LU80974A1 - BENZYLIDENIC DERIVATIVES - Google Patents

Description

J

*

The prison of the invention relates to bonzyliaen drifts, berr i J

I!: Preparation and their application in therapy.

* »J In his Luxembourgish patent No 75 514. the Applicant aeorit the · compounds corresponding to the formula - - - ° H ’* -0-

c = N-C H- “COR

! x / | n 2n • in which X ^ z and X ^, which are identical or different, each represent, independently of one another, a hydrogen or halogen atom, in particular chlorine -or fluorine , or a methyl radical! ! or methoxyl, n represents an integer at least equal to 1 and at most equal to 10 and, R represents a hydroxyl radical, OM, NH2, NH (CK2) COOH, -NH (CH2) 2 ~ COOM; (I "having an alkali metal atom, in particular sodium), NK (CH2) ^ ~ COOC ^ Hg, NH - cycloalkyle, NH - phenyle, NH - benzyle (the radical benzy-le being able to carry a substituent chosen among the halogen atoms and the trifluoromethyl radical) NH - alkyl, N - (alkyl) 2, N - (alkyl) - (benzyl), linear or branched alkyl radicals having from 1 to 4 ato-

K

"mes ce carbon, cycloalkyl radicals having 3 to 6 carbon atoms, with the exception of the compound for which - X ^ - H, X2 = 5-Cl, n - 1 and R = OH.

The compounds of the present application correspond to formula (I)

... i ^ J

t! i / v / OR1 x2 / Cj - N - Cn H2n - C ° -R (I) 0 ~ ^ 3 '\ in which · ·

* X X X and X

il7 2 '3 4 each represents, independently of one of the- I-! tre, a hydrogen or halogen atom, a radical CH ,, CH, 0,

[S - J

j; J * no2, cf3, c (ch3] l3 or ch3co nh, n represents an integer ranging from 1 to 10, R is an OH, OM (M = alkali metal), NH2, NH-cycloalkyl, NH-phenyl radical, NH-benzyl, NH-alkyl, N- (alkyl) 2, N- (alkyl) - J (benzyl), and i.'i R 'represents a hydrogen atom or an alkyl, jLès alkyl having from 1 to 4 carbon atoms, ~. * ^ J with the exception of the compounds in which R '= H when Χ ^, Χ2 and ^ 3 are each independently of each other H, Hal, CH3, CH30 and X4 = 3 and of the compound for which R,; = H, X3 = X3 = X4 = H, X2 = Cl-5, n = 1 and R ^ OH.

"I A group of preferred compounds is constituted by those in · * · which R = OH, OM or NH2 when n is 3.

According to the invention, the compounds are prepared by reaction between a ketone of formula (II)

OH

X2X C = O (II) À “(and a compound of formula (III) NH- —CH- - CO-R (III) in the form 2 n 2. n - - * me of base or hydrochloride, and if if desired, then alkylate the compounds (I) obtained in which R1 = H.

• UJ3 i H ...........

'The reaction is carried out in an alcoholic solvent such as J i:' methanol or ethanol, at a temperature ranging from 10 "C to temoé, i | · * I boiling nature of the solvent, in the presence of 'an alkali metal or' li! HD 'of an alkali metal alcoholato.

S II, ·

A variant for the preparation of the compounds (I) in which R * = H and R is NH2 consists in reacting a hydroxybenzephenene of formula (II) with a compound I ^ N (CH2) n ^ N, ^ Cl (intermediate obtained during the preparation of the compound (illj this formula 'H2N- (CH ^) ^ -CC-Xrb * - then to carry out a solvolysis of the nitrile (IV) obtained by condensatior * according to the following reaction scheme: _i ™ [| + H2N- ( CH2) n-CN, HCl -> '' j 'C = °

Ij-Q i.

X4_.

OH - let X OH

î ^ -s_, ....

