Substituted isoquinolines as ultra short acting neuromuscular blockers

Ultrashort acting neuromuscular blocking agents of Formula (I) which are useful as skeletal muscle relaxants during emergency intubation procedures, routine surgery and post-operative settings are disclosed, wherein: X is a halogen; h is from 1 to 2; Y is hydrogen or methoxy; Z.sup.1 and Z.sup.2 are methyl; W.sup.1 and W.sup.2 are carbon; and A is a pharmaceutically acceptable anion.

The present invention relates to novel compounds, methods for the
 preparation of such compounds, pharmaceutical compositions containing them
 and their use as neuromuscular blocking agents of ultra-short duration.
 In anesthesia, neuromuscular blocking agents are used to provide skeletal
 muscle relaxation during surgery and during intubation of the trachea.
 Neuromuscular blockers are generally classified by both the mechanism of
 action (depolarizing or non-depolarizing) and the duration of action
 (ultrashort, short, intermediate, and long). See, Bedford, R., "From the
 FDA", Anesthesiology, 82(1), 33a. 1995. Non-depolarizing neuromuscular
 blocking agents include long-duration agents such as d-tubocurarine,
 pancuronium, gallamine, diallyltoxiferine and toxiferine,
 intermediate-duration agents such as atracurium and vecuronium, and
 short-duration agents such as mivacurium. See e.g., U.S. Pat. No.
 4,179,507, U.S. Pat. No. 4,701,460, U.S. Pat. No. 4,761,418 and U.S. Pat.
 No. 5,945,510. Conventional non-depolarizing agents typically exhibit a 20
 to 180 minute duration of action when used as skeletal muscle relaxants.
 Presently there are no ultrashort duration, non-depolarizing neuromuscular
 blocking agents in clinical use.
 Depolarizing agents include succinylcholine and decamethonium. Due to their
 depolarizing mechanism of action, these agents can have severe side
 effects such as cardiac arrest and death, hyperkalemia, malignant
 hyperthermia, severe muscle pain, cardiac arrhythmias, increased
 intraocular pressure and increased intragastric tension. Conventional
 depolarizing agents exhibit shorter durations of action, e.g., 10 to 15
 minutes in humans. Succinylcholine has a rapid onset and ultrashort
 duration of action and is the only ultra-short acting neuromuscular
 blocker in clinical use. Despite its undesirable side effect profile, no
 other ultrashort acting agent is available and thus it is currently the
 preferred agent for emergency use. The ultra-short duration of action is
 extremely important in emergency situations. Use of longer duration agents
 could lead to serious brain damage and death.
 Non-depolarizing agents are generally believed to be safer and more
 clinically desirable than depolarizing agents, and clinicians have long
 recognized the need for a non-depolarizing neuromuscular blocker that has
 an ultra-short duration of action. See, Miller, R. D. Anesthesia and
 Analgesia 61(9), 721, 1982; and Belmont, M. R., Current Opinion in
 Anaesthesiology, 8, 362, 1995. However, non-depolarizing agents can
 exhibit side effects not specifically related to their mechanism or
 duration of action. For example, the long-duration agents pancuronium and
 gallamine have effects on the autonomic nervous system and may cause an
 increase in heart rate (tachycardia). Intermediate- and short-duration
 agents such as atracurium besylate and mivacurium chloride may also
 exhibit the side effect of histamine release. Histamine release has
 undesirable effects on blood pressure and heart rate, and some physicians
 believe that release of large amounts of histamine can cause
 life-threatening anaphylaxis in some patients.
 It has now been discovered that compounds of Formula (I) include potent
 non-depolarizing neuromuscular blocking agents of ultra-short duration,
 e.g., about 5 to 15 minutes, that will provide both increased safety over
 known depolarizing ultrashort acting agents, e.g. succinylcholine, and a
 reduced capacity to release histamine over other non-depolarizing agents
 such as atracurium and mivacurium. In addition, they have a rapid onset of
 action and are reversed by treatment with known reversal agents such as
 neostigmine, both very important features in emergency situations and in
 other procedures. These agents maintain their ultrashort duration of
 action and rapid spontaneous recovery when administered by either bolus or
 continuous infusion and are without the cumulative effects observed with
 other neuromuscular blockers (pancuronium, vecuronium). Thus, compounds of
 the present invention should provide a significant advantage in the
 emergency, routine surgical, and post-operative settings.
 Accordingly, the present invention provides compounds of Formula (I):
 ##STR1##
 wherein X is halogen; h is from 1 to 2; Y is hydrogen or methoxy; Z.sup.1
 and Z are methyl; W.sup.1 and W.sup.2 are carbon; and A is a
 pharmaceutically acceptable anion.
 The compounds of Formula (I) contain two substituted isoquinolinium
 moieties connected by an aliphatic linker. The two substituted
 isoquinolinium moieties can be conveniently distinguished by referring to
 them as the "left head" and the "right head", where the left head contains
 W.sup.1 and the right head contains W.sup.2. The aliphatic linker is the
 portion of the compound of Formula (I) denoted by the following Formula
 (i).
 ##STR2##
 The solid and dashed lines (------)indicates a double or single bond.
 A suitable class of compounds of Formula (I) is that wherein X is chlorine
 or fluorine. Particularly preferred halogen substitutions are monochloro,
 monofluoro and difluoro.
 The aliphatic linker portion of compounds of Formula (I), as described by
 Formula (i), comprises a butanedioate or butenedioate moiety. Suitably,
 compounds of Formula (I) wherein the aliphatic linker comprises a
 butenedioate moiety may exist in either the E or Z configuration or as
 mixtures of E and Z isomers. Preferably the to butenedioate moiety of
 compounds of Formula (I) is a fumarate.
 The term fumarate as used herein refers to a butenedioate moiety wherein
 the two ester carbonyl groups are oriented trans to one another.
 A preferred class of compounds of Formula (I) is that wherein the aliphatic
 linker is a butanedioate moiety and X represents chlorine or fluorine and
 h is 1 or 2. A particularly preferred class of compounds of Formula (I) is
 that wherein the aliphatic linker is a butanedioate moiety and X
 represents fluorine and h is 1 or 2. Compounds of Formula (I) wherein the
 aliphatic linker is a butanedioate moiety, X represents fluorine and h is
 2 are most preferred.
 Another preferred class of compounds of Formula (I) is that wherein the
 aliphatic linker is a butenedioate moiety and X represents chlorine or
 fluorine. A particularly preferred class of compounds of Formula (I)
 includes those wherein the aliphatic linker is a butenedioate moiety, X
 represents chlorine or fluorine, h is 1 and the butenedioate moiety is a
 fumarate. Compounds of Formula (I) wherein the aliphatic linker is a
 butenedioate moiety, X represents chlorine, h is 1 and the butenedioate
 moiety is a fumarate are most preferred.
