KR890000093B1 - Process for preparation of tropyl and pseudotrophy alkyl benzoate - Google Patents

Abstract

Title compds. (I)[Ar=(a) or (b) ; n=0,1,3; R1=C1-4 alkyl; R2=C1-4 alkyl, halo, C1-4 alkoxy; R1=R2 if n=2 or 3; R3, R4=H, C1-4 alkyl, alkoxy, halo; R3=alkyl and R4=H in case of tropyl derivs. , useful for hemicrania, were prepd.. Thus, a mixt. contg. 1.76g tropine.HCl and 1.65g 3,4-dimethyl benzoyl chloride was boiled at 130-140≰C for 30 min to give tropyl 3, 4-dimethyl benzoate (m.p.=270-271≰C).

Description

Trophyll and Pseudotrophil Alkyl-Benzoates and Methods for Making the Same

The present invention relates to trophyl and pseudotrofil benzoate derivatives of the following general formula (I) or pharmaceutically harmless salts thereof, and methods for their preparation, which are therapeutic agents for migraines.

N represents 0 or an integer from 1 to 3: R ₁ represents C ₁ to C ₄ alkyl: R ₂ represents C ₁ to C ₄ alkyl, halogen or C ₁ to C ₄ alkoxy, provided that If 2 or 3, R ₂ is the same as R ₁ : R ₃ and R ₄ independently represent hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy or halogen, provided that it is a tropile derivative R ₃ alkyl and R ₄ is hydrogen. The present invention also relates to the treatment of migraine with trophyl and pseudothrofil alkyl-benzoate, and pharmaceutical compositions containing such compounds and methods of treating migraine with such compounds.

Acute seizures of migraine headaches are usually associated with caffeine, ergotamine, and peripheral blood vessel constrictors such as dihydroergotamine: antipyretic analgesics, such as acetylsalicylic acid or p-acetylaminophenol: and / or cycline, metoclo Treatment with an anti-emetic agent such as pramide and triethylperazine. It has been reported that acute migraine attacks can be immediately relieved by the slow intravenous injection of m-toclopramide (10 mg) (J.B.Hughes; Med. J.Aust. 2, No. 17,580,1977).

It is believed that the most important role in the pathophysiology of migraine headaches is 5-hydroxytriphtamine (5-HT), a naturally occurring substance. Increased amounts of 5-HT and its metabolite 5-hydroxyindole-acetic acid are excreted in urine during most seizures. In addition, plasma and platelet 5-HT concentrations are drastically lowered by the onset of seizures, and remain low during headaches. In addition, migraine attacks are clearly associated with the course of thrombocytopenia in some patients. Compounds that block the activity of 5-HT have been suggested for use in the treatment of migraine (J.R. Fozard, International Headache Congress 1980, reported in Adnavces in Neurology, Vol 33, Raven Press, New York 1982).

Known migraines prophylactic agents, methisazide, propranolol, amitriptyline and chloroformazine, have significantly different pharmacological activities, but are all 5-HT D-receptor antagonists at doses used clinically for the treatment of migraine headaches. Metoclopramide is a potent 5-HT M-receptor antagonist and it has been suggested to block the symptoms of acute migraine attacks by blocking M-receptors on afferent sensory neurons (see J.R.Fozard, supra).

The potency of several related compounds including (-) cocaine, and benzoyl pseudotropin (i.e. pseudotropyl benzoate) and benzoyl tropin (i.e., trophyl benzoate), has been reported to be effective as 5-HT D-receptor antagonists (JRZozard et al, Eur. J. Pharmacol., 59 (1979), 195-210), but none except for nor (-) cocaine and benzoyl tropin was potent to the efficacy of metoclopramide. The reported PA ₂ values for nor (-) cocaine, benzoyltropin and benzoyl pseudotropy were 7.7, 7.2 and 7.0, respectively, and the PA ₂ 5-HT value for metoclopramide measured by the same method was 7.2. JRFozard et al., Eur. J. Pharmacol., 49 (1978), 109-112].