(ch2) nc "Jx ^ Vs- (ch,) -cc-Y:; - i '2} let 2 | -2 n 2 b —ί— |) (IV) H 0X1 -> - * HC1 S32 3 Ky * ~ \ Λ4 X.

4

The starting compounds (III) and their preparation are already described in the literature.

i i !.

î! S '_. ·! ; The starting ketones (II) - ml prepared - ’! i - l - - k, jl) or from ccmpQv.tg CH3

XlÎ>:. | ^ t ·· - by reaction with a compound; / ~ A_co Cl ‘, ^ then demethylate the intermediate obtained with aluminum chloride or boron trichloride,

2) either from the compounds Λ O-CH

: <r "ôC

. X2 .V which is reacted with a compound I '· X4> · and the intermediate is hydrolyzed to obtain a compound och3 I! i Y ^ \

he

I J

5! !! ! ! raw one demethylated one car-rose (II) using aluminum chloride; nium or boron trichloride.

! .

The ketones (II) are new with the exception of those for which X ^, X3 are each independently of each other H, -1 Hai, CH ^, CH ^ O, C (CH ^) ^ when X ^ = H. ... /

The new ketones (II) are part of the invention.

The preparation of ketones (II) is illustrated in the examples of preparation of the final compounds (I).

v

The following examples illustrate the invention.

The IR and NMR analyzes and spectra confirm the structure of the * compounds.

In the present application are also exemplified several compounds which correspond to the general formula of the preceding patent (compounds 24 to. 47).

Example 1 · N - 2-phenyl hydroxy-5-trifluoromethyl benzylide-nyl J-4-amino sodium butyrate.

CF3-5 X2 = X3 = X4 = H R '= H R = ONa n = 3 ^ - 1. 2-Hydroxy-5-trifluoromethyl-diphenyl-methanone.

l.'l .. 1.68 g of magnesium (0.0691 mol), 25 ml of anhydrous ether and 1 ml are added to a 250 ml three-necked flask, fitted with an ascending condenser and / with a dropping funnel. Iodine crystal, brought to reflux and introduced about 10% of a solution of 19.52 g of bromobenzene (0.1243 mole) in 30 ml of anhydrous ether. When the reaction is well started, the remainder is introduced. so as to maintain the reflux. After the introduction, the mixture is brought to reflux until disappearance; total magnesium. Then, it is introduced so as to maintain 3 r !: reflux 9.5 g ( 0.0472 jr.ole) of 2-methoxy-5-trifluorcethyl-5-benzenzi-

L ..6 J

: If'- ’I f

Ml! ji trile in 80 ml of anhydrous ether and then heat for 4 hours! ΐ i reflux temperature. Then hydrolyzed cold and under nitrogen H with 40 ml of 2N HCl. A precipitate is formed which is filtered! wash with ether and dry. It is j hydrochloride! j j imine '! j ^^ ° CH3! I> SvNH; HC1

i r? 3 JC

Ml (O) 'j This hydrochloride is taken up in 50 ml of toluene and 50 ml of H2SO4 {at. 25% and takes 8 hours at reflux temperature. The organic phase is decanted, washed several times with water, dried! on> igS04, filters and evaporates the toluene. We get methoxy-2! i 5-trifluoromethyl diphenyl-methanone · '. Eb0, Q7 = 170 ° C

1.2 2.8 g (1 / 1G0 mole) of msthoxy.-2 trifluoromethyl-5 diphenyl-methanone, 100 ml of I are introduced into a 250 ml reaction flask.

methylene chloride and cooled to -60 ° C. 10 g of boron trichloride are then introduced and the mixture is then stirred for 1 hour at room temperature. Pour into 1.5 1 of ice water, add 250 ml of methylene chloride, stir, decant the organic phase, wash it twice with water, dry over 24gSO., Filter and eva-! r * *! pore the solvent.

| Clear yellow crystals are obtained which are recrystallized from t t

| petroleum ether with vegetable charcoal treatment. We get I 2-hydroxy-trifluorcmethvl-5 diphenyl-methanone which melts at 84-85c‘C

