AU592358B2 - Derivatives of diphenoxyethylamine, a process for their production and the pharmaceutical compositions containing the same - Google Patents

Description

COMMONWEALTH OF AUSRAL ;A 5 9 2 3 PATENTS ACT 1952-69 COMPLETE SPECIFICATION (ORIG INAL) Class Application Number: 604'B6/86 Lodged: 5 F81 0 I t. Class Complete Spiflcation Lodged: Accepted: at*$.

Published: 9. *9 9 9 Piority: 9 4199 9 Flelatad Art 44 4* 4 4*44 '1113 ds1mnt w nw~ th Sectioni 49.

and is w pf i, t 4 t 1 4ma of Applicant:, 'SWdrest of Applicant:I A;tuul inventor: ALBERT ROLLAND S.Aii 49, rue Saint; Andre des Arts, 75006 Paris, France JEAN-PIERRE~ LABAUNE Address for Service: EDWD. WVATERS SONS, 50 QUEEN STREETo MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the Invention entitled:.

4" DERIVATIVES OF' DIPHENOXYETIIYLAMINEIA PROCESS FOR THEIR PRODUCTION AND THE PHARMIACEUTICAL COMPOSITIONS CONTAINING THE SAME 1The following statement Is a full description of this invention, Including the best method of performing It known to: US

A)

t4.

-la- DERIVATIVES OF DIPHENOXYETHYLAMINE, A PROCESS FOR THEIR PRODUCTION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME, This invention relates to 44-P derivatives of diphenoxy ethylamine and to o process for producing them, More precisely it relates to N-alkyl derivatives of 2,2-bis phenoxy ethylarnine.

Specifically it provides N-alky. derivatives of 2 ,2-bian henoxy ethylamine of formula I *1 #0 IC 1 CH CU N P 2 Wherein R is a lower alkyl radical having from I to 4 carbon atoms in straight or branched claim.

salt0 This invention also relates to the acid addition sat of the compounds of formula I with a mineral or organic acid, preferably a therapeutically-acceptable acid.

ell Among the suitable acid addition salts of the compoundts of formula 1, it may be cited the hydrobrornides, the

S

15 hydroclorides, the hydroiodides, the sulphates, thle nitrates, the phosphates, the sulphites, the formates, the acetates, the benzoates, the naphtoates, the nicotinates, the isonicotinutes, thle 3,4,5 -trimethoxybenzoates, the syringoates, the benzenesulphomates, the methanesulfonates, the isethionates, 20 the p,toluenesulphonates, the maphtylsulphonates, the tairtarates, the pyruvates) the citrates, the naleates, thle fumarates, the itaconates, the citraconates,the talonates, the gluconates, the lactobionates, the glucose I-phosphaites and the glucose 1,6diphosphates.

A

1 -2- The acid addition salts which derive from acids which may not be used in therapy such as the iodates, the periodates, the ferrocyanides, the strychnates, may be utilized as a mean of identification, or purification. They are further converted to the base of formula I.

In the general formula I, R preferably symbolizes a methyl radical, an ethyl radical, or an isopropyl radical. It may also be a tertbutyl or a sec-butyl.

This invention also provides a process for producing the compounds of formula I and the acid addition salts thereof which consists in converting 2,2-bis phenoxy acetic acid into a functional derivative, reacting the latter with a primary amine of the formula II Iit* R- NH (II) in which R has the previously-given meanings.

to form an amide of formula III t i CH CO-NH-R wherein R has the previously-given meanings reducing this compound with a mixed alkali metal hydride to produce a compound of formula I Optionally the compound of formula I may be converted into an acid addition salt by adding the corresponding mineral or organic.

S As a variant of the above-defined process the compounds of formula I may also be prepared starting from a tertiary amine such as Medifoxamine and submitting the latter to a dealkylating agent such as a quaternising agent as for example a cyanogen halide or an alkyl chloroformate. In this situation the resulting compound is a compound of formula I wherein R is a methyl group.

1 I -3- The process according to this invention may also be defined by the following features which are presently the preferred ones.

the functional derivative of 2,2-bis phenoxyacetic acid is an acid halide, an acid anhydride, or a mixed anhydride resulting from the action thereon of an acylating agent such as a carbodiimide, carbonyl bis imidazole or an alkyl pyrophosphate.

the formation of the amide of formula III is carried out in an inert medium such as for example an aromatic hydrocarbon.

the reduction of the amide of formula III is performed by o0 means of an alkali metdl aluminohydride such as for example, lithium tertbutoxy aluminohydride or lithium isopropyl aluminohydride.

S" A compound of formula I may also be produced starting from a S2,2-bis phenoxy ethyl sulphonic ester such as the methane sulphonate or the p.toluenesulfonate, and reacting it with a primary amine of the formula II R -NH 2 wherein R has the previously-given definitions.

in a high-boiling liquid solvant.

