LU80976A1 - CYCLOALKYLALKYLIC BENZAMIDES - Google Patents

Description

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; The present in go ion concerns me the> case: * / · -2 banz v / ndes- - ·· '- - • i' in the form cg racér-ates or q 1 enantiomerest their srj-s of addition J 'to acids acceptable pharmaceuticals, their preparation and i

j! their application in therapy. J

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. · | The compounds of the invention correspond to the formula (I) j in n i 'n T h:; Ί: k / \ 0CH3 (I)! ; ; î v; ! ! - · i

Π: / CH \ 'I

: i i · 2 i bü! ; i 'i I I j j; ; : in which .

n and m are éçaüi ;, 'independently of each other at. 1,2,3 or 4, and R is the radical CF ^ or an alkylthio radical in which the alkyl is straight or branched and has from 1 to 6 carbon atoms.

If j | The compounds of the invention are active in the field of the system. ! central nervous. i! i! i According to the invention, the comoosés are oriented because condensation of a j j | benzoic (2) memcxy-2-R-5 acid or one of its functional derivatives (halocure ester) and -a ovrrolicir.e, in the form of I! . . ..

I * racemate or a enant.ioir.ere, this rormule (III): | | '| ’Γ T. CH-> NH2 (III) i! ! i; I T!

i (CH-) I

i 2 m! i (CH _) -—- CH_ 2 n 2 Methoxÿ-2-5-trifluoromethyl-5 benzoic acid has already been described in the literature.

2-Methoxy-5-alkylthio-benzoic acids (II) and their chlorides 1 - 1: i: 1 i. i ·; 'coüh 0:; ^ COOH "* C1 so3H —...... · L 1% CH3! Î! \! J

s i: HOOC ^ RS COOH J

ns yy s ~ scsoH r2 so4 r h · (ιι)

CHpNtN N / \ ocïï, NNNoCH

i! 11 SO Cl, | j! -i i! j rs here! ! ‘I OCoch3. "":> I î '! i

The cycloalkyl.alkyl -pyrrolidines (III) are obtained / for example I ’1 according to the methods described by the Applicant in its patents! 74 41 718 in 77 19 391.

j Condensation is carried out at a temperature of 0 to 30 ° C,! -! *; i -! in a solvent such as acetone.

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! ·! I! The following examples illustrate the present invention. ; j IR and RI 111 analyzes and spectra confirm the structure of j! compounds.

Example 1 N- ^ (cyclopropylmethyl-1 pyrrclidinyl-2) rmSthylJnethoxy-2 methylthio-5 · benzamide had its hydrochloride.

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1 * 2-nethoxy-chlorosulfcnvl-5 benzoic. j 1! 44 ml j are introduced into a three-necked flask with stirring and refrigerant; : · Ι then add by p.-small portions 20 g of metho acid; -: y-2 ’'·: ···; ·; Also, at such a speed, the temperature could be between 10 and 15 °. Once the addition is complete on a leash, the medium return to ambient temperature and then maintain it at h. · The temperature is then gradually brought to 60-70 ° (

it is maintained for 1 hour this cui corresoond au rin eu J

/. . . . i ’-cacemsr.Î spoiled. We let arers ie mm eu rcrrcicir eu j; rse this brown licuice in a r.élance of 60 ml of water and 250 g ce; ..- es. A solid appears when it is filtered and washed several times with ice water. It is then dried under vacuum at S0 ° C.

- 'F = 143-5 ° C.