Korean Patent Application No. 82-3631 [corresponds to Greek Patent Application No. 68906; Not yet disclosed] Substituting tropyl benzoate with alkyl, alkoxy or halogen at the 3,3 and 5 or 3,4 and 5 positions of the benzene ring surprisingly has the effect as a 5-HT M-receptor antagonist. Reported to rise. Trophyl-4-chlorobenzoate (PA ₂ 7.0), trophyl-4-methylbenzoate (PA ₂ 7.8), trophyll-3,4-dichlorobenzoate (PA ₂ 7.8) and trophyll-3,4 Tests conducted using dimethoxybenzoate (PA ₂ 7.2) showed that the corresponding substitution at any other position of the benzene ring did not provide an equivalent increase in potency. In addition, the test was performed using pseudotrofil-3,5-dimethoxybonate (PA ₂ 6.6) and pseudothrofil-3,4,5-trimethoxybenzoate (PA ₂ 5.7). Corresponding substitutions in the benzene ring of trophyl benzoate have been shown to substantially reduce its effectiveness as a 5-HT M-receptor antagonist. Surprisingly, however, in the present invention, at least at the 2 or 3,4-position of the benzene ring of trophyl benzoate and pseudotrophil benzoate, and 3,3 and 5 or of the benzene ring of pseudodophyll benzoate or It will be found that substitutions at alkyl at positions 3,4 and 5 substantially enhance the potency as 5-HT M-receptor antagonists.

All of the trophyl benzoate derivatives of formula (I) and pseudodophyl benzoate of formula (I), with the exception of trophyl-2-methylbenzoate, are novel compounds. Trofil-2-methylbenzoate has been described by Al-Yahya et al. [J. chem. soc. perkins Trans. 1. 1979 (9), 2130-2], the pharmacological use of this compound has not been reported.

According to a first aspect of the present invention, the present invention provides a trophyl or pseudotrofil benzoate derivative of formula (I) or a pharmaceutically nontoxic salt thereof, for use in the treatment of migraine and other vascular headaches.

N represents 0 or an integer of 1 to 3, R ₁ represents C ₁ to C ₄ alkyl, and R ₂ represents C ₁ to C ₄ alkyl, halogen or C ₁ to C ₄ alkoxy, provided that If 2 or 3, R ₂ is the same as R ₁ : R ₃ and R ₄ independently represent hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy or halogen, provided that it is a tropile derivative R ₃ alkyl and R ₄ is hydrogen.

According to a second aspect of the present invention, a compound of formula (I) is contained in a mixture with a pharmaceutically innocuous diluent or carrier, or in a combination of other formulas, for effective relief of migraines containing 0.5 to 100 mg of compound per unit dose. Provided is a unit dosage form of pharmaceutical composition used. Generally, the composition contains from 1 to 50 mg, in particular from 3 to 30 mg of compound per unit dose.

According to a third aspect of the invention, the invention provides all of the compounds of formula (I) per se, except for trophyl-2-methylbenzoate. According to a fourth aspect of the present invention, the present invention provides a method for treating migraine, characterized by administering to the patient suffering from migraine an amount of the compound of general formula (I) effective for alleviating migraine. The above-mentioned amounts generally range from 0.01 mg / kg to 10 mg / kg, in particular from 0.03 mg / kg to 3.0 mg / kg. In addition, it is expected that the compound of general formula (I) may be used to prevent migraine headache by administering an effective amount of migraine-prevention of the compound of general formula (I) to patients at risk of migraine.

In the case where the acyclic ring of the compound of the formula (I) is endo coordination, the compound is trophyl benzoate, and in the case of exo coordination, the compound is pseudothrofil benzoate. At present, trophyll benzoate is preferred over pseudotrophyl benzoate. The compound of formula (I) has a benzoyloxy moiety substituted by C ₁ to C ₄ alkyl in at least 2 or 3 positions and optionally in other positions. In particular, R ₁ represents C ₄ to C ₄ alkyl; R ₂ represents C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy or halogen, but when there are two or three R ₂ substituents, they are the same as R ₁ ; C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy or halogen: n is an integer up to 0 or 3, preferably 0, 1 or 2. Trophyl benzoate of formula (I), but not pseudodophylbenzoate, substituted only in 3-position, 3 and 5 or only in 3, 4 and 5 positions is the subject of a pending application Because it was excluded.

In formula (I), Ar may represent substituted phenyl shown in the following Table 1.

TABLE 1

In the above table, R _1, R _2, R ₃ and R ₄ are as defined in general formula (I) except that neither R ₃ nor R ₄ represents hydrogen. Being represented by R _1, R _2, examples of the C ₁ to C ₄ alkyl groups which may be represented by R ₃ and R ₄ is methyl, ethyl, n- propyl, n- butyl, and isopropyl, methyl and ethyl desirable. Examples of C ₁ to C ₄ alkoxy groups which may be represented by R _2, R ₃ and R ₄ are methoxy, ethoxy, n-propoxy, n-butoxy and isopropoxy, ethoxy and especially meth Toxy is preferred. Halogens which may be represented by R _2, R ₃ and R ₄ are bromine, chlorine, fluorine and iodine, with bromine, fluorine and especially chlorine preferred.

