Process of obtaining new amilides.

The present invention concerns novel Nacylanilinas, processes for their preparation as well as the pharmaceutical compositions containing as active principle.

The present invention specifically concerns hat rrocédé aces preparation of n-acylanilines of general formula I:

wherein n is an integer ranging from 0 to 3,

- B represents hydrogen or a lower alkyl radical,

- represents a lower alkyl radical, a radical aleényle lower, lower phenylalkyl radical or a lower cycloalkyl radical,

- EG is electrophilic character to a radical selected from the group consisting of cyano, a trifluoromethyl and lower alcanoyls,

I ^ - represents hydrogen or a lower alkyl radical,

I ^ - represents hydrogen or a lower alkyl radical,

- X and Y, the same or different from each other, each represents a lower alkyl radical or together form an alkylene chain optionally interrupted by one or two heteroatoms, having from 2 to 6 links.

or X and e ^ together form an alkylene chain having from 2 to 4 carbon atoms,

or X ^ b-ATs together form an alkylene chain having from 2 to 4 carbon atoms, optionally interrupted by one or two additional heteroatoms,

or salts of the compounds of the formula I with an inorganic or organic acid, preferably an acid therapeutically is compatible, characterized in that the condensed orthoalcoxy an aniline of general formula II:

sign antibodies

with

the m₂ the II

1

in laouelle substituents H and b " have the

1, 2

ficàtions. given earlier,

an amino carboxylic eoyl ai of the general formula III:

X

VBE1

/

- CH-CH-HUMAN GH - / -) - COOE

B-B.

THE III

4, 3

wherein substituents B, b. the j ^ ^ Β, the X, Y and n have the meanings given earlier,

or a functional derivative thereof,

to obtain an anilide of the formula I which can be, if desired, salifying by adding a mineral or organic acid or split when the chain amino-carbonaceous comprised at least one asymmetric carbon.

The compounds of general formula I have at least one basic nitrogen atom and it is possible to salify the by adding an acid such as for example, hydrochloric acid, bromhydriqus acid, sulfuric acid, nitric acid or phosphoric acid; formic acid, butyric acid, benzoic acid, nicotinic acid, acid Tantric, the glucose 1-phosphoric acid, embonic acid, isethionic acid or ethanesulfonic acid suifonic.

When the chain amino-carbonaceous has at least one asymmetric carbon, it is possible to perform the fanning of the compound of general formula I into its optical isomers, in particular by salt formation with an optically active acid such as e.g., d or 1-tartaric acid, d or 1 a-camphoric, acid ïïjH-dimethyl d or 1 a-tartramic or a bis optically active phosphoric naphthyl.

It is also possible to use as starting raw material an amino alkyl carboxylic already split. The anilide prepared from such a raw material is already in optically active form. The amino alkyl carboxylic acid of general formula III may double by salification with a base ' optically active or by esterification by starting motor. optically active alcohol and then saponifying.

the method of the invention can further be defined

by the following embodiments, currently preferred:

- the functional derivative of the carboxylic alkyl amino acid of general formula III is an acid halide such as the acid chloride, the anhydride, a mixed anhydride or an alkyl ester, or aryl of Arylalkyl as for example, a methyl ester, benzyl, benzyl or phenyl paTanitroparanitro.

- the mixed anhydride is preferably an anhydride formed "in-situ" with a dehydrating reagent such as for example a dialcoylcarhodi-imide resin, a dicyclopentadiene react with carbodiimide, the ethoxy acetylene, a cyanogen halide or carbonyl diimidazoie.

- the condensation is performed in the presence of a proton acceptor such as for example, the mth mineral or organic base such as a trialkoylamine, a base pyridine, dimethyl aniline derivatives, or an excess of the alkoxy aniline of general formula II.

- the condensation is carried out in m inert polar or non-polar solvent such as for example, a halocarbon, aliphatic or cyclic ether, an alkyl nitrite, an aromatic hydrocarbon such as toluene or xylene, a tertiary alcohol, as for example, the tsrbutanol or tertiary amyl alcohol, a polar aprotic solvent such as dimethyl formamide or hexamethyl phosphorotriamide.