'i <j *! i. Acid cithio bis (rr.-itihcxv-4 ber.coïc’cs-3). ! - -g -: “- | If there is a reactor fitted with a mechanical reactor T introduces 100 (3.4 mol) of 2-metbcxy-chlorcsulfonvl-5 ber.zoîcue acid, 750 ml!

euhenol. and 500 ml of 12N concentrated hydrochloric acid. J

-, '. . . „. . . ! :. · The suspension, shake vigorously, add in portions i '..' 30, S g this zinc powder (2 moles), in about 2 hours, so as to maintain the temperature at 15- 2CcC, cooling if necessary, with an ice water bath. j

n end of operation, the medium is filtered. I

u filtrate, abut 1 1 of water, and under acitauicn 70 o chic- J - - i ire ferric. The mixture is left stirring for 1 hour, then the precipitated product is filtered, and washed with water three times. It is unified by dissolution because a solution of bicarbonate this so-! 't ium in the presence of this "black". The insoluble material is separated by filtration, i filtrate myself and is acidified by this excess hydrochloric acid, and i

; ". The resulting precipitate is filtered, and washed 3 times with this water, J

; ^ 'dried. j | close recriszallisation cens ce acétic'je acid; wash by 1! eth-m · - r; .t. m -g p: _0 _ί S Q “g Qppd ·? j st. O · ^ ^ · "Γ * Ç Ç1 Ç g C ji .1 l • i;" '...................... ": Ü!' ' i: '- 212- /] 2, ö ° C.

. i:; i 3. M6thoxy acid “2 nethy3 thi.o-5 Jaenzoïçue and its chloride, ί j j: j! 50 g (0.136 mol) of dithio bis> i acid are introduced into a reactor! ; j!; (4-methoxy-benzoic-3) and a solution of 27.3 g (0.682;

! ! mole) of KaOH in 1 1 of water. j N

; ; 1 To the resulting solution, 34.8 g (0.275 i; mole) of methyl sulfate are added short dropwise. Stir 4 hours then extract j; ; -i · ether. We collect the sharp and acidic nhase. We extract! ; :; / 1:. i- the resulting oil with ether, this mtgné-j is dried over sulfate; sium and evaporates. We collect a solid which is triturated in '. cvclohexane.

:; i: ï i F = 68.5-69 ° C.

: 11! i I i 14.4 ml (0.2 mole) of chloride i - are introduced into an Erlenmever; i I; : of thionvle and 19.8 g (0.1 mole) of acice. We have the temperature -; ; '' 1 \\ S] ambient then we heat with rerlux curant 4 hours. j

(: Evaporate to dryness, and distill the residual oil in a ball tube.

Fb = 180CC.

U Λ 1 (I 4. N- [(cvclopropylrnethyl-1 pyrrolidinyl-2) -raethvl ") 2-methoxy I | 5-methylthio-benzamide. |

10.7 g (0.069 mole) of cclclo- II i propylmethyl-1-aminomethyl-2 pyrrolidine, 9.6 g (0.069 mole of crr-1d; potassium bonate and acetone) are introduced into an Erlenmeyer flask. while cooling with an ice bath and under a stream of nitrogen, dropwise is added "I":> j 15 g (0.069%) of chloride of ir.ethoxy-2 mer chloride. hylthio-5 ber.-

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*! zoicue. We have 2 hours at room temperature. We evaporate I

'I ‘! j dry at a temperature <130 ° C and take up with water and crelo-: j roform. The organic phase is collected, it is extracted in an acid medium, the acid phase is basified and extracted with chloroform.

1 Dry over magnesium sulfate and evaporate. We collect one. oil which is passed through a column of silica eluting S.

j acetone.

| - ^ 0.05 ^ 240 ° C * Λ ______________________________ _i 5. Chlorhyd.rate.

6.68 g (0.02 mole) of N-j (cyclopropylir; ethyl-1 pyrroli-dinyl-2) methyljmethoxy-2-methylthio-5 benzamide are introduced into 100 ml of ether. An equimolecular amount of hydrochloric ether is added dropwise, the oil is separated

It is taken up in 100 ml of ether and stirred, then evaporated to dryness.

The residual oil is triturated in 100 ml of ethyl acetate. After an hour a white solid appears. It is filtered and dried.

F - 111.5—112 ° C

* 'Example 2 Isomer (S) (-) of N- [(1-cyclopropylmethyl-2-pyrrolidinyl) methylj 2-methoxy-5-methylthio-benzamide.