One preferred group of compounds of the present invention are pseudotropille benzoate and trophyll benzoate of formula (I), wherein Ar represents a radical of the following general formula.

Wherein n is 0 or an integer from 1 to 3: R ₁ represents C ₁ to C ₄ alkyl: R ₂ represents C ₁ to C ₄ alkyl or chlorine, provided that n is 2 or 3 R ₂ ′ is the same as R ₁ .

Another preferred group of compounds of the present invention are pseudotrofil benzoate and trophyl benzoate of general formula (I), wherein Ar represents a radical of the general formula:

Wherein R ₁ and R ₃ ′ independently represent C ₁ to C ₄ alkyl. Another preferred group of compounds is pseudotrofil benzoate of formula (I) in which Ar represents a radical of the formula:

In which R ₁ represents C ₁ to C ₄ alkyl and R ₃ ′ and R ₄ ′ independently represent hydrogen or C ₁ to C ₄ alkyl.

In a particularly preferred aspect of the invention, the compound is a general formula wherein Ar represents phenyl substituted by C ₁ to C _{4, in} particular methyl at the 2: 2, 3: 2, 4: 2, 5: or 3, 4 position ( Pseudotrophil benzoate of I) and, preferably, a trophyll benzoate compound. Particularly preferred methyl-substituted compounds mentioned above are as follows:

Trophyl-2-methylbenzoate Pseudotropy-2-methylbenzoate

Trophyll-2,3-methylbenzoate Pseudotrophil-2,3-methylbenzoate

Trophyll-2,4-methylbenzoate Pseudotrophil-2,4-methylbenzoate

Trophyll-2,5-methylbenzoate Pseudotrophil-2,5-methylbenzoate

Trophyll-3,4-methylbenzoate Pseudotrophil-3,4-methylbenzoate

In another particularly preferred aspect of the invention, the compound is a pseudo-formula of formula (I) wherein Ar represents phenyl substituted only at C ₃ to C ₄ alkyl, especially methyl at the 3: 3,5 or 3,4,5 position Trophyll benzoate. Particularly preferred methyl-substituted compounds mentioned above are as follows: pseudotrofil-3-methylbenzoate, pseudotropyl-3,5-dimethylbenzoate, pseudotropyl-3,4,5-trimethylbenzoate.

In addition to the above-mentioned preferred compounds, specific examples of the compound of general formula (I) include the following compounds:

Trophyll-2-methyl-3-chlorobenzoate Trophyll-2-ethylbenzoate

Trophyll-2-methyl-4-chlorobenzoate Trophyll-3,4-diethylbenzoate

Trophyl-2-methyl-5-chlorobenzoate

Trophyl-2-methyl-4-methoxybenzoate

Trophyll-2,3,5-trimethylbenzoate

Pseudotrophil-2,3,5-trimethylbenzoate

Trophyl-2,3,4,5-tetramethylbenzoate

Pseudotropil-2-methyl-4-chlorobenzoate

Formula (I) compounds block the M-receptor for 5-hydroxy-triptamine (5-HT) on afferent neurons, which are certain to aid pain transmission. As mentioned above, such blockade of M-receptors is believed to be a mechanism that can alleviate the symptoms of migraine headaches. Therefore, the compound of formula (I) is effective for the treatment of migraine when administered in an amount sufficient to effectively block the above-mentioned M-receptor.

The activity of compounds against 5-HT is described by Euroza J. Pharmacol. 59, 195-210 (1979)), can be evaluated by measuring their PA ₂ values in the heart of isolated rabbits. In the methods described herein to measure the molar concentration of antagonist which reduced the effects of twice the ED ₅₀ of 5-HT in 5-HT ED ₅₀ of the effectiveness of the antagonist in the load load. The PA ₂ value is the negative number of the molarity mentioned above. In general, compounds with higher PA ₂ values are more potent compounds.