 The compounds of Formula (I) contain four chiral centres. The carbon atoms
 (denoted as W.sup.1 and W.sup.2) and each quaternary nitrogen atom in the
 isoquinolinium moieties are chiral. Each of the four chiral centres may
 independently exist in either the R or S configuration. Accordingly, it
 would be apparent to those skilled in the art that each compound within
 Formula (I) may exist in sixteen distinct optical isomeric forms. The
 scope of the present invention extends to cover each and every isomer of
 the compounds of Formula (I) either individually or in admixture with
 other isomers, and all mixtures of such isomers. Suitably W.sup.1 is in
 the R configuration, the N attached to Z is in the S configuration, W is
 in either the R or S configuration, and the N attached to Z.sup.2 is in
 either the R or S configuration. Preferably W.sup.1 is in the R
 configuration, the N attached to Z.sup.1 is in the S configuration,
 W.sup.2 is in the S configuration, and the N attached to Z.sup.2 is in
 either the R or S configuration. Compounds of Formula (I) wherein W.sup.1
 is in the R configuration, W.sup.2 is in the S configuration, the N
 attached to Z.sup.1 is in the S configuration and the N attached to
 Z.sup.2 is in the R configuration are most preferred.
 Particularly preferred compounds of Formula (I) include:
 (Z)-2-Chloro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3{(1R,2S)-6,7-dimethoxy-2-m
 ethyl
 -1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}pro
 pyl}-2-butenedioate dichloride,
 2,2-Difluoro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}1-{3-{(1R,2S)-6,7-dimethoxy-2-m
 ethyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio
 } propyl}-butanedioate dichloride,
 (Z)4-{3-[(1S,2R)-6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-
 tetrahydro-2-isoquinoliniolpropyl}-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[
 (3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}
 propyl}-2-fluoro-2-butenedioate dichloride and
 2,2-Difluoro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-2-methyl-6,7,8-t
 rimethoxy-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinol
 inio}propyl}butanedioate dichloride.
 Since the pharmacological activity of the compounds of the invention
 resides in the cation, the nature of the anion A.sup.- is relatively
 unimportant. However, for therapeutic purposes it is, preferably,
 pharmaceutically acceptable to the recipient of the compounds. Examples of
 pharmaceutically acceptable anions include iodide, mesylate, tosylate,
 bromide, chloride, hydrogen sulphate, sulphate/2, phosphate/3, hydrogen
 phosphates, acetate, besylate, succinate/2, maleate, naphthalenesulphonate
 and propionate. Both pharmaceutically acceptable salts and salts which are
 not thus acceptable may be useful for isolating and/or purifying the
 compounds of the invention. The unacceptable salts may also be useful in
 that they may be converted into acceptable salts by techniques well known
 in the art.
 The compounds of Formula (I) are used as neuromuscular blocking agents
 during surgery, for intubation of the trachea or during electroshock
 therapy. They may be administered parenterally, e.g., by intramuscular or
 intravenous injection of a solution. Accordingly, the present invention
 also provides a method for producing muscle relaxation in a mammal, which
 comprises administering to the mammal an effective neuromuscular blocking
 amount of a compound of Formula (I). The dosage for each subject may vary,
 however, a suitable intravenous amount or dosage of the compounds of
 Formula (I) to obtain paralysis in mammals would be 0.01 to 5.0 mg/kg of
 body weight, and most preferably, 0.02 to 0.5 mg/kg of body weight, the
 above being based on the weight of the di-cation which is the active
 ingredient. The dosage for intramuscular administration is two to eight
 times the intravenous dose.
 In a further aspect, the present invention provides compounds of Formula
 (I) for use in therapy, for example to induce neuromuscular blockade in
 surgery or for intubation of the trachea. The present invention also
 provides the use of a compound of Formula (I) in the manufacture of a
 medicament for inducing neuromuscular blockade in a mammal, including in a
 human.
 While it is possible for the compounds of Formula (I) to be administered as
 the bulk active chemicals, it is preferred to present them in the form of
 a pharmaceutical formulation for parenteral administration. Accordingly,
 the present invention provides a pharmaceutical formulation which
 comprises a compound of Formula (I), as hereinbefore defined and a
 pharmaceutically acceptable carrier.
 Where the pharmaceutical formulation is for parenteral administration, the
 formulation may be an aqueous or non-aqueous solution or mixture of
 liquids, which may contain bacteriostatic agents, antioxidants, buffers or
 other pharmaceutically acceptable additives. Alternatively the compounds
 may be presented as lyophilized solids for reconstitution with water (for
 injection) or dextrose or saline solutions. Such formulations are normally
 presented in unit dosage forms such as ampoules or disposable injection
 devices. They may also be presented in multi-dose forms such as a bottle
 from which the appropriate dose may be withdrawn. All such formulations
 should be sterile.
 A suitable dose to obtain a neuromuscular block for adult humans (150 lbs.
 or 70 kg) is 0.5 to 150 mg and more preferably 3.5 to 50 mg. The compounds
 of this invention may optionally be administered before or after (but not
 simultaneously with) the depolarizing agents specified above. Thus a
 suitable pharmaceutical parenteral preparation for administration to
 humans will preferably contain 0.1 to 20 mg/ml of the compounds of Formula
 (I) in solution or multiples thereof for multi-dose vials.
 A simple and preferred formulation is a solution of the compound of Formula
 (I) in water or dextrose solution. This may be prepared by dissolving the
 compound in pyrogen-free, sterile water or water containing dextrose, with
 or without a preservative and sterilizing the solution. Alternatively, it
 may be prepared by dissolving the sterile compound in pyrogen-free,
 sterile water or a sterile dextrose solution under aseptic conditions.
 Particularly preferred formulations have a pH of about 2.0 to 5.0.
 The compounds of Formula (I) may also be administered as an infusion of a
 dextrose solution or saline solution, e.g., Ringer's solution in drip
 form.
 The compounds may also be administered in other solvents (usually as a
 mixed solvent with water) such as alcohol, polyethylene glycol and
 dimethylsulphoxide. They may also be administered intramuscularly (as a
 drip if required) as a suspension a or solution.
 General Description of Processes
 Unless otherwise indicated, Y, X.sub.h, and A.sup.- described in the
 formulae which follow are as defined in Formula (I) above. W corresponds
 to W.sup.1 and W.sup.2 of Formula (I), Z corresponds to Z.sup.1 and
 Z.sup.2 of Formula (I) and X.sup.1.sub.h and X.sup.2.sub.h correspond to
 X.sub.h of Formula (I). Unless otherwise specified T represents hydroxyl
 or halide.