10.7 g (0.069 mole) of 2-aminomethyl-cyclopropylmethyl-1 pvrrolidine (S), 9.6 g (0.069 mole) of potassium carbonate and acetone are introduced into an Erlenmeyer flask. While cooling with an ice bath and under a stream of nitrogen, 15 g (0.069 mole) of 2-methoxy-5-methylthio-benzoic acid chloride dissolved in acetone are added dropwise.

The mixture is left to return to room temperature and stirred for two hours. The residual oil is evaporated to dryness and triturated in water and ether. The organic phase is collected and extracted in an acid medium, it is made alkaline with sodium carbonate and extracted with ether. It is dried over magnesium sulfate and evaporated, an ‘oil is collected which is passed over a column of silica, eluting with ethyl acetate and then with acetone. The oil obtained is distilled.

Ebn n_ = 220 ° C ° \ 20 = _83 ° (c = 1 'uMP *

0.0c L J D

The hydrochloride is obtained in hydrochloric ether.

F = 116 - 116.5 ° C

(* Κΐ d = + 21 ° [c = I DM?) 6

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: Example 3 îï - £ (cyc 1 opropyIméthy1-1 pyrrolidinvl-2) me thy ij ::, ethoxy-2 •! '5-ethylthio benzamide.

; 1 i ^ ^ I I J 1 · 2-methoxy-ethyltnio-5 benzoic acid and its chloride.

<! i 1; One operated cOiijne cans 1 'example 1 acess the sultete of metnvle' because of ethyl sulfate. t? = c; _Qc „,,. ! : - - 3û-9 c for 1 acice.

: i 'i! Sb0.05 = 150 ° c Fcur acid chloride. __ _______ [_! · I; i; j; e j! i 2. N- j, (cyclopropylmethyl-l pyrrolidlnvl-2 'methyl ~ lmethoxy-2 éthvl-j: thio-5 benzsmice. - ______________________ ______

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•; ‘In a Erlenmeyar, 9.4 g (0.0611 mole) of cyclopro- are introduced | '' 'i pylmethyl-1 thin.ethyi-2 pyrrolidine, 8.5 g (0.0611 mole) - de-car-η—;! bonate this potassium and acetone. a, a te ~ opf-5f '"' e« c. iocC and!,!! ~ ~ j; j | under nitrogen flow, 14.1 g (0.0611 mole) cout is added dropwise; ! 2-Nethcxy-5-ethylthio-benzoic acid chloride in ace-j;; I: tone. Agitation is carried out for 2 hours at ambient temperature. Evaporation is carried out dry, taken up in water and chloroform, - the 1 ii 1 organic phase is separated, the extract in an acid medium, basified, extracted with chloroform, dried over magnesium sulfate and evaporated.

he j! ! ! We collect an oil and we break it up. I [“* ί i 1 j silica eluting with acetone. An oil is collected which is dis-; tille. (!;! h Ebo, os = 24o ° c-!

Example 4 N- £ (cyclopropylmethyl-1 pyrrolidinyl-2) methylj methoxy trifluoromethyl-5 benzamide and its hydrochloride.

6.37 g (0.0413 mole) of aminomethyl cyclopropylmethyl-1 pyrrolidine, 5.7 g (0.0413 mole) of potassium carbonate and 125 ml of acetone are introduced into an Erlenmeyer flask and then cooled to approximately 5 ° C and slowly poured in dropwise (T <5 ° C) 9.55 g (0.0413 mol of 2-methoxy-5-trifluoromethyl-5 benzoic acid chloride in 50 ml of acetone, under a stream of After the addition, the mixture is stirred for 2 hours in melting ice and 1 hour at room temperature then evaporated to dryness. The residue is taken up between water and ether, it is decanted and the waters are re-extracted twice. mothers and wash the organ extracts. 7. Prepare the eh! orhy / spleen or benzamice by a 03. state 5 on g an s this dry ether using HCl in 11 ether. and the solid is dried. The solid is recrystallized twice from this acetone and a fine white powder is obtained:

