NEW ARYL- AND HETEROARYLETHENYLENE DERIVATIVES AND PROCESS FOR THEIR PREPARATION

The present invention relates to new aryl- and heteroaryl- ethenylene derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents.

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

wherein

Y is a mono- or bicyclic ring system chosen from (A), (B), (C), (D), (E), (F) and (G)

R is a group of formula (a), (b), (c), (d), (e), (f), (g), (h), (i) or (j)

CN CN CN -CH=C-COR, -CH=C-CN -CH=C-' CSNH,

(a) (b) (c)

in which R is -OH or -NH_ and Ph means phenyl; R^ _^ is hydrogen, C^-C. alkyl or C -C alkanoyl; R is hydrogen, halogen, cyano or C, -C. alkyl; n is zero or an integer of 1 to 3: n is zero

or an integer of 1 to 3 when Y is a ring system (A); it is zero, 1 or 2 when Y is a ring system (B), (E), (F) or (G); or it is zero or 1 when Y is a ring system (C) or (D); and the pharmaceutically acceptable salts thereof; and wherein each of the substituents R, OR ₁ and R_ may be independently on either of the aryl or heteroaryl moieties of the bicyclic ring system (A), (E), (F) and (G), whereas only the benzene moiety may be substituted in the bicyclic ring system (B).

The invention includes within its scope all the possible iso ers, stereoisomers, in particular Z and E isomers and their mixtures, and the metabolites and the metabolic precursors or bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I).

The εubstituent R is preferably linked to position 1 σr 2 in ring system (A) and (B), to position 4 in ring system (C) and (D), to position 5 or 8 in ring system (E) and (F) and to position 3 or 7 in ring system (G). The substituent R. may be independently on either of the rings in the bicyclic ring systems (A), (B), (E), (F) and (G). When Y is a bicyclic ring system as defined under (A), (E) or (F) the -OR _j groups are preferably on the same benzene moiety as the R group. In any of ring systems (A) to (G) the substituent R- is preferably located on the same 6-membered ring as the substituent -OR ₁ in the ortho-, meta- or para- position with respect to -OR _j . Preferably R ₂ is located in a position ortho- or para- to -OR _j .

A εubstituent -OR _χ is preferably linked to position 1, 2, 3, 4, 5 or 8, in particular to position 1, 2 , 3 or 4, in ring systems (A) and (B). A εubstituent -OR ₁ is preferably linked to position 2 , 3, 4 or 5, in particular to position 3, 4 or 5, in ring systems (C) and (D). A subεtituent -OR. is preferably linked to position 3, 4, 5, 6, 7 or 8, in particular to position 5, 6, 7 or 8, in ring system (E) and (F). A substituent -OR ₁ is preferably linked to position 3, 4, 5, 6 or 1 , in particular to position 4, 5,

6 or 7 in ring system (G). Of course only one of the substituents R, -0R _χ and R_ can be linked to the same position in ring systems (A) to (G).

When n is 2 or 3, the -OR ₁ groups may be the εame or different. »

The alkyl groups, and the alkyl moiety in the alkanoyl groups, may be a branched or straight alkyl chain. A C _χ -C ₆ alkyl group is preferably a C ₁ -C ₄ alkyl group, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert- butyl, in particular methyl or ethyl. A C ₂ -C ₆ alkanoyl group is preferably a C_-C _< alkanoyl group, in particular acetyl, propionyl or butyryl.

A halogen is, preferably, chlorine, bromine or fluorine, in particular bromine.

Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts, with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acids, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic,. malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids, and salts with inorganic, e.g. alkali metal, especially sodium or potassium, bases or alkaline-earth metal, especially calcium or magnesium bases, or with organic bases, e.g. alkylamines, preferably triethyl-a ine.

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

- r-

chosen from Y is a monocyclic or bicyclic ring system/ (A) to ( G ) , as defined above;

R is a group of formula (a), (b), (c), (d), (e), (i) or (j) as defined above; R is hydrogen, C_-C alkyl or C--C alkanoyl;

R is hydrogen; n is a defined above; and the pharmaceutically acceptable salts thereof.

More preferred compounds of the inventionare the compounds of formula (I), wherein

Y is a bicyclic ring system of formula (A), (B) or (E), as defined above;

R is a group of formula (a) , (d),(e)-(i) or (j), as defined above; ^ and R.are hydrogen ; n is zero or 1; and the pharmaceutically acceptable salts thereof.

