CS266313B2 - Process for preparing derivatives of benzamide - Google Patents

Abstract

The present invention relates to a process for the production of benzamide derivatives of formula I wherein R1 and / or R2 are hydrogen or a halogen atom, with at least one of them is halogen, R2 is alkyl C 1 -C 5 or benzyl, A 2 and A2 is the same or different, is hydrogen, alkyl of 1 to 5 carbon atoms or C 1 -C 6 acyl as well as salts of these substances and their optical isomers, by reacting with halogen or a halogen-dioxane complex of formula II wherein R 2, A 2 and A 2 have as defined above, followed by isolation the product in free salt or optical form isomer.

Description

The invention relates to a process for the preparation of novel benzamide derivatives which have a pharmacological effect and which can be processed in a conventional manner into pharmaceutical compositions.

The benzamide derivatives produced by the process of the invention can be used to treat emesis, psychosomatic diseases and psychiatric disorders.

U.S. Patent No. 3,342,826 discloses sulpiride as a compound of formula h _{2 nso 2}

This substance is currently on the market as an antipsychotic. This compound has very weak extrapyramidal side effects in humans and causes poor catalepsy in experimental animals.

U.S. Patent No. 4,232,037 discloses antipsychotic agents of the general formula

wherein alkyl has 1 to 3 carbon atoms, the same or different represents hydrogen, chlorine or bromine.

A compound of the formula is also mentioned among these substances

designated FLA 731. The compounds of U.S. Patent No. 4,232,037 have less antipsychotic effects than the compounds of the invention.

The present invention relates to a process for the preparation of benzamide derivatives of the general formula I

where.

_and , the same or different, represent a hydrogen atom or a halogen atom, respectively. at least one of them represents a halogen atom.

CS 266 313 B2 means alkyl of 1 to 5 carbon atoms, or benzyl,

A ^x and the same or different represent a hydrogen atom, an alkyl having 1 to 5 carbon atoms or an acyl having 1 to 6 carbon atoms.

The invention also relates to a process for the preparation of physiologically acceptable salts or optical isomers of the abovementioned substances.

The compounds of formula I have been shown to have valuable therapeutic properties.

The present invention therefore relates to a process for the preparation of physiologically acceptable compounds and their salts, all of which can be used for the treatment of vomiting, psychosomatic diseases, for example gastric and duodenal ulcers, and for the treatment of psychiatric diseases, for example depression, anxiety and in particular psydhosis. for example schizophrenia.

The halogen atoms in formula I may be chlorine, bromine, iodine or fluorine.

The alkyl group in formula I may be a straight-chain or branched alkyl group having 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, tert-butyl, pentyl, -methylbutyl and 2,2-dimethylpropyl.

The acyl groups in formula I may be represented by the formula alkyl-CO-, wherein alkyl group is as defined above.

. . 12.

A first preferred subgroup of compounds of formula I are those in which R 1 and R 2 are the same or different and represent a hydrogen atom or a halogen atom, at least one of which 312 represents a halogen atom, R represents alkyl or benzyl and one of the substituents A and A represents alkyl and a second hydrogen atom.

Of this first subgroup of compounds of formula I, those substances are preferred in which

R represents a bromine atom or a chlorine atom, R represents a hydrogen atom or a bromine atom, R also represents a 2 ethyl group, and one of the substituents A and A represents methyl or ethyl and the other a hydrogen atom.

A second preferred subgroup of compounds obtainable by the process of the invention are those compounds of formula I in which R 1 and R 2 are the same or different and represent a hydrogen atom or a halogen atom, at least one of which represents a halogen atom, R ³ represents 19 alkyl or benzyl and one of the substituents A and A is alkyl and the other of these substituents is acyl, as defined above.

Of this second subgroup of compounds of formula I, those compounds are preferred in which R ³ is bromine, R ² is hydrogen, R ³ is ethyl, A ¹ is methyl and A is acetyl.

A third preferred subgroup of compounds of formula I which can be obtained by process 12 'according to the invention are those in which R 1 and R 2 are the same or different and represent a hydrogen atom.

or a halogen atom, at least one of which represents a halogen atom, A and A are the same or different and represent a hydrogen atom, an alkyl or an acyl atom, and R ³ represents an alkyl group other than an ethyl group, or benzyl.

