH-, where Y is CH₂₍ O or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; wherein R_γ and R^, R and R ', R₃ and R₃', 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.

DETAILED DESCRIPTION Definitions

As used herein, the term "alkyl" means a hydrocarbon radical having from 1 to 20 carbon atoms. In this invention alkyl can be substituted or non-substituted, for example, methyl, butyl, octyl, and dodecyl. A preferred alkyl group is methyl.

As used herein, the term "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.

As used herein, the term "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. As used herein, the term "aryl" refers to aromatic hydrocarbon radicals.

Examples include phenyl, naphthyl, and anthracyl.

As used herein, the term "aralkyl" refers to aryl hydrocarbon radicals including an alkyl portion as defined above. Examples include benzyl, phenylethyl, and 6- napthylhexyl. As used herein, the term "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.

As used herein, the term "cycloalkyl" refers to an alkyl group that has its carbon atoms arranged into a ring. Examples include cyclohexyl, cyclobutyl, and cyclododecyl. As used herein, the term "cycloalkenyl" refers to an alkenyl that has its carbon atoms arranged into a ring. Examples include cyclohexenyl and 1,5-cyclododecadienyl.

As used herein, the term "bicycloalkyl" refers to an alkyl that has its carbon atoms arranged into two rings. Examples include decahydronaphthyl, norbornyl, and bicyclo [2.2.2]octyl. As used herein, the term "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.

As used herein, the term "polycycloalkyl" refers to an alkyl that has its carbon atoms arranged into three or more rings.

As used herein, the term "polycycloalkenyl" refers to an alkenyl that has its carbon atoms arranged into three or more rings.

As used herein, the term "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). Also the term "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).

In case of the quaternizing aralkyl or aralkenyl groups, "mono-acyloxy substituted" refers to one acyloxy group, which replaces a hydrogen atom of the aromatic group of the aralkyl or aralkenyl moiety.

As used herein, the term "alkyl-cycloalkyl" refers to a hydrocarbon radical including an alkyl and a cycloalkyl group. Examples include 3-methylcyclohexyl and 4- hexylcycloheptyl.

As used herein, the term "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.

As used herein, the term "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). As used herein, the term "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.

As used herein, the term "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.

As used herein, the term "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.

As used herein, the term "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. As used herein, the term "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.

As used herein, the term "tropine" refers to tropine (8-methyl-8-azabicyclo- [3.2.1]octan-3α-ol, also known as alpha- or endo-tropine), and pseudotropine (8- methyl-8-azabicyclo[3.2.1]octan-3β-ol, also known as beta- or exo-tropine), dependent on the configuration of the hydroxy group attached to the C3 atom of tropine.

As used herein, the term "granatanol" refers to 9-methyl-9- azabicyclo[3.3.1]nonan-3α-ol or 9-methyl-9-azabicyclo[3.3.1]nonan-3β-ol, and also 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. As used herein, 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.

A variety of 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.

SYNTHESIS

There will now be described various synthetic pathways for preparing the compounds of the present invention. These pathways will be illustrated using N-methyl- 8-azabicyclo[3.2.1]octan-3-ol (tropine) as an example of the starting material. Other suitable cyclic aminoalkanols can be used as well.

SYNTHETIC PATHWAY A

III

III + 2 RX

IV

Referring to eq. A of Synthetic pathway A, the procedure is carried out as follows. To a cooled solution of one equivalent of the appropriate acid chloride (II) in dry methylene chloride in an ice bath is added dropwise two equivalents of tropine in dry methylene chloride, and then the mixture is allowed to warm up to room temperature. After the reaction mixture is poured into the cold water, the aqueous layer is basified to pH 10-11 with 2 N NaOH aqueous solution, and extracted with chloroform. The diester (III) is then purified by a chromatographic technique.

In eq. B, one equivalent of the purified diester (III) is taken up in 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.

SYNTHETIC PATHWAY B

2 V + II

Referring to eq. C of Synthetic Pathway 2, 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. Then, as shown in eq. D, 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.

An alternative to synthetic pathway A is illustrated in Synthetic Pathway C.

Synthetic Pathway C

HCI

VII

VII + 2 RX Formular 1/b (Eq. F)

Other 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. Regarding side effects, 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. Furthermore, 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. As 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. Likewise, 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.

The invention will be better understood by reference to the following examples, which are included merely for purposes of illustration and are not to be construed as limiting the scope of the present invention.

