The present invention relates to aryloxy- and hetero- aryloxy-alkenylene derivatives of amines, to a process for their preparation and to pharmaceutical compositions containing them.

The invention provides compounds having the following general formula (I)

herein

each of A and B, independently, is a group of formula (i) to (iii)

wherein

Y is -0-, -S- or -NR- in which R is hydrogen or

C ₁ -C ₆ alkyl; each of R_, R., R_ and R_ which may be the same or 3 4 5 b different, independently is; a) hydrogen, halogen, hydroxy, cyano or nitro; b) ^C ,-C _c alkyl unsubstituted or substituted by halogen,

1 o c) C -C _ alkoxy or C -C. alkylthio; l b I D d) C -C_ alkyl-sulfonyl; 1 b e) a -NR R group in which each of R and R , independently, 7 8 7 8 is hydrogen or C -C_ alkyl; or one of R_ and R_ is l b 7 8 hydrogen or C -C _c alkyl and the other is a -C0R_ group, 1 o 9 wherein R is hydrogen, C -C. alkyl, C -C_ alkoxy or y l b l

-NR1..0-.R1,„1 in which each of R1_0_ and R1,1, is indep ^r endently - hydrogen or C -C_ alkyl;

1- 6 f) a -C0 ₁₂ group wherein R is C -C alkoxy, C -C alkyl or wherein R and R are as defined above; or g) two adjacent of R , R , R and R , taken together, form a C -C alkylenedioxy group; each of R and R independently is hydrogen, C ₃ -C ₈ alkynyl, C ₃ ~C alkenyl; or C -C alkyl unsubstituted or substituted by phenyl; or

R and R , taken together with the nitrogen atom to which they are linked, form a substituted or unsubstituted, saturated heteromonocyclic ring optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen; and the pharmaceutically acceptable salts thereof.

The invention includes within its scope all the possible isomers, stereoiso ers, in particular Z and E (cis and trans) isomers and their mixtures, and the metabolites and the metabolic precursors or bio-precursors of the compounds of formula (I). In formula (I), the symbol (* _^ ^->) indicates that the substituents around the carbon-carbon double bone are in the Z or E configuration or both, i.e. a mixture of Z and E isomers is present. A halogen atom is e .g. chlorine, bromine or fluorine, preferably it is chlorine of fluorine.

The alkyl, alkenyl, alkynyl, alkylsulfonyl and alkoxy groups may be branched or straight chain groups.

A C -C alkyl group is preferably a C -C. alkyl group, e.g. l 1 methyl, ethyl, propyl, isopropyl,butyl , sec.butyl or tert. butyl, more preferably it is methyl or ethyl.

A C -C. alkyl group substituted by halogen may be a 1 b di- or tri-halo-substituted alkyl group in particular a trihalo-C 1 -C b_ alkyl group . A trihalo-C -C_ alkyl group is preferably a

1 b trihalo-C -C alkyl group, e.g. trichloro-C -C alkyl or trifluoro-C -C alkyl, more preferably it is trifluoromethyl

A C -C. alkenyl group is preferably a C -C alkenyl group, 3 b 3 4 in particular allyl.

A C -C alkynyl group is preferably a C -C alkynyl group, 3 6 3 4 in particular propargyl. A C -C_ alkoxy group is preferably a C -C. alkoxy group, l 1 4 e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert.butoxy, more preferably it is methoxy or ethoxy.

A C -C alkylthio group is preferably a C -C alkylthio group, in particular ethylthio or methylthio, more preferably methylthic.

A C -C alkylenedioxy group is in particular a C -C alkylenedioxy group, preferably methylenedioxy.

A C -C. alkyl sulfonyl group is preferably a C -C. alkyl- l 1 4 sulfonyl group in particular methylsulfonyl or ethylsulfon l. When one or both of A and B is thienyl, it is e.g. 2- or 3-thienyl, in particular 2-thienyl.

When one or both of A and B is furyl, it is e.g. 2- or

3-furyl, in particular 2-furyl.

When one or both of A and B is pyrrolyl,it is e.g. 2- or 3-pyrrolyl, in particular 2-pyrrolyl.

When one or both of A and B is naphthyl, it is e.g. 1 -or

2-naphthyl.

When one or more of R , R , R and R is a -NR R group, as defined above under e), it is preferably: e ) amino, C -C alkylamino or di (C.-C alkyl) amino;

e ) an acetamido or propionamido group; e ) a -NHC00C -C alkyl group; or e ) an ureido or a N' , N'-bis di (C -C alkyl) ureido group.

When one or more of R_, R., R_ and . is a -COR., group,

3 4 b 1__ as defined under f), it is preferably f ) -COC -C alkyl, in particular acetyl, propionyl or butyryl; f ) -C00C -C alkyl, in particular methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl. f ) -CONH , a methylamino-, ethylamino- or propylamino- carbonyl group or a dimethylamino-, diethylamino- or dipropylamino- carbonyl group.

When R and R , taken together with the nitrogen atom to which they are linked, form a heteromonocyclic ring as defined above, it is typically a 5- or 6-membered ring.

Such a ring may be for example a ring chosen from the group including piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, which may be unsubstituted or substituted at carbon atoms or, in the case of piperazine, at a nitrogen atom by a substituent independently chosen from the group including:

C -C_ alkyl; benzyl; phenyl unsubstituted or substituted 1 b by one to three substituents independently chosen from halogen, C -C. alkyl, C,-C,. alkoxy, trifluoro-methyl and l b l hydroxy-C -C. alkyl.

1 6

When and R , taken together w th the nitrogen atom to which they are linked, form an heterocyclic ring as defined above, preferably it is selected from the group including: a') unsubstituted morpholine and piperidine; and b') piperazine unsubstituted or substituted by hydroxy-C.-C alkyl, or by phenyl unsubstituted or substituted by one or two εubstituents independently chosen from halogen, trifluoromethyl, C 1.-C. alkyl and alkoxy.

