MXPA99008725A - Substituted isoquinolines as ultra short acting neuromuscular blockers - Google Patents

Abstract

Se describen agentes bloqueadores neuromusculares de acción ultra corta de la fórmula (I) que sonútiles como relajantes del músculo esquelético durante el proceso de entubación de emergencia, cirugía de rutina y los medios post-operatorios en donde:X es halógeno, h es 1ó2;Y es hidrógeno o metoxi;Z1 y Z2 son metilo;W1 y W2 sonátomos de carbono;y A es un anión farmacéuticamente aceptable.

Description

NEUROMUSCULAR BLOCKERS OF ULTRA SHORT ACTION The present invention relates to new compounds, methods for the preparation of these 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 relaxation of the skeletal muscle during surgery and during intubation of the trachea. Neuromuscular blockers are classified in general both by the mechanism of action (depolarizing or non-depolarizing) and by the duration of action (ultra short, short, intermediate, and prolonged). See, Bedford, R., "From the FDA", Anesthesiology, 82 (1), 33a, 1995. Non-depolarizing neuromuscular blocking agents include the long-term agents such as d-tubocuranine, pancuronium, galamin, diallyltoxycerin and toxiferin, agents of intermediate duration such as atracurium and vecuronium, and agents of short duration such as mivacurium. See, for example, U.S. Patent No. 4,179,507, U.S. Patent No. 4,701,460, U.S. Patent No. 4,761,418, and U.S. Patent No.

REF. 31356 5,454,510. Conventional non-depolarizing agents typically exhibit a duration of 20 to 180 minutes of action when used as skeletal muscle relaxants. Currently, there are non-depolarizing neuromuscular blocking agents, without ultra-short duration, in chemical use. Depolarizing agents include succinylcholine and decamethonium. Due to their depolarizing mechanism of action, these agents can have various side effects such as cardiac stress and death, hyperkalemia, malignant hyperthermia, severe muscle pain, cardiac arrhythmias, increased intraocular pressure and increased intragastric tension. Conventional depolarizing agents exhibit short durations of action, for example, to 15 minutes in humans. Succinylcholine has a rapid onset and an ultra short duration of action and is the only ultra-short-acting neuromuscular blocker in clinical use. Despite its profile of undesirable side effects, another agent of ultra short action is not available and thus is currently the preferred agent for use in emergencies. The duration of ultra short action is extremely important in emergency situations. The use of agents of longer duration could lead to serious brain damage and death. Non-depolarizing agents are generally believed to be safe and more clinically desirable than depolarizing agents, and clinicians have long recognized the need for a non-depolarizing neuromuscular blocker having an ultra-short duration of action. See, Miller, R.D. Anesthesia and Analgesia 61 (9), 721, 1982; and Belmont, M.R., Current Opinion in Anesthesiology, 8, 362, 1995. However, non-depolarizing agents may exhibit lateral defects and not specifically related to their mechanism or duration of action. For example, the agents of prolonged duration, pancuronio and galamina have effects in the autonomic nervous system and can cause an increase in the heart rate (tachycardia) Agents of intermediate and short duration such as atracurium besylate and mivacurium chloride may also exhibit the side effect of histamine release. The release of histamine has undesirable effects on blood pressure and heart rate, and some vectors believe that the release of large amounts of histamine can cause life-threatening anaphylaxis in some patients. It has now been discovered that the compounds of Formula (I) include potent non-depolarizing neuromuscular blocking agents of ultra short duration, for example about 5 to 15 minutes, which will provide such increased safety over depolarizing ultra short acting agents., known, for example, succinylcholine, and a reduced ability to release histamine over other non-depolarizing agents such as atracurium and mivacurium. In addition, they have a rapid onset of action and are invested by treatment with known investment agents such as neostigmine, both of very important characteristics in emergency situations and in other procedures. These agents maintain their ultra short duration of action and rapid spontaneous recovery when administered either by bolus or continuous infusion and are without the cumulative effects observed with other neuromuscular blockers (pancuronium, vecuronium). In this way, the compounds of the present invention should provide a significant advantage in emergency, routine surgery, and postoperative means. Accordingly, the present invention provides compounds of Formula (I): wherein X is halogen, h is from 1 to 2; And it is hydrogen or methoxy; Z1 and Z2 are methyl; 1 and W2 are carbon atoms; and A is a pharmaceutically acceptable anion. The compounds of Formula (I) contain two substituted isoquinolinium portions connected by an aliphatic linker. The two substituted isoquinolinium portions can be conveniently distinguished by referring to them as the "left header" and the "right header", where the left header contains W1 and the right header contains W2. The aliphatic linker in the portion of the compound of the Formula (I) is denoted by the following Formula (I).