 Another aspect of the present invention is a process for the preparation of
 compounds of Formula (I). Compounds of Formula (I) may be prepared by
 reacting two equivalents of a compound of Formula (III):
 ##STR3##
 wherein Y is hydrogen or methoxy; Z is methyl; W is carbon; n is 0 or 1;
 and A is a pharmaceutically acceptable anion;
 with one equivalent of a compound of Formula (VII):
 ##STR4##
 in an aprotic solvent. The preferred method of coupling compounds of
 Formula (III) with compounds of Formula (VII) involves mixing the diacid
 or diacid chloride derivative of (VII) (wherein T is hydroxyl or halide,
 e.g. Cl) with two equivalents of a compound of Formula (III) in a
 chlorinated organic solvent at ambient or elevated temperatures.
 A further aspect of the present invention provides another process for the
 preparation of compounds of Formula (I). Compounds of Formula (I) may be
 prepared by coupling two different compounds of Formula (III) with one
 equivalent of a compound of Formula (VII). Reactions of this type are
 preferably carried out by preparing an equimolar solution of two different
 compounds of Formula (III) in a chlorinated organic solvent followed by
 addition of one equivalent of a diacid chloride derivative of (VII) (e.g.,
 T is Cl). This technique generates a statistical mixture of 3 different
 compounds of Formula (I) (ignoring stereochemical considerations and
 linker regiochemistry) and the major component of this mixture is always
 the compound of Formula (I) containing two different head groups; i.e., a
 mixed-head compound of Formula (I). One or more of these compounds may be
 separated from the mixture by chromatographic techniques. This may be
 followed by the introduction of pharmaceutically acceptable counterions
 (A.sup.-) by conventional ion exchange techniques. Compounds of Formula
 (III) wherein n is 0 are novel intermediates for the preparation of
 compounds of Formula (I) and represent a further aspect of the invention.
 Compounds of Formula (III) may be prepared by two general processes which
 form a further aspect of the invention. A first process involves
 quaternization of compounds of Formula (V) (defined herein):
 ##STR5##
 wherein Y is hydrogen or methoxy; Z is methyl; W is carbon, and n is 0 or 1
 with compounds of Formula (VIII) (defined herein):
 ##STR6##
 where the substituent A in (VIII) is a suitable leaving group (e.g.,
 wherein A is I, Br, Cl, OSO.sub.2 Me, OSO.sub.2 PhCh.sub.3) and
 corresponds to the anion, A.sup.- ; and optionally converting the anion
 (A.sup.-) in the resulting compound of Formula (III) into another anion
 (A.sup.-) by conventional ion exchange techniques. Reactions of compounds
 of Formula (V) with compounds of Formula (VIII) are preferably carried out
 in polar aprotic solvents at elevated temperatures in the presence of
 sodium carbonate. Compounds of Formula (III) prepared by this process are
 generated as mixtures of cis/trans stereoisomers and separation of
 cis/trans isomers of (III) typically requires chromatographic techniques,
 wherein the terms cis and trans refer to the spatial orientation of the
 aryl group attached to W relative to that of the alkanol group attached to
 N.
 A second process for the preparation of compounds of Formula (III) involves
 alcoholysis or hydrolysis of zwitterionic compounds of Formula (IX)
 (defined herein):
 ##STR7##
 wherein Y is hydrogen or methoxy; Z is methyl; W is carbon; and n is 0 or
 1.
 Alcoholysis of a compound of Formula (IX) may be performed in any suitable
 alcohol in the presence of a mineral acid and is preferably carried out in
 methanol solutions of hydrogen chloride at ambient temperature. Compounds
 of Formula (IX) are prepared by the quaternization of compounds of Formula
 (V) with cyclic sulfates of Formula (IV):
 ##STR8##
 Reactions of compounds of Formula (V) with compounds of Formula (IV) are
 preferably carried out in polar aprotic solvents at elevated temperatures.
 Compounds of Formula (IX) prepared by this process are generated as
 mixtures of cis/trans isomers; however, cis/trans mixtures of compounds of
 Formula (IX) may be separated by selective crystallization of the trans
 isomer of compounds of Formula (IX) from the mixture. Selective
 crystallization of trans isomers of compounds of Formula (IX) are
 preferably accomplished with polar aprotic solvents such as acetonitirile
 or acetone. This process is the preferred method of preparation of
 compounds of Formula (III), especially trans isomers of compounds of
 Formula (III) where the alkanol side chain ((CH.sub.2).sub.3 OH) and the
 phenyl (n=0) or benzyl (n=1) substituent are oriented trans to one another
 in space, and represents a further aspect of the present invention.
 Compounds of Formula (IX) are novel intermediates and represent another
 aspect of the invention.
 Another aspect of the invention comprises a novel process for the
 preparation of compounds of Formulae (I) and (II). The preparation of
 compounds of Formula (I) involves coupling a compound of Formula (II):
 ##STR9##
 wherein T is hydroxyl or halide; Y is hydrogen or methoxy; Z is methyl; W
 is carbon; n is 0 or 1; h is 1 or 2; and A is a pharmaceutically
 acceptable anion to a compound of Formula (III).
 These reactions are preferably carried out by addition of a compound of
 Formula (III) to the acid or acid chloride derivative of (II) (wherein T
 is hydroxyl or halide, e.g. Cl) in a chlorinated organic solvent at
 ambient or elevated temperatures. The acid chloride derivatives of
 compounds of Formula (II) (e.g., wherein T is Cl) may be prepared from the
 corresponding carboxylic acids of compounds of Formula (II) (e.g., wherein
 T is OH) by methods well known to those skilled in the art.
 Compounds of Formula (II) (e.g., wherein T is OH) are obtained by ring
 opening of compounds of Formula (VI) (defined herein):
 ##STR10##
 with compounds of Formula (III). These reactions are preferably carried out
 by mixing compounds of Formulae (III) and (VI) in chlorinated organic
 solvents at ambient or elevated temperatures. If necessary, these
 reactions may be facilitated by the addition of a catalyst such as
 imidazole. These methods may be followed by the introduction of
 pharmaceutically acceptable counterions (A.sup.-) by conventional ion
 exchange techniques. Ring opening of halogenated cyclic anhydrides of
 compounds of Formula (VI) (e.g., X is Cl or F) with compounds of Formula
 (III) can occur selectively to give compounds of Formula (II) (e.g., X is
 Cl or F; T is OH). In these reactions, the hydroxyl group of (III) reacts
 preferentially at the carbonyl group of compounds of Formula (VI) adjacent
 to the halogen atom. This process is the preferred method for the
 preparation of mixed-head compounds of Formula (I). Compounds of Formula
 (II) are novel intermediates in the preparation of compounds of Formula
 (I) and represent another aspect of the invention.
