LU80975A1 - METHOXY-2 BENZAMIDES - Google Patents

Description

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i ........-........... -..........-.......... — ...... .......-........ 1 i The present invc · t J. we have for object · ". :: y-2 b ^ zaric: s, in the form oe raslr.ütûs or â 1 OnantJ on * res, their salts ad * 1 on to pharmaceutical acids are acceptable, their preparation and their therapeutic use.

The compounds of the invention correspond to the general formula (I) R - ^^ j ^ -CO-Nn-CE -2 TX f, H!

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(Cn2) f- - Ch 2! v i: in which i “i n is 1, 2, 3 or 4! R is either a radical SC ^ NR- ^ R.-, in which R ^ and independently of one another represent a hydrogen atom or an alkyl, or a radical S (0) R-, in which R, is an alkyl and m is O,] or 2, either a halogen atom or the radical CF ^,

Alkyl islands having this 1 to 4 atoms this carbon.

I i i | The compounds of the invention are active in the field of the system | central nervous.

i: f i The compounds of the invention are prepared by reaction between a pyrrolidine I, in racemical or optically active form, of formula <; . (III) ---

; - ”KE2" CH2 — kNX

I (III) (ciC) ------- CH_ t n 2 and a benzoic acid or one of its functional derivatives, halogen-

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I nure or alkyl ester, this formula (τχ) i · • i11)

R ^ COOK

î! The pyrrolidines (ïrl) are obtained in a classic way from /! 'of Y-nnrvrolactcne or chloride ΥΙ, -, μ α i' nr.

2

i reacted an arJ’nê. I

i (CH)! S I 1 then we transform the cycloalkyl-1 cxo-2 pyrrolich2 ^^ 2 dinner obtained in c y c 1 o a 1 ky 1-1 n i t r c - r. i e a h y 1 a r. a - 2 pyrrolicine as hydrogen as aminomethyl-2 cycloalkyl ~ l pyrrolia5.ne.

Condensation is carried out at a temperature of 0 to 30 ° C

i i: The following examples illustrate the invention. j

The IR and NMR analyzes and spectra confirm the structure of these! compounds. ,

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Example 1. N-j (cyclopropyl-1 pyrrolidinvl-2) "g C!; Raëthyl-2-methoxy-sulfarnoyl-5 fcenzamide and its methane- · 'sulfonate. | 1. Cvclooropylaminocarbonyl-3 propyl chloride. J

In a 2 liter reactor in place 57.1 g (1 mole) of cclclo- i • ** distilled propylamine, 101.2 g (1 mole) of triethylsmine and 750 ml of dry ether. Cool in an ice-salt bath to about -10 ° C and slowly introduce a solution of 112 ml therein; (= 141 g: 1 mol) this chloride ce ^ -chlorobutyryl in 150 ml; ether ensuring that the temperature does not exceed -5 °. This addition takes several hours. The reaction mixture is then allowed to warm up and stand overnight. 500 ml of water and chlc-j roform are added in sufficient quantity so that any solid has disappeared, the aqueous phase is stirred and decanted. The organic phase is washed with acidic water, then with bicarbonate water and finally with water and the! dry over magnesium sulfate. The mineral is filtered and the filtrate is evaporated to dryness. A white solid is collected. j

It is recrystallized from approximately 350 ml of isopropyl ether. j? T = 69.5-7l ° C j! 2. Cyclopropyl-1 oxo-2 pyrrolicine. j

37 g (0.77 mole) of hydridej sodium are placed in a 2 liter erlenmeyer flask, which is washed 4 times with petroleum ether and covered with · 1 liter of dry DMSO. It is gently heated to 50-60 ° and the gas evolution is allowed to end, proving the formation of the cimsyie ion.

3 when i 1 Γ, -t le- :: m born,: n made the nHar, o reactive d, ns i '^, glzctyt introduced drop by drop fairly quickly a solution of 113.5 g (0.733 i, w - ut <-rpci '? nt in 3Π0 ml of D'ÎSO then leave' mole) of amide chlorine uru · -! '· ju <- i. a. · -p-r. ambient temperature. Shake for 10 h and leave to; rest ... do not harm the r - i ... nn i ^ tte then on 2 kg of ice, add • ooser * again one- night; · j-u salt to saturation and extracted with chloroform 3 times.