The solid and striped lines () indicate a double or individual link. An individual class of the compound of Formula (I) is that where X is chlorine or fluorine. Particularly preferred halogen substitutions are monochloro, monofluoro and difluoro. The aliphatic linker portion of the compounds of Formula (I), as described by Formula (I), comprises a butanedioate or butenedioate moiety. Suitably, the compounds of the Formula (I), wherein the aliphatic linker comprises a butanedioate moiety, can exist in either the E or Z configuration or as mixtures of the E and Z isomers. Preferably, the butanedioate moiety of the compounds of Formula (I) is a fumarate. The term "fumarate" as used herein refers to a portion of butanedioate wherein the two ester carbonyl groups are oriented trans to each other. A preferred class of compounds of Formula (I) is one in which the aliphatic linker is a butanedioate moiety and X represents chloro or fluorine and h is 1 or 2. A particularly preferred class of compounds of Formula (I) is that in wherein the aliphatic linker is a butanedioate moiety and X represents fluorine and h is 1 or 2. More preferred are compounds of Formula (I) wherein the aliphatic linker is a butanedioate moiety, X represents fluorine and h is 2. Another class Preferred of compounds of Formula (I) is one in which the aliphatic linker is a butanedioate moiety and X represents chloro or fluoro. A particularly preferred class of compounds of Formula (I) includes those in which the aliphatic linker is a butanedioate moiety, X represents chloro or fluoro, h is 1 and the butanedioate moiety is a fumarate. More preferred are compounds of Formula (I) wherein the aliphatic linker is a butanedioate moiety, X represents chloro, h is 1 and the butanedioate moiety is a fumarate. The compounds of Formula (I) contain four chiral centers. The carbon atoms (denoted as 1 and W2) and each quaternary nitrogen atom in the isoquinolinium portions are chiral. Each of the chiral centers can exist independently in either the R or S configuration. Accordingly, it will be apparent to those skilled in the art that each compound within Formula (I) can exist in sixteen distinct optical isomeric forms. The scope of the present invention is extended to cover each and every isomer of the compounds of Formula (I) either individually or in admixture with other isomers, and all mixtures of these isomers. Suitably, 1 is in the R configuration, the N attached to Z1 is in the S configuration, W2 is in either the R or S configuration, and the N bound to Z2 is in either the R or S configuration. Preferably, 1 is in the R configuration, the N attached to Z1 is in the S configuration; W2 is in the S configuration, and the N attached to Z2 is in either the R or S configuration. More preferred are the compounds of the Formula (I) wherein W is the entire configuration of R, 2 is in the S configuration , the N bound to Z1 is the S configuration and the N bound to Z2 is in the R configuration. The particularly preferred compounds of the Formula (I) include: Dichloride of (Z) -2-chloro-4-. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -! -. { 3- . { (1 R, 2S) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium. propyl} -2-fluoro-2-butenedioate. 2, 2-difluoro-4- dichloride. { 3- [(SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} l-. { 3-. { (IR, 2S) -6,7-Dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -butanedioate.

Dichloride of (Z) -4-. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3- . { IR, 2S) -6,7-dimethoxy-2-methy1-1- [3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinio. Propyl} -2-butenedioate and 2, 2-difluoro-4- dichloride. { 3- [(SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} 1- . { 3-. { (IR, 2S) -2-methyl-6,7,8-trimethoxy-1- [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -butanedioate.

Since the pharmacological activity of the compounds of the invention resides in the cation, the nature of the anion A "is relatively unimportant, however, for therapeutic purposes, it is pharmaceutically acceptable, preferably, to the receptor of the compounds. Examples of pharmaceutically acceptable anions include iodide, mesylate, tosylate, bromide, chloride, hydrogen sulfate, sulfate / 2, phosphate / 3, hydrogen phosphate / 2, acetate, besylate, succinate / 2, maleate, naphthalenesulfonate and propionate. Pharmaceutically acceptable salts such as salts that are not thus acceptable may be useful for the release and / or purification of the compounds of the invention.Anacceptable salts may also be useful since they can be converted into acceptable salts by techniques well known in the art. The technique The compounds of Formula (I) are used as blocking agents during surgery, for intubation of the trachea or during electro-shock therapy. They can be administered parenterally, for example, by intravenous 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 dose for each subject may vary, however, an adequate intravenous amount or dose of the compounds of Formula (I) to have paralysis in a mammal will be from 0.01 to 5.0 mg / kg of body weight, and preferably 0.02 to 0.5 mg / kg body weight, which is based on the weight of the di-cation which is the active ingredient. The dose 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, for inducing neuromuscular block in surgery or for intubation of the trachea. The present invention also provides the use of a compound of Formula (I) and the manufacture of the 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 active chemicals in bulk, it is preferred to present them in the form of a pharmaceutical formulation for parenteral administration. Accordingly, the present invention provides a pharmaceutical formulation comprising a compound of Formula (I), as defined hereinbefore and a "pharmaceutically acceptable carrier." Where the pharmaceutical formulation is for parenteral administration, the formulation can be a aqueous or non-aqueous solution or liquid mixture, 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 (by induction) or dextrose or solution of salinas These formulations are normally presented in unit dose forms such as ampules or disposable injection devices. They may also be present in forms of various doses such as a bottle from which the appropriate dose can be withdrawn. All these formulations must be sterile. A suitable dose for obtaining a neuromuscular block for adult humans (150 pounds or 70 kg) is 0.5 or 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. In this way, a parenteral, pharmaceutical preparation suitable for administration to humans will preferably contain from 0.1 to 20 mg / mol of the compounds of Formula (I) in solution or multiples thereof for bottles of various doses. An individual and preferred formulation is a solution of the compound of Formula (I) in water or dextrose solution. This can be prepared by dissolving the compound in sterile, pyrogen-free water, or water containing dextrose with or without a preservative and by sterilizing the solution. Alternatively, it can be prepared by dissolving the sterile compound in sterile, pyrogen-free or sterile dextrose solution under aseptic conditions. Particularly preferred formulations have a pH of about 2.0 to 5.0. The compounds of Formula (I) can also be administered as an infusion of a solution of dextrose or saline, for example, Ringer's solution in the form of a drip. The compounds can also be administered in other solvents (usually as a solvent mixed with water) such as alcohol, polyethylene glycol and dimethyl sulfoxide. They can also be given intramuscularly (as a drip if required) as a suspension or a solution.