- - -

Examples of specific compounds of the invention are the following compounds which, when appropriate, may be either

Z- or E- diastereomers or Z, E- mixtures of said diastereomers ^;

2-cyano-3- (2-hydroxynaphth-l-yl)acrylamide;

2-cyano-3- (3-hydroxynaphth-l-yl)acrylamide;

2-cyano-3- (4-hydroxynaphth-l-yl)acrylamide;

2-cyano-3- (l-hydroxynaphth-2-yl)acrylamide;

2-cyano-3- (3-hydroxynaphth-2-yl)acrylamide;

2-cyano-3- (4-hydroxynaphth-2-y1)acry1amide;

2-cyano-3- (2-hydroxynaphth-l-yl)acrylic acid;

2-cyano-3- (3-hydroxynaphth-l-yl)acrylic acid;

2-cyano-3- (4-hydroxynaphth-l-yl)acrylic acid;

2-cyano-3- (l-hydroxynaphth-2-yl) acrylic acid;

2-cyano-3- (3-hydroxynaphth-2-yl) acrylic acid;

2-cyano-3- (4-hydroxynaphth-2-yl) acrylic acid;

2-cyano-3- (2-hydro.cy.naphth-l-yl)thioacrylamide;

2-cyano-3- (3-hydroxynaphth-l-yl)thioacrylamide;

2-cyano-3- (4-hydroxynaphth-l-yl)thioacrylamide;

2-cyano-3— (' l-hydroxynaphth-2-yl)thioacrylamide;

2-cyano-3- (3-hydroxynaphth-2-yl)thioacrylamide;

2-cyano-3- (4-hydroxynaphth-2-y1)thioacrylamide; 2-(4-hydroxyphenyl)-3-(naphth-1-yl)acrylamide; 2-(4- ydroxyphenyl)-3-(naphth-2-yl)acrylamide; 2-(4-hydroxyphenyl)-3-(naphth-l-yl)acrylic acid; 2-(4-hydroxyphenyl)-3-(naphth-2-yl)acrylic acid;

-?-

2-cyano-3- 2-hydroxy-5,6,7,8-tetrahydronaphth-l-yl)acrylamide;

2-cyano-3- 3-hydroxy-5,6,7,8-tetrahydronaphth-l-yl)acrylamide; -

2-cyano-3- !4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylamide;

2-cyano-3- l-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide ;

2-cyano-3- 3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide;

2-cyano-3- 4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide;

2-cyano-3- 2-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylic acid;

2-cyano-3- ^' ,3-hydroxy-5,6,7,8-tetrahydronaphth-l-yl)acrylic acid;

2-cyano-3- 4-hydroxy-5,6,7,8-te rahydronaphth-1-yl)acrylic acid;

2-cyano-3- l-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylic acid;

2-cyano-3- ^' 3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylic acid;

2-cyano-3- 4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylic acid

2-cyano-3- 2-hydroxy-5,6,7,8-tetrahydronaphth-l-yl)thioacrylamid

2-cyano-3- 3-hydroxy-5,6,7,8-tetrahydronaphth-l-yl)thioacrylamid

2-cyano-3- 4-hydroxy-5,6,7,8-tetrahydronaphth-l-yl)thioacrylamid

2-cyano-3- l-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) hioacrylamid

2-cyano-3- ^' 3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)thioacrylamid

2-cyano-3- ^' 4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)thioacrylamid 2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-1-yl)acrylam ide; 2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-2-yl)acrylam ide; 2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-1-yl)acrylic aci 2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-2-yl)acrylic aci 2-cyano-3-(3-hydroxyquinolin-2-yl)acrylamide; 2-cyano-3-(4-hydroxyquinolin-2-yl)acrylamide; 2-cyano-3-(2-hydroxyquinolin-3-yl)acrylamide;