 A further aspect of the present invention provides a process for the
 conversion of one compound of Formula (II) into another compound of
 Formula (II). Monohalogenated alkenedioates of Formula (IIb) (e.g., X is
 Cl or F; h is 1):
 ##STR11##
 may be prepared by a process which involves elimination of hydrogen halide
 (HX.sup.2) from vicinal dihalo alkanedioates of Formula (IIa) (e.g.,
 X.sup.1 and X.sup.2 are independently Cl or F; T is hydroxyl or halide; h
 is 1):
 ##STR12##
 Compounds of Formula (IIa) are prepared by the reaction of compounds of
 Formula (III) with compounds of Formula (VIa) (X.dbd.Br, Cl, F and h is
 1):
 ##STR13##
 These reactions are preferably carried out by mixing compounds of Formulae
 (III) and (VIa) in chlorinated organic solvents at ambient or elevated
 temperatures. If necessary, these reactions may be facilitated by the
 addition of a catalyst such as imidazole. These methods may be followed by
 the introduction of pharmaceutically acceptable counterions (A.sup.-) by
 conventional ion exchange techniques.
 The transformation of compounds of Formula (IIa) into compounds of Formula
 (IIb) is typically performed by treatment of (IIa) with an excess of a
 tertiary amine, such as triethyl amine, in polar aprotic or chlorinated
 organic solvents at 0.degree. C. In this elimination process, the hydrogen
 atom (H) vicinal to the ester carbonyl oxygen in (IIa) (.alpha. to the
 ester carbonyl) is abstracted selectively. The resulting compounds of
 Formula (IIb) may be converted to monohalogenated alkenedioates of Formula
 (I) by methods described herein.
 Another aspect the present invention provides a process for the conversion
 of one compound of Formula (I) into another compound of Formula (I).
 Monohalogenated alkenedioates of Formula (Ib):
 ##STR14##
 may be prepared by elimination of hydrogen halide (HX) from geminal dihalo
 alkanedioates of Formula (Ia) (e.g., X is Cl or F; h is 2).
 ##STR15##
 Elimination of HX from compounds of Formula (Ia) are preferably carried out
 with potassium carbonate in polar aprotic solvents, such as
 dimethylformamide, at ambient temperature.
 Mixed head monohalobutenedioates of Formula (I) (e.g., X is Cl or F; h is
 1) exist as 1:1 mixtures of regioisomers when synthesized by said process
 which comprises reacting two equivalents of a compound of Formula (III)
 with one equivalent of a compound of Formula (VII). However, mixed head
 monohalobutenedioates of Formula (I) (e.g., X is Br, Cl, F; h is 1) exist
 as pure regioisomers when synthesized by said processes comprising
 conversion of compounds of Formulae (Ia) to (Ib) or conversion of
 compounds of Formulae (IIa) to (IIb). Thus, the latter two processes are
 preferred methods for the preparation of mixed head monohalobutenedioates
 of Formula (I).
 Alkenedioate derivatives of Formulae (I) and (II) may exist as E and Z
 geometric isomers; however, monohalogenated butenedioate analogs of
 Formula (I) preferentially exist as halofumarates such that the two ester
 carbonyl groups are oriented trans to one another. Compounds of Formula
 (I) may also exist as mixtures of diastereomers and one or more
 diastereomers may be separated from the mixture by conventional
 techniques; for example, chromatographic techniques.
 Compounds of Formulae (IV), (V) and (VI), diacid chloride derivatives of
 (VII) and compounds of Formula (VIII) are commercially available or may be
 prepared by published processes for the preparation of the same or
 structurally analogous compounds. Pure enantiomers of (V) are obtained by
 published asymmetric synthetic methods, known classical resolution
 techniques, or chiral preparative HPLC.
 Experimental
 Melting points are uncorrected. All reagent chemicals were used without
 purification. Analytical high performance liquid chromatography (HPLC)
 analyses were performed on a 4.times.250 mm 5.mu. Si60 LiChrosorb column
 (E. Merck, Darmstadt, Germany) at a flow rate of 1.6 mL/min. The mobile
 phase consisted of 0-25% methanol (MeOH)/dichloromethane (CH.sub.2
 Cl.sub.2) mixtures containing 0.25 mL of methanesulfonic acid/L. Medium
 pressure liquid chromatography (MPLC) separations were performed on twin
 Porasil 15-20.mu. cartridges (Waters/Millipore, Milford. Mass., USA)
 eluting with 0-20% MeOH/CH.sub.2 Cl.sub.2 mixtures containing 0.25 mL of
 methanesulfonic acid/L. Proton nuclear magnetic resonance (.sup.1 NMR)
 spectra of all products were consistent with the proposed structures.
 Positive ion flow injection electrospray mass spectra (MS) are reported in
 the form m/z (doubly charged positive ion, relative intensity). Elemental
 analyses were performed by Atlantic Microlab, Norcross, Ga.
 Chlorofumaryl chloride was prepared by a reported procedure (Akhtar, M.;
 Botting, P. N.; Cohen, M. A. Tetrahedron 1987, 43, 5899-5908).
 3,4-Dihydroisoquinoline derivatives were prepared by Bishler-Napieralski
 cyclization of the corresponding amides with phosphorous oxychloride
 (Whaley, K. W.; Govindachari Org. Reactions 1951, 6, 74-150). Racemic
 1,2,3,4-tetrahydroisoquinoline derivatives were prepared by reduction of
 their 3,4-dihydroisoquinoline precursors with sodium borohydride/methanol.
 N-Methylations of 1,2,3,4-tetrahydroisoquinoline derivatives were carried
 out with formaline/formic acid (Kaluszyner, A.; Galun A. B. J. Org. Chem.
 1961, 26, 3536-3537).
 The following starting materials were prepared by chiral catalytic
 hydrogenation of their corresponding 3,4-dihydroisoquinolines by a
 procedure similar to that described by Noyori et al. (Uematsu, N.; Fujii,
 A.; Hashiguchi. S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996,
 118,4916-4917) followed by N-methylation:
 (1R)-6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydrois
 oquinoline;
 (1S)-6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydrois
 oquinoline.
 The following starting material was obtained by classical resolution of its
 corresponding 3,4-dihydroisoquinoline derivative by a procedure similar to
 that described by Brossi et al. (Brossi, A.; Teitel, S. Helv. Chim. Acta
 1973, 54, 1564-1571) followed by N-methylation:
 (1R)-6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydrois
 oquinoline; and
 (1S)-6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydrois
 oquinoline;.
 The following starting materials were obtained by classical resolution of
 their corresponding racemic mixtures by a procedure similar to that
 described by Swaringen et al. (U.S. Pat. No. 4,761,418 Aug. 2, 1988):
 (R)-(-)-5'-Methoxylaudanosine;
 (S)-(+)-5'-Methoxylaudanosine; and
 (1R)-2-Methyl-6,7,8-trimethoxy-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-t
 etrahydroisoquinoline.