General Description of the Processes Unless otherwise indicated, Y, Xh. and A "described in the formulas that follow are as described in Formula (I) above W corresponds to W1 and 2 of Formula (I), Z corresponds to Z1 and Z2 of Formula (I) and Xxh and X2h correspond to Xh of Formula (I) Unless otherwise specified, T represents hydroxyl or halide Another aspect of the present invention is a process for the preparation of the compounds of Formula (I). Formula (I) can be prepared by reacting two equivalents of a compound of Formula (III): wherein Y is hydrogen or methoxy; Z is methyl; it is coal; n is 0 or 1; and A is a pharmaceutically acceptable anion; with an equivalent of a compound of the Formula (VII): (VII) in an aprotic solvent. The preferred method for copying the compounds of Formula (III) with the compounds of Formula (VII) comprises mixing the diacid or diacid chloride derivative of (VII) (wherein T is hydroxyl or halide, for example, Cl) with two equivalents of a compound of the 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 the compounds of the Formula (I). The compounds of Formula (I) can 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 the addition of one equivalent of a diacid chloride derivative of (VII) (per example, T is Cl). This technique generates a statistical mixture of three different compounds of the Formula (I) (ignoring the stereochemical considerations and the regiochemistry of the linker) and the main component of this mixture is always the compound of the Formula (I) which contains two different groups of header; that is, a header, mixed compound of Formula (I). One or more of these compounds can be separated from the mixture by chromatographic techniques. This can be followed by the introduction of the pharmaceutically acceptable counterions (A ") by conventional ion exchange techniques The compounds of the Formula (III), wherein n is 0 are new intermediates for the preparation of the compounds of the Formula (I) and represent a further aspect of the invention The compounds of Formula (III) can be prepared by two general processes that form a further aspect of the invention A first process comprises the quaternization of the compounds of the Formula (V ) (defined in this) wherein Y is hydrogen or methoxy; Z is methyl; it's carbon; and n is 0 or 1, with the compounds of Formula (VIII) (defined herein) A (CH2) 3OH (VIII) wherein the substituent A in (VIII) is a suitable leaving group (eg, where A is I, 'Br, Cl, OS02Me, 0S02PhCh3) and correspond to the anion A ", and optionally converting the anion (A ~) into a resulting compound of Formula (III) in another anion (A ") by conventional ion exchange techniques.

The reactions of the compounds of the Formula (V) or the compounds of the Formula (VIII) are preferably carried out in polar aprotic solvents at elevated temperatures in the presence of sodium carbonate. The compounds of the Formula (III) prepared by this process are generated as mixtures of the cis / trans stereoisomers in the separation of the cis / trans isomers of (III) typically requires chromatographic techniques where the terms cis and trans refer to the partial 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 the compounds of the Formula (III) comprises the hydrolysis of the zwitterionic compounds of the Formula (IX) (defined in the present) : wherein Y is hydrogen or methoxy; Z is methyl; W is carbon; and n is 0 or 1. The alcoholysis of a compound of the formula (IX) can be returned in any suitable alcohol in the presence of a mineral acid and is preferably carried out in methanol solutions of hydrogen chloride at room temperature. The compounds of the Formula (IX) are prepared by the quaternization of the compounds of the Formula (V) with cyclic sulphates of the Formula (IV).

(IV) The reactions of the compounds of the formula (V) with the compounds of the formula (IV) are preferably carried out in polar aprotic solvents at elevated temperatures. The compounds of the Formula (IX) prepared by this process are generated as mixtures of the cis / trans isomers. However, cis / trans mixtures of the compounds of Formula (I) can be separated by selective crystallization of the trans isomer from the compounds of Formula (IX) from the mixture. The selective crystallization of the cis / trans isomers of the compounds of the Formula (IX) is preferably achieved with polar aprotic solvents such as acetonitrile or acetone. This process is the preferred method of preparing the Formula (III), especially the trans isomers of the compounds of Formula (III) wherein the alkanol side chain ((CH2) 3OH) and the phenyl substituent (n-0) or benzyl (n = l) are trans-oriented with each other in space, and represents a further aspect of the present invention. The compounds of Formula (IX) are new intermediates and represent another aspect of the invention. Another aspect of the invention comprises a new process for the preparation of the compounds of Formulas (I) and (II). The preparation of the compounds of the Formula (I) comprises the coupling of a compound of the Formula (II): wherein T is hydroxyl or halide; And it is hydrogen or methoxy; Z is methyl; W is carbon; and 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 the addition of a compound of the Formula (III) to an acid or acid chloride derivative of (II) (wherein T is hydroxyl or halide, for example, Cl) in an organic solvent Chlorinated at room temperature or elevated. The acid chloride derivatives of the compounds of the Formula (II) (for example, where T is Cl) can be prepared from the corresponding carboxylic acids of the compounds of Formula (II) (for example, where 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 the ring opening of the compounds of Formula (VI) (defined herein): (SAW) with the compounds of Formula (III). These reactions are preferably carried out in the mixtures of the compounds of the formulas (III) and (IV) in chlorinated organic solvents at ambient or elevated temperatures. If necessary, these reactions can be facilitated by the addition of a catalyst such as imidazole. These methods can be followed by the introduction of the pharmaceutically acceptable counterions (A ") by conventional ion exchange techniques.The ring opening of the halogenated cyclic anhydrides of the compounds of the Formula (IV) (for example, X is Cl or F) with the compounds of the formula (III) can selectively cover to give compounds of the formula (II) (for example, X is Cl or F, T is OH) In these reactions, the hydroxyl group of (III) reacts preferentially in the carbonyl group of the compounds of Formula (VI) adjacent to the halogen atom This process is the preferred method for the preparation of the mixed, header compounds of Formula (I) The compounds of Formula (II) ) are novel intermediate compounds in the preparation of the 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 a comp of Formula (II) in another compound of Formula (II). The monohalogenated alkenedioates of the Formula (Iib) (for example, X is Cl or F; h is 1): they can be prepared by a process comprising the removal of hydrogen halide (HX2) from vicinal dihalo-alkanedioates of the Formula (Ha) (for example, X1 and X2 are independently Cl or F, T is hydroxyl or halide, is 1): The compounds of the Formula (Ha) can be prepared by the reaction of the compounds of the Formula (III) with the compounds of the Formula (Via) (X = Br, Cl, F and h is 1).