The following example illustrates Synthetic Pathway A

Example 1 - Preparation of Bis(gr-uιatan-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 CHC1₃. The combined organic layer is dried over MgSO₄ and concentrated. The resulting oil is purified by column chromatography (CHC1₃ to MeOH : CHC1₃ : NE .OH = 4:5: 1) yield 9.3 g (70%) of bis(granatan-3-yl) glutarate as a thick oil.

Similarly by substituting glutaryl chloride with: malonyl chloride succinyl chloride thiodiglycolyl chloride

2-ketoglutaryl chloride adipoyl chloride sebacoyl chloride

4, 4'-dithiodibutyryl chloride

1,11-undecanedicarbonyl dichloride fumaryl chloride chlorofumaryl chloride trαws-traumatyl chloride acetylenedicaboxylyl chloride trø/M-cyclobutane-1 ,2-dicabonyl dichloride

1,3-cyclohexanedicabonyl dichloride

1,1 '-cyclopentanediacetyl dichloride phthaloyl chloride

4,5-dichlorophthaloyl chloride tra/?s-3,6-endomethylene-l,2,3,6-tetrahydrophthaloyl chloride

one can obtain: bis(granatan-3-yl) maloate bis(granatan-3-yl) succinate bis(granatan-3 -yl) thiodiglycolate bis(granatan-3 -yl) 2-keroglutarate bis(granatan-3-yl) adipate bis(granatan-3-yl) sebacate bis(granatan-3-yl) 4, 4'-dithiodibutyrate bis(granatan-3-yl) 1,11-undecanedicarboxylate bis(granatan-3-yl) fumarate bis(granatan-3-yl) chlorofumarate bis(granatan-3-yl) trα/zs-traumatate bis(granatan-3-yl) acetylenedicarboxylate bis(granatan-3-yl) cyclobutane-l,2-dicaboxylate bis(granatan-3-yl) cyclohexane-l,3-dicarboxylate bis(granatan-3-yl) cyclopentane- 1 , 1 '-diacetate bis(granatan-3-yl) phthalate bis(granatan-3-yl) 4,5-dichlorophthalate bis(granatan-3-yl) tra»s-3,6-endomethylene-l,2,3,6-tetrahydrophthalate

Similarly by substituting other cyclic aminoalkanols for granatanol as indicated in Formulae a and b as starting material and the acid chlorides listed, one can obtain the corresponding dicarboxylic acid esters.

Example 2 - Preparation of Bis-[N-(4-acetoxybenzyI)granatanium-3-yI] glutarate dibromide

A solution of bis(granatan-3-yl) glutarate (4.0 g, 9.85 mmol) and 4- acetoxybenzyl bromide (5.0 g, 21.7 mmol, prepared from 4-hydroxybenzaldehyde through acetylation of the hydroxy groups, reduction of the aldehyde into the corresponding alcohol, and its bromination) in 100 mL of acetone is heated at 60°C for 10 hours. The precipitate is collected by filtration, washing with acetone and ether, and drying under vacuum; yielding 7.5 g (83%) of bis[N-(4-acetoxybenzyl)granatanium-3- yl] glutarate dibromide as a white powder. Similarly by substituting 4-acetoxybenzylbromide with: 2-acetoxybenzyl bromide 3 -acetoxybenzyl bromide 4-propionyloxybenzyl bromide 2-butyryloxybenzyl bromide

3-benzoyloxybenzyl bromide 4-acetoxyphenethyl bromide 3 -(4-acetoxyphenyl)propen-2-yl bromide 4-acetoxy- 1 -naphthylmethyl bromide,