The pharmaceutically acceptable salts of the compounds of formula (I) include those formed with an inorganic acid, e.g. hydrochloric acid or sulphuric acid, or with an organic acid, e.g. citric, tartaric, malic, aleic, mandelic, fumaric or methanesulphonic acid.

As stated above the present invention also includes within its scope pharmaceutically acceptable bloprecursors (otherwise kno as pro-drugs) of the compounds of formula (ϊ), i.e. compounds which have a different formula to formula (I) above but which nevertheless upon administration to a human being are converte directly or indirectly in vivo into a compound of formula (I).

Preferred compounds of the invention are the compounds of formula (I), wherein each of A and B, independently, is a group of formula (a) to (aaa)

(a) (aa) (aaa)

wherein each of R ■_, R 4, R_ and R b independently is hydrogen, halogen, hydroxy , ^' cyano. C -C alkylsulfonyl , nitro, C 1-C4. alkyl, trihalo-C1 -C4. alkyl , C1-C alkoxy, a -NR_7R8_ group in which and R are independently hydrogen or

7 8

C -C alkyl, or one of R and is hydrogen or C -C alkyl and the other is a -COR group .wherein R is

9 9 hydrogen, C -C alkyl, C -C alkoxy or -NR R in which each of R and is hydrogen or C -C. alkyl; a -CO group, wherein R is C -C alkoxy, C -C alkyl or

-NR, _Λ R _< . in which R,_ and R„ „ are as defined hereabove; 10 11 10 11 or two adjacent of R , R., R_ and R_ taken together from

3 4 5 6 a C -C alkylenedioxy group; each of R and R independently is hydrogen. C -C. alkenvl, 1 . ' 4 ^*

C--C _a alkynyl; or C -C. alkyl unsubstituted or substituted - A 1 4 by phenyl; or R and R taken together with the nitrogen atom to which they are linked form a piperazine ring unsubstituted or N-substituted by C -C. unsubstituted or

1 4 substituted by hydroxy or a ring chosen from piperidine, morpholine, thiomorpholine, and pyrrolidine; and the pharmaceutically acceptable salts thereof.

More preferred compounds according to the present invention are the compounds of formula (I), wherein each of A and B is a group of formula (b)

(b) wherein each of R, and R which may be the same or different is

. 4 hydrogen, halogen, C -C alkoxy, C _χ -C alkyl, cyano, nitro, amino. trifluoromethyl, C -C alkylsulfonyl , C -C alkanoyl or

1 4 * ^■ •> two adjacent of R, and taken together form a methylene-

3 4 dioxy group; each of R and R , independently, is hydrogen or C -C alkyl; and the pharmaceutically acceptable salts thereof. Preferred examples of specific compounds according to the present invention are: c -p _h enoxy- β(-p _h enyl-β-methylaminomethyl-ethylene; -( 2-ethoxyphenoxy )-c ^* t-phenyl-β-methylaminomethyl-ethylene ; t=( -( 2-chlorophenoxy )-o<-phenyl-β-methylaminomethyl-ethylene ; (E)-^ -( 2, 6-dichlorophenoxy )-<a<-phenyl-β-methylaminomethyl-ethylene : o -(3,4-dichlorophenoxy )- -phenyl-β-me thy laminome thy 1 -ethyl ene; o( -( -trif luoromethylphenoxy )-t -p_henyl-β-methyla l_rwπet yl-ethylene ^• ^_ ⁽ 2-nitrophenoxy )-o^.-ρ enyl- ^β -methylaminomethyl-ethylene, q _ ⁽ 2-aminophenoxy)-«^-phenyl- ^β -methylaminomethyl-ethylene; c^- ⁽ 2-ureidophenoxy)- ^β <r-phenyl- ^β -methylaminomethyl-ethylene; -( 2-thienyloxy)-K _r phenyl-β-methylaminomethyl-ethylene; - - ⁽ 1-naphthyloxy ) -c.-phenyl- ^β -me thy lamino e thy 1 -ethyl ene ; 0{- ⁽ 2-naphthyloxy ⁾ -c -phenyl- ^β -methylaminomethyl-ethylene ;

- 9 -

4-cyanophenoxy )- ^ -phenyl-β-methylaminomethyl-ethylene ;

C(- 3-chlorophenoxy)-^-phenyl-β-methylaminomethyl-ethylene;

°- 4-chlorophenoxy)-^-phenyl-β-methylaminomethyl-e hylene;

« ⁽ - 2-methylphenoxy)-c(-phenyl-β-methylaminomethyl-ethylene;

(E)-O(- 2, 6-dimethoxyphenoxy)-C-v-phenyl-β-methylaminomethyl-

-ethylene;

(E - 4-nitrophenoxy)-Q(-phenyl-β-methylaminomethyl-ethylene;

3,4-dimethoxyphenoxy)-C-phenyl-β-methylaminomethyl-

-ethylene; - 2-me thoxyphenoxy ) -Oζ-pheny 1-β-methylaminσmethyl-ethylene ;

4-acetylphenoxy)-0(-phenyl- ^β -methylaminome hyl-ethylene;

*.- 3- ethσxyphenoxy )-o(-phenyl-β-methylaminomethyl-

-ethylene

<*,- 4-methoxyphenoxy)- -phenyl-β-methylaminomethyl-

-ethylene;

< .- 4-cyano-3-methoxyphenoxy)-θ(-phenyl-β-methylamino-

-methyl-ethylene ; C^-( 2-cyanophenoxy )-0\-phenyl-β-methylaminomethyl-ethylene; Q(-(3-cyanophenoxy)-u^-phenyl-β-methylaminomethyl-ethylene; C^-(4-methylsulfonylphenoxy)-^-phenyl-13-methylaminomethyl-

-ethylene. o<-phenoxy-c-(2-thienyl)-β-methylaminome hyl-ethylene; cK-phenoxy-^-O-chlorophenyl )-β-methylaminomethyl-ethylene;