These reactions are preferably carried out by mixing the compounds of Formulas (III) and (Via) in organic solvents tested at ambient or elevated temperatures. If necessary, these reactions can be facilitated by the addition of a catalyst such as imidazole. These methods can be followed by the introduction of pharmaceutically acceptable counterions (A ~) by conventional ion exchange techniques. The transformation of the compounds of the Formula (Ha) in compounds of the Formula (Hb) are typically made by the treatment of (Ha) with an excess of a tertiary amine, such as triethylamine, in chlorinated organic or polar aprotic solvents, at 0 ° C in this process With elimination, the hydrogen atom (H) vicinal to the ester carbonyl oxygen in (Ha) (a to the ester carbonyl) is selectively extracted. The resulting compounds of Formula (Ilb) can be converted to monohalogenated alkenedioates of Formula (I) by methods described herein. Another aspect of the present invention provides a process for the conversion of a compound of the Formula (I) into another compound of the Formula (I). The monohalogenated alkenedioates of the Formula (Ib) they can be prepared by the removal of halide and hydrogen (HX) from gemloal dialo-alkanedioates of Formula (Ia) for example, X is Cl or F, h is 2).

The removal of HX from the compounds of Formula (la) can be carried out preferably with potassium carbonate in polar aprotic solvents, such as dimethylformamide, at room temperature. The mixed monohalobutenodioates of the heading (I) (for example, X is Cl or F; h is 1) exist as 1: 1 mixtures of regioisomers when they are synthesized by this process comprising the reaction of two equivalents of a compound of Formula (III) with one equivalent of the compound of Formula (VII). However, the mixed header monohalobutenodioates of the Formula (I) (for example, X is Br, Cl, F, h is 1) exist as pure regioisomers when synthesized by this process comprising the conversion of the compounds of the Formula (a) a (Ib) or the conversion of the compounds in the formulas (la) or (Ib). In this way, these two last processes are preferred methods for the preparation of monohalobutadodioate-headed, blended of the Formula (I). The alkenedioate derivatives in the Formulas (I) and (II) can exist as geometrical isomers E and Z. However, the monohalogenated butenediioate analogs of Formula (I) preferably exist as halofumates such that the two ester carbonyl groups are oriented trans to each other. The compounds of Formula (I) may also exist as diastereomer samples and one or more diastereomers may be separated from the mixtures by conventional techniques. For example, chromatographic techniques. The compounds of Formulas (IV), (V) and (VI), the diacid chloride derivatives of (VII) and the compounds of the Formula (HIV) are commercially available or can be prepared by published processes for the preparation of the same analogous structural compounds or compounds. The pure enantiomers of (V) are obtained by published asymmetric synthetic methods, known classical resolution techniques, or chiral preparative HPLC.

Experimental part The melting points are not corrected. All chemical reagents were used without purification. Analytical analyzes of high performance chromatography (HPLC) were performed on a 5 μ Si60 LiChrosorb column of 4 x 250 mm (E. MercK, Darmstadt, Germany) at a flow rate of 1.6 mL / min. The mobile phase consisted of mixtures of 0-25% methanol (MeOH) / dichloromethane (CH2C12) containing 0.25 mL methanesulfonic acid / L. The separations in liquid chromatography of half appearance (MPLC) were carried out in twin cartridges Porasil 15-20 μ (aters / Millipore, Milford, MA, USA) eluting with 0-20% mixtures of MeOH / CH2Cl2 containing 0.25 mL of acid methanesulfonic / L. The proton nuclear magnetic resonance (NMR1) aspects of all the products were consistent with the proposed structures. The mass spectrums by electrospray by positive ion flow (MS) injection are reported in the form m / z (double charged positive ion, relative intensity). Elemental analyzes were performed by Atlantic Microlab, Norcross, Georgia. Chlorofumamyl chloride was prepared by a reported procedure (Akhtar, M.; Botting, P.N .; Cohen, A. Tetrahedron 1987, 43, 5899-5908). The 3,4-dihydroisoquinoline derivatives were prepared by Bishler-Napieralski cyclization of the corresponding amides with phosphorus oxychloride (Whaley, K. W .; Govindachari Org. Reactions' 1951, 6, 74-150). The racemic 1, 2, 3, 4-tetrahydroisoquinoline derivatives were prepared by reduction of their 3,4-dihydroisoquinoline precursors with sodium borohydride / methanol. The N-methylations of the 1,2,3,4-tetrahydroisoquinoline derivatives were carried out with formalin / formic acid (Kaluszyner, A., Galun A.B.J. Org Chem. 1961, 26, 3536-3537). The following starting materials were prepared by the chiral catalytic hydrogenation of their corresponding 3,4-dihydroisoquinolines by a process similar to that described by Noyori et al. (Uematsu, N.; Fujii, A.; Hashiguchi, S .; Ikariya, T: Noyori, RJ Am. Chem. Soc. 1996, 118, 4916-4917) followed by N-methylation: (IR) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3-tetrahydroisoquinoline; (SS) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydroisoquinoline.

The following starting material was obtained by the classical resolution of its corresponding derivative of 3,4-dihydroisoquinoline 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: (IR) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydroisoquinoline; and (SS) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydroisoquinoline.

The following starting materials were obtained by the classical resolution of their corresponding racemic mixtures by a procedure to that described by Swaringen et al. (US Patent No. 4,761,418; August 2, 1988): (R) - (-) - 5 '-methoxylaudanosine; (S) - (+) - 5 '-methoxylaudanosine; Y (IR) -2-methyl-6,7,8-trimethoxy-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydroisoquinoline.