SYNTHETIC EXAMPLE 1
 (a) (1S,2R)- and
 (1S,2S)-6,7-Dimethoxy-2-(3-hydroxypropyl)-2-methyl-1-(3,4,5-trimethoxyphen
 yl)-1,2,3,4-tetrahydroisoquinolinium chloride
 To a mixture of
 (1s)-6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroi
 soquinoline (56.0 g, 0.15 mol), sodium iodide (45.0 g, 0.30 mol), sodium
 carbonate (4.0 g, 0.038 mol), and 2-butanone (600 mL) was added
 3-chloropropanol (25.0 mL, 28.3 g, 0.30 mol) and the suspension was heated
 to reflux for 18hours (h) under nitrogen atmosphere. Solvent was
 evaporated and the residue was dissolved in H.sub.2 O and washed with
 ethyl acetate (EtOAc). The aqueous phase was stirred with Dowex
 1.times.8-50 (1.0 L), filtered, and saturated with sodium chloride. The
 aqueous mixture was extracted with chloroform (CHCl.sub.3) and the
 combined organic layers were dried and concentrated to provide a 3:1
 mixture of the (1S,2R)- and (1S,2S)-title products, respectively as a
 white solid (69.5 g, 99% yield): MS m/z 432 (M.sup.+, 9).
 (b) (1R,2S)- and
 (1R,2R)-6,7-Dimethoxy-2-(3-hydroxypropyl)-2-methyl-1-[(3,4,5-trimethoxyphe
 nyl)methyl]-1,2,3,4-tetrahydroisoquinolinium chloride
 (R)-(-)-5'-Methoxylaudanosine (23.5 g, 61.0 mmol) was subjected to a
 procedure to give a 2.3:1 mixture of the (1R,2S)- and (1R,2R)-title
 products, respectively as a yellow, hygroscopic solid (31.5 g, 100%
 yield). The isomers were separated by MPLC (12% MeOH/CH.sub.2 Cl.sub.2,
 0.25 ml methanesulfonic acid/L). The minor (1R,2R) isomer eluted first.
 The appropriate fractions were combined and most of the MeOH was removed
 by coevaporation with CHCl.sub.3. The remaining CHCl.sub.3 solution was
 washed with 1:1 brine/H.sub.2 O, dried and concentrated to provide the
 (1R,2S)-title product (10.4 g, 35% yield) and the (1R,2R)-title product
 (3.7 g, 13% yield) as yellow hygroscopic solids: MS (each isomer) m/z 446
 (M.sup.+, 100).
 Example 1.01
 (c)
 (Z)-2-Chloro-1-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxypheny
 l)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-4-{3-{(1R,2S)-6,7-dimethoxy-2
 -methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolin
 io}propyl}-2-butenedioate dichloride and
 (Z)-2-Chloro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxypheny
 l)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-6,7-dimethoxy-2
 -methyl-1-1[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinoli
 nio}propyl}-2-butenedioate dichloride (1:1)
 To a solution of the product mixture from step a (2.4 g, 5.1 mmol) and the
 (1R,2S)-isomer from step b (2.34 g, 4.9 mmol) in 1,2-dichloroethane (DCE)
 (30 mL) was added chlorofumaryl chloride (0.83 g, 4.4 mmol) and the
 solution was stirred at room temperature (rt) for 18 h. The solvent was
 evaporated and the remaining residue was purified by MPLC (5-20%
 MeOH/CH.sub.2 Cl.sub.2, 0.25 mL methanesulfonic acid/L). The appropriate
 fractions were combined and most of the MeOH was removed by coevaporation
 with CHCl.sub.3. The remaining CHCl.sub.3 solution was washed with 1:1
 brine/H.sub.2 O, dried and concentrated. Lyophilization provided a 1:1
 mixture of the title products as a white solid (0.70 g, 15% yield): MS m/z
 496 (M.sup.2+, 100).
 The following compounds were prepared by a procedure similar to Synthetic
 Example 1:
 Example 1.02
 (Z)-2-Chloro-1-{3-[(1R,2S)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-4-{3-{(1R,2S)6,7-dimethoxy-2-m
 ethyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio
 }propyl}-2-butenedioate dichloride and
 (Z)-2-Chloro-4-{3-[(1R,2S)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxypheny
 l)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-6,7-dimethoxy-2
 -methyl-1-[(3,4,5-trimethoxyphenyl)methyl]1,2,3,4-tetrahydro-2-isoquinolini
 o]propyl}-2-butenedioate dichloride (1:1)
 MS m/z 496 (M.sup.2+, 100).
 Example 1.03
 (Z)-2-Chloro-1-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-4-{3-{(1R,2S)-2-methyl-6,7,8-t
 rimethoxy-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinol
 inio}propyl}-2-butenedioate dichloride and
 (Z)-2-Chloro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxypheny
 l)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-2-methyl-6,7,8-
 trimethoxy-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquino
 linio}propyl)-2-butenedioate dichloride (1:1)
 MS m/z 511 (M.sup.2+, 100).
 Example 1.04
 (Z)-2-Chloro-1-{3-[(1R,2S)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-4-{3-{(1R,2S)-2-methyl-6,7,8-t
 rimethoxy-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinol
 inio}propyl}-2-butenedioate dichloride and
 (Z)-2-Chloro-4-{3-[(1R,2S)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxypheny
 l)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-[(R,2S)-2-methyl-6,7,8-t
 rimethoxy-1-(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinoli
 nio}propyl}-2-butenedioate dichloride (1:1)
 MS m/z 511 (M.sup.2+, 22).
 SYNTHETIC EXAMPLE 2
 (Method A)
 (a) (2R*,3R*)-2,3-Dichlorosuccinic anhydride
 A solution of maleic anhydride (10.6 g, 108 mmol) and benzoyl peroxide (5
 mg, 0.02 mmol) in CHCl.sub.3 (250 mL) was saturated with chlorine gas and
 the resulting bright yellow solution was stirred for 5 h at rt. Residual
 chlorine was removed with a stream of nitrogen and the reaction mixture
 was partially concentrated. Four crops of the white, solid title product
 were obtained by filtration (11.9 g, 65% yield): mp 90-92.degree. C.