The invention also concerns a method for production of compounds of formula I wherein generated X and Y each represents a lower alkyl radical or together form an alkylene chain which may be interrupted by one or two hetero atoms other than the nitrogen atom to which it is bonded and having from 2 to 6 links,

characterized in that the condensed at an ortho alkoxy aniline of general formula II:

/

the m₂

the II

G K_T-

wherein ^ and e are as defined above, with an acid carboxylic alkyl - substituted of general formula IV:

the P

^H 4

Z

VI

wherein H, set top and s ^ are defined as above,

and Z is a substituent which can easily cleaved étrs, selected from the group consisting of a radical-sulfonyloxy, a radical alkyl lower alkylsulfonyloxy, halogen or trialcoyl silyloxy groups ;■

or a functional derivative thereof, to form an alkoxy aniline of general formula V:

wherein the definition of the substituents of b, environmental innovation to Hg " bypass th ^ _n the JT.-, Z-Ù3tû2ur.=unchanged,

condenses it with an amine derivative of general formula VI:

VBE1 THEREIN HN-VI.

wherein X and Y each represents a lower alkyl radical or together form a chain aleoylene optionally interrupted by one or two the instructions téro ATs bearing designs having from 2 to 6 and links,

wherein substituents B, b. ^ GB, bypass,®4>^{the n} are as defined above,

and X and Y have the specific meanings provided above, which can be, if desired, by adding a Large salifisr mineral or organic or doubling by salification by an optically active acid.

In a preferred manner, the substituent Z in the compounds of general formula - ^ IV is a halogen atom such as chlorine or the presence luor or in the absence of an alkali metal iodide. It may also ître sulphonyloxy methane radical, a radical pp.tolu ene toluenesulfonyloxy, methanesulfonyloxy or naphthyl.

The reaction between the compound of general formula Tg

1 and¹orthoalcoxyaniline of general formula II is carried out in an inert solvent such as for example, a chloroaleane, 1 * acetonitrile, nitro methane, an aliphatic ketone such as methyl=sthyl ketone or methyl isobutyl ketone or acetone, a linear or cyclic ether such as tetrahydrofuran or isopropyl ether, an organic base such as dimethyl aniline derivatives, pyridine or 4-dimethyl aminopyridine, dimethyl formamide with, the hexaffiéthyl phosphoramide or dimethyl sulfoxide.

the compound of general formula IV may be in free acid or salified © forums or as a functional derivative such as a halide, an aryl or alkyl ester, anhydride or a mixed anhydride, the preferably, the halide is formed "in-situ" by reaction in the solvent of the reaction of the acid of formula IV with a halogenating agent such as thionyl chloride in a polar solvent such as, hexamethyl phosphoramide compound.

the functional derivative can be also a mixed anhydride formed in the reaction medium with a dehydrating agent such as a carbodiimide imiàe, ethoxy acetylene or carbonyldiimidazole.

The reaction between the compound of general formula V and the amine derivative of general formula VI is preferably performed in a polar solvent as a base pyridine or dimethyl formamide or in an aromatic hydrocarbon such as benzene, toluene or xylene.

In the definitions provided herein, the term "lower alkyl" means here and hereinafter a radical having from 1 to 6 hydrocarbon sensor carbon atoms as for example, methyl, ethyl, isopropyl, terbutyle, n-hexyl or neo-pentyl. The term "lower alkenyl" defines a hydrocarbon chain having a carbon-carbon double bond and having from 2 to 6 carbon atoms as for example, allyl or pentenyl.

The term "lower cycloalkyl" defines a structured cyclic saturated 3 to 7 having carbon atoms as for example, cyclopropyl, 2.2 and diméthylcyclopropyle or cyclohexyls.

The term "lower alcanoyls" defines the acyl radical of a carboxylic acid lower alkyl having from 1 to 6 carbon atoms in a straight or branched chain such as for example, an acetyl, propionyl, butyryl or propionyl methyl.

Lorscue I-d e Y together Ou X and R, or X and assembly

3

I, together form a radical alcoylèns, ' the cycle thus formed

4

may be preferably piperidine, pyrrolidine, hexa -

azocine hexahydro imine or methylene. These nitrogen heterocycles may further include, as one or two hétéroatornesexempie, nitrogen, oxygen or sulfur " the heterocycle can thus be an oxazolidine ring, thiazolidine derivatives, morpholino, thiasorpholine, homomorpholina, imidazolidins, isoxazoliâinetetrahyd or ER. oxazin.