one can prepare: bis[N-(2-acetoxybenzyl) granatanium-3-yl] glutarate dibromide bis[N-(3-acetoxybenzyl) granatanium-3-yl] glutarate dibromide bis[N-(4-propionyloxybenzyl) granatanium-3-yl] glutarate dibromide bis[N-(2-butyryloxybenzyl) granatanium-3-yl] glutarate dibromide bis[N-(3-benzoyloxybenzyl) granatanium-3-yl] glutarate dibromide bis[N-(4-acetoxyphenethyl) granatanium-3-yl] glutarate dibromide bis[N-(3-(4-acetoxyphenyl)propen-2-yl) granatanium-3-yl] glutarate dibromide bis[N-(4-acetoxy-l -naphthylmethyl) granatanium-3-yl] glutarate dibromide. It will be realized by one skilled in the art that both starting materials could be substituted. For example if 3-propionyloxybenzyl bromide is substituted for 4- acetoxybenzyl bromide and bis(tropan-3-yl) glutarate, bis(tropan-3-yl) sebacate, and bis(tropan-3-yl) cyclobutane-l,2-dicarboxylate are substituted for bis(granatan-3-yl) glutarate, then one obtains: bis -(3-propionyloxybenzyl)tropanium-3-yl] glutarate dibromide, bis-[N-(3-propionyloxybenzyl) tropanium-3-yl] sebacate dibromide, and bis- [N-(3-propionyloxybenzyl)tropanium-3-yl] cyclobutane-l,2-dicarboxylate dibromide.

The following example illustrates Synthetic Pathway B.

Example 3 - Preparation of N-(4-propionyIoxybenzyl) tropinium chloride. -lo-

The mixture of 7.1 g (50 mmol) of tropine and 11.9 g (60 mmol) of 4-propionyl- oxybenzyl chloride in 200 mL of acetone is heated at 60-70°C for 10 h. The precipitate is then filtered, washed, and recrystallized (ethanol-methylene chloride) to yield 14.4 g (85%) of N-(4-propionyloxybenzyl) tropinium chloride as a white powder. Similarly by substituting:

4-acetoxybenzyl chloride 2-butyryloxyphenethyl chloride 3-(3-acetoxyphenyl)propyl bromide 4-(diphenylacetoxy)benzyl bromide one can prepare:

N-(4-acetoxybenzyl) tropinium chloride N-(2-butyryloxybenzyl) tropinium chloride N-(3-(3-acetoxyphenyl)propyl) tropinium bromide N-(4-(diphenylacetoxy)benzyl) tropinium bromide

Example 4 - Preparation of Bis-[N-(4-propionyloxybenzyl)tropanium-3-yl] cycIobutane-l,2-dicarboxyIate dichloride

N-(4-propionyloxybenzyl) tropinium chloride (13.0 g, 38.3 mmol) and 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.

Similarly by substituting:

N-(4-acetoxybenzyl) tropinium chloride

N-(2-butyryloxybenzyl) tropinium chloride

N-(3-(3-acetoxyphenyl)propyl) tropinium bromide

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 following example illustrates the preparation of an asymmetrical diammonium ester.

Example 5 - Preparation of [N-(4-acetoxybenzyl)tropanium-3-yl], [N-(2- propionyloxy- benzyl)tropanium-3-yl] glutarate dibromide.

To a solution of 18.9 g (50 mmol) of bis(tropan-3-yl) glutarate in 500 mL of dry acetone in a sealed bottle is added 11.5 g (50 mmol) of 4-acetoxybenzyl bromide. After the mixture is heated at 50°C for 5 h, 12.1 g (50 mmol) of 2-propionyloxybenzyl bromide is added to the cooled mixture. Then the mixture is heated again at 70-75°C for another 10 h. The resulting white precipitate is collected by filtration, and purified by recrystallization from MeOH-methylene chloride to yield 12.7 g (30%) of [N-(4- acetoxybenzyl)tropanium-3-yl], [N-(2-propionyloxybenzyl)tropanium-3-yl] glutarate dibromide as a white powder.

Similarly by substituting 3-acetoxyphenethyl bromide and 4-benzoyloxybenzyl bromide for 4-acetoxyphenethyl bromide and 2-propionyloxybenzyl bromide, respectively, one can obtain [N-(3-acetoxyphenethyl)tropanium-3-yl], [N-(4- benzoyloxybenzyl)tropanium-3-yl] glutarate dibromide.

The following example illustrates Synthetic Pathway C. Example 6 - Preparation of Bis[quinucIidin-3-yl] sebacate To a solution of sebacoyl chloride (4.78 g. 20.0 mmol) in 40 mL of methylene chloride in a sealed tube is added 3-quinuclidinol hydrochloride (7.85 g, 48.0 mmol). - ₁l_Co-

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 CHC1₃. The combined organic layer is dried over MgSO and concentrated. The resulting oil is purified by column chromatography (silica gel, 10% MeOH in CHC1₃) to yield 6.7 g (80%) of bis[quinuclidin-3-yl] sebacate as a thick oil.