2-cyano-3-(4-hydroxyquinolin-3-yl) crylamide; 2-cyano-3- (2-hydroxyquinolin-4-yl)acrylamide; 2-cyano-3- (3-hydroxyquinolin-4-yl)acrylamide; 2-cyano-3- (3-hydroxyquinolin-2-yl)acrylic acid; 2-cyano-3- (4-hydroxyquinolin-2-yl)acrylic acid; 2-cyano-3- (2-hydroxyquinolin-3-yl)acrylic acid; 2-cyano-3- (4-hydroxyquinolin-3-y1)acry1ic acid; 2-cyano-3- (2-hydroxyquinolin-4-yl) crylic acid; 2-cyano-3- (3-hydroxyquinolin-4-yl)acrylic acid; 2-cyano-3- (3-hydroxyquinolin-2-yl)thioacrylamide; 2-cyano-3- (4-h ^' ydroxyquinolin-2-yl)thioacrylamide; 2-cyano-3- (2-hydroxyquinolin-3-yl) hioacrylamide; 2-cyano-3- (4-hydroxyquinolin-3-yl)thioacrylamide; 2-cyano-3- (2-hydroxyquinolin-4-yl)thioacrylamide; 2-cyano-3- (3-hydroxyquinolin-4-yl)thioacrylamide;

2-(4-hydroxypheny1)-3-(quinolin-2-y1)acry1amide;

2-(4-hydroxyphenyl)-3-(quinolin-3-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(quinolin-4-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(quinolin-2-yl)acrylic acid;

2-(4-hydroxypheny1)-3-(quinolin-3-yl)aerylie acid;

2-(4-hydroxyphenyl)-3-(quinolin-4-yl)acrylic acid;

3- ^" (3-hydroxy-l-naphthyl)methylene_7-2-oxindole;

3-, ^" (4-hydroxy-l-naphthyl)methylene_7-2-oxindole;

3-/~(l-hydroxy-2-naphthyl)methylene_7-2-oxindole;

3-_T(4-hydroxy-2-naphthyl)methylene_7-2-oxindole;

3- ^* (3-hydroxy-5,6,7,8-tetrahydronaphth-l-yl)methylene_7-2 -oxindole;

3-^ ^" (4-hydroxy-5,6,7,8-tetrahydronaphth-l-yl)methylene.7-2 -oxindole;

3- ^" (l-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)methylene_7-2 -oxindole

3-/f(4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)methylene7-2 -oxindole

3- \7-hydroxyquinolin-5-yl)methylene7-2-oxindole;

S-^δ-hydroxyquinolin-δ-yl)methylene_7-2-oxindole; 3-Z ^* (7-hydroxyquinolin-6-yl)methylene_7-2-oxindole; .3-Z ^* (8-hvdroxyquinolin-6-yl)methylene7-2-oxindole, and, i_ the case, the pharmaceutically acceptable salts thereof.

3 -

The compounds of the invention, and the pharmaceutically acceptable salts thereof, can be obtained by a process comprising the condensation of an aldehyde of formula (II)

wherein

Y, R , R and n are as defined above with a compound of formula (a ¹ ), (b'), (C), (d'), (e ¹ ), (f), (g'), (h ¹ ), (i') or (j ¹ ), respectively,

NC-CH.-COR- NC-CH -CN. NC-CH -CSNH

(a ¹ ) ( b ^< ) (C)

(f) (g'i

- \o -

wherein R and Ph 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 ^.nto a free compound, and/or, if desired, separating a mixture of isomers of a compound of formula (I) into the single isomers. The reaction of a compound of formula (II) with a compound of formula (a ¹ ), (b'), (C), (d ¹ ), (e'), (f), (g ¹ ), (h'), (i' ) or (j' ) , is an analogy process which can be carried out according to known methods, as herebelow described; preferably in the presence of a basic catalyst, e.g. pyridine, piperidine, dimethylamine,or a suitable alkali etal hydroxide or alkoxide. For example the reaction of a compound of formula (II) with acompound of formula (a ¹ ), (b ¹ ), (C), (e ¹ ), (f). (g') or (h ¹ ), respectively, may be carried out under the conditions of the fhoevenagel reactions as described e.g. by G, Jones in Organic Reactions 1_5, 204 (1967). Suitable catalyst are organic bases such as pyridine, piperidine or diethylamine.

The condensation may be performed in an inert organic solvent e«g« pyridine, ethanol, ethanol, benzene or dioxane at temperature ranging from about 0°C to about 100°C. Preferably the reaction is carried out in varm ethanol solution in the presence of piperidine catalyst.