Among the compounds of the invention, cite a particular, exemplary compounds currently preferred ii

the ^ - 1 -! ii-to-méihylpipérid-to-2 yl) acetylamino 7 2-methoxy 5-trifluoromethyl benzene and its hydrochloride.;

- l - / "" (è7-to-éthylpipérià-to-3 yl) earboxamidçÿ⁷ 2-methoxy 5-trifluoromethyl benzene;

1 - the - (|3 a-morpholinylethyl cyclopropl) 2-methoxy 5 a-eyanobenzene;

1 - - theΦ<cyclopropl - methyl - pyrrolidinyl) 5-acetyl 2-methoxy benzene.

the compounds of the invention are distinguished by valuable pharmacological properties. They exhibit a positive effect on gastric emptying and a clear effect gastric secretion inhibitor. They demonstrated little or no effect on the central nervous system " yne also, the compounds of the invention do not exhibit anti-emetic.

Ynfin, their toxicity is very small.

They are used as pharmaceutical compositions containing as active ingredient at least one compound of general formula I or a salt thereof with an inorganic or organic acid, in combination with an excipient inerts nontoxic pliarmaceutijusment acceptable carrier.

Among the pharmaceutical compositions, more particularly those examples that are suitable for oral administration, parenteral, rectal or perlingual; as for example, the uncoated or coated tablets, sugar-coated tablets, capsules or solutions injectable suspensions packaged in vials or ampules for multiple syringes self-injectable, the suppositories, tablets or sublingual lingual solutions for percutaneous use.

The starting compounds of general formula II are obtained by methods known from the literature including by performing the alkylation, alkenylation, the cycloalcoylation phenylalalcoylation or an aminophenol of formula:

wherein to Eg represents cyano, trifluoromethyl or lower acyl.

The following examples are intended to illustrate the invention without however limiting same,

I-IXUMPLU

1 - (fI morfolynil cyclopropl) 2-methoxy 5-cyano-benzene

Step a

the L - (P chloropropionylamino) 2-methoxy 5 a-cyanobenzene are put into solution in 100 ml of benzene and 8g6 triethylamine, 12g5 of 2-methoxy 5-cyano-aniline was prepared using the method described by BlanksmaÆec ^ and kneaded. Su. Chem. The Netherlands 66 (1947) ^ 7 * 365 - 37 Are added to this solution 10g7 acid chloride 3-chloropropionic in solution in 40 ml of benzene.

The mixture is maintained at room temperature for 12 hours.

It appears a precipitate which is filtered, washed with water and dried. The compound thus isolated is purified by recrystallization from a mixture of methylene chloride-hexane-. An analytical sample of 1 - (0 to-chloropropionyl alkylamino) 2-methoxy 5-cyano-benzene melts at 137 - 141 degrees.

1 - (β- morpholicyclopropl nyl) 2 meth5-cyano-benzene-oxy

Is suspended in 50 ml of toluene 4g4 of

1 - ({J of the Chl opropionyl gold - alkylamino) 2-methoxy 5-cyano-benzene obtained in step if: 5 g of ipo sim-heap. Is added to the suspension dropwise morpholine 1g6. The suspension is refluxed solvent during 15 hours. Separating the insoluble by filtration and washing the plant a little toluene. The solutions toluenic joined are then placed in the ice chest and the morpholino derivative begins to crystallize. After two hours of rest in cooler, -. the crystals are separated by filtration, dewatered, washed and then dried at cold toluene in a cabinet.

Again the product is purified by chromatography on silica gel and elution with a mixture chloroform-methanol..

The 1 - cyclopropl φ - morpholinylethyl) 2-methoxy 5-cyano-benzene crystallizes the eluate. It melts at 148 - 150 degrees. Thin layer chromatography year,, the product is greatly accelerated ' TREs homogeneous.

Analysis :⁼ 2^9, 3

G-HR Ε ICs

Calculated 62.28 6.62 14.53

Found 62.02 6.81 14.08

In the same way, at the start of the 1 - (alkylamino - chloropropionyl) 2-methoxy 5-cyano-benzene and an appropriate amine, was obtained respectively:

the 1 - (amino-diméthylaminopropionyl) - 2-methoxy 5-cyano-benzene, the j?=128 - 132 degrees.

the 4 - (diethylamino cyclopropl) - 2-methoxy 5-cyano-benzene whose hydrochloride melts at 237 - 240 degrees.

1 - the - (piperidino cyclopropl - 00) 2-methoxy 5-cyano-benzene, p=136 - 14 © degrees

1 - the - (|cyclopropl a j-pyrrolidinyl) 2-methoxy 5-cyano-benzene, 1 = 106-108DEGREES

- the 1 - (β oxazolidinyl cyclopropl) 2-methoxy 5-cyano-benzene.