2. N-jj> {- phenyl hydroxy-2-trifluoromethyl-5 benzylidenylJ-4-aminc sodium butyrate.

1.15 g of 4% amino-butyric acid 97%, 300 ml of methanol and 0.62 g of sodium methylate are introduced into a 1-liter flask and the gold stirred for 2 to 3 min. 2.8 g of 2-hydroxy-5-trifluoromethyl-diohenylmethanone and 300 ml of ethanol are then introduced. We evaporate at the ί * | atmospheric pressure (100 ° C). Finally, we evaporate the entire <_ / •] r * '............. r ’* ...........

of cold water. Acidified to pH ~ 4 with citric acid, extract | · With chloroform, dry the chloroform phase on MgSO ^, filter! and evaporates the chloroform. An oil is obtained which crystallizes from petroleum ether. It is filtered, drained, washed with petroleum ether, filtered and recrystallized from ether with treatment with vegetable charcoal. The acid is obtained which melts at 154-155 ° C.

i i 2.5 g of acid are dissolved in 150 ml of methanol and 0.38 g i ί of sodium methylate is added. Evaporated to dryness and the sodium salt is obtained which is dried for 1 hour at 80 ° C. in a desiccator.

P = 216-217 ° C.

3 '·' Example 2 N-jX - (2-dichloro ', 4' phenyl) 5-chloro-2-hydroxy-benzylidenylJamino-4 butyramide.

· '[X = Cl-5 X2 = H X3 = Cl-2' X4 = Cl-4 'R = NH2 R' = H n = 3j - ✓ 1. Hydroxy-2 trichloro-2 ', 4', 5 diphenylmethanone .

1.1 To an agitated solution brought to the reflux temperature of 25.7 g of p-chlorophenol and 30.3 g of triethylamine in 1.2 1 of ether, an ethereal solution of 2-dichloro chloride is added slowly, 4 benzoyl. Then we heat to the temperature of

NOT

reflux, stirring for 3 hours and leaving the products in contact overnight. The Et3N, HCl precipitate is filtered and washed with ether. The organic phase is washed with water, bicarbonate water and water. It is dried over MgSO 4, filtered and concentrated to about 3/4. 2,4-dichloro benzoate p-chlorophenyl precipitates.

. Cool, filter, spin dry and dry in a heated desiccator at 6 ° C.

Mp 124-125 ° C.

1.2 35.5 g of the above ester are heated until fusion. Stir and add 35.5 g of AlCl 4. Then heated to 190 ° and stirred for 15 min at this temperature. After cooling, the residue is ground and hydrolysis. It is poured with stirring into 800 g of a mixture of water + ice + 100 ml of concentrated hydrochloric acid.

Then extracted with chloroform, dried over MgSO 4, filtered and evaporated to dryness. Recrystallized from petroleum ether, drained and π ^ n T * \ a ".J m. J_ >>. · U T ^ ___- J .. J X. JC _. _ Ä Λ / “A T Ο Λ ί j! Ιί ....... T; ',! ·. 2. Η · - * ^ - (dichloxo-2 *, 4 * phenyl) chloro-5 hydroxy ~ 2 benzylidenylj- j j u · *.

| ·; ~ amino - 4 butyramide.

. i * I * • Evaporated to dryness, a solution of 12.3 g of the ketone obtained in i 1 / 5.3 g of ^ -amino-butyramide in the form of hydrochloride and 2.4 ç of MeONa in 500 ml of methanol.

Ansuite we evaporate 350 ml of alcohol 4 times in a row and we finish | the last 2 evaporations under reduced pressure. The residue is! ; dissolved in CHCl-j. Wash with water, dry over MgSO 4, filter and | evaporates to dryness. The residue crystallizes from ether. We filter i j <. | on sintered and wrung. We then treat with charcoal in methane! j I filter and evaporate at. dry. We recrystallize from alcohol, filter

! j I

<= -: j wash with ether, spin and dry in a heated desiccator.