Synthetic Example 1 _ (a) Chloride of (1S, 2R) - and (lS, 2S) -6,7-dimethoxy-2- (3-hydroxypropyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) -1, 2, 3, 4-tetrahydroisoquinolinio.

To a mixture of (SS) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3-tetrahydroisoquinoline (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 18 hours (h) under nitrogen atmosphere. The solvent was evaporated and the residue was dissolved with H20 and washed with ethyl acetate (EtOAc). The aqueous phase was stirred with Dowex 1 x 8-50 (1.0 L), filtered and saturated with sodium chloride. The aqueous mixture was extracted with chloroform (CHC13) and the combined organic layers were dried and concentrated to provide a 3: 1 mixture of (IS, 2R) - and (SS, 2S) -products of the title, respectively as a white solid (69.5 g, 99% yield): MS m / z 432 (M +, 9). (b) Chloride of (1R, 2S) - and (IR, 2S) -6,7-dimethoxy-2- (3-hydroxypropyl) -2-methyl-1 - [(3, 4, 5-trimethoxyphenyl) methyl] -1,2,3, 4-tetrahydroisoquinolinium.

The (R) - (-) - 5 '-methoxylaudonosine (23.5 g, 61.0 mmol) was subjected to a procedure to give a 2.3: 1 mixture of (IR, 2S) - and (IR, 2R) - title products, respectively as a yellow, hygroscopic solid (31.5 g, 100% yield). The isomers were separated by MPLC (12% MeOH / CH2Cl2, 0.25 ml methanesulfonic acid / L). The minor isomer (IR, 2R) was eluted first. The appropriate fractions were combined and most of the MeOH was removed by co-evaporation with CHCl3. The CHCl3 solution was washed with brine / H20, 1: 1, dried and concentrated to give the (IR, 2R) -product title (10.4 g, 35% yield) and the (IR, 2R) -product of the title (3.7 g, 13% yield) as yellow hygroscopic solids: MS (each isomer) m / z 446 (M +, 100). (c) (Example 1.01) (Z) -2-chloro-l- dichloride. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -4-. { 3-. { IR, 2S) -6,7-dimethoxy-2-methyl-1- [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate and (Z) -2-chloro-4- dichloride. { 3- [1S, 2R) -6,7-dimethoxy-2-methyl- (3, 4, 5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l. { 3- . { (IR, 2S) -6,7-Dimethaxy-2-methyl-1 - [(3, 4, 5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate (1: 1) To a solution of the product mixture from step a (2.4 g, 5.1 mmol) and the (IR, 2S) -isomer from step b (2.4 g, 4.9 mmol) in 1,2-dichloroethane (DCE) (30 mL ) chlorofumamyl chloride (0.83 g, 4.4 mmol) was added and the solution was stirred at room temperature (rt) for 18 hours. The solvent was evaporated and the remaining residue was purified by NPLC (5-20% MeOH / CH2Cl2, 0.25 ml methanesulfonic acid / L). The appropriate fractions were combined and most of the MeOH was removed by coevaporation with CHC13. The remaining CHC13 solution was washed with brine / H20 1: 1, dried and concentrated. Lyophilization afforded a 1: 1 mixture of the title products as a white solid (0.70 g, 15% yield) MS m / z 496 (M2 +, 100). The following compounds were prepared by a procedure similar to Synthetic Example 1: (Example 1.02): dichloride (Z) -2-chloro-l-. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -4-. { 3- . { IR, 2S) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium Jpropil} -2-butenedioate and (Z) -2-chloro-4- dichloride. { 3- [(IR, 2S) -6,7-dimethoxy-2-methyl-1- (3,4-, 5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -1- . { 3- . { (IR, 2S) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -2-butanedioate. MS m / z 496 (M2 +, 100).

(Example 1.03): Dichloride of (Z) -2-chloro-l-. { 3- [(1S, 2R) -6,7-Dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium) propyl} -4-. { 3-. { IR, 2S) -2-methyl-6, 8-trimethoxy-1 - [(3, 4, 5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium) propyl} -2-butanedioate and (Z) -2-chloro-4- dichloride. { 3- [1S, 2R) -6,7-dimethoxy-2-methyl-1- (3, 4, 5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3-. { IR, 2S) -6,7,8-trimethoxy-1- [3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate (1: 1) MS m / z 511 (M2 +, 100).

(Example 1.04): Dichloride _ of (Z) -2-chloro-l-. { 3- [IR, 2S) -6,7-dimethoxy-2-methyl-1- (3, 4, 5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -4- . { 3- . { IR, 2S) -6,7,8-trimethoxy-1- [(3, 4, 5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate and (Z) -2-chloro-4- dichloride. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3- . { IR, 2S) -2-methy1-6,7,8-trimethoxy-1- [(3, 4, 5-trimethoxyphenyl) ethyl] -1,2,3-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate (1: 1) MS m / z 511 (M2 +, 22).

Synthetic Example 2 (Method A) (a) Anhydride (2R *, 3R *) -2, 3-dichlorosuccinic A solution of maleic anhydride (10.6 g 108 mmol) and benzoyl peroxide (5 mg, 0.02 mmol) in CHC13 (250 mL) was saturated with chlorine gas and the resulting bright yellow solution was stirred for 5 hours at room temperature. The residual chlorine was removed with a stream of nitrogen and the reaction mixture was partially stirred. Four harvests of the white solid product were obtained by filtration (11.9 g, 65% yield): m.p. 90-92 ° C. (b) (Z) -2-chloro-l- monochloride. { 3- [IR, 2S) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) -methyl] -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -hydrogen-2-butenedioate.