5ZWLS LL

1 - (J->- pyrrolidinyl methyl cyclopropl) 5-acetyl 2-methoxy benzene

1 - {p-chlo -eR<%propionylamin - methylthe O) 2 a-wathe XY 5-acetyl benzene

After having dissolved 24g8 of 2~5 a-aeétyl methoxy aniline-i. ûtînus lounge the method described by Glscbl ^ ^ * 9.ï rzneimitt.

8 532 - 539 rorschung (1958} j7 plex 1 $0 of Li Fe-benzene, is added a solution of acid chloride 10g6'd * 3 a-cblurois obutyric in

' 40 ml of benzene. The mixture is kept under stirring for two hours at ordinary temperature and then added with 250 ml of aau.

The benzene phase is decanted. The aqueous phase is exhausted twice to benzene. One joins lessolutions benzene, washed with hydrochloric acid and then with the 22î/at, the benzene solution is then dried, filtered and then evaporated to ΣeE. The dry residue is recrystallized in ether isopropyllque. This results in DS - 1 15g5 (^ - cyclopropl chlcroet-methyl) 2-methoxy benzene 5-acetyl, or a yield of 77 F. ". The bottom product the K 92 - 97⁰ •

1- (tFs-pyrrolidinyl cyclopropl<1-methyl) 2-methoxy 5-acetyl of Benzene

Added to each solution of 8 g of chloro-to-métîyl cyclopropl - ΐ - φ) 2 a-méthcxy 5-acetyl benzene in 90 ml of benzene, 1g8 of anhydrous potassium carbonate and then, dropwise, 2g1 pyrrolidine. The reaction mixture is maintained at reflux soilefore during 5 hours and then filtered. The separated precipitate is washed twice by toluene. The solutions toluenic are joined, and then evaporated to dry. The dry residue is taken over by a solution saturated sthérée ' hydrochloric gas. Hydrochloride (Y)- 1 - cyclopropl pyrrolidinyltf-methyl) 2-methoxy 5-acetyl benzene precipitates. The LS is separated and purified by crystallization of 1' acetonitrile derivative. The pure hydrochloride melts at 115 and then 140° (with O-interlayment dec OMPs).

Analysis : GRAMS_{the V?} Β ^ N-₂ 0 ., CHLOROPHYLL B ≈ 340.8

H lii 01 the j #.

Calculated 59.91 7.40 8.23 10.41

Found 59.63 7.50 8.13 10.37

. 1 ·) ℮. the afjae - so, at the start of the 1 ** (w ^ chlorine cyclopropl FS-methyl) 2-methoxy 5-acetyl benzene and 1^F. suitable amiss, were respectively:

- the I - (GBP - dimethylamino a CT-methyl cyclopropl) 2-methoxy benzene 5 a-aeétyl '^;

- l - - $àiéthylamino<^ L-I miétlpropienylâmiud)* 2 - 5~méihoxyacétyi benzene

1 - - the (00 - cyclopropl morpholinylût-methyl) 2-methoxy benzene 5-acetyl

the ^ - 1 - 0 - methyl - pipéridyldt cyclopropl) 5 a-aeétyl 2-methoxy benzene

5 Ζ ΜΗ. 3, 3 THE III

~1 / - (N-methyl-piperidyl-2) acetylamino 7 e-matte boxytrifluoromé~5the Thyl " benzene and its hydrochloride

The ACstructu (the n-memCyl-piperidyl-2) ^ aostiquétehlor DRAsthe Tet 77 is dissolved grams the DS-I-methyl acetate pipériâyl confectioneries^F. ethyl in 730 mt diacid chtorhydriqne 6n d e. oH-door VBE1 TMs solution at reflux during ii '. hsùre s * y the solvent is then, distilled the^{the R} dry residue taken up in hot llàcétenitrilè. By -, cools telling the crystallization begin construction, . Left to stand over 4 hours GnRH year. cooler then divides the crystals, strips; washer^: the dominating ' acétonitrils and dried under reduced pressure ": -

This results; 72gi of. hydrochloride 1 * acids (H-methyl piperidyl-2) acetic, either, a rendeffl3nt.de 91 ^, melts at 160 then 185° (decomposition).

Analysis t-O-Η<%=19c/7;

.' HM^; M M G1 %

Calculated 49.61 8.33 7.23 18.30.