S 20 This invention also relates to the pharmaceutical compositions c containing as active ingredient at least a compound of formula I or an acid addition salt thereof with a mineral or organic acid, cf I in admixture or conjunction, with an inert non-toxic pharmaceutically-acceptable carrier or vehicle.

The carriers or vehicles suitable for this use are those adapted for administration through the parenteral, oral, pertaneous or rectal ways o administration.

The pharmaceutical compositions according to the invention are in the form of tablets, coated tablets, dragees, pills, sachets, flavoured or unflavoured powders, drinkable solutions or suspensions, injectible solutions packed in ampuls, in multi-doses flasks, or auto-injectible syringues, lyophilised preparations, suppositories or solutions in a polar solvent for percutaneous applications.

The pharmaceutical compositions contain from 0,025 g to 0,250 g of a compound of formula I or a salt thereof as active ingredient and preferably from 0,05 g to 0,20g, per unit dosage.

The daily doses expressed in compound of formula I or a salt thereof may vary depending on the weight of the patient, the age of the patient, the therapeutic use and the severity of the illness. Generally speaking the daily dosology ranges in the adult 5 from 0,05 g to 0,15 g.

*15 The compounds of formula I and the acid addition salts thereof found a therapeutic use as anti-depressant drugs. They are .especially suitable for improving or curing the obsessional t" conditions, the maniaco-evolutive psychosis, the reactional psychosis ot the depressions arising from with-drawal symptoms.

They clearly differentiate from similar products and specifically "s C from Medifoxamine for their ability to improve the reuptake of I t Noradrenaline and to decrease that of Tryptamine.

They are also able, at least on pharmacological tests in animals, S 25 to reload the pre-synaptic neuronal granules in adrenergic Stransmitters as well as restitute to them a normal action potential.

The following examples are merely intended to illustrate the invention. They do not limit it in any manner.

EXAMPLE I 2,2-bis phenoxy N-methylamino ethane Step A Methyl 2-bromophenoxy acetate This compound is obtained by bromination according to the method disclosed by J.L COLIN and LOUBINOUX (Synthesis 1983 p.568).

A mixture of methyl phenoxy acetate (20 g ie 0,12 mol), N-bromo succinimide (25,6 g 0,14 mol) and a catalytic amount of benzoyl peroxyde (100 mg) in 500 ml tetrachloro methane are heated to boiling. The performance of the reaction may be followed by TLC, using the mixture ethyl acetate 30 Hexane 70 as the eluating solvent.

C C C z t t t t r t t t C t I I After one hour reflux, the reaction is achieved. The mixture is filtered and evaporated off. An oily residue is recovered which is pure enough for being used for the next step without further purification I.R C N.M.R spectrum 3,8 6,4 7,2 Step B 2,2-bis phenoxy acetic acid.

0 at 1770 cm1 ppm (CH 3 ppm CH ppm aromatic f j 1 t C1 "FV 25 2,2-bis ph6noxy acetic acid.

Raw methyl 2-bromophenoxy acetate is dissolved in 200 ml toluene containing 2 g t4trabutylammonium bromide (0,0062 mol) to which ml of an aqueous solution of Sodium hydroxyde at 50 and 12,42 g phenol (0,132 mol) are added. The mixture is kept under stirring for a night. The aqueous phase is thereafter made acidic and extracted with ether. The organic phase is washed, dried and distilled off.

r -6- 2,2-bis phenoxy acetic acid thus-obtained is purified by column chromatography using the mixture methylene chloride-methanol (95:5) as the eluating solvent.

-1 I.R spectrum CO at 1750 cm NMR spectrum 5,9 ppm (CH) 7,0 ppm aromatic 8,8 ppm (OH) step

C

2,2-bis phenoxy N-methyl acetamide To 3 g of 2,2-bis phenoxy acetic acid previously dissolved in ml dry toluene, 1,5 eq of oxalyl chloride are added. The mixture is heated to 40° for 2 hours. The performance of the reaction is observed through the I.R spectrum.

The resulting acid choride which is very unstable, is used directly. A stream of methyl amine is bubbled therein for 30 mn.

Ie Stirring is kept for 10 hours at room temperature. After treatment by acid then a base the thus-obtained amide is recovered with a sufficient degree of purity.

I.R spectrum CO at 1670 cm-1 NMR spectrum 2,75 ppm (CH 3 5,7 ppm (CH 3 6,9 ppm aromatic 6,8 ppm NH Step D 2,2-bis phenoxy N-methyl-amino-ethane 0,4 g (2,8 eq) of Lithium Alumino hydride are suspended in 30 ml dry ether. The mixture is added with 1 g 2,2-bis phenoxy N-methyl acetamide in 50 ml ether, at o0C. After 30 mn standing, the inner 1;c': temperature is let to revert to room temperature and stirring is maintained for 12 further hours. After acido-basic treatment, 2,2-bis phenoxy N-methyl amino ethane is recovered.