©<-phenoxy-**-V(4-chlorophenyl )-β-methylaminomethyl-ethylene; _c -phenoxy--9-(2-hydroxyphenyl)-β-methylaminomethyl-ethylene;

cx-phenoxy-tsv ( 3 , 4-methylenedioxyphenyl )-β-mehylaπ nomethyl-«thylene ; c*-phenoxy • ^■■■■ ■ - (3-methoxy phenyl )-β-methylaminomethyl-ethylene ; ( E ) ^• *-( 3-hydroxyphenoxy )-<-phenyl-β-methylaminomethyl- ethylene ; « - ( 3,4-πιethylenedioxypherκ)xy)^-pheryl-βHrethylarrJ_oιιe Uyl^

•*-phenoxy--*σ-phenyl-β-dime thy laminome thy 1-e thy lene; e -( 2-ethoxyphenoxy )-σ^-phenyl- ^β -dimethylaminome hyl-e hylene;

^«• < ^• -( 2-chlorophenoxy )-o-phenyl- ^β -dimethylaminomethyl-ethylene; c -(3,4-dichlorophenoxy )-oς-phenyl-β-dimethylaminome hyl-ethyle ex - ( - tri f luoro e thy lphenoxy )-*^ hervl- →3ine^lamiraιwι-lyl-e^le^ ; rt-(4-nitrophenoxy )-X-phenyl-β-dimethylaminomethyl-ethylene; ex.- ( ?-aminophenoxy )-«.-phenyl-β-dimethylaminomethyl-ethylene ;

<=<-(2-ureidophenoxy)-^-phenyl-β-dimethylaminometh yl-ethylene;

^• =<-( 2-thienyloxy )-σ -phenyl- ^β -dimethylaminomethyl-ethylene ;

---.-{ 1-naphthyloxy )-< -phenyl-β-dimethylaminomethyl-ethylene ; o<-(2-naphthyloxy )-c-phenyl-β-dimethylaminomethyl-ethylene; -phehoxy-v( 2-thienyl )-β-dimethylaminomethyl-ethylene ; β -phenoxy- i.-(3-chlorophenyl)-β-dimethylaminomethyl-ethyleπe;

—-phenoxy -o- ( -ch 1 orophenyl ) -β-dime thy 1 aminome thvl-e thy lene ; ©<-phenoxy ■**■=> ^■ --,- ( 3 , 4-me thy 1 enedi oxypheny 1 ) -fl-diirethylaninomethyl-e thy c -phenoxy- <.-( 3-methoxyphenyl )-β-dimethylaminomethyl-ethylene ;

~-^-{3, 4-methylenedioxyphenoxy ) - ~-i -phenyl-β-dimethylaminomethyl ethylene; and αt-phenoxy- =■>•. -phenyl-β-propargylaminomethyl-ethylene , in particular, unless specified, both as single Z and E isomers and a mixture thereof, and the pharmaceutically acceptable salts thereof.

The coπpounds of the invention and the salts thereof can be obtained by a process comprising:

a) reacting a compound of formula (II)

B c (ID

wherein

A and B are as defined above, with an amine of formula (III)

R NH ₂ (III)

wherein R is as defined above, in the presence of a reducing agent, so as to obtain a compound of formula (I), wherein R is as defined above .and R is hydrogen; or b) reducing a compound of formula (IV)

wherein

A, B , R and are as defined above ; or c ) reacting a compound of formula (V )

C> B

II

CH ( V)

CH Z

2

where in

A and B are as defined above and Z is a leaving group , wi t an amine of formul a (VI )

"l

HN ( VI )

^R 2 wherein R and R are as defined above; and, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired converting a compound of formula (I) into a pharmaceutically acceptable salt thereof and/or, if desired, converting a salt into a free compound, and/or, if desired, separating a mixture of isomers into th single isomers.

The processes a) to c) described above are analogy processe concerning reactions well known in organic chemistry.

The reaction of a compound of formula (II) with an amine of formula (III) is a reductive amination, which can be performed by treatment with a suitable reducing agent for example an alkaline boronhydride, e.g. NaBH or NaBH.CN. The reaction may be carried out in a suitable organic solvent, e.g. an aliphatic alcohol, preferably a lower alkanol, e.g. e hanol or ethanol, at a temperature rang¬ ing from about 0 ^C C to about 20°C, in the presence of an excess of the amine of formula (II), as described e.g. in J. Med. Cher.. 198C, 23, 750.

The reduction of a compound of formula (IV) may be, in general effected by the methods usually employed for the reduction of a i e s , for example by treatment with L AlH , A1H or BH in an inert anhydrous solvent, preferably an aliphatic ether, e.g. diethyl ether, or tetrahydrofuran, or a mixture of these solvents at temperatures varying from about 0°C to about 20°C, as described e.g. in J. Med. Chem. 1981, 24, 982, or by treatment with an alkaline boronhydride, e.g. NaBH , in the presence of alkaline metals as described, for exaπple, in Tetr. Lett. 1969, 4555.

When Z in a compound of formula (V) is a leaving group it is e.g. chlorine or a esyloxy, tosyloxy or trifluoroacetate group.

The reaction of a compound of formula (V) with an amine of formula (VI) is a common nucleophile substitution well descri ed in literature. The reaction is preferably performed in a

suitable organic solvent, e.g. dimethylformamide, dimethyl- sulfoxide or C -C ₄ alkanol, preferably methanol or ethanol, dioxane, tetrahydrofuran or mixture thereof, at a temperature ranging preferably from about 20°C to about 100 ^e C. A compound of formula (I) may be converted, as stated above, into another compound of formula (I) by known methods. For example, a free hydroxy group may be etherified by ^' reaction with a suitable alkyl halide in the presence of a base such as NaOH, KOH, Na CO , K CO , NaH, NaNH , sodium ethoxide or sodium ethoxide, in a solvent selected appropriately from the group consisting, for example, of methanol, ethanol, dioxane, acetone, dimethylformamide, hexamethylphosphorotriamide, tetrahydrofuran, water and their mixtures,at a temperature rainging preferably between about O ^β C and about 150 ^β C. Alkylation of a free amino group may be carried out according to known methods. For example a compound of formula (I) wherein one of R and R , being as defined above, is hydrogen may be alkylated to obtain the corresponding alkyl, alkenyl, alkynyl or aralkyl derivative. The alkylation reaction may be performed, for example, by treatment with the appropriate alkyl, alkenyl, alkynyl or aralkyl halide or with a reactive ester, e.g. tosylate or mesylate, of the appropriate alcohol. The alkylation may be carried out either in the absence of solvents or in a solvent such as, e.g. an aliphatic alcohol, e.g. ethyl or