These extracts are then washed 4 times with approximately 120 ml of boiled water 2 times with salted water and finally dried over magnesium sulphate '. After filtration the solvent is evaporated under vacuum and the residue is - distilled with a small adiabatic column under reduced pressure.

! After 2 top fractions containing mainly DMSO; ; (Sb13: 75-112 °) the product is collected: Sbl3 = 112-U4eC.

3 · Cyclo? Ropyl-l nitromethylgne ~ 2 pyrroliàine.

3b, 05 g (0.28 mole) of the preceding lactam and 35.32 g (0.28 mol) of surelate dimethyl / are placed in a b00 ml eriemnever / -then this mixture is heated to 60 pencanu 4 h. It is re-cooled in this ice cream and poured into a solution of sodium metnylate (prepared from this 6.44 g (0.28 atg) of sodium in 80 ml of methanol) and then heated to. 50 ° for 1/2 h.

Again cooled to 0 ° and poured dropwise 25.64 g (0.42 mole) of nitrc-iaethane. It is left to stand for 12 hours at room temperature and heated for 5 hours at 50 °. Leave to stand for one night. The methanol is evaporated to dryness and the residue is taken up between chloroform and water, stirred, decanted and reextracted 2 times the aqueous phase with chloroform. The chloroform extracts are washed with water and then dried over magnesium sulphate, filtered and dried dry. A slightly gummy yellow solid is obtained which is reorend 'with isopropyl ether, stirred, cooled and drained. These yellow crystals are obtained.

Recrystallized from isopropyl ether with a hot isopropyl alcohol egg, cooled and wrung a yellow solid.

FT = 115.5-116.5 ° C.

4 4. Cyclcpropyj. “1 a: i: b: cr: ethyj -2 pyrrolidine. !

In a hycrcgenerating apparatus, 18.5 g (0.11 r.ole) of the above pyrrolicine, methanol and nickel are placed, this Raney is then hydrogenated under ordinary pressure at room temperature. Vite 9,5 1 of hydrogen is fixed enough then the absorption stops. The mixture is left to stir for 1 hour and then the catalyst is filtered, rinsed with methanol several times and the filtrates are evaporated to dryness. A 1 inarron nile is collected which is distilled under reduced pressure. A colorless oil is collected. i nn21 = 1.4825 nb13 "'___________________________1 5 .. Np ^ (cycloprouvl-1 ryrrolidinyl-2) -nernyll .tarneny-2 sulrarpyl-S oenzamice. ^ i

In a 250 μl Erlenmeyer flask, 6.03 g (0.043 m) is placed with the preceding pyrrolidine with 5.95 g (0.043 mole) of this potassium carbonate in acetone (^ 120 ml). Cooled to between 0 and 5 ° and poured therein dropwise a solution of 10.73 g (0.043 parts) of 2-methoxy-5-sulfamoyl-5 benzoic acid chloride in about 100 ml of acetone. Then allowed to return to room temperature and stirred 2 h at 20 °. The aestene is evaporated to dryness (T <.30), then the solid residue is taken up between water and ether, the mixture is stirred and wrung out, and the residue is wrung out, washed thoroughly with water and with water! -rr. A white-beige solid is obtained.

It is recrystallized from a methanol / ethanol mixture (50/50), hot filtering a slight haze then allowed to recrystallize, drained, washed and dried the white solid.

FT = 172-172.5eC (dec).

6. Methane sulfonate.

In a little methanol 5.3 g (0.015 mole) of the preceding base are suspended and 1.44 g (0.015 mole) of methanesulfonic acid are added thereto. Everything dissolves. The solvent is evaporated to dryness and the residual gum is taken up in boiling acetone, which rsiu crystallizes a fine white solid which is stirred, cooled and wrung.

It is recrystallized from ethanol and a powder is obtained; i

white. I

t π _ ·, ~> o i n c ri t -__ \) L: ^ uPl! X.a h ~ (eyclchc-xvi-1 pyrrolidinyl-2) riÄthyl "] methcxy ~ 2 sulf an.ovi-3 and its methane" suifouate.