In this third subgroup of compounds of formula I, the preferred compounds are those in which R is chlorine or bromine, R is hydrogen, A is methyl, 93

A is methyl and R is methyl, n-propyl, allyl or benzyl.

The novel compounds prepared by the process of the invention can be used for the treatment of the above-mentioned diseases in the form of racemic mixtures of the (+) and (-) forms, which are usually obtained by

CS 266 313 B2 synthesis. These mixtures can also be divided into the corresponding enantiomers, which can be used as such. The individual forms can also be obtained by reacting the corresponding enantiomers of 2- (aminomethyl) -1-alkyl / alkenylpyrrolidine with a benzoic acid residue.

The compounds prepared by the process of the invention may be administered in free form or in the form of _H salts with notoxic acids. Typical examples of these salts are hydrobromides, dihydrochlorides, malonates, sulfates, sulphonates, citric, lactic, malic or tartaric acid salts.

The compounds of this invention may be administered orally, rectally or by injection in the form of pharmaceutical preparations which contain the active substance either in the free form _from or in the form of a nontoxic pharmaceutically acceptable acid addition salts such as hydrochloride, hydrobromide, lactate, acetate, sulfate, sulfamate, and the like, together with a pharmaceutically acceptable carrier. Thus, the term compounds produced by the process of the invention always refers to the free substances as well as the acid addition salts of these substances, unless stated otherwise.

The carrier may be a solid, semi-solid or liquid diluent or capsule. The pharmaceutical preparations usually contain 0.1 to 99% by weight of active ingredient, preferably 0.5 to 20% by weight for injection and 2 to 50% by weight for oral administration.

Pharmaceutical compositions containing the compounds of the invention for oral administration may be prepared by admixing the selected compound with a solid powdered carrier, for example lactose, sucrose, sorbitol, mannitol, starch, for example potato starch, maize starch or amylopectin, a cellulose derivative. or a gelatin and a glidant, for example, magnesium stearate, calcium stearate, polyethylene glycol wax and the like, after which the resulting mixture is compressed into tablets. If coated tablets are desired, the core obtained in the above manner can be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talc, titanium dioxide and the like. The tablet can also be coated with a lacquer dissolved in a volatile organic solvent or in a mixture of organic solvents. A colorant can be added to the coatings, in particular to distinguish tablets which contain different active ingredients or different amounts of the same active ingredient.

In the manufacture of soft gelatine capsules consisting of gelatin and, for example, glycerol in closed form, the active ingredient is mixed with, for example, vegetable oil. Hard gelatin capsules may contain the granulate of the active ingredient in admixture with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives or gelatin.

Unit doses for rectal use may be presented as suppositories which contain the active ingredient in admixture with a neutral fatty base, or may be in the form of gelatin rectal capsules containing the active ingredient in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral administration may take the form of a syrup or suspension, for example solutions containing 0.2 to 20% by weight of active ingredient, the remainder being sugar and a mixture of ethanol, water, glycerol and propylene glycol. These liquid preparations may also contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as thickeners.

Solutions for parenteral injection can be obtained as aqueous solutions of water-soluble pharmaceutically acceptable salts of the active ingredient, preferably in a concentration of 0.5 to 10% by weight. These solutions may also contain stabilizers and / or buffers and may be prepared in various forms. single doses.

A suitable dose of the compounds produced by the process of the invention for oral administration is 100 to 500 mg, preferably 200 to 300 mg.

CS 266 313 B2

The present invention relates to a process for the preparation of benzamide derivatives of the general formula I

(I) where

12.

R 1 and / or R 3 represent a hydrogen atom or a halogen atom, at least one of which represents a halogen atom,

3v

R is alkyl of 1 to 5 carbon atoms or benzyl,

A and Λ, the same or different, denote a hydrogen atom, an alkyl having 1 to 5 carbon atoms or an acyl having 1 to 6 carbon atoms, as well as salts of these substances and their optical isomers, characterized in that they are reacted with halogen or a complex of halogen and dioxane, a compound of formula II

where>

1 2

R, A and A are as defined above, followed by isolation of the product in free form, in the form of salts or an optical isomer.