 (b)
 (Z)-2-Chloro-1-{3-[(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphen
 yl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}hydrogen
 2-butenedioate monochloride
 A solution of the (1R, 2S)-title product from Synthetic Example 1, step b
 (3.5 g, 6.10 mmol) and the product from step a (1.7 g, 10.1 mmol) in DCE
 (38 mL) and acetonitrile (MeCN) (2 mL) was stirred at rt overnight. The
 mixture was concentrated and the remaining solid was triturated with EtOAc
 and dissolved in MeCN (25 mL). A solution of
 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.68 g, 11.0 mmol) in MeCN (6
 mL) was added dropwise at 0.degree. C. and the reaction mixture was
 stirred at ice bath temperature for 1 h. The solvent was evaporated and
 the remaining solid was dissolved in CHCl.sub.3 (150 mL). This solution
 was washed with 2:1 brine/water containing methanesulfonic acid (4 mg/mL)
 and with brine. The organic layer was dried and concentrated to provide
 the title product as a foam (2.6 g, 69% yield): MS m/z 578 (M.sup.+, 100).
 Example 2.01
 (c)
 (Z)-2-Chloro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxypheny
 l)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-6,7-dimethoxy-2
 -methyl-1-(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolini
 o}propyl}-2-butenedioate dichloride
 A solution of oxalyl chloride (36 mmol) in CH.sub.2 Cl.sub.2 (18 mL) was
 added dropwise to a stirring solution of the product from step b (2.22 g,
 3.61 mmol) in DCE (25 mL). The reaction mixture was stirred 1 h at rt and
 then heated at reflux for 5 min. Excess oxalyl chloride was removed in
 vacuo and the resulting foam was dissolved in DCE (15 mL). A solution of
 the product mixture from Synthetic Example 1, step a (2.00 g, 3.58 mmol)
 in DCE (5 mL) was added and the solution was stirred overnight at rt. The
 solvent was evaporated and the mixture was purifed by MPLC as described in
 Synthetic Example 1, step c. Lyophilization provided the title product as
 a white solid (731 mg, 19% yield): MS m/z 496 (M.sup.2+, 100).
 The following compounds were prepared by a procedure similar to Synthetic
 Example 2:
 Example 2.02
 (Z)-2-Chloro-4-{3-[(1S,2S)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-6,7-dimethoxy-2-
 methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolini
 o}propyl}-2-butenedioate dichloride
 MS m/z 496 (M.sup.2+, 100).
 Example 2.03
 (Z)-2-Chloro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-2-methyl-6,7,8-t
 rimethoxy-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinol
 inio}propyl}-2-butenedioate dichloride
 MS m/z 511 (M.sup.2+, 100).
 Example 2.04
 (Z)-2-Chloro-4-{3-[(1R,2S)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-2-methyl-6,7,8-t
 rimethoxy-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinol
 inio}propyl}-2-butenedioate dichloride
 MS m/z 511 (M.sup.2+, 100).
 SYNTHETIC EXAMPLE 3
 (Method B): Alternative method for the preparation of the compound of
 Example 2.01
 (a) 1,3-Dioxa-2-thiane 2,2-dioxide
 To a solution of 1,3-propanediol (50.0 g, 0.65 mol) in carbon tetrachloride
 (CCl.sub.4) (650 mL) was added thionyl chloride (57.5 mL, 93.7 g, 0.79
 mol) and the mixture was heated to reflux for 1.5 h. The solution was
 cooled to 0.degree. C. and diluted with MeCN (650 mL) followed by
 sequential addition of ruthenium (III) chloride hydrate (81 mg, 0.39
 mmol), sodium periodate (210.0 g, 0.98 mol), and H.sub.2 O (980 mL). The
 resulting orange mixture was stirred at rt for 1.5 h and then diluted with
 diethyl ether (Et.sub.2 O) (6 L). The separated organic phase was washed
 with water, saturated NaHCO.sub.3 and brine. The Et.sub.2 O layer was
 dried and filtered through a bed of silica gel. The filtrate was
 concentrated and the resulting oil was treated with Et.sub.2 O (50 mL) and
 hexanes (100 mL) and stored at 5.degree. C. for 18 h. Filtration of the
 resulting precipitate afforded the title compound as an off-white solid
 (79.0 g, 87% yield): mp 54-56.degree. C.
 (b)
 3-[(1S,2R)-6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetra
 hydro-2-isoquinoliinio]propyl-1-sulfate
 A mixture of
 (1S)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroi
 soquinoline (36.8 g. 98.6 mmol) and the product from step a (23.7 g, 171.7
 mmol) in MeCN (350 mL) was heated at 65.degree. C. for 5 h. The mixture
 was cooled to rt and the resulting precipitate was collected by filtration
 and triturated with MeCN to afford the title compound as an off-white
 powder (30.0 g, 60% yield): mp 207-209.degree. C.; MS m/z 534 (M+23, 60),
 512 (M+1, 30), 432 (M-SO.sub.3, 100).
 (c)
 (1S,2R)-6,7-Dimethoxy-2-(3-hydroxypropyl)-2-methyl-1-(3,4,5-trimethoxyphen
 yl)-1,2,3,4-tetrahydroisoquinolinium chloride
 Acetyl chloride (35.0 mL, 38.8 g, 0.49 mol) was added dropwise to ice-cold
 MeOH (350 mL) and the resulting solution was stirred for 10 minutes (min).
 The product from step b (28.1 g, 0.05 mol) was added and the reaction
 mixture was stirred at rt for 6 h. The solution was neutralized by careful
 addition of excess NaHCO.sub.3 and the solid was filtered through a pad of
 celite. The filtrate was evaporated and the residue was dissolved in
 CHCl.sub.3. The resulting solid was filtered through a pad of celite and
 washed with CHCl.sub.3. The filtrate was evaporated, the remaining residue
 was dissolved in H.sub.2 O, and the aqueous solution was saturated with
 sodium chloride. The aqueous phase was extracted with CHCl.sub.3 and the
 organic layers were dried and concentrated to give the title compound as a
 hygroscopic white solid (25.0 g, 98% yield): MS m/z 432 (M.sup.+, 100).
 (d) 3-{(1R,2S)-6,7-Dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)
 -methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl-1-sulfate
 (1R)-(-)-5'-Methoxylaudanosine (52.6 g, 0.13 mmol) was subjected to
 procedure b. The resulting material was triturated with acetone to yield
 the title product as an off-white powder (49.3 g, 69% yield): mp
 191-193.degree. C.; MS m/z 526 (M+1, 100).
 (e) (1R,2S)-6,7-Dimethoxy-2-(3-hydroxypropyl)-2-methyl-1-[(3,4,5
 trimethoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinolinium chloride
 The product from step d (54.5 g, 0.10 mmol) was subjected to procedure c to
 afford the title compound as a hygroscopic white foam (50.7 g, 100%
 yield): MS m/z 446 (M.sup.+, 100).