F = 149.5 - 150 ° C

Example 5 Isomer (S) (-) of N - ["(eyclopropylmethyl-1 pyrrolicinyl-2) raethylj 2-methoxy-5-triflucromethyl-benzam.ide - -

2.15 ç (0.0139 mol) of amincmethyl-1-cyclopropylmethyl-1 pyrrolidine (S), 1.92 g (0.0139 mol) of potassium carbonate and 100 ml of acetone are introduced into an Erlenmeyer flask. While cooling in an ice bath and under a nitrogen stream, 3.32 g (0.0139 mole) of chloride and 2-methoxy-trifluoro-methyl-5-benzoic acid are added dropwise to acetone. It is allowed to return to ambient temperature and stirred for two hours.

Evaporated to dryness, taken up in water and ether. The organic phase and the extract are collected in an acid medium. It is basified with sodium carbonate, extracted with ether, this magnesium is dried over sulphate and evaporated.

An oil is collected which is distilled.

Eb 0.05 = 250 ° C

lhcl 20 = - 75.5 ° (c = I; DM?]

jy — LEAU

_ - ’~" - - V ’‘ '1' ’2 ^

Compound R m n Fusion or boiling (° C) base Ebn nR = 240 1 CH ^ S 1 1 '; J HCl F = 111.5-112 2 CH S 1 1 base Eb ης = 220 (S) 3 u'Ui HCl F = 116 - 116.5 I>. __— - .____ - - - __, ——--—--- 3 SH5S 1 1 Eb base 0.05 = 240 4 CF ^ 1 1 HCl F = 149.5-150 5 CF 1 1 Eb base Q5 = 250 (s)

The compounds of the invention have been subjected to pharmaceutical, ecological tests in the field of the central nervous system.

The toxicity was evaluated in male mice ~ Swiss CD1, of an average weight of 20 g i.p.

The LD 50 ranges from 75 to 200 mg / kg. - The neuroleptic activity was determined by the antagonism with respect to "climbing" induced by 1 aocinomnine che2 the mouse Gouret C. (1973) J. Pharmacol. (Paris) A_r 341 j.

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The DA 50 varies from 0.03 to 0, G8 mg / kcr, i.p.

Compounds. of the invention can be used in the treatment of various psychological ailments and mental disorders (depressive states and psychoses).

JL.'invention includes all pharmaceutical compositions containing "compounds (I) and their salts as active ingredients, in combination with any excipients suitable for their administration by oral, endorectal or parenteral.

All pharmaceutical forms suitable for the oral, endorectal or parenteral routes are suitable.

The daily dosage can range from 1 to 200 mg.

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Claims (5)

1. Benzamides, in the form of racemates or enantiomers / corresponding to the formula (I) * γγεο -NH - CHa -O (I) CH (CH ^ J ^ cH2 in which - n and m are equal, independently l 'from one another to 1,2,3 or 4, and R is the radical CF ^ or an alkylthio radical in which the alkyl is straight or branched and has from 1 to 6 carbon atoms, as well as their salts d addition to pharmaceutically acceptable acids. 2. Benzamides according to claim 1, characterized by the fact that m and n are equal to 1. 3. Benzamides according to claim 2, characterized in that R is CF3, CH ^ S or C ^ i ^ S. 4. Process for the preparation of the compounds according to claim 1, process characterized in that a 2-methoxy-R-5 benzoic acid (II) or one of its functional derivatives C 0 OH '^ \\\ ( II) OCH3 with a pyrrolidine, in the form of a racemate or an enantiomer, of formula (III). 0-cV "ï 1 1 9 5. Medicament, characterized in that it contains a compound as specified in any one of claims 1 to 3. \ l UUn v- v V V 'V'v. m »» w f