'| ‘F = 141-142 ° C.

Example 3 Acid - (4-chloro-phenyl) 5-tert-butyl hydroxy-benzylidenylJ - 4-amino butyric acid.

fx. = C (CHj_-5 = H X = Cl-41 X. = H n = 3 'u 1 3 3 2 3 4 R * = H R = oa] 1. Tertiobutyl - 5 chloro - 4' hydroxy - 2 diphenyl-methanone.

* i 1.1 At 120 g. of p.tertiobutyl-anisole in 1 lb 0 ml. of tetra-. ’. chloroethane, added with stirring 128 g. of chloro-benzoyl chloride and 0.25 g of freshly ground and ground ZnCl 4. Then, the mixture is heated to 140 ° C., with stirring, for 40 h.

Then the solvent is evaporated and distilled under pressure.

$ reduced. The distillate crystallizes in petroc ether. the. The t-butyl-5-chloro-41-methoxy-2-phenphenyl-methanone is recrystallized from petroleum ether with treatment with vegetable charcoal.

F 46 - 47 ° C

'i. * '* \.-¾ .1.2 To 88 g of the compound obtained above in 150 ml of benzene is added, with stirring, 46.3 g of Aie 1 ^ and the mixture is heated at 70 °, for 12 hours. Then, after cooling, the mixture is hydrolyzed by pouring onto ice and concentrated hydrochloric acid and stirring. Decanted, washed with water, dried over Mgso./ filter and evaporated to dryness. The residue crystallizes * "in petroleum ether. Filtered on sintered, drained and recrystallized from inethanol with treatment with vegetable charcoal. It is dried in a desiccator.

- ’F 64 - 65 ° C

2. N - (4 'chloro-phenyl) tert-butyl-5-hydroxy-2-benzylidenyl-4-amino-butyric acid.

A 5.4 g solution is evaporated to dryness. 4-amino butyric acid, 3g of MeoNa and 15.4g. ketone obtained previously in 500 ml of inethanol and 300 ml of alcohol. 600 ml of alcohol are added and evaporated to dryness, finishing under reduced pressure. This operation is repeated twice. The residue is dissolved in acidified water to pH 4 with citric acid.

{Extracted with chloroform, dried over MgSO., Filtered and evaporated. -J · to dryness. The precipitate obtained is entrained on a frit with petroleum ether. We recrystallize from ethyl acetate! with treatment with vegetable charcoal. It is dried in a heated desiccator.

I - F 140 - 141 ° C

i * · 1 ί. ! · I *.

"·. Example 4 N - (4-chloro-phenyl) 5-fluoro-2-methoxy-benzylidenyl-4-amino-butyramide.

£ χχ = F-5 X3 = Cl-4 'X2 = X4 = H R = NH2 R' = CH3

n =? J

A solution of 3.4 g of N-J ^ - (4-chloro-phenyl) fluoro-5-hydroxy-2-benzylidenylJ-amino-4-butyramide and of 0.55 g of sodium methylate in 150 ml of methanol is evaporated to dryness. Then dry with a drying dryer at 120 °.

After cooling the residue is dissolved in 100 ml this DMSO

Π! ......... 7 ..............— '..................:' .. ...................'.............: ........ ~; Ί Γ Shake and introduce, drop by drop, into the stirred solution,

; i i

• I J

. i! i 3 g of methyl chloride in 25 ml of DMSO. Then we stir at j j; ! dd room temperature for 30 min.

i j Evaporate to dryness under reduced pressure, dissolve the residue in j i · "| 200 ml of chloroform, wash with water, dry and evaporate to dryness.

The residue is entrained on a frit with ether. We recrystallize.

j occurs in alcohol, washes with acetone and ether,! wring it out and dry it in a heated desiccator.