 (f)
 (Z)-2-Chloro-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphen
 yl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}hydrogen
 2-butenedioate monochloride
 A solution of the product from step e (15 g, 31.1 mmol) and the product
 from Synthetic Example 2, step a (6.4 g, 37 mmol) in CH.sub.2 Cl.sub.2 (50
 mL) was stirred overnight at rt. The reaction mixture was diluted with
 CH.sub.2 Cl.sub.2 (150 mL), cooled to -20.degree. C. and triethylamine
 (18.2 mL, 130.4 mmol) was added dropwise. The reaction was warmed to 0C,
 CHCl.sub.3 (200 mL) was added and the mixture was washed with 2:1
 brine/water containing methanesulfonic acid (4 mg/mL). The CHCl.sub.3
 layer was separated and the combined aqueous layers were saturated with
 sodium chloride, acidified with concentrated hydrochloric acid (HCl) (9
 mL) and back-extracted with CHCl.sub.3. The combined CHCl.sub.3 layers
 were dried and concentrated and the resulting foam was triturated with
 Et.sub.2 O. The title product was collected by filtration as a tan solid
 (16.3 g, 86% yield): spectral data identical to that of the title product
 from Synthetic Example 2, step b.
 Example 3.01
 (g)
 (Z)-2-Chloro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxypheny
 l)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)6,7-dimethoxy-2-
 methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolini
 o}propyl}-2-butenedioate dichloride
 The product from step f (7.0 g, 11.4 mmol) was treated with oxalyl chloride
 and then reacted with the product from step c (6.62 g, 11.9 mmol) as
 described in Synthetic Example 2, step c. The reaction mixture was
 concentrated and the resulting material was purified by MPLC as described
 in Synthetic Example 1, step c. Lyophilization provided the title product
 as a white solid (8.7 g, 72% yield): spectral data identical to that of
 the title product from Synthetic Example 2, step c.
 SYNTHETIC EXAMPLE 4
 (Method C) Alternative method for the preparation of the compounds of
 Examples 2.01 or 3.01
 (a)
 (E)-2-Chloro-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphen
 yl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}hydrogen
 2-butenedioate monochloride
 To a solution of the product from Synthetic Example 3, step e (2.5 g, 5.2
 mmol) and imidazole (0.35 g, 5.2 mmol) in CH.sub.2 Cl.sub.2 (35 mL) at
 -15.degree. C. was added a solution of chloromaleic anhydride (0.69 g, 5.2
 mmol) in CH.sub.2 Cl.sub.2 (10 mL). After 10 min, the mixture was diluted
 with CHCl.sub.3 and washed with 2:1 brine/H.sub.2 O containing
 methanesulfonic acid (4 mg/mL). The organic layers were washed with brine,
 dried and evaporated to give the title compound as a yellow hygroscopic
 solid: MS m/z 578 (M.sup.+, 100).
 Example 4.01
 (b)
 (Z)-2-Chloro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-6,7-dimethoxy-2-
 methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolini
 o}propyl}-2-butenedioate dichloride
 A solution of the product from step a (198 mg, 0.32 mmol), oxalyl chloride
 (281 .mu.L, 3.2 mmol), and dimethyl formamide (DMF) (1 drop) in CH.sub.2
 Cl.sub.2 (4 mL) was heated at reflux for 2 h. The mixture was coevaporated
 with CH.sub.2 Cl.sub.2 and dried in vacuo. The residue was dissolved in
 DCE (5 mL), the product mixture from Synthetic Example 1, step a (300 mg,
 0.64 mmol) was added and the mixture was stirred at rt for 18 h. The
 solvent was evaporated and the crude material was purified as described in
 Synthetic Example 1, step c. Lyophilization provided the title product as
 a white solid (80 mg, 23% yield): spectral data identical to that of the
 title product from Synthetic Example 2, step c.
 The following compound was prepared by a procedure similar to Synthetic
 Example 4:
 Example 4.02
 (Z)-2-Bromo-4-{3-[(1S,2R)6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-
 1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-6,7-dimethoxy-2-me
 thyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2
 isoquinolinio}propyl}-2-butenedioate dibromide
 MS m/z 518 (M.sup.2+, 100).
 SYNTHETIC EXAMPLE 5
 (Method A)
 (a) 2,2-Difluorosuccinic anhydride
 A mixture of 2,2-difluorosuccinic acid (1.15 g, 7.46 mmol), thionyl
 chloride (4 mL, 20.6 mmol) and benzene (4 mL) was heated at reflux for 2.5
 h. The mixture was filtered and the filtrate was concentrated to afford
 the title product as an oil that crystallized on standing (838 mg, 6.16
 mmol, 83% yield).
 (b) 2,2-Difluoro-1-{3-{(1R,2SR)-6,7-dimethoxy-2-methyl-1-[(3,4,5
 trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}hydroge
 n butanedioate monochloride
 A solution of the 2.3:1 product mixture from Synthetic Example 1, step b
 (2.7 g, 5.60 mmol) and the product from step a (838 mg, 6.16 mmol) in DCE
 (80 mL) was stirred overnight at rt. The solvent was evaporated to yield a
 2.3:1 mixture of the (1R, 2S)- and (1R, 2R)-title products, respectively
 as a yellow hygroscopic solid (3.5 g, 5.60 mmol, 100% yield): MS m/z 582
 (M.sup.+, 70).
 Example 5.01
 (c)
 2,2-Difluoro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxypheny
 l)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}1-{3-{(1R,2S)-6,7-dimethoxy-2-
 methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolini
 o}propyl}-butanedioate dichloride
 The product mixture from step b (2.0 g. 3.24 mmol) was treated with oxalyl
 chloride and then reacted with the product mixture from Synthetic Example
 1, step a (1.73 g, 3.10 mmol) as described in Synthetic Example 2. step c.
 The reaction mixture was concentrated and the resulting material was
 purified by MPLC as described in Synthetic Example 1. step c.
 Lyophilization provided the title product as a white solid (466 mg, 27%
 yield): MS m/z 498 (M.sup.2+, 100).
 SYNTHETIC EXAMPLE 6
 (Method B): Alternative method for the preparation of the compound of
 Example 5.01
 (a)
 2,2-Difluoro-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphen
 yl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}hydrogen butanedioate
 monochloride
 The product from Synthetic Example 3, step e (3.0 g, 6.22 mmol) was treated
 in a fashion similar to that described in Synthetic Example 5, step b. The
 title product was obtained as a yellow hygroscopic solid (3.21 g, 83%
 yield): spectral data were consistent with the proposed structure.
 Example 6.01
 (b)
 2,2-Difluoro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxypheny
 l)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-6,7-dimethoxy-2
 -methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolin
 io}propyl}butanedioate dichloride
 The product from step a (3.0 g, 4.85 mmol) was treated with oxalyl chloride
 and then reacted with the product mixture from Synthetic Example 1, step a
 (2.44 g, 4.37 mmol) as described in Synthetic Example 2, step c. The
 reaction mixture was concentrated and the resulting material was purified
 by MPLC as described in Synthetic Example 1, step C. Lyophilization
 provided the title product as a white solid (1.3 g, 37% yield): the
 spectral data were identical to that of the title product from Synthetic
 Example 5, step c.