1. Cyclohexyl-1 oxo-2 pyrrolidine.

86.1 g (1 mole) of ^ -buty-rolactone, 105 g (1.058 mole) d-cyclohexvlamine and a few hydroquinone crystals are added to a 500 ml bomb. |

A stream of nitrogen is passed, then the bomb is closed and heated to 330 ° C for 10 hours. We received '~' 51ie ^ "'le eue on cistil- ii T. o —.— --07b a-9 r> SLjri tmx——” rii - ____________________. __________ _____--— · - * -XXÏ ^ XX see ur D XTutiA-Cj j% 2. Cyclohexyl-1 nitrcméthylène-2 pyrrolidine.

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66.9 g (0.4 mole) of the above lactam and 50.44 g (0.4 mole) of methyl sulfate are introduced into a 500 ml Erlenmever.

It is heated for 2 hours at 60 ° C. The mixture is cooled with an ice bath and the prepared sodium methoxide is added dropwise; from 9.2 g (0.4 mole) this ha in 150 ml this methanol. We ; 1 hour at room temperature cooked while cooling in ajou! -: “- -! ~; drip 36.6 g (0.5 mole) of nitremethane. At the end of this i: a few minutes a yellow solid precipitated, we continue to agitate! . tion for 2 hours.

. Water is added, then the yellow solid is filtered. We wash it; water then ether, dissolve in chloroform, dry on! , magnesium sulfate and evaporates. A solid is collected which is recrystallized from an iscpropyl ether / ethyl acetate mixture.

r i F - 149-149.5 ° C.

3. Cyclohexyl-1 anincnethyl-2 pyrrolidine.

Hydrogenate at room temperature and at atmospheric pressure, 21 g (0.1 mole) of the above compound with Raney nickel as catalyst, in methanol. When the theoretical amount of hycroçene has been absorbed, the catalyst is filtered. and evaporates the alcoholic solution.

The residual oil is distilled.

β 4. N- (cyclohoxyl - 1 pyrrο 1 i d5.n y 1 ~ 2) .-. Éhhyl rethoxv ~ 2 syilf arr.oy 1-JSi benzanlue.

9 g (0.0493 walnut) of amine and 12.2 g (0.047 mol) of ethyl ester of 2-methyl-5-sulfamoyl-5 benzoic acid and 50 ml of water are introduced into an Erlenmeyer flask.

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The mixture is heated at reflux for 5 hours.

I Cooled and triturated between water and ether, filtered the solid; White. It is dissolved in chloroform, dried over magnesium sulfate and evaporated. A solid is collected which is recrystallized and read from isoorooanol.

! i F = 194-194.5 ° C.

5. Methanesulfonate.

11.1 g (0.028 mole) of base in methanol and 2.69 g (0.028 mole) of methanesulfonic acid in methanol are introduced into a flask.

The residual oil is evaporated to dryness and triturated in isopropyl alcohol.

: Salt crystallizes. It is filtered and recrystallized from an ethyl alcohol / methyl alcohol mixture.

Mp 196-197 ° C.

] EXAMPLE 3 N - [(cyclopropyl-Γ pyrrolidinyl-2) methylJmethcxy-2 nethylthio-5 benzamide and its hydrochloride.

n = 1, m = O, R3 = CH3J

6.6 g (0.047 mole) of this N- | _ (cy-clopropyl-1-pyrrolidinyl-2) methÿl amine and 6, are placed in a lapped Erlenmeyer flask, cooled in an ice bath and placed under a stream of nitrogen. 5 g (0.047 mole) ootassiuin carbonate in 100 ml of acetone. The mixture is cooled to 1-2 ° C., and a solution of 10.2 μl (0.047 mol) of 2-methyl 2-ethyl 1-thio-5 benzoyl chloride is poured into it dropwise. acetone. It is left for 2 hours at room temperature, on. evaporates the solvent s ___ sicczhtfL · et_.cn. -r eor e n d — 1- e — r é s-i du - d an s- ce - I.

i T f '' ”* ........." “- 1 1 C-3U and had chloroform. Cn: 'r-ure la r ha r. <3 organic, only in 1: .VC with water and know on sulfate ce; ce; cs: .a. stud filtration: i "t. and distillation, the viscous residue is husbands because of ether, - treats because of carbon black and filtered on Hvfio -supercel, which allows it to eliminate a resinous gum.