.) -

The reaction of a compound of formula (II) with a compound of formula (d') may be carried out according to the noe- venagel method as described above but using special condition

Especially higher reaction temperatures are used in considera of the fact that during the condensation also a decarboxylati occurs. For instance the condensation may be performed in an organic base such as pyridine (which at same time is solvent and catalyst) at temperatures ranging from about 50° to about

140°C. The reaction of a compound of formula (II) with a compound of formula (i ¹ ) may be carried out as described by R.E. Buckles et al. in J.Am.Chem.Soc. 7_3, 4972 (1951). According to this method equimolar amounts of the aromatic aldehyde and the phenylacetic derivative are reacted in 3-5 molequivalents of acetic anhydride in the presence of about 1 molequivalent triethylamine at temperatures ranging from about 100 to about 40°C.

The condensation of a compound of formula (II) with a compound of formula (j ¹ ) may be carried out in alcoholic solution using a metal alkoxide, e.g. sodium ethoxide, potassium t-butoxide, or a metal hydroxide, e.g. sodium hydroxide, as catalyst;at temperatures ranging from about 0°C to about 100°C. Preferably equimolar amounts of reactants are condensed in ethanol soluti at room temperature in the presence of sodium ethoxide usingab molequivalent for each acidic hydrogen of the latter.

A compound of formula (I) can be converted into another compound of formula (I) according to known methods. For example the de-etherification of a compound of formula (I), wherein one or more Rl. substituents arecl-Co alkyl, so as to

- ιz -

obtain a compound of formula (I) wherein one or more R are substituents / hydrogen may be performed by well known methods in organic chemistry. In the case of a phenolic methyl ether the cleavage can be carried out for » example with boron tribromide as described by J.F.N. McOmie in

Tetrahedron 2_4 , 2289 (1968). It is advisable to use about 1 mole of boron tribromide for each ether/ ⁸ Together with an extra mol of reagent for each group containing a potentially basic nitrogen or oxygen. The reaction may be performed in an inert organic solvent such as methylene chloride, pentane inert, e.g. or benzene under an / nitrogen, atmosphere at temperatures rang¬ ing from about -78°C to about room temperature. The acylation of a compound of formula (I) wherein one or more R substituent is hydrogen, so as to obtain a correspond- ing compound of formula (I) wherein one or more R substituent is a C_-C alkanoyl group, may be obtained by reaction with a reactive derivative of a suitable carboxylic acid, such as an anhydride or halide, in the presence of a basic agent, at • temperatures ranging from about 0°C to about 50°C. Preferably the acylation is carried out by reaction with the respective anhydride in the presence of an organic base, such as pyridine.

Analogously the conversion of a compound of formula (I),

CN wherein R is a group of formula -CH=C-C00H or -CH=CH-C00H, into another compound of formula (I) wherein R is a group of formula -CH=C-C0NH or -CH=CH-C0NH , respectively, may be carried out according to known methods. For example a reactive

derivative of the carboxylic acid, e.g. a suitable halide, preferably the chloride, can be reacted with aqueous ammonium hydroxide solution at a temperature ranging from about 5°C to about 40°C. « The optional salification of a compound of formula (I) 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.

For example the separation of a mixture of geometric isomers, e.g. cis- and trans-isomers, may be carried out by fractional crystallization from a suitable solvent or by chromatography, either column chromatography or high pressure liquid chromato¬ graphy.

The compounds of formula (II) may be obtained according to known methods from compounds of formula (III).

wherein Y, R , R and n are as defined above.

For example the phenolic compound of formula (III) may be treated with chloroform and alkali hydroxides in an aqueous or aqueous alcoholic solution according- to the well known method of Reimer-Tiemann. If the starting material is an aromatic methylether the method described by N.S. Narasimhan et al. in Tetrahedron 31, 1005 (1975) can be applied. Accordingly the

- m -

methylether of formula (III) is lithiated with butyl lithium in refluxing ether. Treatment of the organometallic compound with N-methylformanilide furnishes the formyl derivative. The compounds of formula (III) are known or may.be obtained by known methods from known compounds.

PHARMACOLOGY

The compounds of the present invention possess specific tyrosine kinase inhibiting activity. Hence they can be useful in the treatment of cancer and other pathological proliferative conditions.