A solution of the (IR, 2S) -product of the title 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 room temperature overnight. The mixture was concentrated and the resulting 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 ° C and the reaction mixture was stirred at the temperature of the ice bath for 1 hour. The solvent was evaporated and the remaining solid was dissolved in CHC13 (150 mL). This solution was washed with brine / water 2: 1 containing methanesulfonic acid (4 mg / mL) and with brine. The organic layer was dried and concentrated to give the title product as a foam (2.6 g, 69% yield): MS m / z 578 (M2 +, 100). (c) (Example 2.01) Dichloride (Z) -2-chloro-4-. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3-. { IR, 2S) -2-methyl-6,7-dimethoxy-2-methyl-1 - [(3, 4, 5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate A solution of oxalyl chloride (36 mmol) in CH2C12 (18 mL) was added dropwise to a stirring solution of the product during step b (2.22 g, 3.61 mmol) in DCE (25 mL). The reaction mixture was stirred 1 hour at room temperature and then heated to reflux for 5 minutes. 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 room temperature. The solvent was evaporated and the mixture was purified by MPLC as described in Synthetic Example 1, step c. Lyophilization afforded the title product as a white solid (731 mg, 19% yield) MS m / z 496 (M2 +, 100). The following examples were prepared by a procedure similar to Synthetic Example 2: (Example 2.02): Dichloride (Z) -2-chloro-4-. { 3- [SS, 2S) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -1- . { 3- . { IR, 2S) -2-methyl-1-6, 7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate MS m / z 496 (M2 +, 100).

(Example 2.03): Dichloride of (Z) -2-chloro-4-. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3- . { IR, 2S) -2-methyl-6,7,8-trimethoxy-1 - [(3, 4, 5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate.

MS m / z 511 (M¿ 100) (Example 2.04): Dichloride (Z) -2-chloro-4-. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -1- . { 3- . { IR, 2S) -2-methyl-6,7,8-trimethoxy-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate MS m / z 511 (M2 +, 100).

Synthetic Example 3 (Method B): Alternative method for the preparation of the compound of Example 2.01 _ (a) 1,2-dioxa-2-tio 2,2-dioxide To a solution of 1,3-propanediol (50.0 g 0.65 mol) in carbon tetrachloride (CC14) (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 hours. The solution was cooled to 0 ° C and diluted with MeCN (650 mL) followed by the sequential addition of ruthenium (III) chloride hydrate (81 mg, 0.39 mmol), sodium periodate (210.0 g, 0.98 mol), and H20 (980 mL). The resulting orange mixture was stirred at room temperature for 1.5 hours and then diluted with diethyl ether (Et20) (6 L). The separated organic phase was washed with water, saturated NaHCO and brine. The Et20 layer was dried and filtered through a pad of silica gel. The filtrate was concentrated and the resulting oil was treated with Et20 (50 mL) and hexanes (100 mL) and stored at 5 ° C for 18 hours. Filtration of the resulting precipitate gave the title compound as a completely white solid (9.0 g, 87% yield): in m.p. 54-56 ° C. (b) 3- (1S, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-triethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl- 1-sulfate.

A mixture of (SS) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydroisoquinoline (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 ° C for 5 hours. The mixture was cooled to room temperature and the resulting precipitate was collected by filtration and triturated with MeCN to give the title compound as a completely white powder (30.0 g, 60% yield): 207-209 ° C; MS m / z 534 (M + 23, 60), 512 (M + 1, 30), 432 (M-S03, 100). (c) (1S, 2R), 6,7-dimethoxy-2- (3-hydroxypropyl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) -1,2,3,4-tetrahydroquinolinio chloride Acetyl chloride (35.0 mL, 38.8 g, 0.49 mol) was added dropwise to ice-cooled MeOH (350 mL) and the resulting mixture 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 room temperature for 6 hours. The solution was neutralized by the careful addition of excess NaHCO 3 and the solid was filtered through a pad of celite. The filtrate was evaporated and the residue was dissolved in CHCl3. The resulting solid was filtered through a pad of celite and washed with CHC13. The filtrate was evaporated, the remaining residue was dissolved in H20, and the aqueous solution was saturated with sodium chloride. The aqueous phase was extracted with CHCl3 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 (M2 +, 100). • (d) 3-. { IR, 2S) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) -methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl-l-sulfate The (IR) - (-) - 5'-methoxylaudanosine (52.6 g, 0.13 mmol) was subjected to procedure b. The resulting material was triturated with acetone to produce the title product as a completely white powder (49.34 g, 69% yield): p.f. 191-193 ° C; MS m / z 526 (M + 1, 100). (e) Chloride of (IR, 2S) -6,7-dimethoxy-2- (3-hydroxypropyl) -2-methyl-1 - [(3, 4, 5-trimethoxyphenyl) methyl] -1,2,3, 4-tetrahydroisoquinolinio.

The product from step d (54.5 g, 0.10 mmol) was subjected to procedure c to give the title compound as a white hygroscopic foam (50.7 g, 100% yield): MS m / z 446 (M +, 100). (f) (Z) -2-chloro-l- (3- [IR, 2S) -6, -dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) methyl] -1,2-chloro-1 monochloride. , 3, 4-tetrahydro-2-isoquinolinium] propyl} -hydrogen-2-butenedioate.