The PA ₂ values of some representative Formula (I) compounds are listed in Table II below:

TABLE 2

The PA ₂ values of several compounds related to the compounds of the present invention are listed in Table 2 below for comparison:

TABLE 3

From the Tables 2 and 3, it can be seen that in this test, the compound of general formula (I) exhibits potency as a 5-HT M-receptor antagonist at least one step larger than trophylbenzoate or pseudotrofil benzoate. The activity of the compound on 5-HT is assessed by measuring the effect of the compound on Von Bezold-Jarisch Reflex induced by intravenous injection of 5-HT in rats in vivo. Paintal AS, Pysiol. Rev. 53,159-227,1973. Transient cardiac bradycardia is caused by increased centrifugal vagus nerve activity, caused by afferent sensory fiber excitability in and around the heart by 5-HT.

It is believed that the compound of formula (I) has a high selective activity against the 5-HT M-receptor. The effect of the general formula (I) compound on other 5-HT receptors and other convulsives, in particular oxytocin, acetylcholine, histamine and calcium, appears to be at least two levels below the effect on 5-HT M-receptors. Thus, there are no other side effects associated with the use of the general formula (I) compound in the treatment of migraine headache. The general formula (I) compound can be administered in various ways to achieve the desired effect. The compounds may be administered orally or parenterally, for example subcutaneously or intravenously, to a patient to be treated, either alone or in the form of a pharmaceutical formulation. The amount of compound administered can vary and can be any of the amounts effective for migraines-relaxation. Depending on the patient and the method of administration, the amount of compound administered can vary widely from about 0.01 mg to about 10 mg, typically 0.03 to 3.0 mg, per kg of patient weight per dose. Unit dosage forms of these compounds may contain, for example, 0.5 mg to 100 mg, generally 1 to 50 mg, preferably 3 to 30 mg, for example 1 to 4 times daily.

As used herein, the term "unit dosage form" refers herein to one or several dosage forms containing a certain amount of the active ingredient in a mixture with a diluent or carrier or in a combination of other formulas, and the term "quantity" described above Generally one or more predetermined units for a therapeutic single dose. In the case of several dosage forms, such as liquids or grooved tablets, the above-mentioned predetermined unit means one fraction, such as 5 ml (tspoon) of liquid, or half or one quarter of grooved tablet, in several dosage forms. do.

In the composition of the present invention, there is provided a pharmaceutical formulation in which the active compound type of the present invention is generally used. Such formulations are prepared by methods known in the pharmaceutical art and generally comprise one or more active compounds of the invention in admixture or otherwise in combination with a pharmaceutically toxic carrier or diluent. To prepare these preparations, the active ingredient is generally mixed with a carrier, diluted with a diluent or filled or enclosed in capsules, sachets, casets, paper or other containers. The carrier or diluent may be a solid, semisolid or liquid substance and is provided as a vehicle, excipient or medium for the active ingredient. Suitable carriers or diluents are well known per se.

The formulations of the present invention can be used internally or parenterally, and can be administered to the patient in the form of tablets, capsules, suppositories, solutions, suspensions and the like. Specific examples set forth below describe specific examples of suitable pharmaceutical formulations. Derivatives of formula (I) may be used in migraine therapy in combination with migraine treatments having different modes of action. Such agents include prophylactic agents such as barbiturate, diazepam, chlorpromazine, amitriphthalin, propranolol, methisurged, pizotiben, ciproheptadine, dihydroergotamine and clonidine and ergotamine And agents used in acute seizures, such as vasoconstrictors such as dihydroergotamine, analgesics / anti-inflammatory agents such as aspirin, paracetamol and indomethacin or anti-inflammatory agents such as cyclin, metoclopramide and liethyl-perazine. (See Fozard, JR, J. Pharm, Pharmacol. 27, 297-321 (1975); Saper, JR, J. Amer. Med. Assoc. 239,480-484 (1978); Fozard, JR, supra). For example, the compound of general formula (I) can be advantageously used in combination with 300 to 1200 mg of aspirin or 2 to 6 mg of methisazide per day.

The compound of formula (I) can be prepared from tropin or pseudotropin and the acid halide of the following formula (IV) by a method known per se.

XOC-Ar (IV)

Wherein Ar is as defined for general formula (I) and X represents halogen, in particular chlorine.

In the case of preparing the trophyl benzoate derivative, the reaction is generally carried out by heating the hydrohalide salts of the acid halides and tropins to a temperature in the range of 140 ° to 160 °, for example, with stirring, in the absence of a solvent. Hydrogen halide is released and the mixture is primarily liquid but then solid. After solidification, heating is continued for about 15 minutes, then the mixture is cooled and added to water. The product is a hydrohalide of the compound of general formula (I), which can be obtained by extracting the free base with a suitable organic solvent such as sodium carbonate or ethyl acetate and methyl chloride which does not hydrolyze the ester. The organic solution is then evaporated and the residue is recrystallized from, for example, aqueous methanol.