I.R spectrum NMR spectrum -i NH et 0 at 3300 cm 1 2,7 ppm (broad peak binding to NH,CH 3 3,4 ppm (broad peaks CH 2 6,4 ppm tert butyl group 7,0 ppm aromatic protons 9,8 ppm (broad peak NH) V C C at V C 0 at I tt a at a at

C

a a C C{C C a: This base is converted into a hydrochoride by dissolving it in ethanol and saturating the solution with a stream of gazeous hydrochloric acid. The hydrochloride which precipitates, is separated, washed with ethanol and dried under reduced pressure.

15 Similarly the maleic acid or the fumaric acid addition salt of 2,2-bis phenoxy N-methyl amino ethane are prepared by adding an ethanolic solution of fumaric or maleic acid to the base.

EXAMPLE II 2,2-bis phenoxy N-isopropylamino ethane Operating as shown at step C of example I and starting from 2,2-bis phenoxy acetic acid and isopropylamine, 2,2-bis phenoxy N-isopropyl acetamide is obtained.

This amide is reduced using lithium alumino hydride as the reducing agent, operating according to the process of step D of example I.

2,2-bis phenoxy N-isopropyl amino ethane is an oil which is converted into its hydrochloride by action of hydrochloric acid in an organic solvent.

a: I~ -8- EXAMPLE III Pharmacological study of the compounds of formula I according to the invention.

The showing of the anti-depressant properties has been carried out using the usual pharmacological assays test of antagonism v.the hypothermia induced by injection of Reserpine test of increase of the Group-toxicity induced by injection of Yohimbine.

Table I, collects the various results obtained during the testing of the compounds of formula I.

t t t These compounds show, when orally administered at doses ranging form 50 to 100 mg/kg in these tests, an activity at least equal to 4""4 that of Medifoxamine selected as reference substance.

Moreover in the despair test in the mice, the compounds of formula I are as active at doses of 50 mg/kg p.os than Medifoxamine at a doses of 100 mg/kg.

SEXAMPLE

IV

Sr Search of a mean lethal doses S 20 The mean lethal doses in the mice has been determined in administering to batches of 5 mice p.o. increasing amounts of the compounds of formula I. An approximate mean lethal doses has been graphically calculated according to the method of Tainter and Miller.

It has been stated that at 200 mg/kg no mortality appears, at 350 mg/kg 3 out 5 of the animal die and at 500 mg/kg all the animals die.

1 I 1 I I: -9- The mean lethal doses is in average of about 300 mg/kg.

EXAMPLE V Biological study of the compounds according to this invention The action on the tests of inhibition or reuptake adrenergic mediators has been determined.

of the main The obtained results in comparison with those with conventional antidepressive drugs are shown in Table II.

EXAMPLE VI Tablets with 0,25 g of 2,2-bis phenoxy N-methylamino-ethane as the hydrochloride.

C,

i If 4L 4, E~ *i15 Active ingredient Calcium Sulphate Microcristalline Cellulose Arabic gum Ethyl Cellulose Povidone K 15 (poly vinyl pyrrolidone) Talc for 10.000 tablets having a mean weight 2834,1 1510 325 16 24 65 g of 0,48 g 4 i "1 .II Ct €L

C

'FABLE I CHMCL TOXICITY HYPOTHERMY HYPOTHERMY TOXICITY DESPAIR TEST CH IENJ PRODUCT STRUCTURE (MICE) RIrSERPINE APOtIORNOINE Y014 I MR INE N TYR.I STUTREP 0 2] 150 P.O I9 ED5.. 10 A TR 601 ME.DIFXAMIN 700 MEDI OXA I NE800 5/10 f ,2 b is 200 0/5 E~ i phenoxy 0-7 S T 6/10 52% t N-methyl ZN 350 3/

S

amino CH 500 je thane r a a a a a a a a a a a a a a a a 4) 1~ a, 71

I

TABLE I I PRODUCTS UIJAKE "IN VITROl UPTAKCE ofEX VIVO

IC

50 M Y. inhibition NAd 5-lIT 1 VA N~d 5-11T 1 DES IPRAfNI1E I MI PRAM I MEI DO PA 141 H E lIED 1 F OX A 111 M E 2 2-bis-ph~noxy N-m~thyl amino 6thane 1,3 x 10- f 1,9 x 0G 2,0 x 1- 5,7 x 1- 8.13 x 10- 5 1,5 x 1O- 6 Bolt) x 1 03,3 x 1- 3,0 x 0-6 -51% iug/kg) inactive 23 (100 nig/kg) inactive 1%

HS.

inactive inactive Nad Nor adr~naline 511T S~rotonino DA Dopamiine w so 0 0 a. 0 0 0 0 55 0 0 0 44 44 S. a 0 44 44 S a S a a a 4' U.

5 .4 4.