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i i J After the solvent has evaporated, there remains a pale yellow oil which

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. jjeluted on a dry alumina column (1700c, ÛSC) using chic- ‘i 1; ; shape. Far fractionation, we collect a pale yellow oil ccn-: * j ning a single spot in chromatography (Silica-acetone and Alumina-: j, chloroform) and decomposing if it tries to distill it.

,; i • - i: g Oil oil is transformed into hydrochloride by reaction of the base. > i! “With hydrochloric acid in the ether. [Ccyclopropyl-1 pyrrolidinyi-2) methyl "hydrochloride | 2-methoxy-5-methylthio-5-benzamide melts at 155-166 ° C.

; !; i I i:; ! . EXAMPLE 4 N- £ (cvclcpentyl-1 pvrrolidinyl-2) methvljêthylthio-5 i j i iïîétoxox-2 benzamide and its chlorhvcrats.

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j! ; | [n = 37 ° 'R3 = C2a5J

; ; il 1 In a vial of Erienneyer, cooled in a bath this ice and pla! ceded under a stream of nitrogen, 5.84 g (0.0346 mole) of N- £ (cyclcpentyl-1 pyrrol.idinyl-2) Dethyl ethyl amine and 4.8 g (0.0346 mol; potassium ice carbonate) are introduced 8g (0.0346 mol) of ethylthio-5-methyl-2-benzoyl chloride in acetone is added dropwise to acetone, and the flask is allowed to return to the temperature; j ratura ambient and stirred for 2 hours.

i ^ jdAfter evaporation in solvent, the residue is taken up because of water and • | , | da -'euher / the organic phase is extracted in an acid medium; then j j jon. alkalized and extracted with ether. After drying over sulphate of: | ; imagnesium, 1 ether is evaporated and an oil is collected; I | purifies by passing over a column of silica with elution at 1 · acetone.

1 î! I; | rar urartement ce this base with acid chlcrhvdricue i | j, ___ r i; in 1 erher, the hydrochloride is prepared es h— \ (cvclccentvl — 1 tVi · j polrcinyl-2) meuhylj éthylthio-5 méthcxy-2 bsr.zrrnce which melts at i i i

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r ..... Ί i · ....... ................. '' 1 1 d; 'F: "r'V.? ÎÆ 5 h · Γί.-vc-r -y rrolidinyl - 2) m.étbyl jm.éthoxy- · 2; i | ........- LJ ί I ji é thy 1 - s υ 1 f ο π y 1 - 5 benzanide and g on hydrochloride.; il ri;:; η- 1, m ~ 2, R ^ t = CH3j

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1 In an Erlenmeyer flask, 5.33 g (0.038 mole) of p- ^ (cyclopropyl-i pyrrolidinyl-2) methylj amine are dissolved in 100 ml of anhycra acetone and 5.25 g (0.038 mole) of this carbonate are added. this potassium. This suspension is cooled to approximately 2 ° and there is added dropwise a solution of 9.45 g (0.038 mole) of 2-methylphenyl 5-benzcyl chloride in 200 ml of acetone, while stirring. Then remove the ice bath and leave the nslance I IJ ...... „

J isous aciraticnra the temperature amberants Cendant 2 hours. We evaporate i 1 I

the solvent to dry and the residue is taken up with this water and chloroform. The organic phase is washed. with water, then with salt water and is finally dried over magnesium sulfate.

Il / j i i [After filtration and evaporation of the solvent, an oil remains | ! brown which, scraped under acetate of athyle, is transformed into solid i j i pink which one wrings, washes and dries.

_ F = 140-141 ° C.

! After recrystallization from isopropyl alcohol, the isopropyl-1-pyrrolidinyl-2-methoxy-2-methoxy-methylsu ironyl-b benzs.- mide is a white solid melting at 140.5-141, 5 ° C.