When preparing pseudodophyll benzoate derivatives, the reaction is generally carried out by stirring the acid halide and pseudotropine in an aprotic solvent, preferably methylene-chloride or acetonitrile at ambient temperature. After about 2 to 16 hours, the solvent is evaporated off, usually under reduced pressure, and the aqueous solution of the product is made alkaline with an aqueous base such as sodium carbonate or potassium carbonate that does not add water to the residue and then does not hydrolyze the ester. The desired free base is then extracted with a suitable organic solvent such as, for example, diethyl ether, ethyl acetate, and methylene chloride. The organic solution is then washed with water to remove excess pseudotropes and dried. The organic solvent is removed by evaporation and the free base is recrystallized from, for example, aqueous methanol. The crude free base can also be converted to an acid addition salt, preferably hydrochloride, by addition of an ethereal solution of acid. Acid addition salts are for example recrystallized from ethanol or isopropanol.

As mentioned above, the general formula (I) compounds can be used in the form of their pharmaceutically toxic acid addition salts. Pharmaceutically nontoxic acid addition salts are suitable acids, for example inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, or organic carboxylic acids (eg glycolic acid, maleic acid, hydroxymaleic acid, malic acid, tartaric acid, Citric acid, salicylic acid, O-acetyloxybenzoic acid, nicotinic acid or isonicotinic acid) or organic sulfonic acid (e.g. methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, toluene-P-sulfonic acid or naphthalene- Non-toxic addition salts with organic acids such as 2-sulfonic acid).

Apart from pharmaceutically toxic acid addition salts, addition salts with other acids, such as picric acid or oxalic acid, may be provided as intermediates in the purification of compounds or in the preparation of other pharmaceutically toxic acid addition salts. Useful for characterization. Acid addition salts can be prepared according to known methods, for example as bases, for example metal hydroxides or alkoxides (for example alkali or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide); Metal carbonates (e.g. alkali or alkaline earth metal carbonates or acid carbonates such as sodium carbonate, potassium carbonate or calcium carbonate or acid carbonate): such as trialkylamines: or by treatment with cation exchange resins can be converted into free compounds .

Acid addition salts can also be converted to other acid addition salts according to known methods, for example by treating salts with inorganic acids with metal salts (eg, sodium, barium or silver salts) or acids in a suitable diluent, The inorganic salts produced in are insoluble and therefore are separated from the reaction medium. Acid addition salts can also be converted to other acid addition salts by treatment with ion exchange agents. The invention is specifically illustrated in the following non-limiting examples.

Example 1

Trophyl-3,4-dimethylbenzoate (ie 3,4-dimethylbenzoic acid endo-8-methyl-8-azabicyclo- [3,2,1] oct-3-yl ester) [General formula (I), Endo. Ar = 3,4-dimethylphenyl]

The stirred mixture of tropine hydrochloride (176 g) and 3,4-dimethyl benzoyl chloride (1.65 g) is heated at 130 to 140 ° C. for 30 minutes, during which the mixture liquefies, releases hydrogen chloride and re-stocks. The solution of cooled solid in water is basified with a solution of potassium carbonate and the base is extracted with ethyl acetate. The ethyl acetate solution is washed several times with water, dried over magnesium sulfate and evaporated to give a free base, which is converted to hydrochloride by adding etheric hydrogen chloride. The precipitated solid is recrystallized from ethanol to give crystals of trophyll 3,4-dimethylbenzoate hydrochloride having a melting point of 270 to 271 ° C.

The following compounds are prepared in the same manner. Trophyl 2-methylbenzoate hydrochloride, Melting point 262-263 degreeC: Trophyll 2, 4- dimethylbenzoate hydrochloride, Melting point 256 degreeC: Trophyll 2, 5- dimethylbenzoate hydrochloride, Melting point 269.5-270 degreeC

Example 2

Pseudotrophil 3,5-dimethylbenzoate (ie, 3,5-dimethylbenzoic acid exo8-methyl-8-azabicyclo [3,2,1] oct-3-yl ester] [formula (I), exo , Ar = 3,5-dimethylphenyl]

Pseudotropin (1.41 g) and 3.5-dimethylbenzoyl chloride (1.65 g) in methylene chloride (50 ml) are stirred at ambient temperature for 3 hours. The solvent is removed by evaporation under reduced pressure, the residue is treated with water (50 ml) and saturated aqueous potassium carbonate solution (5 ml) is added. The liberated oil is extracted with diethyl ether and the ethereal solution is washed several times with water and then dried over anhydrous magnesium sulfate. The dried etheric solution is distilled off to give a residue which is treated with anhydrous diethyl ether and ethereal hydrogen chloride. Precipitation is recrystallized from ethanol to give pseudotrofil-3,5-dimethylbenzoate hydrochloride having a melting point of 245 ° C.