Recent studies on the molecular basis of neoplastic transforma¬ tion have identified a family of genes, designed oncogenes, whose aberrant expression causes tumorigenesis. For example, the RNA tumor viruses possess such an oncogene sequence whose expression determinesneoplastic conversion of infected cells. Several of their oncogene-encoded proteins, such as p _P 60 ^V - ^srC , _P 70 ^gag - ^yeS , _P 130 ^{gag"f s} and _P 70 ^gag - ^fgr display protein tyrosine kinase activity, that is they catalys the transfer of the 0 -phosphate from adenosine triphosphate (ATP) to tyrosine residues in protein substrate. In normal cel several growth factor receptors, for example the receptors for PDGF, EGF, θ -TGF and insulin, display tyrosine kinase activit Binding of the growth factor (GF) activates the receptor tyros kinase to undergo autophosphorylation and to phosphorylate closely adjacent molecules on tyrosine.

Therefore, it is thought that the phosphorylation of these

- is- -

tyrosine kinase receptors plays an important role in signal transduction and that the principal function of tyrosine kinase activity in normal cells is to regulate cell growth. Perturbation of this activity by oncogenic tyrcsine kinase that are either overproduced and/or display altered sub¬ strate specificity may cause loss of growth control and/or neoplastic transformationAccordingly, a specific inhibitor of tyrosine kinases can be useful in investigating the mechanism of carcinogenesis, cell proliferation and differen- tiation and it can be effective in prevention and chemothe¬ rapy of cancer and in other pathological proliferative conditions. The tyrosine specific protein kinase activity of these compounds is shown, e.g., by the fact that they are active in the in vitro test described by B. Ferguson et al., in J. Biol. Chem. 1985, 260, 3652.

The enzyme used is the Abelson tyrosine kinase p 60 ^V"abl .

Its production and isolation is performed according to a modification of the method of B. Ferguson et al. (ibidem).

5 As substrate D -casein or (Val )-angiotensin is used. The inhibitor is preincubated with the enzyme for 5 min at 25°C. The reaction conditions are:

100 M MOPS buffer, 10 M MgCl., 2 uM ( - ³² P) ATP (6Ci/mmol), 1 mg/ml -casein /_an alternative substrate is (Val ) angiotensin 11/ and 7.5 _g/ml of enzyme in a total volume of 30 μl and pH 7.0.

The reaction is incubated for 10 min at 25°C.

- I t -

Trichloroacetic acid precipitation of protein is followed by rapid filtration and quantification of phosphorylated substrate by a liquid scintillation counter. Alternatively the reaction mixture is subjected to sodium dotiecyl sulfate - polyacrylamide electrophoresis and the phosphorylated

32 substrate measured by autoradiography or P -counting of the excised spot.

In view of their high activity and low toxicity, the compounds of the invention can be used safely in medicine . For example , the approximate acute toxicity ( LD_ _ ) of the

50 compounds of the invention in the mouse, determined by single administration of increasing doses and measured on the sevent day after the treatment was found to be negligible. The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar of film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; paren- terally, e.g. intramuscularly, or by intravenous injection of infusion; or topically. 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 may range from about 10 to about 150-200 mg pro dose, from 1 to 5 times daily. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response.

The invention includes pharmaceutical compositions compris¬ ing a compound of the invention in association with a pharma¬ ceutically acceptable excipient (which can be a carrier or diluent). The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods 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, saccharose, cellulose, corn starch or potato starch; lubrican e.g. silica, talc, stearic acid, magnesium or calcium stearat and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, ethylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starc alginic acid, alginates or sodium starch glycolate, efferve¬ scing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting sugar-coating or film-coating processes. The liquid dispersion for oral administration may be e.g. syrups, emulsions and suspensions.

The syrup may contain as carrier, for example, saccharose or

- \ β -

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, methylcellulose, carboxymethylcellulose or polyvinyl alcoho The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharma¬ ceutically acceptable 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 infusion may contai 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 sorbitan fatty acid ester surfactant or lecithin.

Compositions for topical application e.g., creams, lotions or pastes, can be prepared by admixing the active ingredien with a conventional oleaginous or emulsifying excipient. The following examples illustrate but do not limit the invention.