Example 7 - Preparation of Bis[N-(4-propionyloxybenzyI)quinucIidinium-3-yl] sebacate dibromide.

A solution of bis[quinuclidin-3-yl] sebacate (2.5 g, 5.95 mmol) and 4- propionyloxybenzyl bromide (3.18 g, 13.1 mmol) in 50 mL of acetone is heated at 60°C in a sealed tube for 5 hours. The white solid (4.5 g, 84%) precipitated out is collected and dried under vacuum for 1 hour.

Similarly by appropriate choices of starting materials several other symmetric and asymmetric bisquarternary ammonium salts of the general structures of 1/a and 1/b can be made, for example:

[N-ethyl, N-(4-acetoxybenzyl) nor-granataninium-3-yl], [N-ethyl, N-(3-benzoyl- oxybenzyl) nor-granataninium-3-yl] cyclobutane- 1,2-dicaboxylate dibromide, bis [N-(2-propionyloxybenzyl) quinuclidinium-3-yl] isophthalate dibromide, bis[N-(4-propionyloxyphenethyl) l,2,6-trimethylpiperidinium-4-yl] thioglycolate dibromide.

Example 8 - In vivo animal testing of the Biological Activity of Neuromuscular Blocking Agents.

The neuromuscular blocking activity (main pharmacological action) and other effects (e.g. cardiovascular side effects) of these agents are investigated on different experimental animals. 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.

The new substances, subjects of the present invention, have been carefully investigated, first in "screening" experiments in rats, for determining neuromuscular blocking potency, and subsequently, selected compounds have been tested for specific effects, e.g. onset, duration of action and side effects on additional species of animals, such as rabbits and pigs.

The following is a description of the methods as used in the rat and the pig; these methods were also utilized on other species, when needed. a) Adult, male albino rats were anesthetized with pentobarbital injected intraperitoneally. The trachea was cannulated for artificial ventilation via a small animal ventilator. The carotid artery was cannulated for recording blood pressure via a transducer and heart rate by a cardiotachograph on a polygraph. One external jugular vein was cannulated for i.v. drug administration. 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. The intensity, onset and duration of neuromuscular block and its type, was determined with each agent. Through administ- ering several doses, the doses corresponding to 50%o, 80% and/or 90% neuromuscular block were determined. All agents were compared with standard neuromuscular blocking compounds, e.g. succinylcholine, pancuronium, mivacurium, or rocuronium.

b) Young, Duroc pigs of 10-12 kg were anesthetized with a mixture of 70 mg/kg alpha chloralose and 0.5 g/kg ethylurethane intraperitoneally. Shielded needle electrodes were used to stimulate the sciatic nerve, and the muscle response was recorded. Blood pressure and heart rate changes were recorded from appropriately cannulated arteries via a blood pressure transducer and cardiotachograph.

The resulting data for a number of compounds according to the invention as determined in rat, rabbit, pig and monkey, respectively, are shown in TABLES 1-4, wherein:

ED₅₀ = intravenous dose, μg/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.

Δ BP= change in arterial blood pressure, % at 80-85% neuromuscular blocking dose.

Δ HR = change in heart rate, %, at 80-85% neuromuscular blocking dose.

No = number of animals tested.

When all animal experiments are considered together, the novel neuromuscular relaxants are 2-10 times faster and shorter acting than the comparison compounds. Figure 1 illustrates the neuromuscular blocking effect of bis[N-(4-acetoxybenzyl) granatanium-3-yl] glutarate dibromide and bis[N-(4-acetoxybenzyl) tropanium-3α-yl] glutarate dibromide, as compared with rocuronium, mivacurium and bis[N-(4- methoxybenzyl)tropanium-3α-yl] glutarate dibromide in the rat. Shown are the response for muscle relaxation and the blood pressure response against time in minutes.