In the following examples relating to pharmaceutical compositions, the term "active compound" is used to denote the compound trophyll-2,4-dimethyl-benzoate. This compound may be substituted in these compositions with any other compound of formula (I), for example pseudodotropin-3,5-dimethylbenzoate. The amount of medicament needs to be adjusted or desired, depending on the activity of the medicament as is well known in the art.

Example 3

Specific examples of the composition for hard gelatin capsules are as follows;

(a) 5 mg of active compound

(b) 5 mg talc

(c) lactose 90 mg

The formulations are prepared by passing anhydrous powders (a) and (b) through a microscopic screen and mixing them well. The powder is then filled into hard gelatin capsules at a net fill amount of 100 mg per capsule.

Example 4

Specific examples of the composition of the tablet are as follows;

(a) 5 mg of active compound

(b) starch 43mg

(c) lactose 50mg

(d) 2 mg magnesium stearate

Compound (a) and a portion of starch are mixed with lactose and the granules are dried with a starch paste and sieved to mix with magnesium stearate. The mixture is compressed into tablets weighing 100 mg each.

Example 5

Specific examples of injectable suspension compositions include the following 1 ml ampoules for intramuscular injection;

weight %

(a) active compound 0.01

(b) polyvinylpyrrolidone 0.5

(c) lecithin 0.25

(d) Distilled water for injection is added to make 100.0.

The materials of (a) to (d) are mixed, homogenized, filled into 1 ml ampoules, sealed, and autoclaved at 121 ° C. for 20 minutes. Each ampoule contains 1.0 mg of compound (a) per ml.

Example 6

mg / suppositories

Active compound 5

Theo Bro Mayu (cocoa) 995

The drug is powdered and passed through a B.S. 100 sieve and polished at 45 ° C. with deobroma molten oil to produce a soft suspension. The mixture is stirred well and poured into molds each having 1 G volume to prepare suppositories.

Claims (9)

Tropin or pseudotropin is reacted with the corresponding acid halide of the following general formula (IV) to form a trophyl or pseudotropyl benzoate derivative of the general formula (I) or a pharmaceutically toxic salt thereof How to prepare.

In the above formula,

N represents 0 or an integer from 1 to 3: R ₁ represents C ₁ to C ₄ alkyl, provided that when n is 2 or 3, R ₂ is equal to R _1, and R ₃ and R ₄ are Independently hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxy or halogen, provided that in the case of a trophile derivative R ₃ is alkyl and R ₄ is hydrogen and X represents halogen. The compound of claim 1, wherein Ar '

Wherein n is 0 or an integer of 1 to 3, R ₁ represents C ₁ to C ₄ alkyl, and R ₂ ′ is the same as R ₁ . The method of claim 2, wherein both R ₁ and R ₂ ′ represent methyl. The method of claim 2, wherein n is 1 and Ar ′ is phenyl substituted at the 2,3 position: 2,4 position: or the 2,5 position. The process of claim 2, wherein the tropine is reacted with an acid halide to obtain the corresponding trophyl benzoate of formula (I). The process of claim 1, wherein the troffin is reacted with an acid halide of the general formula (IVa) to obtain the corresponding trophyl benzoate of general formula (I).

Wherein R ₁ and R ₃ ′ independently represent C ₁ to C ₄ alkyl groups, and X represents halogen. The method of claim 6, wherein both R ₁ and R ₃ ′ are methyl. The process according to claim 1, wherein the pseudodopine is reacted with an acid halide of the following general formula (IVb) to obtain the corresponding pseudothrophile benzoate of general formula (I).

Wherein R ₁ represents C ₁ to C ₄ alkyl, R ' ₃ and R' ₄ independently represent hydrogen or C ₁ to C ₄ alkyl, and X represents halogen. The method of claim 8, wherein R ₁ represents methyl and R ′ ₃ and R ′ ₄ independently represent hydrogen or methyl.