 The following compounds were prepared by procedures similar to Synthetic
 Example 6:
 Example 6.02
 2,2-Difluoro-4-{3-[(1S,2S)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-6,7-dimethoxy-2-
 methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolini
 o}propyl}butanedioate dichloride
 MS m/z 498 (M.sup.2+, 100).
 Example 6.03
 (2RS)-4-{3-[(1S,2R)-6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3
 ,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-
 1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propy
 l}-2-fluorobutanedioate dichloride
 MS m/z 489 (M.sup.2+, 55).
 Example 6.04
 (2RS)-4-{3-[(1S,2S)-6,7-Dimethoxy-2-methyl-1-(3,4,5
 trimethoxyphenyl)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)
 -6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahyd
 ro-2-isoquinolinio}propyl}-2-fluorobutanedioate dichloride
 MS m/z 489 (M.sup.2+, 30).
 SYNTHETIC EXAMPLE 7
 Alternative method for the preparation of the compounds of Examples 5.01
 and 6.01
 Example 7.01
 (a)
 2,2-Difluoro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxypheny
 l)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-6,7dimethoxy-2-
 methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolini
 o} propyl}butanedioate dichloride
 Neat oxalyl chloride (25 mL, 0.28 mol) was added dropwise to a solution of
 the product from Synthetic Example 6, step a (7.0 g. I 1.0 mmol) in DCE
 (150 mL). The solution was stirred at rt for 3.5 h. The solvent and excess
 oxalyl chloride were removed at reduced pressure and the remaining foam
 was reconstituted in DCE (35 mL). A solution of the product from Synthetic
 Example 3, step c (4.7 g, 10.0 mmol) in DCE (35 mL) was added and the
 reaction mixture was stirred overnight at rt. The solvent was evaporated
 and the product was purified by MPLC as described in Synthetic Example 1,
 step c. Lyophilization provided the title product as a white solid (5.63
 g, 53% yield) with spectral data identical to that of the title product
 from Synthetic Example 5, step c.
 The following compound was prepared by procedures similar to Synthetic
 Example 7:
 Example 7.02
 2,2-Difluoro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl
 )-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-2-methyl-6,7,8-t
 rimethoxy-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinol
 inio}propyl}butanedioate dichloride
 MS m/z 513 (M.sup.2+, 100).
 SYNTHETIC EXAMPLE 8
 Example 8.01
 (Z)4-{3-[(1S,2R)-6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-
 tetrahydro-2-isoquinolinio]propyl}-1-{3-{(1R,2S)-6,7-dimethoxy-2-methyl-1-[
 (3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propyl}-
 2-fluoro-2-butenedioate dichloride
 Solid K.sub.2 CO.sub.3 (97 mg, 0.702 mmol) was added to a solution of the
 title product from Synthetic Example 7 (750 mg, 0.702 mmol) in DMF (5 mL)
 and the mixture was stirred at rt for 1 h and then filtered. The filtrate
 was diluted with CHCl.sub.3 (50 mL) and washed with 1:1 brine/H.sub.2 O
 (pH.about.1). The organic layer was dried and concentrated and the residue
 was triturated with Et.sub.2 O and purified as described in Synthetic
 Example 1, step c. The title product was obtained as a white powder (404
 mg, 0.385 mmol, 52% yield): MS m/z 488 (M.sup.2+, 80).
 The following compound was prepared by a procedure similar to Synthetic
 Example 8:
 Example 8.02
 (Z)4-{3-[(1S,2R)-6,7-Dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-
 tetrahydro-2-isoquinoiinio]propyl}-1-{3-{(1R,2S)-2-methyl-6,7,8-trimethoxy-
 1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-isoquinolinio}propy
 l}-2-fluoro-2-butenedioate dichloride
 Anal. Calcd for C.sub.54 H.sub.71 N.sub.2 O.sub.15 Cl.sub.2 Fo5H.sub.2 O:
 C, 55.52; H, 6.99; N, 2.40; Cl, 6.07. Found: C, 55.52; H, 6.96; N, 2.40;
 Cl, 6.15.
 Biological Activity
 Cats were anesthetized with alpha-chloralose (80 mg/kg) and pentobarbital
 (10 mg/kg) i.p. See J. J. Savarese Anesthesia and Analgesia, Vol. 52, No.
 6, November-December, (1973). Square-wave stimuli were applied at
 supramaximal voltage to the peroneal nerve at 0.15 Hz and the evoked
 twitches of the tibialis anterior muscle were recorded.
 Rhesus monkeys were anesthetized with ketamine (5 mg/Kg) and pentobarbitol
 (5 mg/Kg) given intramuscularly or intravenously. Anesthesia was
 maintained with a mixture of halothane (0.25-0.75%), nitrous oxide (60%)
 and oxygen (40%). The common peroneal nerve was stimulated supramaximally
 with square wave pulses of 0.2 m sec duration at a rate of 0.15 Hz. Twitch
 contractions were recorded via the tendon of the extensor digitorum
 muscle.
 In all animals, the trachea was intubated and ventilation was controlled at
 12-15 ml/kg, 18-24 breaths per minute. Animals not receiving inhalation
 anesthetics were ventilated with room air. The left femoral vein and
 artery were cannulated for drug administration and for recording or
 arterial pressure, respectively. Compounds of Formula I listed in Table 1
 were administered intravenously. The ED.sub.95, i.e., the dose required to
 produce 95% block of the twitch response of compounds of Formula (I) is
 provided in Table 1. Absence of data for particular parameters of
 particular example numbers indicates that data were not available.
 TABLE 1
 Neuromuscular Blocking Activity in Rhesus Monkey
 Example ED95 Onset Duration Hist Rel
 No. (mg/kg) (min) (min) (mg/kg) Comment
 Example 1.01 0.1-0.15 1.2-1.5 3.5-7.0 3.2-6.4
 Example 1.02 0.3 0.8 3.1
 Example 1.03 0.07 10.5 1.2
 Example 1.04 0.06 9.5 1.2-1.6
 Example 2.01 0.05-0.08 1 5.5 3.2-6.4 Same as
 3.01, 4.01
 Example 2.02 0.3 3.5
 Example 4.02 0.3 3.5
 Example 5.01 0.05-0.07 1 6.0 3.2-6.4 Same as
 6.01, 7.01
 Example 6.02 0.25 7.0
 Example 6.03 0.04 32.0
 Example 6.04 0.3 27.0
 Example 7.02 0.035 9.5 3.2
 Example 8.01 0.12 1 4.0 6.4
 Example 8.02 0.06 8.0-9.0 3.2