49.43 8.1&7.27 18,297 - Found

the (H-methyl piperidyl-2) ethyl acetate, product. starting, is obtained using the method described by Spsrbsr

/ βwith am. OC. Mal, SODs. - 00 (1959) 704 - 70 the L^7

Stage 3

1 - ^ f mé4hyl PIPseridyl and 2)acétylamin<7, 2- méthox5 a-trifluorométhÿl benaene therein

Is 10g hydrochloride (H-methyl piperidyl-2)' acetic acid obtained in step to in solution in 380 ml of hexamethyl phosp-to-horotriamidê, then dropwise, 3 ml8 chloride thionylsfraiehement redistilled. The mixture is maintained under stirring for 4 hours to 5 - 10° then added 9g9 of 5 a-trifluorométbyl 2-methoxy benzene prepared using the method described by Poraî-to-KoshitzZbur ^. Priklad. Khim, 2§969 - 973 (955 ΐ · ^ 7 the reaction mixture is maintained under stirring overnight and then diluted with ether. L®-hydrochloride 1 - ^ F. " (n-methyl-piperidyl-2) acetyl Amin to 7^2-methoxy 5-trifluoromethyl benzene precipitates. It is separated by filtration, the wrings, washed with ether and dried. The pure hydrochloride is obtained after recrystallization from ethanol and water. It melts at î66 then ΐ 84⁰ (decomposition). It contains 4.5 $> of water of crystallization.

Analysis ii grams₁₆H_2<| Atrial kg., c1h + ' 4.5 1 * water=366.8 0 hr■N. the I

Calculated 52.39 6.05 7.64

52.19 5.98 7.82 Found

The mimics makes the respectively;

- the piperidyl-2) acetylamino? 2-ethoxy 5-trifluoromethyl benzene.•.

the~1 - / - (the R-methyl piperidyl-2) acetylamino 7 2 a-allyloxygroups 5-trifluoromethyl benzene

the~1 - / - (hence he-methyl piperidyl-2)* 2 a-oxy acétylaminçÿ 5-trifluoromethyl benzene.'

In-using as raw material the acid (n-ethyl pyirolidinyl and 2) acetic acid and 2-methoxy 5-trifluoromethyl aniline compounds, obtained the 1 / - " O-ethyl pyrrolidinyl 2) aeétylamino 7 2-methoxy 5-trifluoromethyl benzene.

Initially acid (K éihyl piperidyl-3) earboxylic and 2-methoxy 5-trifluoromethyl aniline compounds, obtained the / - 1" (the L-ethyl substituted piperidyl-3) carboxamido-/ 2-methoxy 5-trifluoromethyl benzene.

The 2 a-aleoxy or 2 a-alkenyloxy or 2 a-cycloalcoyloxy 5-trifluoromethyl aniline starting materials are prepared by alkylation or alkenyl&thine or cycloalcoylation of 2-chloro or 2 fluoro 5-trifluoromethyl 1-nitrobenzol followed by reducing the nitro compound.

IR-JtorlM

Tablets to 20' mgs de - L $-to-morph's

5 a-eyanp. benzene derivatives.

2 a-méihûxy

benzene 200 grams starch de corn 225 grams Uthyl cellulosic 5 grams calcium carbonate 1500 grams magnesium stearate 25 grams 25 grams of talc colloidal cut silica 20 g per 10,000 tablets about finished weight of 200 mg tablets 50 mg of 1 - (1H-mëthyl piperidyl-2} acétflamincÿ⁷ 2-methoxy 5-trifluoromethyl benzene

1 - /~(hence he-to-métiiyl piperidyl-2) - 5 - methoxy acétylaminoZ ^

trifluoremethyl benzene

500 grams

caleium carbonate

Bthyleellulose_;

Magnesium phosphate,

Methyl_:déHuiose. the I - VBE1•. '

For 10,000 tablets about finished. pOs CelllDs^:dàv250-to-orXag sxmpLg therein :

^ irude pharmacological upon

has)

1200 grams

* 300 grams

50 - 430 grams 25 grams gms

according present invention ^

The acute toxicity of the compounds according to L^{the R} invention has been determined

on batches of strain mouse Pvoeklanà SP

between 1 and 22 grams δ " each compound is administered to the^: increasing intraperitoneally suspended in an aqueous solvent * cotyledon is the subsided when fitted after b-d ** is determined ÿoûrs observing lethal dose for each product, each graphical method/mean by " according to the compounds * s^{: t-} 0 between 250 and 500 mg level/kg body weight. :

the K as compared e * is the 2s ^ Q of the BétoclGpraffiide 125 is entered: