JPS5846511B2 - 2-methoxybenzamide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 2-methoxybenzamide derivatives, pharmacologically acceptable acid addition salts of the derivatives, methods for producing secondary compounds, and compositions containing these as active ingredients.

Conventionally, 2-methoxy-benzamides such as N-pyrrolidinyl-alkyl-benzamides have a substituent on both the phenyl nucleus and the pyrrolidine nucleus, and in particular have a lower alkyl group or an allyl group on the nitrogen atom of the pyrrolidine nucleus. Benzamide derivatives are known (French Medicine Special Patent No. 5916M).

Although these compounds are used as antiemetics, they have undesirable side effects when applied to the human body.

This is particularly true of the therapeutic index, ie LD5o/AD, of the above-mentioned known benzamide derivatives.

This is based on the fact that safety is low and the safety range is extremely narrow.

In fact, N-((1-ethyl-pyrrolidinyl-2)-methyl2-methoxy-5-sulfamoyl-benzamide (sulpiride, 5ulpi-rid
e) is LD as shown in the pharmacological test described below;
While the o value (intraperitoneal administration) is relatively low at 170 .mu./ky, the AD o value (intraperitoneal administration) is high at 60 .mu./ky and the therapeutic index is only about 2.8.

However, the AD50 (oral administration) of sulpiride in its antagonizing effect on apomorphine-induced stereotypy actually exceeds 600 .mu./-, and it has the disadvantage that it cannot actually exhibit its activity by oral administration.

The present invention provides a novel 2-methoxy-benzamide derivative which completely overcomes the drawbacks of the low therapeutic index and narrow safety range of the above-mentioned known benzamide derivatives.

The above derivative of the present invention is represented by the following general formula (1).

In the formula, R1 is a chlorine atom, 5O2CH3 or 5O2NR2
R3 (R2 and R3 are a hydrogen atom or a methyl group), and is particularly preferably SO2NH2.

Further, m represents an integer of 2 to 5, and represents a cyclobutyl, cyclopentyl, or cyclohexyl group.

The compounds of the present invention have asymmetric carbon atoms and therefore include racemates or optical isomers.

The compounds of the present invention are useful in the treatment of humans and animals, particularly in the treatment of neurological and psychosomatic diseases.

The compounds of the present invention can be produced by known methods.

For example, it can be obtained by reacting a substituted 2-methoxy-benzoic acid halide represented by the general formula (1) with an amine represented by the general formula (1) as shown below.

R1 and m in gII) and (III) above have the same meanings as those in general formula (1), and X represents a halogen atom, particularly a chlorine atom or a bromine atom.

The above reaction is preferably carried out at a relatively low temperature (-5° to +3°
0° C.), in non-polar solvents such as ketones and in the presence of alkali metal carbonates.

The compound of the present invention also has the formula Compound and general formula represented by [In the formula, m is the same as above.

X represents Ct or Br.

] It can also be produced by reacting with a compound represented by ※※.

The primary amines used as starting materials can be produced from furan derivatives according to the following reaction formulas, and these also constitute one embodiment of the method for producing the compounds of the present invention.

Next, the primary amine obtained above may be used for producing an amide.

Furthermore, as an alternative method, a method can be adopted in which the primary amine used as a starting material is ring-shortened from *the present pyridine derivative according to the following reaction formula.

[In each formula, m and X are the same as above.

[Resolution of the compound of the present invention can be carried out according to known methods, but there is a method in which an acid having an appropriate optical activity is added to the racemate and the resulting salt is separated by utilizing the difference in solubility in an appropriate solvent. Can be adopted.

Hereinafter, in this specification, salts will be abbreviated using the following symbols.

d or l represents an optical isomer of the base, ie, the compound of the present invention.

Further, D or L indicates the optical isomer of the acid used.

The enantiomeric salts obtained above are separated by taking advantage of the substantial insolubility of the salts obtained by addition of bases and acids having the same symbols in ethanol heated to reflux temperature.

Insoluble neutral salts (hereinafter referred to as d-D-d and 1-L-1) are usually produced in relatively good yields (50% above the theoretical maximum).
(at least 34%).

This is a salt designated by other symbols (d-L-d and l-D-
This is because g still remains in the solution as a solute.

Therefore, when D(-1-)-dibenzoyltartaric acid is used, a dextrorotary base is recovered, whereas when L←)-dibenzoyltartaric acid is used, a levorotatory base is obtained.

Furthermore, it is also possible to recover for racemization optical isomers which are known in the art to be pharmacologically inactive in this field.

The resulting racemate is then resolved to obtain useful optical isomers.

The present invention will be illustrated below by way of examples.

Example 1 Racemized N-(1-cyclopropylmethyl-2-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide, its (SX-)-optical isomer and its (S
)(+)-methanesulfonate 1; m=2; R1=
So2NH2 code number 5L-BO75) Ethyl ester of racemic 2-methoxy-5-sulfamoylbenzoic acid 7.78r (0.03 mol), 2-aminomethyl-1-cyclopropylmethylpyrrolidine (boiling point: 58~
60°C70,25mmH? , elemental analysis value; calculated value C7
0.08%, Hll, 76%.

N18.16%, actual value C70.21%, HI3.06
4.861 (0,0315 mol) of ★, N18.15%) and 121 rLl of water are placed in a 250 rILl round bottom flask and the mixture is heated at 100° C. for 9 hours.

Solids precipitate during heating.

Cool the mixture and dilute with water.

The suspension is stirred and filtered, then the solid is washed with water and ether and dried.

Yield -7,62S', Yield -69,14%, Melting point = 15
9.5-160.5°C (S)←)-isomer 1-cyclopropylmethyl-2-aminomethyl-(S)
(-)-Pyrrolidine 8.8P (0,057 mol), 2-
Ethyl ester of methoxy-5-sulfamoylbenzoic acid 14.07Lj! (0,054 mol) and 18 ml of water
into an Ersinmeyer flask.

This mixture is heated at ioO<0>C for 10 hours.

When this is cooled, a solid precipitates out.

Add ether and water and stir the mixture.

Drain the solid and dissolve in chloroform.

The solution is dried over magnesium sulphate and evaporated.

The solid obtained is recrystallized from ethyl acetate.

Melting point = 134-134.5°C [α] Back = -77°C (
C=1. DMF'') (S)(1)-Methanesulfonate Methanesulfonate is obtained by reacting the above benzamide and methanesulfonic acid in acetone.

Melting point -120.5~121.5°G [α] Sweet +5.2°C (C=1.DMF) Example 2 N-(1-cyclopentylmethyl-2-pyrrolidinylmethyl)-2-methoxy- (Sx→- optical isomer of 5-sulfamoylbenzamide and its (S)(-1-)-
Methanesulfonate ([I); m=4; R1=So
2NH2 code number 5L-8145) ■-cyclopentylmethyl-2-aminomethyl-(S)
(-)-pyrrolidine 13.2f (0,0724 mol),
Place potassium carbonate IOS' and acetone into an Ersinmeyer flask.

18 L of 2-methoxy-5-sulfamoylbenzoic acid chloride at a temperature below 10°C? ((10724 mol) was added dropwise.

Stir the mixture for 2 hours.

The mixture is evaporated to dryness and triturated with a water-ether mixed solvent.

The solid is drained and dissolved in chloroform.

The solution is dried over magnesium sulphate and evaporated.

The solid obtained is recrystallized from ethyl acetate.

Melting point = 123-123.5°C [α] -99.5°C (C = 0.5, DMF
) The methanesulfonate of the benzamide is obtained by reacting the benzamide with methanesulfonic acid in acetone to obtain a white solid, which is then recrystallized from isopropanol.

Melting point -123~124°C [α] +2.5°C (C=1.DMF) The compounds obtained in Examples 1 and 2 above and the compounds obtained in the same manner are shown in Table 1 below. show.

After testing the compounds of the present invention for acute toxicity, a series of neuropharmacological tests were conducted to determine their psychoactive activity.

The compounds of the invention were administered intraperitoneally in the form of their salts, namely hydrochloride (CZ) or methanesulfone (MS).

Sulpiride HC7 (Sul pi) was used as a control substance.
I chose ride・HC/:).

Acute toxicity due to intraperitoneal administration was observed in Swiss C.
Both sexes of DI mice were examined.

The 50% lethal dose (LD50) of each compound was determined by graphical methods.

The results are shown in Table 2 below. From Table 2 above, it can be seen that the compounds of the present invention generally have larger LD and o values than sulpiride and exhibit lower toxicity.