methyl alcohol, a glycol, e.g. ethylenic or propylenic glycol , benzene or dimethylforma ide or a mixture of these solvents in the presence of an acid acceptor such as triethylamine, an alkaline carbonate or bicarbonate or an 5 excess of the amine, at temperatures ranging from room tempera ture to solvent reflux temperature according to the procedures described, e.g. in J. Org. Che . 1938, 2, 139 ; Org. Synt. Coll., vol. II, 1943, 1B3 ; J. A er. Chem. Soc., 1932, 54, 4457. C The monoalkylation may be effected, alternatively, by the methods described for example in J. Org. Chem. 1975, 40, 3453 ; J. Chem. Soc, 1969, 2223 ; J. Med. Chem. 1974, 17, 654.

Alsc the optional salification of a compound of formula (I) 5 as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods.

The separation of a mixture of geometric isomers may be tarried out, for example, by fractional crystallization . 0 or by separation on column chromatography.

The separation of the isomers, e.g. Z and E isomers, into the single isomers, may be performed on the end-products of formula (I), or on the intermediate products thereof.

In the processes described in the specification, when required, reactive functional groups may be protected with suitable pro¬ tecting reagents, which may be removed after the reaction by known methods, which are available from the chemical literature.

The compounds of formula (II) can be obtained by reducing a compound of formula (VII)

•n> B

C ' II

CH

\ (VII)

CCW

wherein

A and B are as defined above and W is e.g. halogen, in particular chlorine, or lower alkoxy, through a suitable selective reducing agent.

In particular when W is chlorine, triterbutoxy lithium aluminium hydride can be used, analogously when W is lower alkoxy, di- isobutyl aluminium hydride can be used, as described respective e.g. in Eur. J. Med. Chem. 1984, 19, 235 or in J. Org. Chem.

1976, 41, 3512.

The reaction can be performed in organic solvents, e.g. tetrahydrofuran, diglyme or toluene, at temperatures rang¬ ing from about -60 ^β C to about 20°C. Alternatively the compounds of formula (II) can be obtained by reacting a compound of formula (VIII)

B-CfC-CHO (VIII)

wherein B is as defined above, with a hydroxy derivative of formula A-OH , in which A i _{ε as} defined above. The reaction can be performed in a suitable C 1-C4. alkanol, e.g. methanol or ethanol, in the presence of a basi agent e.g. pyridine, as described e.g. in J. Chem. Soc. Perk I, 1981, 1103, or in aprotic dipolar solvents e.g. DMF o D SO.

The compounds of formula (IV) can be obtained e.g. by reacti a compound of formula (VII), in which W is halogen, e.g. chlorine, with an aqueous solution of an amine of formula

HNR R , in which and are as defined above, at room temperature.

The same reaction may be performed by using a compound of formula (VII) wherein W is lower alkoxy, e.g. C.-C alkoxy, preferably methoxy or ethoxy, and a DMF, DMA or dioxane solution of the amine HNR R , at a temperature ranging from about 80°C to about 100°C.

The compounds of formula (V) can be obtained by reducing a compound either of formula (II) or of formula (VII) into the corresponding alcohol and then converting the alcoholic group into a Z leaving group, as defined above. Reduction of a compound of formula (II) is preferably obtained through an alkaline boronhydride, e.g. NaBH., in a lower alkanol. Similarly reduction of a compound of formula (VII) is prefer¬ ably carried out by LiAlH in diethylether or tetrahydrofuran at temperatures ranging from about -10 ^β C to about 50 ^β C. The subsequent conversion of the alcoholic group into a Z leaving group can be obtained by reaction e.g. of mesyl- or tosyl-chloride or of a reactive derivative of trifluoroacetic acid, e.g. trifluoro acetic anhydride,on the alkaline salt - of the alcohol, in an aprotic dipolar solvent, such as DMF or DMSO, so as to obtain a compound of formula (V) in which Z is mesyloxy or tosyloxy or respectively trifluoroacetate. By reacting the alcohol with triphenylphosphine and CC1., as described in J. Org. Chem. 1972, 37, 1466, can analogously be obtained a compound of formula (V) in which Z is chlorine. The compounds of formula (VII) wherein W is lower alkoxy, e.g C C --CC aallkkooxxyy, can be obtained starting from a compound of formula (IX)

wherein A and B are as defined above, trough reaction wit a Wittig reagent, e.g. a phosphorous ylide of formula (X)

Θ ©

(Q) P-CH-COW' (X)

wherein 0 is C -C alkyl or aryl e.g. phenyl and W'is lower alkoxy, according e.g. the procedure described in French

Patent No. 24B0283.

A co rTun of formula (VII) wherein W is halogen e.g. chlori can be obtained e.g. 1) by hydrolizing the corresponding carboxylic ester of formula (VII) to the free carboxylic aci e.g- by basic hydrolysis in an alcoholic or aqueous-alcoholi medium and then 2) heating the sodium salt of the carboxylic acid and dichloromethyl-methylether at temperatures from abo 50 ^β C to about 100 ^e C, as described e.g. in Ber. 1969, 92, 83.

The compounds of formula (III), (VI), (VIII), (IX) and (X) are known or may be obtained by following known methods in organic chemistry.