Those skilled in the art will further appreciate that the present invention may be embodied in other specific forms without departing from the spirit or central attributes thereof. In that the foregoing description of the present invention discloses only exemplary embodiments thereof, it is to be understood that other variations are contemplated as being within the scope of the present invention. Accordingly, the present invention is not limited to the particular embodiments, which have been described in detail herein. Rather, reference should be made to the appended claims as indicative of the scope and content of the present invention.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

Claims

Claims:

1. A compound according to the formula

where Ri and Ri' are mono-acyloxy substituted aralkyl or aralkenyl; R₂ and R₂' are alkyl, alkenyl or alkynyl; A is normal or substituted alkanedicarbonyl, alkene- dicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkenedicarbonyl, polycycloalkanedicarbonyl, polycycloalkenedicarbonyl or aromatic dicarbonyl; n is 0, 1, or 2; m is 0, 1, or 2; p is 0, 1, or 2; R₃ and R₃' are H, CH₃, or lower alkyl; R> and R,' are H, CH₃, or lower alkyl; or R₃ and R» together form -CH=CH-, -(CH₂)_h-Y-(CH₂)_k-, or Y -CH-CH-, where Y is CH₂, 0 or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; or

R₃' and R together form -CH=CH-, -(CH₂)_h-Y-(CH₂)_k-, or

Y / \

-CH-CH-, where Y is CH , O or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; wherein Ri and Ri', R₂ and R₂', R₃ and R₃', and j and R-j' can be the same or different; X is a pharmaceutically acceptable anion.

2. The compound according to claim 1 wherein R₃ and R together form ..-CH=CH-, -

(CH₂)_h-Y-(CH₂)_k-, or

Y / \ -CH-CH-, where Y is CH₂, 0 or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; and R₃' and

RV together form -CH=CH-, -(CH₂)_h-Y-(CH₂)_k-, or

Y / \

-CH-CH-, where Y is CH_2> O or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3.

3. The compound according to claim 2 wherein R_x is the same as Ri', R₂ is the same as R₂', R₃ is the same as R₃', and R_j is the same as Rj'.

4. The compound according to claim 3 wherein A is selected from the group consisting of oxalyl, malonyl, succinyl, glutaryl, adipoyl, pimeloyl, suberoyl, azelaoyl, sebacoyl, fumaryl, chlorofumaryl, trα/w-3, 6-endomethylene- 1, 2,3,6- tetrahydrophthaloyl, 1,9-nonanedicarbonyl, cyclobutane- 1,2-dicarbonyl and cyclohexane-l,3-dicarbonyl.

5 The compound of claim 4 wherein A is selected from the group consisting of. cyclobutane- 1 ,2-dicarbonyl, trans-3 , 6-endomethylene- 1,2,3,6- tetrahydrophthaloyl, glutaryl, adipoyl and fumaryl; R_t is the same as Ri' and is acyloxy substituted aralkyl; R₂ is the same as R₂' and is methyl; n and m = 1; R₃ and R together are -(CH₂)₂-; and R₃' and t' together are -(CH₂)₂-.

6. A compound according to claim 5 selected from the group consisting of - bis[N-(4-acetoxybenzyl) tropanium-3α-yl] cyclobutane- 1,2-dicarboxylate dibromide;

- bis[N-(3-acetoxybenzyl) tropanium-3α-yl] cyclobutane- 1,2-dicarboxylate dibromide;

- bis[N-(2-acetoxybenzyl) tropanium-3α-yl] cyclobutane- 1,2-dicarboxylate dibromide; - bis[N-(4-propionyloxybenzyl) tropanium-3α-yl] cyclobutane- 1,2-dicarboxylate dibromide;

- bis[N-(4-acetoxybenzyl) tropanium-3α-yl] trans-3, 6-endomethylene- 1,2,3, 6- tetrahydrophthalate dibromide; - bis[N-(3-acetoxybenzyl) tropanium-3α-yl] trø7.s-3,6-endomethylene-l,2,3,6- tetrahydrophthalate dibromide;

- bis[N-(2-acetoxybenzyl) tropanium-3α-yl]

tetrahydrophthalate dibromide;

- bis[N-(4-propionyloxybenzyl) tropanium-3α-yl] tr< s-3,6-endomethylene- 1,2,3,6 tetrahydrophthalate dibromide;

- bis[N-(4-acetoxybenzyl) tropanium-3α-yl] glutarate dibromide;

- bis[N-(3-acetoxybenzyl) tropanium-3 -yl] glutarate dibromide;

- bis[N-(2-acetoxybenzyl) tropanium-3α-yl] glutarate dibromide;

- bis[N-(4-propionyloxybenzyl) tropanium-3α-yl] glutarate dibromide; - bis[N-(4-acetoxybenzyl) tropanium-3α-yl] adipate dibromide;

- bis[N-(3-acetoxybenzyl) tropanium-3α-yl] adipate dibromide;

- bis[N-(2-acetoxybenzyl) tropanium-3α-yl] adipate dibromide;

- bis[N-(4-propionyloxybenzyl) tropanium-3α-yl] adipate dibromide; and

- bis[N-(4-acetoxybenzyl) tropanium-3α-yl] fumarate dibromide.