Furthermore, LD is better than sulpiride. Compounds with slightly lower values, i.e. 5
L-8164 is effective against apomorphine-induced stereotypy, which will be described later.
In the antagonistic effect test, it shows significantly higher activity than sulpiride.

Neuropharmacological activity was then investigated using the following tests.

The method of Janssen et al.
im.

Forsch, 1960, 10.1003), the average weight is 130? A male Sprague-Dawley rat (Sp
rague-Dawley (Chorles Rive
r) Determination of antagonism to apomorphine-induced stereotypy for rats).

The obtained test results were calculated as 50% active dose. (AD50) as shown in Table 3 below.

The results obtained for hydrochloride (cg) and methanesulfonate (ms) in Table 3 above are expressed in terms of weight of base (b).

From Table 3 above, it can be seen that the compound of the present invention has A
It can be seen that the D5o value is significantly small, indicating high activity.

In particular, from the results in Tables 2 and 3, all of the compounds of the present invention have extremely large therapeutic coefficients (LD5) compared to sulpiride.
0/AD50), and from this point it can be seen that it has an extremely wide range of safe application and is a more effective medicine.

The above test results demonstrate that the compounds of the present invention are useful as psychotropic agents, such as therapeutic agents for psychosis or neurosis.

In addition, the activity of the compound of the present invention differs between its racemate and optical isomer, and the dextrorotatory one is 1.5 times or (depending on the evaluation method) twice as much as the racemate. It's powerful.

Therefore, this isomer can be expected to have the following uses.

(a) In low or moderate doses, ■ as a psychotropic drug for use in the treatment of anxiety conditions of various psychosomatic disorders, such as gastro-duodenal ulcers, migraines, and dizziness; and ■ depressive and psychotic disorders, especially in the elderly. It's advantageous.

It also has an improved therapeutic index compared to the racemate.

(b) Can be used in high doses for psychotic disorders such as severe behavioral disorders, delirium and obsessive-compulsive disorders.

The compounds of general formula (I) are useful in the treatment of various psychosomatic disorders, such as gastric-duodenal ulcers, migraines, and vertigo, and also in depressive and psychotic disorders, especially in early old age, and in high doses, psychosis. It can be used as a psychotropic drug useful in sexual disorders such as severe behavioral disorders, delirium and obsessive-compulsive disorder.

Therefore, the present invention encompasses all pharmaceutical compositions containing Compound (I) and its salts as active ingredients together with various excipients suitable for oral, rectal or parenteral administration.

Secondary pharmacological compositions can also include other pharmacological substances that are pharmacologically and therapeutically compatible with Compound (I).

For oral administration, all pharmacological forms suitable for this method of administration are available.

Thus, tablets, dragees, gelatin-coated pills, capsules, cachets, and potable solutions and suspensions are available.

The dosage unit dose of the compound vAI) can vary from 5 to 200 ■, and the daily dosage can be from 10 to 400 ■.

For rectal administration, suppositories containing 10 to 200 μ of compound (1) are available, which give the patient 1 to 3 doses per 24 hours.
Units may be administered.

For parenteral administration, injection solutions and buffered solutions can be prepared in advance or at the time of use.

The unit dose may be 5 to 100 µ and the daily dose may be 5 to 300 µ.

Claims (1)

[Claims] 1. General formula [wherein R0 is a chlorine atom, 5O2CH3 or 5O2NR]
2R3 (R2 and R3 are hydrogen atoms or methyl groups), and m is an integer of 2 to 5. A 2-methoxybenzamide derivative represented by the following formula and having a racemic or optical isomer form, and a pharmacologically acceptable acid addition salt of the derivative. 2N-((1-Cyclopropylmethyl-pyrrolidinyl-2)-methyl2-methoxy-5-methylsulfonyl-benzamide and the compound according to claim 1, which is a pharmacologically acceptable acid addition salt thereof. 3 Represented by the general formula [wherein R1 represents a chlorine atom, 02CH3 or 5O2NR2R3 (R2 and R3 are a hydrogen atom or a methyl group], m represents an integer of 2 to 5), and is a racemate or an optical isomer. The active ingredient is at least one compound selected from 2-methoxybenzamide derivatives in the form of 2-methoxybenzamide derivatives and pharmacologically acceptable acid addition salts of the derivatives, and is a pharmacologically acceptable compound that is compatible with the compound. Psychotropic drugs containing carriers that