Object of the present invention are also the compounds of formula (II)

_^ ° ^B A C

II

CH (ID

CHO

wherein

each of Λ and B, independently, is a group of formula (i) to (iii)

wherein Y is -0-, -S- or -NR- in which R is hydrogen or C ₁ -C ₆ alkyl;

each of R 3, R4 R5 and R independently is a) hydrogen, halogen, hydroxy, cyano or nitro; b) C,-C_ alkyl unsubstituted or substituted by halogen,

1 6 c ) C -C . alkoxy or C , -C . alkyl thio ; l b l

d ⁾ C^C _g alkyl-sulfonyl ;

e ) a -NR R group in which each of R and R , independently ,

7 8 » 8 is hydrogen or C -C_ alkyl; or one of R_ and R_ is hydrogen

I D 7 B or C,-C_ alkyl and the other is a -C0R_ group, wherein R

1 o 9 9 is hydrogen, C.-C. alkyl, C,-C_ alkoxy or -NR,_R,, in which

1 6 1 6 1U 11 each of R._ and R,. is independently hydrogen or C,-C alkyl lu ll f) a - ^C0R ₁₂ 8 ^rou P wherein R _χ? is C^ _^ -C alkoxy, C -C alkyl or -NR.,.-*-*,, wherein R and i are as defined above; or g) two adjacent of R_, R., R. and R , taken together, form

3 4 o _a C ₁ -C ₄ alkylenedioxy group; and wherein, when both of

A and B are as defined under (i), and A is an unsubstituted o a p-NO substituted phenyl ring, then at least one of the remaining subεtituents either on the A or B ring is other than hydrogen; which are new and are useful intermediate products, according to process a) herein described.

PHARMACOLOGY

The compounds of the present invention can be used as drugs, in particular drugs active on the central nervous system, in particular as antidepressant,antiobesity, antis oking and anti -alcoholabuse agents.

The antidepressant activity was evaluated for example in mice on the basis of the prevention of reserpine-induce blepharospasm and hypothermia. Reserpine was administered endoperitoneally at a dosage of

2.4 mg/kg, and the tested compounds were orally administered 30 minutes before the administration of reserpine. Recording of blepharospasm evaluated in scores according to the techn que described by Rubin B. et al. in J.Pharmacol. ,1957, 120, 125] ans measurement of body temperature (by means of a rectal thermocouple) were taken an hour, and respectively four hours after the administration of reserpine. Some activity data of a representative group of compounds according.to the present invention are shown in the followin table in comparison with a reference compound.

Table

BLEPH. = Blephqrospasm HYP0TH.= Hypothermia

The compounds of the invention have been found to be active in regulating biogenic amines balance, e.g. by inhibi¬ tion of reuptake of noradrenal ine and/or dopa ine and/or serotonine Therefore the compounds of the present invention can be used i 5 the alleviation, treatment and amelioration of numerous illnes ses which are sensitive to changes in biogenic amines balance. By virtue of their activity the compounds of the invention can be used not only as antidepressants but also as anti-obesity, anti-smoking and anti-alcohol abuse agents.

¹⁰ The toxicity of the compounds of the invention is low, there¬ fore they can be safely used in therapy. Nine hours food de¬ prived mice were treated orally with single administration of increasing doses, then housed and normally fed. The orientative acute toxicity (LD ) was assessed on the seventh day after the

•■■•5 treatment.

The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories, parenterally , e.g.

20 intramuscularly, or by intravenous injection or infusion. The dosage depends on the age, weight, conditions of the patient and administration route; for example the dosage adopted for oral administration to adult humans of the compσind (Z)e(-phenoxy-tf-phenyl- -β-methylaminomethyl ethylene ranges from about 2 to about 100 mg pro dose, 5 from ι to 5 times daily. The invention includes pharmaceutical cαrpositions

comprising a compound of the invention in association with a pharmaceutical¬ ly acceptable excipient (which can be a carrier or diluent). The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional method and are administered in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, sac¬ charose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, ethylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervesc¬ ing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbateε, laurylsulphates; and, in general, non- toxic and pharmacologically inactive substances used in pharma¬ ceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film coating proces- ses.

The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or, saccharose with glycerine and/or mannitol and/or sorbitol. The suspensions and the emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methyl- cellulose, carboxymethylcellulose, or polyvinyl alcohol. The

suspensions or solutions for intramuscular injections may conta together with the active compound, a pharmaceutically accept¬ able carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions*.

The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. cocoa- butter, polyethylene glycol, a polyoxyethylene εorbitan fatty acid ester surfactant or lecithin.

The following examples illustrate but do not limit the inven- tion.

9

- 26 -

Example 1

A solution of 1.12 g (5x10 -3 moles) of (E) 3-phenoxy-3-

« phenylpropenal and 2 ml (2x5x10 moles) of 36# aqueous methylamine in 8 ml of methanol is treated with 0.19 g _3 (5x10 moles) of NaBH added in portions under stirring over 45 min, keeping the temperature below 10 ^β C.

The reaction is allowed to rise at room temperature and poured after 1 h in water, extracted with ethyl acetate, washed with water, dried over Na _? S0 and evaporated to dryness. -

The residue is purified by flash chromatography (mobile phase: chloroform/ methanol/ 309έ ammonium hydroxide = 190/10/1) to obtain 2.73 g of free base which is treated with 0.176 g of fumaric acid in ethanol/diethylether to obtain 0.68 g of (E) c*-phenoxy-< ^* Λ-phenyl-β-methylaminomethyl-ethylene hemi¬ fumarate m.p. 121-124°C.