The chlorination is carried out by heating the starting material with chlorine in the optional presence of a Lewis acid catalyst or with N-chloramides of hypochlorous acid in the presence of an acid catalyst in a suitable solvent, for example chloroform or nitrobenzene.

The bromination is carried out with bromine in the optional presence of a Lewis acid catalyst or by bromination in acetic acid in the presence of a base, for example sodium acetate, or using a complex of bromine and dioxane. It is also possible to use other reagents, for example HOBr and N-bromamides, in particular N-bromosuccinimide using an acid catalyst.

The invention will be illustrated by the following examples. *

Example 1

The following examples illustrate the process for the preparation of pharmaceutical compositions containing the compounds produced by the process of the invention. The term active ingredient means a compound prepared by the process of the invention or a salt thereof, preferably N-ethyl-2- (3-bromo-2-hydroxy-6-methoxybenzamidomethyl) pyrrolidine or its 3-bromo-6-hydroxy- 2-methoxy substituted isomer.

Form A - Soft gelatin capsules

500 g of active ingredient are mixed with 500 g of corn oil and the mixture is filled into soft gelatin capsules, each capsule containing 100 mg of mixture, i.e. 50 mg of active ingredient.

CS 266 313 B2

Form B - Soft gelatin capsules

500 g of active ingredient are mixed with 750 g of peanut oil and the resulting mixture is filled into soft gelatine capsules, each capsule containing 125 mg of mixture, i.e. 50 mg of active ingredient.

Foi inu C · Tul »Ιυ (γ kg of active substance is mixed with 20 kg of silica (Aerosil). 45 kg of potato starch and 50 kg of lactose are mixed with the above mixture and the mixture is moistened with a starch heel prepared from 5 kg of potato starch. and distilled water, after which the mixture was granulated by sieving, the resulting granulate was dried and extruded through a sieve, and 2 kg of magnesium stearate was added to the granulate, and the resulting mixture was compressed into tablets each weighing 172 mg.

Form D - Effervescent tablets

100 g of active ingredient, 140 g of finely divided citric acid, 100 g of finely divided sodium bicarbonate, 3.5 g of magnesium stearate and the required amount of flavors are mixed and the resulting mixture is compressed into tablets, each containing 100 mg of active ingredient.

Form E - Sustained-release tablets

200 g of active ingredient are melted together with 50 g of stearic acid and 5.0 g of carnauba wax. The mixture obtained is cooled and ground into particles with a diameter of at most 1 mm. The mixture thus obtained is mixed with 5 g of magnesium stearate and compressed into tablets weighing 305 mg. Each of these tablets contains 200 mg of active substance.

Form F - Solution for injection

The solution for injection can be prepared from the following ingredients:

Component Amount active substance 3,000 mg sodium metabisulphite 0.500 mg sodium edetate 0.100 mg sodium chloride . 8,500 mg sterile water for injection into 1.00 ml

Pharmacological data

Many studies mention that the antipsychotic action of neuroleptics is in some way related to the reduction in catecholamine transmission in the brain caused by these substances and is more specifically associated with central blockade of dopamine receptors in the cortex and subcortical areas. The brain. Most antipsychotic agents affect several dopamine systems in the brain. It can be shown that the antipsychotic effect can be associated with the blockade of dopamine receptors in subcortical and cortical limbic structures, as described in J. Pharm. Pharmacol. 25, 346, 1973 and Lancet, November 6, 1976, p. 1,027, whereas the well-known extrapyramidal side effects induced by neuroleptics are caused by blockade of dopamine receptors in the nitroneostriatal dopamine system, as described in Intern. J. Neurol. 6, 27-45, 1967

Clearly, there are several ways to study dopamine receptor blockade in the brain in vivo. One of these methods is based on the ability of antipsychotics to block apomorphine-induced behavior in rats. It is known that apomorphine to some

CS 266 313 B2.