It t; I; .The hydrochloride, prepared because reaction of the above base with! with hydrochloric acid in acetone, methanol and ethanol, melts I · a. 165-166 ° C.

! !

In table r, the ccmcosés (i) prepared from. i ’- - - similarly and a compound (No. 1) which exemolifies the radicals of the main patent.

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The enantiomers of the compounds (I) are obtained, either by splitting or by stereospecific synthesis.

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| ! ! Cor .pose n ° n R Point ca fusion ('C) ij? _________._ __________________________________ ____________________________________________________________________, _______________________________________ 1 (ex. 1) 1 SO „KH„ Me thanesulfonate 173-180 base 172-172,5 - v Methanesuifonate 196- 7 2 {eX · 2) 4 S02llh2 base 194-194,5 i ~~ | 3 2 S02NH2 Hase 171-172

Chlcrhvdrste 237.5-238.5 i *! ! ______________ „_______________ i j i | j 4 (ex. 3) 1 CH ^ S Hydrochloride 165-166 * j S___________________. j 5 2 CH3S Hydrochloride 117.5- 118

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; r ““ 6 3 CH3S Hydrochloride 130.5-131.5 d _____________________ ______________________________ η 4 CH3S Base Eb0.05 = 250 ’Hydrochloride 127.5-128.5; 8 (£ X> 4) 3 C ^ H5S Hydrochloride 125.5-127.5 i 9 4 C2H5S Hydrochloride 95-96 10 (ex. 5) 1 SO CS3 Base 140.5-141.5

Hydrochloride 155-166 1η. 2 S02.CH3 Base 136.5-137.5

Hydrochloride 177-178 12 3 S02CH3 hydrochloride 157-158, 13 4 S02CH3 hydrochloride 140-141 14 1 C? 3 hydrochloride 151-151.5 I 15 2 CP3 hydrochloride 140-140.5 i Π "....... .........'......... '..........!' The compounds of this invention were so -;: -. 5.s to these phar- · I -Ρ.Ί trials will go colchic in the area gu central nervous system .: i

Acute toxicity was assessed in these male mice, P miss; CDl, with an average weight of 20 g, i.p. · The neuroleptic activity was determined by the antaconisrr.e; vis-à-vis the "climbing" induced by apemorphine: 1 in mice according to the protocol of Gouret C., J. Pharmacol. (Paris)! i! 4., 341 (1973).

I I! i 1! The LD 50 range from 60 to 10C0inc / lc because i.o.

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! i * I | The DA 50 in the straightening test varies from 0.3 to 1 mg / kg! | i.p. ; it is 0.5 mg / kg / 0.6 mg / kg or 0.3 mg / kg! | 'for, respectively, compounds 4, 10 and 14.

| jl I I The compounds of the invention can be used for the treatment of various psychosomatic conditions and this psychological disorder (depressive states and psychoses).

The invention includes all pharmaceutical compositions comprising: closing the compounds (I) and their salts as active principles, in combination with any excipients aporooriês to their administration "i" "; j by oral, endorectal or parenteral route;;"; All the pharmaceutical forms suitable for the oral, endorectal or Darenterale routes are suitable. The daily dosage can range from 5 to 300 mg.

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t:: - i! i j! :: !! 1 'l! »L * s:! ! :; M <. i î i; not a word ; ; Γ • i.

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Claims (2)

1 CjC i ^ i with an oyrrolidine, in the form of a racemate or this enantiomer, of -! j î i formula (III)! i: | φ; * J * I «ni: i r: ï:! i! I | kN> -c, J2 ": ™ 2 _: j! cüv (xxI)! X \! (CH2Jn- ch2 i i the radicals having the meanings given in the claim.] i J * 1 i 5. Medicine containing as active principle at least one of these! i I; ; c starched specified in one cruelconcue these rmemicstions 1 and 2. it '·' J *! i i i I h \ \ \ 1 il i 1 vv'V'Anw! ^ V Vv i i Ni! ! I i i J I i I I! I, - i l i 1 t i t