Analogously and if desired using the suitable salif ing agents, the fol¬ lowing compounds can be obtained:

(Z)o(-phenoxy-^-phenyl-β-methylaminomethyl-ethylene hemifumara m.p. 140-144 ^e C;

- -phenoxy-o*V-phenyl- ^β -propargyl aminomethyl-ethylene fumarate (E) isomer m.p. 131-136°C, (Z) isomer m.p. 126-127 ^e C; <* _* -( 2-ethoxyphenoxy)-cX-phenyl-β-methylaminomethyl-ethylene hem fumarate (E) isomer m.p. 165-167 ^e C, (Z) isomer m.p. 140-141 ^e C

^•• ^- ⁽ 2-c ^hl oro ^p henoxy ⁾ -< -phenyl- ^β -methylaminomethyl-ethylene hemifumarate (E) isomer m.p.152-155 ^e C, (Z)isσmer m.p. 177-181 ^e C; ^o - ⁽ 3-hydroxyphenoxy K- (phenyl )-β-methylaminomethyl-ethylene; hemifurate (E) isomer m.p. 193.5 - 198°C; ⁽ E ⁾ - - ⁽ 2, ⁶ - ^d i chl orophenoxy ⁾ - ^< - ⁽ phenyl)- ^β -methy laminome thy 1-e thy le dr ⁽ 3, ⁴ -dichlorop ^h enoxy ⁾ -c phenyl ⁾ - ^β -methylaminomethyl-ethyle hemifu arate (E) isomer m.p.l37-141 ^e C ,(Z) isomer m.p.159-162 ^e < - ⁽ 3, 4-me thy lenedi oxyphenoxy )-W,-( phenyl )-β-me thy la inome thy 1 - ethyl ene ; . ^- ⁽⁴ -trifluoromethylphenoxy)-Λ-(phenyl)-β-methylaminomet hyl- ethylene hemifumarate (E) isomer m.p. 144-148 ^e C, (Z) isomer m.p. 135-140°C;

•o^-(2-nitrσphenoxy)-c-(phenyl)-β-methylaminomehtyl-e thylene; o\-(2-aminophenoxy)-o-,-(phenyl)-β-methylaminomethyl-ethyle ne; e^-(2-ur ido-phenoxy)-cλ-(phenyl )-β-methylaminomethy1-ethylene;

^-(2-thienylσxy)-cK-(phenyl)-β-methylaminomethyl-ethyle ne; {-( 1-naphthyloxy)-σ,-(phenyl)-β-methylaminomethyl-ethylene; o ^* (-(2-naphthyloxy)-c phenyl)-β-methylaminomethy1-ethylene;

^Q (-(4-cyanophenoxy)-( -pheny1-β-methylaminomethy1-ethylene hemifumarate (E) isomer m.p. 159-163°C, (Z) isomer m.p.

130-136°C; o(-(3-chlorophenoxy)-^-phenyl-β-methylaminomethy1-ethylene hemifumarate (E) isomer m.p. 123°C, (Z) isomer m.p.

174-178°C; o(-(4-chlorophenoxy)-6c;-phenyl-β-methylaminomethyl-ethylen e hemifumarate (E) isomer m.p. 147-150°C, (Z) isomer m.p.

135-138°C;

^-(2-methylphenoxy)-oC-phenyl-β-methylaminomethyl-ethylene hemifumarate ( ^£ ) isomer m.p. 139.5 - 140°C, (Z)isomer m.p. 179-182°C; σ(-(2,6-dimethoxyphenoxy)-#-phenyl-β-methylaminomethyl- 5 ethylene hemifumarate (E) isomer m.p. 181.5-184°C; o(-(4-nitrophenoxy)-ύ(-phenyl-β-methylaminomethy1-ethylene hemifumarate (E) isomer m,p. 153.5°C; o-(3,4-dimethoxyphenoxy)-<X,-phenyl-β-methylaminomethyl- ethylene (E) isomer (fumarate) in.p. 100-lϋ5°C, (Z) isomer ^lt -' (hemifumarate) m.p. 145-149°C; o-(2-methoxyphencxy)-σ(-phenyl-β-methylaminomethyl-ethylen e hemifumarate (E) isomer m.p. 145.5-149.5°C, (Z) isomer m.p.

185-191°C; v>(-(4- acetylphenoxy )-ύ-phenyl-β-methylaminomethyl-ethylene 15 ^' fumarate (E) isomer m.p. 77-87°C, (Z ) isomer m.p.118-122°C; -(3-methoxyphenoxy)-0-phenyl-β-methylaminomethyl-ethylene:

0<r( 4-methoxyphenoxy )-o-phenyl-β-methylaminomethyl-ethylene ; ς - ( 4-cyano-3-me thoxy-phenoxy ) -o(-phenyl-β-me thylaminome thyl- ethylene; 20 0<-(2-cyanophenoxy)-0(-phenyl-β-methylaminomethyl-ethyle ne : o<-(3-cyanophenoxy)-l\-phenyl-β-me thylaminome thyl-ethylene;

0- ( 4-me thylsulf onylphenoxy ) -0-phenyl-β-me thylaminome thyl- ethylene;

0<-phenoxy-0(- ( 2-thienyl ) -β-me thylaminome thyl -eth l ene ; 25 ø(-phenoxy-0(- ( 3-chlorophenyl )-β-methylaminomethyl-ethylene ;

° 4-chlorophenyl )-β-methylaminomethyl-ethylene; ci -phenoxy-K-(2-hydroxyphenyl)-β-methylaminomethyl-ethylene; o{-phenoxy-K-O,4-methylenedioxyphenyl)-β-methylaminomethyl- ethylene hemifurate (E) isomer m.p. 145-149°C, (Z) isomer m.p. 147-151°C; c -(phenoxy-^-(3-methσxyphenyl )-β-methylaminomethyl- ethylene hemifumarate (E) isomer m.p. 135.5-138.5°C, (Z) isomer m.p. 144.5-148.5°C.

Example 2

Aluviinium hydride suspension is prepared in situ by addi tion of a

_2 solution of 1.3 g (1x10 moles) of aluminium chloridiee i:n -2

30 ml of ether to a stirred suspension of 1.2 g (3x10 moles) of lithium aluminium hydride in 75 ml of anhydrous tetrahydrofuran and 30 ml of ether at 10-15°C.

_2 A solution of 2.53 g (1x10 moles) of (E) N-methyl-q-'- phenoxy-cinnamoylamide in 15 ml of anhydrous tetrahydrofuran is dropped into the suspension previously prepared.

The reaction mixture is stirred at 30-35°C for 4h, then is cooled and decomposed by the addition of 3 ml of H O, 3 ml of 20% NaOH, and 5 ml of H O.