Measures work just like dopamine. Several studies show a good agreement between the blockade of dopamine receptors in vivo in apomorphine text and the therapeutic effect of various antipsychotics. Apomorphine induces a typical syndrome in rats and other animals, consisting of repeated stereotyped movements and hyporactivity, which is probably due to activation of postsynaptic dopamine receptors in the brain, as described in J. Pharm. Pharmacol.

19, 627, 1967, J. Ncurol. Trannm. 40, 97-113, 1977. Stereotypic movements, such as chewing, biting or licking, appear to be induced by activation of those dopamine receptors that are associated with the neostriatal dopamine system, as described in J. Psychist.

Res., 11, 1, 1974, whereas the increased amount of movement and hyperactivity is probably due to the activation of dopamine receptors in mesolimbic structures, for example in the nucleus olfactorium, nucleus acumbons, i.e. in the mesolimbic dopamine system, as described in

J. Pharm. Pharmacol. 25, 1 003, 1973.

A number of studies have shown that neuroleptics of various structures block stereotyped movements after apomorphine in rats, and this blockade is related to the blockade of dopamine transmission, which can be measured biochemically or neurophysiologically. That is, the antiapomorphine effect is related to the changes in dopamine metabolism that are induced by neuroleptics, as described in Eur. J. Pharmacol., 11, 303, 1970.

Work on dopamine binding to receptors according to Life Science. 17, 993-1002, 1976, as well as work on antipsychotic effects such as Nature, 263> ³³⁸ 341, 1976, give the same results. ,

Methods

Sprague-Dawley rats, male 225-275 g, were observed in cages 40 cm long, 25 cm high and 30 cm high, and their behavior was recorded 5, 20, 40 and 60 minutes after apomorphine administration. The active substances were administered 60 minutes before the administration of 1 mg / kg of apomorphine hydrochloride, which was administered subcutaneously into the neck of the animals. This dose and form of administration elicit a good response and little variation in response. In addition, apomorphine also induces reproducible hyperactivity when administered subcutaneously.

Immediately after injection, the animals were caged one at a time and stereotyped movements were evaluated in two ways. The first method was a modified method according to Costall and Naylor (1973). The intensity of stereotypical movements was evaluated according to a scale with degrees.

to 3 as follows:

No change in behavior compared to control trials using sodium chloride

Stereotypical movements appear from time to time, especially sneezing ‘2 Sneezing is continuous

Sneezing is continuous, in addition to chewing, biting and licking. - *

According to the second system, the number of animals with hyperactivity is a decisive assessment. Each group contains 6 to 8 animals. Control experiments are performed with sodium chloride. ED _5Q is the first dose rating system that reduces stereotyped movements to 50% for 60 minutes. In the second method of evaluating the ED _5Q dose which reduces by 50% the number of animals with hyperactivity for 60 minutes. ED ₅₀ values are calculated from dose-response curves using the least squares method of four to six doses used using six to eight animals per dose.

Results

The compounds prepared by the process of the invention were compared with previously known substances such as sulpiride (Life Science, 17, 1551-1556, 1975) and N-ethyl-2- (3-bromo-3,6-dimethoxybenzene).

CS 266 313 B2 amidomethyl) pyrrolidine, (racemic and levorotatory), designated FLA 731 and FLA 731 (-)

The compounds produced by the process of the invention are very potent inhibitors of dopamine receptors in the brain.

Given their ability to antagonize both stereotypic movements and hyperactivity after apomorphine, it is thought that these agents are likely to block dopamine receptors in both the striatal and limbic regions, as described in the introduction to the pharmacological tests. The compounds of the present invention are more effective than the previously known compounds FLA 731 and FLA 731 (-) in inhibiting apomorphine effects. In addition, they are far more effective than the antipsychotic sulpiride. Because there is a high statistically significant correlation between blockade of apomorphine and clinical antipsychotic activity, as described by Nature, 263, 338-341, 1976, it is very likely that the compounds of the invention will have high antipsychotic activity in humans.

Example 2.