7. The compound of claim 4 wherein A is selected from the group consisting of. succinyl, glutaryl, cyclobutane- 1,2-dicarbonyl, adipoyl,thiodiglycol and fumaryl; wherein Ri is the same as Ri' and is acyloxy substituted aralkyl; R₂ is the same as R ' and is methyl; n and m = 1 ; R₃ and R together are -(CH )₃-; and R₃' and *' together are -(CH₂)₃-.

8. A compound according to claim 7 selected from the group consisting of

- bis[N-(4-acetoxybenzyl) granatanium-3-yl] succinate dibromide;

- bis[N-(4-acetoxybenzyl) granatanium-3-yl] glutarate dibromide; - bis[N-(4-propionyloxybenzyl) granatanium-3-yl] glutarate dibromide; - bis[N-(4-acetoxybenzyl) granatanium-3-yl] cyclobutane- 1,2-dicarboxylate dibromide;

- bis[N-(4-propionyloxybenzyl) granatanium-3-yl] cyclobutane- 1,2-dicarboxylate dibromide; - bis[N-(4-acetoxybenzyl) granatanium-3-yl] adipate dibromide;

- bis[N-(4-acetoxybenzyl) granatanium-3-yl] thiodiglycolate dibromide;

- bis[N-(4-propionyloxybenzyl) granatanium-3-yl] thiodiglycolate dibromide;

- bis[N-(4-acetoxybenzyl) granatanium-3-yl] fumarate dibromide; and

- bis[N-(4-propionyloxybenzyl) granatanium-3-yl] fumarate dibromide.

9. The compound according to claim 13 wherein Ri is the same as Ri' and is acyloxy substituted aralkyl; A is selected from a group comprising malonyl, succinyl, glutaryl, l, -cyclohexyldiacetyl, sebacoyl, fumaryl or tr «5^,-3,6-endomethylene-l, 2,3,6- tetrahydrophtaloyl; n = 1, and p =2, and m= 0; and R₃ and R-. together are -(CH₂)₂-; and R₃' and R,' together are -(CH₂)₂-.

10. A compound according to claim 9 selected from the group consisting of

- bis[N-(4-propionyloxybenzyl) quinuclidinium-3-yl] sebacate dibromide;

- bis[N-(4-acetoxybenzyl) quinuclidinium-3-yl] trα«.s-3,6-endomethylene-l,2,3,6- tetrahydrophtalate dibromide; and

- bis[N-(4-propionyloxybenzyl) quinuclidinium-3-yl] trans-3, 6-endomethylene- 1,2,3,6 tetrahydrophtalate dibromide.

11. A method of relaxing the muscles of a patient comprising administering an effective amount of a compound according to claim 1.

12. A pharmaceutical composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

13. A compound according to the formula

where Ri and Ri' are mono-acyloxy substituted aralkyl or aralkenyl; R₂ and R₂' are alkyl, alkenyl or alkynyl; A is normal or substituted alkanedicarbonyl, alkene- dicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkenedicarbonyl, polycycloalkanedicarbonyl, polycycloalkenedicarbonyl or aromatic dicarbonyl; n is 0, 1, or 2; m is 0, 1, or 2; p is 0, 1, or 2; R₃ and R₃' are H, CH , or lower alkyl; R» and R»' are H, CH₃, or lower alkyl; or R₃ and R-, together form -CH=CH-, -(CH₂)_h-Y-(CH₂)_k-, or Y

-CH-CH-, where Y is CH₂, O or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; or R₃' and R_,' together form -CH=CH-, -(CH₂)_h-Y-(CH₂)_k-, or

Y -CH-CH-, where Y is CH₂₎ O or S, h is 0, 1, 2 or 3, k is 0, 1, 2 or 3; wherein Ri and R , R₂ and R ', R₃ and R₃', and R₄ and R₄' can be the same or different; X is a pharmaceutically acceptable anion.

14. A pharmaceutical composition comprising an effective amount of the compound of claim 13 and a pharmaceutically acceptable carrier.

15. A method of relaxing the muscles of a patient comprising administering an effective amount of a compound according to claim 13.