The mixture is filtered and concentrated to dryness. The residue is purified by flash chromatography (mobile phase: chloroform/methanol/30% ammonium hydroxide =190:10:1) to have 1.05 g of free base which is treated with 0.25 g of fumaric acid in methanol/diethylether to obtain 0.90 g

of (E)!X-phenoxy-Cf _\ -phenyl-β-methylaminomethyl-ethylene hemifumarate m.p. 121-124°C.

Analogously and if desired, using the suitable salifyng agents, the following compounds can be obtained: (Z)0^-(phenoxy)-&(-(phenyl)-β-methy1aminomethy1-ethylene hemifumarate m.p. 140-144°C;

θ -(2-ethoxyphenoxy)-θ(-phenyl-β-methylaminomethyl-ethylene hemifumarate (E) isomer m.p. 165-167°C, (Z) isomer m.p. 140-141°C; o(-(2-chlorophenoxy)-i -phenyl-β-methylaminomethyl-ethylene hemifumarate (E) isomer m.p. 152-155°C, (Z)isomer m.p. 177-181°C; j-(3,4-dichlorophenoxy)-o-(phenyl)-β-methylaminomethyl- ethylene hemifumarate (Ξ) isomer m.p. 137-141°C,(Z) isomer m.p. 159-162°C;

< -(3,4-methylenedioxyphenoxy) -0[-(phenyl)-β-methylaminomethyl- ethylene; _θ -(4-trifluoromethylphenoxy)-{^-(phenyl )-β-methylaminomethyl- ethylene hemifumarate (E) isomer m.p. 144-148°C, (Z) isomer m.p. 135-140°C;

^e ^-(l-naphthyloxy)-«\-(phenyl)-β-methylaminomethyl-et hylene; <Λ-(2-naphthyloxy)-**.-(phenyl)-β-methylaminomethyl-eth ylene; o^-phenoxy-o^-O-chlorophenyl)-β-methylaminomethyl-ethylene; ©(-phenoxy-Λ-(4-chlorophenyl)-β-methylaminomethyl-ethylen e; ctf-phenoxy-Λ-(3,4-methylenedioxyphenyl)-β-methylaminometh yl- ethylene; and c*-phenoxy-c-(3-methoxyphenyl)-β-methylaminomethyl-ethylene .

Examp e 3 To a stirred suspension of 0.19 g (4.77x10 -3 moles) of 60% NaH in 5 ml of anhydrous DMF, 1.08 g (4.77 _x 10~ ³ moles) of (E)

3-phenoxy cinna yl alcohol, in 10 ml of anhydrous DMF, is added at 10°C.

After an hour at room temperature, a solution of 0.85 g

_3 (4.5x10 moles) of p.toluenesulfonyl chloride in 7 ml of anhydrous DMF is added dropwise and heated at 40 ^e C for 4 h.

The mixture is poured in water and extracted with ethyl acetate, washed with water, dried over Na.SO. and evaporated to dryness.

The crude oil, residue (1.7 g) is used for t"he next step without further purification. To a solution of 1.7 g (4.4x10 -3 moles) of the crude tosylate

-2 in 30 ml of methylene chloride, 0.90 ml (13.2x10 ΠΓDI ) of proparg 1 ami is added inder stirring at room temperature.

After 1 hour, the reaction is heated at 50-60 ^e C for 3 h. After work-up the residue obtained is purified by flash crhomatography (mobile phase: ethyl acetate/hexane = 100/100)to obtain 0.2 g of the free base, which is trea- 5. ted with 0.088 g of fumaric acid in methanol/diethyle¬ ther to give 0.22 g of (E) « -phenoxy-øC-phenyl-β-propar- gylaminomethy1-ethylene fumarate m.p. 131-136°C.

Analogously and if desired using the suitable salifying agents, the following compounds can be obtained:

10. (Z)-χ-phenoxy-tf-phenyl-β-methylaminomethy1 ethylene hemifumarate m.p. 140-144°C; o-(2-ethoxyphenoxy)-oC-phenyl-β-methynaminomethyl ethylene hemifumarate (E) isomer m.p. 165-167°C, (Z) isomer m.p. 140-141°C;

15. oi-(2-chlorophenoxy)-Λ-pheny1-β-methylaminomethy1-ethylene hemifumarate (E) isomer m.p. 152-155°C, (Z) isomer m.p. 177-181°C; ø(-(3-hydroxyphenoxy)-^-(phenyl)-β-methylaminomethyl- ethylene;

20. oL-(4-hydroxyphenoxy) -&.-(phenyl)-β-methy1aminomethy1-ethy- lene; o-(3,4-dichlorophenoxy)-#-(phenyl)-β-methylaminomethyl- ethylene-hemifumarate (E) isomer m.p. 137-141°C, (Z) isomer m.p. 159-162°C;

25. oc-(3,4-methylenedioxyphenoxy) -ύ(-(phenyl)-β-methylamino¬ methyl-ethylene;

c^-( -1rifluoromethylphenoxy)-o(-(phenyl )-β-methy1aminome- thyl-ethylene hemifumarate (E) isomer m.p. 144-148°C,

(Z) isomer m.p. 135-140°C;

⁽ X-(2-nitrophenoxy)-x-(phenyl)-β-methylaminomethyl-eth ylene; 5. o-.-(2-aminophenoxy)-0(-(phenyl)-β-methylaminomethyl-ethyle ne;

0(-(2-ureido-phenoxy)-θ(-(phenyl)-β-methylaminomethyl- ethylene ;

<χ-(2-thienyloxy)-0(-(phenyl)-β-methylaminomethyl-et hylene ;

Λ-( 1-naphthyloxy)-#-(phenyl )-β-methylaminomethyl-ethylene; 10. <λ- ( 2-naphthyloxy)-0(-(phenyl )-β-methylaminomethyl-ethylene ; o-phenoxy-( -( 2-thienyl)-β-methylaminomethyl-ethylene ; o-phenoxy-o<-( 3-chlorophenyl)-β-methylaminomethyl-ethy- lene ; c<-phenoxy-c-<- ( 4-chlorophenyl ) -β-methylaminomethyl-ethy- 15. lene ; c -phenoxy-o<-( 2-hydroxyphenyl )-β-methylaminomethyl-ethy- lene ;

°-phenoxy-o-(3,4-methylenedioxyphenyl)-β-methylamino- methyl-ethylene; and 20. 0(-phenoxy-o-(3-methoxyphenyl)-β-methylaminomethyl-ethylene .