5-bromo-N- (1-ethyl-2-pyrrolidinylmethyl) -2-hydroxy-6-methoxybenzamide (FLA 908)

To a solution of 2.4 g of 0.008 6 mol of N- (1-ethyl-2-pyrrolidinylmethyl) -6-methoxysalicylamide in 50 ml of acetic acid was added dropwise at 20 ° C a total of 0.46 ml (0.008 6 mol) of bromine in 5 ml of acetic acid. After 15 hours the solvent is evaporated off, gas chromatography of the residue weighing 3 g shows a mixture of 80% of the 3-bromoisomer and 20% of the desired isomer. After separation by reverse phase high-performance liquid chromatography (Waters LC 500 Gg column 30x5 cm) using a mixture of methanol, 0.5 M NH 4 OAc and 14 M ammonia in a ratio of 60: 40: 1, 0.6 g of pure product is obtained. mp 62-63 ° C after recrystallization from hexane.

¹³ C NMR (CDCl 3) δ ppm 169.08 CONH; 163.22 COH (shift-14.9 Hz after addition of D ₂ O); 156.03 COCH ₃ (shift + 1.5 Hz); 136.95 p-CH; 116.31 m-CH; 109.68, 105.16 CBr, 62.03 CH ₃ O.

Analysis: for C ₁₃ H ₂ BrN ₂ O ₃ calculated 7.84,% N;

found 7.41% N.,

In a similar manner to Example 2, the compounds listed in Tables I and IA can also be obtained.

Some of the salts, which are indicated in the table ¹¹ , were hygroscopic and their purity was therefore verified by gas chromatography. The NMR of these substances was consistent with the expected structure. . ·

Table I

R ^Z OA ¹

Temperature

Compound no. R ¹ R ² R ³ A ¹ A ² X melting point ° C 1 rac Br H ^C 2 «5 H H - 166-68 2 rac Br H ^C 2 ^H 5 CH ₃ H - 68-69 3 (-) Br H ^C 2 ^H 5 ^CH 3 H HC1 ^A sínteruje 4 (-) Cl H ^C 2 ^H 5 CH ₃ H HCl sintered ³ 5 rac Br H ^C 2 ^H 5 ^C 2 ^H 5 H - 83-84 6 (-) Br H ^C 2 ^H 5 ^C 2 ^H 5 H - 74-76

20 ° D

-45.5 ° (free base)

-51.4 ° (free base)

-66.7 °

CS 266 313 B2

Table I continued

Compound no. R ¹ R ² R ³ A ¹ A ² X Melting point ° C 7 (-) Br Br ^C 25 CH ₃ H EATING sintered -8.6 ° 8 rac Br II c ₂ n ₅ ^CH 3 cn ₃ co- HC1 156 (decomposition) 9 rac Br H ^ 2 ^ 5 H CH ₃ - 62-63 10 (-) Br H CHJCH,) ' ₂ - ^CH 3 ^CH 3 - 103-104 -85.4 ° (free base) 11 (-) Cl Cl c ₂ h ₅ H ch ₃ - 48-49 -64 ° 12 (-) Br H CH, (CH,) 2 ' ^CH 3 H HC1 140-141 -78 ° 13 (-) Br H Ph-CH ₂ ^CH 3 H HCl 207-209 14 (-) Br H ch ₃ (ch ₂ ) 2 ' ^H CH ₃ HC1 137-138 -68 °

Table I continued B. Calculated Analysis in % found C H Br Cl N 0 · 48.99 5.58 8.16 13.89 48.0 5.53 7.68 14.1 50.43 5.92 22.37 7.84 13.44 50.4 5.99 22.4 7.87 13.6 45.76 5.63 7.12 12.19 45.76 5.63 7.12 12.19 10.15 8.02 10.1 7.70 51.76 6.24 21.52 7.55 12.93 51.7 6.09 21.4 7.36 13.0 51.76 6.24 21.52 7.55 12.93 51.7 6.02 21.9 7.31 13.1 38.12 4.48 5.93 10.16 37.9 4.51 6.13 9.96 46.86 5.55 18.34 8.13 6.43 47.1 5.70 18.3 8.12 6.23 51.73 6.08 20.36 8.04 50.1 6.07 22.3 7.44 52.99 6.54 20.74 7.27 53.2 6.67 21.3 7.18 51.88 5.80 20.42 8.07 13.82 51.74 5.70 20.50 8.07 13.99

CS 266 313 B2

Table I continued

Β.