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 CH2C12 (50 mL) was stirred overnight at room temperature. of reaction was diluted with CH2C12 (150 mL), cooled to -20 ° C and triethylamine (18.2 mL, 130.4 mmol) was added dropwise, the reaction was warmed to 0 ° C, CHC13 (200 mL) was added and the mixture was washed with 2: 1 brine / water containing ethanesulfonic acid (4 mg / mL) The CHC13 layer was separated and the combined aqueous layers were saturated with sodium chloride, acidified with concentrated hydrochloric acid (CH1) (9 mL) and extracted again with CHC 13. The combined CHCl3 layers were dried and concentrated and the resulting foam was triturated with Et20.The title product was collected by filtration as a tan solid (16.3 g, 86% of performance): the spectral data were identical to those of the product of the title of the Synthetic Example co 2, step b. (g) (Example 3.01) Dichloride of (Z) -2-chloro-4-. { 3- [(1S, 2R) -6,7-dimethoxy-2-methyl-1- (3, 4, 5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3- " { IR, 2S) -6,7-dimethoxy-2-methy1-1- [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl.} -2-butenedioate The product of step f (7.0 g, 11.4 mmol) was treated with oxalyl chloride and then reacted with the product of 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 afforded the title product as a white solid (8.7 g, 72% yield): the spectral data were identical to those 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) Monochloride of (E) -2-chloro-l-. { 3- [IR, 2S) -6,7-dimethoxy-2-methyl-1- (3, 4, 5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinio Jpropil} -hydrogen-2-butenedioate.

A solution of the product of Synthetic Example 3, step e (2.5 g, 5.2 mmol) and imidazole (0.35 g, 5.2 mmol) in CH2C12 (35 mL) at -15 ° C was added a solution of chloromaleic anhydride (0.69 g, 5.2 mmol) in CH2C1_ (10 mL) . After 10 minutes, the mixture was diluted with CHC13 and washed with brine / H20 2: 1 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 +, 100). (b) (Example 4.01) (Z) -2-chloro-4-dichloride. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3-. { IR, 2S) -6,7-dimethoxy-2-methy1-1- [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium) propyl} -2-butenedioate A solution of the product from step a (198 mg, 0.32 mmol), oxalyl chloride (281 μL, 3.2 mmol), and dimethylformamide (DMF) (1 drop) in CH2C12 (4 mL) was heated to reflux for 2 hours. The mixture was coevaporated with CH2C12 and then dried in vacuo. The residue was stirred in DCE (5 mL), the product mixture from Synthetic Example 1, step (300 mg, 0.64 mmol) was added and the mixture was stirred for transmission for 18 hours. The solvent was evaporated and the crude material was purified as described in Synthetic Example 1, step c. Lyophilization afforded the title product as a white solid (80 mg, 2e% yield). The spectral data were identical to those of the title product of Synthetic Example 1, step c. The following compound was prepared by a procedure similar to Synthetic Example 4.

(Example 4.02): Bromide of (Z) -2-bromo-4-. { 3- [(1S, 2R) -6,7-dimethoxy-2-methyl-1- (3, 4, 5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium) propyl} -l- { 3-. { IR, 2S) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate MS m / z 518 (M2 +, 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 to reflux for 2.5 hours. The mixture was filtered and the filtrate was concentrated to give the title product as an oil which crystallized on standing (838 mg, 6.16 mmol, 83% yield). (b) 2,2-difluoro-l- monochloride. { 3, . { (IR, 2SR) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -hydrogen-butanedioate.

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 dried overnight at room temperature. The solvent was evaporated to yield a 2.3: 1 mixture of the (IR, 2S) and (IR, 2R) -product title, respectively as a yellow hygroscopic solid (3.5 g, 5.60 mmol, 100% yield): MS m / z 582 (M +, 70). (c) (Example 5.01) 2, 2-difluoro-4- dichloride. { 3- [(1S, 2R) -6,7-dimethoxy-2-methyl-l (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} l-. { 3-. { (IR, 2S) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -butenedioate.

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.The lyophilization afforded the title product as a white solid (466 mg, 27% yield): MS m / z 498 (M2 +, 100).

Synthetic Example 6 (Method B): Alternative method for the preparation of the compound of Example 5.01 (a) 2, 2-difluoro-1- monochloride. { 3- . { IR, 2S) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) ethyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -hydrogen-butanedioate.

The product from Synthetic Example 3, step e (3.0 g, 6.22 mmol) was treated in a similar manner as that described in Synthetic Example 5, step b. The title product was obtained as a yellow hygroscopic solid (3.21 g, 83% yield): the spectral data were consistent with the proposed structure. (b) (Example 6.01) 2, 2-difluoro-4- dichloride. { 3- [(SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3- . { (IR, 2S) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -butanedioate.

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 Example Synthetic 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 afforded the title product as a white solid (1.3 g, 37% yield): the spectral data were consistent with those 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- dichloride. { 3- [(SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3- . { (IR, 2S) -6,7-Dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} butanedioate S m / z 498 (M ^ 100 (Example 6.03): Dichloride of (2RS) -4-. { 3- [(SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- (3- { (IR, 2S) -6,7-dimethoxy-2-methyl-1 - [(3, 4, 5-trimethoxyphenyl) methyl] -1,2,3, 4-tetrahydro- 2-isoquinolinium, propyl, 2-fluorobutanedioate, MS m / z 489 (M2 +, 55).

(Example 6.04): Dichloride of (2RS) -4-. { 3- [(SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium) propyl} -l- { 3- . { (IR, 2S) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl-1, 2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-fluorobutanedioate. MS m / z 489 (M2 +, 30). ' Synthetic Example 7 Alternative method for the preparation of the compounds of Examples 5.01 and 6.01 (a) (Example 7.01): 2, 2-difluoro-4- dichloride. { 3- [(1S, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3-. { (IR, 2S) -6,7-Dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} butanedioate Pure oxalyl chloride (25 mL, 0.28 mol) was added dropwise to a solution of Synthetic Example 6, step a (7.0 g, 11.0 mmol) in DCE (150 mL). The solution was stirred at room temperature for 3.5 hours. The solvent and excess oxalyl chloride were removed under reduced pressure and the remaining foam was reconstituted in DCE (35 ml). To a solution of the product of 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 room temperature. The solvent was evaporated and the product was purified by MPLC as described in Synthetic Example 1, step c. Lyophilization afforded the title product as a white product (5.63 g, 53% yield) with the spectral data that were identical to those 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- dichloride. { 3- [(SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -! -. { 3- . { (IR, 2S) -2-methyl-6,7,8-trimethoxy-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} butanedioate MS m / z 513 (M2 +, 100).