Example 4

_2 A mixture of 3.0 g (1.18 x 10 moles) of (E) methy1-

3-phenoxy cinnamate (Gazz. Chim. ital. 1981, 111, 249) and 15 ml of 36% aqueous methylamine in 35 ml of dioxane

5. is placed in a bomb at 80°C for 24 h.

After cooling, the solution if concentrated, poured into water and extracted with ethyl acetate, washed with water, dried over Na SO and evaporated to drynesε. The crude residue (Ξ) N-methyl-tf-phenoxy-cinnamoylamide

10. is used for the next step without further purification.

Analogously, the following compounds can be obtained: (E) N, N-dimethyl-o(-phenoxy-cinnamoylamide; (E) N-ethyl-o(-phenoxy-cinnamoylamide; and (E) N,N-diethyl-ø(-phenoxy-cinnamoylamide.

15. Example 5

—3 A solution of 0.5 g (2.5 x 10 moles) of (Z) #-phenoxy-

© ^* _\ -phenyl-β-methylaminomethyl-ethylene and 1.65 ml of

37% aqueous formaldehyde in 10 ml of methanol is heated under reflux for 45 min.

_3 20. The solution is cooled and 0.165 g (4.37 x 10 moles) of NaBH is added in small portions at 10°C, under stir¬ ring, over 30 min. After 1 h the solution is poured

into water, extracted with ethyl acetate, washed with v/ater, dried over Na SO and evaporated to dryness to give 0.56 g of the free base which is treated 0.27 g of fumaric acid in metnanol-dimethyl ether to give 0.6 g

5. of (Z).'<-phenoxy-ft-phenyl- ^β -dimethylamiDomethyl-ethylene fumarate m.p. 138-140°C.

Analogously ar.d i desired using the suitable salifying agents, the following compounds can be obtained: (E)o(-phenoxy-e -phenyl-β-dimethyl minomethyl-ethylene fumarate m.p. 168-170°C;

10. o-(2-ethoxyphenoxy)-<-phenyl-β-dimethylaminomethyl- ethylene; o(-(2-chlorophenoxy)-< -phenyl-β-di ethylaminomethyl- ethylene; o-(3, 4-dichlorophenoxy)-c<-(phenyl )-β-methylaminomethy1-

15. ethylene;

0(-(3,4-methylenedioxyphenoxy)-o(-(phenyl)-β-dimethyla- mino ethyl-ethylene; o(-(4-trifluoromethylphenoxy) -0- (phenyl)-β-dimethyla¬ minomethyl-ethylene;

20. cχ-(2-nitrophenoxy)-tf-(phenyl)-β-dimethylaminomethyl- ethylene; o(-(2-ureido-phenoxy)-o<'-(phenyl)-β-dimethylaminomethyl - ethylene; o<-(2-thienyloxy)■*■©(-(phenyl)-β-dimethylaminometh yl-

25. ethylene;

o<-(l-naphthyloxy ) -θ(- {phenyl)-β-dimethylaminomethyl- ethylene; o-(2-naphthyloxy)-#-(phenyl)-β-dimethylaminomethyl- ethylene;

5. o(-phenoxy-0(-(2-thienyl)-β-dimethylaminomethyl-ethylene; _C ^-(2-aminophenoxy)-o<'-phenyl-β-dimethylaminomethy l-ethy¬ lene; o-phenoxy-o^-(3-chlorophenyl)-β-dimethylaminoπethyl- ethylene;

10. X'-pheno ^' xy-0-(4-chlorophenyl)-β-dimethylaminomethyl- ethylene; o-phenoxy-c-r-(3,4-methylenedioxyphenyl)-β-dimethy1ami- nomethyl-ethylene; and 0^phenoxy-X-(3-methoxyphenyl)-β-dimethylaminomethyl-

15. ethylene.

Example 6

_2 To a solution of 2.39 g (1 x 10 moles) of (E)^-phe- noxy-σ(-phenyl-β-methylaminomethyl-ethylene in 20 ml of

_3 methanol 0.58 g (5 x 10 moles) of fumaric acid in 10 ml

20. of methanol is added, obtaining a complete solution, which is concentrated to dryness. The residue is ground in diethylether and filtered to give 2.50 g of (E) oC-phenoxy-^-phenyl-β-methylaminomethyl-ethylene hemi¬ fumarate m.p. 121-124°C.

Analogously, the following compounds can be obtained as hemifumarate:

(Z)o(-phenoxy-o<-phenyl-β-methylaminomethyl-ethylene m.p. 140-144°C

5. (E)£^-(2-ethoxyphenoxy)-C-phenyl-β-methylaminomethyl- ethylene m.p. 165-167°C

(Z)o(-(2-ethoxyphenoxyJ-Λ'-phenyl-β-methylaminomethyl- ethylene m.p. 140-141°C (E)-*-(4- riiluoromethylphenoxy)-c-(phenyl)-β-methyla-

10. minomethyl-ethylene m.p. 144-148°C

( b(-(4-trifluoromethylphenoxy ) -o -(phenyl)-β-methyla- mino ethyl-ethylene m.p. 135-140°C.

Example 7

Tablets, each weighing 150 mg and containing 500 mg 15. of the active substance can be manufactured as follows;

Composition (for 10.000 tablets) (E)ø(-phenoxy-α-phenyl-β-methylaminomethyl- ethylene hemifurate 500 g

Lactose 710 g

20. Corn starch 237.5 g

Talc powder 37.5 g

Magnesium stearate 15 g

(E)o(-phenoxy-o('-phenyl-β-methylaminomethylethylene hemifurate, lactose and a half of the corn starch are mixted; the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (18 g) is suspended in warm water (180 ml).

The resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve of size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed, and processed into tablets using punches of 8 mm diameter.