Calculated Analysis in% per 1 r> 7.rmn

C H Hr CJ N O 4 7 J11 5.88 19.63 8.71 6.87 47.11 5.97 19.42 8.68 6.89 53.62 5.27 17.56 7.79 6.15 53.65 5.14 17.43 7.70 6.06 47.11 5.88 19.63 8.71 6.87 47.09 6.02 19.50 8.65 6.89 T a b π 1 k a .Α

R ² OA ¹

Designation

compounds R ¹ R ² R ³ A ¹ A ² Melting point ° C FLA 925 Br 'H Ph-CH ₂ - CH ₃ ch ₃ FLA 981 (-) H H ^C 2 ^H 5 H ^CH 3 141-142 FLA 954 (-) H F ^C 2 ^H 5 H ch ₃ 154-155, FLA 961 (-) n AND ^ 2 ^ 5 H CH ₃ oil FLA 968 (-) Br Cl ^C 2 ^H 5 H ^CH 3 249-250 -52 ° FLA 967 (-) Cl Br ^C 2 ^H 5 H ch ₃ 61-63 -55 ° FLA 950 (-) F Br c ₂ h ₅ H C ^h ₃ 136-137 Table IA continuation B. Calculated ^ found Analysis 7% compound name C H Br Cl N O F FLA 981 (-) 55.64 7.74 * 10.95 8.65 55.92 7.24 10.93 8.60 FLA 954 (-) 52.71 6.78 10.37 8.20 52.16 6.54 10.14 8.06

CS 266 313 B2

Table II

Ability to block stereotypes and hyperactivity induced by apomorphine

Compound no. Designation π 1oučnniηγ Structure Blockade of the effect of apomorphine ^ imol / kq i.p. ni <· »* u> t ypy hypoi / tkl Ivll./t Sulpiride and ₃ 203 50 .3 FLA 797 y — CONHCH ₂ - 1.1 0.22 Br OH | c ₂ h ₅ FLA 797 (-) and ₃ 0.38 0.035 4 FLA 814 —Conhch ₂ - rr - - Cl OH c ₂ h ₅

FLA 814 (-)

FLA 659

FLA 659 (-) rac FLA-901

1.1 0.14

2.3 0.40 rac FLA 908

FLA 870

3.4

1.1

FLA 870 (- FLA 903

2.4 0.11

0.53 0.28

CS 266 313 B2

Table II continued

Compound No.

Designation of the compound

Structure

Blockade of the effect of apomorphine ED _ro , / imol / kg i.p. stereotypes hyperactivity

FLA 889

FLA 889 (-) 0.75 0.27

The compounds prepared by the method of the invention were also compared to sulpiride at the same rest periods after oral administration. The results are shown in the following table.

Table

Ability to block the effects of apomorphine after oral administration in rats

Compound number ΕΒ ^ θ, / imol / kg p.o. sterotype hyperactivity

797 (-) 22 3 814 (-) 25 4.4 90). (-) 34 3.0 659 (-) 12 3.2 Supirid > 586 > 586

It is clear that sulpiride loses all activity when administered orally, in contrast to the compounds produced by the method of the invention, which are highly effective in rats even after oral administration.

Claims (1)

BACKGROUND OF THE INVENTION Process for the preparation of benzamide derivatives of general formula I where R ¹ and / or R ² represent a hydrogen atom or a halogen atom, at least one of which represents a halogen atom, R ³ represents alkyl of 1 to 5 carbon atoms or benzyl, Λ ¹ _n and ^{2, the} same or different, denote a hydrogen atom, an alkyl having 1 to 5 carbon atoms or an acyl having 1 to 6 carbon atoms, as well as salts of these substances and their optical isomers, characterized in that: CS 266 313 B2 in reaction with halogen or a complex of halogen and dioxane a compound of general formula II OA ¹ (II) wherein they are as defined above, followed by isolation of the product in free form, in the form of salts or an optical isomer.