Synthetic Example 8 (Example 8.01): Dichloride of (Z) -4-. { 3- [1S, 2R) -6,7-dimethoxy-2-methyl-1- (3, 4, 5-trimethoxyphenyl) -1, 2, 3, 4-tetrahydro-2-isoquinolinium] propyl} -! -. { 3- . { IR, 2S) -6,7-dimethoxy-2-methyl-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-fluoride-2-butenedioate Solid K2CO3 (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 room temperature for 1 hour and then it leaked The filtrate was diluted with "CHCl3 (50 mL) and washed with 1: 1 brine / H20 (pH about 1) .The organic layer was dried and concentrated and the residue was triturated with Et20 and purified as described in Example 1. 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 (M2 +, 80).

The following compound was prepared by a procedure similar to Synthetic Example 8: (Example 8.02): Dichloride of (z) -4-. { 3- [1S, 2R) -6,7-dimethoxy-2-methyl-1- (3, 4, 5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -1- . { 3- . { IR, 2S) -2-methyl-6,7,8-trimethoxy-1 - [(3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-fluoride-2-butenedioate Anal. Calculated for C54H7iN20? 5Cl2Fo5H20: 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) ip See JJ Savarese Anesthesia and analgesia, Vol. 52, No. 6, November-December, (1973) Square wave stimuli were applied at supramaximal voltages to the peroneal nerve at 0.15 Hz and the contractions produced from the anterior tibialis muscle were recorded.Rhesus monkeys were anesthetized with ketamine (5 mg / kg) and pentobarbitol (5 mg / kg) given intramuscularly intravenously. Anesthesia was maintained with a mixture of halothane (0.25-0.75%) nitrous oxide (60%) and oxygen (40%). The common peroneal nerve stimulated supramaximally with square wave pulses of a duration of 0.2 m seconds at a speed of 0.15 Hz. Nerve contractions were recorded and washed via the tensor digitorum muscle tendon. In all animals, the trachea was incubated and ventilation was controlled at 12-15 ml / g, 18-24 breaths per minute. The animals that did not receive anesthetics by inhalation were ventilated with ambient air. The left femoral band and artery were cannulated for drug administration and for blood pressure grading, respectively. The compounds of Formula I listed in Table 1 were administered intravenously. The ID_5, that is, the dose required to produce 95% blocking of the stimulus response of the compounds of the Formula (II) is given in Table 1. The absence of data for the particular parameters of the particular example numbers they indicate that the data was not available.

Table 1. Activity of Intramuscular Blocking in Rhesus Monkeys It is noted that in relation to this date, the best method known by the applicant, to carry out the aforementioned invention, is that which is clear from the present description of the invention. invention. Having described the invention as above, the content of the following is claimed as property.

Claims (9)

1. A compound of the Formula (I) characterized in that: X is halogen, h is 1 to 2; And it is hydrogen or methoxy, Z1 and Z2 are methyl; 1 and 2 are carbon atoms; and A is a pharmaceutically acceptable anion.

2. A compound of Formula (I) characterized in that it includes: Dichloride of (Z) -2-chloro-4-. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3- . { IR, 2S) -6,7-dimethoxy-2-methyl-l- [3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate. 2,2-difluoro-4- dichloride. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3-. { IR, 2S) -6,7-dimethoxy-2-methyl-1- [3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-butenedioate Dichloride of (Z) -4-. { 3- [SS, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinium] propyl} -l- { 3-. { IR, 2S) -6,7-dimethoxy-2-methyl-1- [3,4,5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl} -2-fluoride-2-butenedioate 2, 2-difluoro-4- dichloride. { 3- [1S, 2R) -6,7-dimethoxy-2-methyl-1- (3,4,5-trimethoxyphenyl) -1,2,3,4-tetrahydro-2-isoquinolinio] propyl} -l- { 3-. { IR, 2S) -2-methyl-6,7,8-trimethoxy-1 - [3, 4, 5-trimethoxyphenyl) methyl] -1,2,3,4-tetrahydro-2-isoquinolinium} propyl) -2-butenedioate.

3. A pharmaceutical composition characterized in that it comprises a compound according to claim 1 or 2, - in association with one or more pharmaceutically acceptable carriers.

4. A method for inducing neuromuscular paralysis in a mammal, characterized in that it comprises administering to the mammal an effective neuromuscular paralyzing amount of a compound according to claim 1 or 2.

5. A compound according to claim 1 or 2, for use in therapy.

6. The use of a compound according to claim 1 or 2, for the manufacture of a medicament for inducing neuromuscular block.

7. A compound of Formula (II) characterized in that: T is hydrogen-hydroxyl or halide; And it is hydrogen or methoxy; Z is methyl; it's carbon; n is 0 or 1 h is 1 or 2; and A is a pharmaceutically acceptable anion.

8. A process for the preparation of the compound of the Formula (Ib) where h is 1; and: X, Y, Z1, Z2, W1, W2 and A are as defined in claim 1, characterized in that it comprises reacting a compound of the Formula (Ia) where h is 2; and X, Y, Z1, Z2, 1, W2 and A are as defined in claim 1 with a base in a polar aprotic solvent.

9. A process for the preparation of a compound of the Formula (1), characterized in that it comprises reacting a compound of the Formula (II) as defined in claim 7, with a compound of the Formula (III) wherein: Y is hydrogen or methoxy; Z is methyl; it's carbon; n is 0 or 1; and A is a pharmaceutically acceptable anion in an organic solvent.