F = 154 / 5-155 / 50C ... _}> j The following table shows the compounds prepared at i j! j, title of examples-illustrating the formula (I).

". * --s i i.

I \ c * e t-

. The>. J

.................. “................_.............. ..................................

TABLE I

Compound X3 X ^ n R R1 F (° C) 1 ’N02 ~ 5 H Cl-A * H 3 OH H 240 (dec) 2. : H3CO NH-5 H HH 3 KH2 H 240 (dec) - '3 CF3-5 Ή- VCF3-4' H 3 * ONa h 238 (dec) 4. CF3-5 H cf3 ~ 3 'h 3 0Na H 218 (dec) 5-' cf3-5 h 'cf3 “4' H 3 NH2 H 119.6 6. CF3-5 H cf3 ~ 3 'H 3 NH2 H 98 , 7, 7 'ÇF -, - 5 H F-4' H 3 OH H 173.5 •! j ~ · "'ONa‘ H> 250:: "j 8 n02-5 H Cl-4' h 3 NH2 H 172.5; ! I 9 CF3'5 h F-4 'H 3 NH_ H 120.6! 1 ° 2! ! 10 - F-5 H N02-47 h 3 OH H 169-70 [i ONa H 180 (dec)! ’11 - F“ 5 H NO „-4 'H 3 NH0 H 190-1 1 d 2 2 I I 12 CF3 ~ 3 H h h 3 OH H 154-5! J, 0 ONa H 216 (dec) I J 13 cf3 5 H H H 3 H H 2 H 93-94! ! 24 CÎCH3) 3 “5 h c1“ 4 / H 3 OH H 140-1 I ji - 15 C (CH3) 3-5 H Cl-4 'H -3 NH2 H 121-2 J 16 N02-5 HH H 3 OH H 177-8 I ONa H 227 (dec) 17 NO -5 HH H 3 NHL H 185-6 I, 2 I 'j 18 C ^ CH3 ^ 3 ~ 5 HHH 3 NH2 H 135-6! ; 19 · C (CH3 ^ 3 “5 h H h 3 OH h 131-2: 20 * C1-5 H Cl-4 'Cl-2/3 NH 2 H 141-2 j 21 Cl-5 H Cl-4' C1-2V 3 CH H 172-4 I ONa H 245 (dec) | 22 F “5 H ΟΓ3 ~ 4 'K 3 \ NH2 H 151-2 -;' 23 F ~ 5 H Cl-4” H. -X .KK2 CH3 1S5- • 24 Cl-5 H Br-41 H 3 ~ NH? 169-170 25 Br-5 H Cl-4 'H 3 NK2 H 15 6-157 26 Br-5' HHH 3 NH2 H 134- 135 27 Br-5 H Br-4 'H 3 ΝΗ? H 164.5--166 ^ 28 F-5 H Cl-21 H 3 CH H 85.5-87

K I

° H

! xi-ÇjT

x / ^^ c = 0. (II) 2 0- ·.

x „4! jwith a compound of formula (IV) NH —C H0 -COR 2 n 2n! in the form of a base or of hydrochloride, and, if desired, the compounds (I) obtained in'lesquels R ”- are then alkylated - H for - '- prepare the compounds (I) in which R' = alkyl, the radicals having the meanings given in claim! 15. Medicine characterized in that it contains a compound such as! t ·! ! ^ specified in any one of claims 1 to 3; 6. Ketones needed as intermediates for the preparation of! compounds of formula (IJ "corresponding to the formula. (II)

OH

jfY

Xr10Ac - o un 4 Γ •: | . in which X4 X ^, X2, X ^ and X4 each independently of one another! a hydrogen or halogen atom, a radical CH, CH ^ O, NO2, CF3, c (ch3) 3 or ch3co NH, with the exception of the compounds for which X ^, X, X3 are each independently of each other H, Hal, CK3, CH ^ O, when x4 - \ ·, l '' \ f 1 - v-