-- 1 3 -

Example 1

2-cyano-3-(8-hydroxyquinolin-5-yl) acrylamide [I,Y = E, R = a, R. = R_ = H, n = 1, R.= NH.J

A solution of 5-formyl-8-hydroxyquinoline(173 mg, 1 mmol), cyanoacetamide (92 mg; 1.1 mmol) and piperidine (60 mg,

0.7 mmol) in absolute ethanol (20 ml) is heated for 4 h at

50°C. The reaction mixture is chilled to 0-5°C, the precipitate filtered, the residue washed with ice-cooled ethanol and thendried under vacuum. Pure title compound is so obtained in 70% yield (167 mg).

Compounds of higher purity are obtained by crystallization from ethanol,m.p.275° .

C,_H _o N_0_ requires: C 65.27 H 3.79 N 17.56 13 9 3 2 found : C 65.15 H 3.65 N 17.49 MS m/z 239

IR cm ^"1 (KBr) : 3311000 - 3600 (NH,0H), 2200 (CN), 1690(CONH

1610, 15S0, 1560. 1510 (C = C)

According to the above described procedure the following compounds can be prepared:

2-cyano-3-(2-hydroxynaphth-l-yl)acrylamide; 2-cyano-3-(3-hydroxynaphth-l-yl)acrylamide; 2-cyano-3-(4-hydroxynaphth-l-y1)acrylamide;

- ≥o -

2-cyano-3- ⁽ l-hydroxynaρhth-2-yl) acrylamide;

2-cyano-3- ^■ (3-hydroxynaphth-2-yl) acrylamide;

2-cyano-3- ^• (ι 4-hydroxynaphth-2-yl ) acrylamide ;

2-cyano-3- ^■ (i 2-hydroxy-5 ,6,7, 8-te trahydronaphth-1-yl ) acrylamide ;

2-cyano-3- ^• (l 3-hydroxy-5 , 6,7, 8-te trahydronaphth-1-yl ) acrylamide ;

2-cyano-3- ^■ ((4-hydroxy-5, 6, 7, 8-te trahydronaphth-1-yl ) acrylamide ;

2-cyano-3- ^• (l l-hydroxy-5 ,6,7, 8-te trahydronaphth-2-yl ) acrylamide ;

2-cyano-3- ^• ((3-hydroxy-5, 6, 7, 8-te trahydronaphth-2-yl) acrylamide ;

2-cyano-3- ^■ (l 4-hydroxy-5 , 6 , 7, 8-te rahydronaphth- 2-yl ) acrylamide ;

2-cyano-3- ^■ (l3-hydroxyquinolin-2-yl) acrylamide;

2-cyano-3- ^■ (4-hydroxyquinolin-2-yl)acrylamide;

2-cyano-3- ^• (l -hydroxyquinolin-3-yl ) acrylamide ;

2-cyano-3- •((4-hydroxyquinolin-3-yl) acrylamide;

2-cyano-3- • (( 2-hydroxyquinol in-4-y 1 ) crylamide ;

2-cyano-3- • (( 3-hydroxyquinol in-4-y 1 ) crylamide ;

3-β.1-naphthyl )rnethylene7-2-oxindole ;

3- T 2-hydroxy-l-naphthyl )methylene7-2-oxindole ;

3-Z ^* ( 3-hydroxy-l-naphthyl )methylene7-2-oxindole ;

3- (4-hydroxy-l-rιaphthyl )methylene7-2-oxindole ;

3-/ 2-naphthyl )methylene7-2-oxindole ;

3-A l-hydroxy-2-naphthyl )methylene7-2-oxindole ;

3-/T 3-hydroxy-2-naphthyl )methylene7-2-oxindole ;

3-/T 4-hydroxy-2-rιaphthyl )methylene7-2-oxindole ;

3-/ ^* ( 5,6,7, 8-tetrahydronaphth-l-yl )methylene -2-oxindole ;

3-Z 2-hydroxy-5 ,6,7, 8-tetrahydronaphth-l-yl )methylen§7-2-oxindole ;

3-£( 3-lτydroxy-5 ,6,7, 8-tet ^* r*ahydronaphth-l-yl )me thyleneJ-Σ-oxindole ;

3-Z ^" ( 4-hydroxy-5 ,6,7, 8-tetrahyd ^* _naphth-l-yl )methylene7-2-oxindole ;

3-_ ^" ( 5,6,7, 8-tetr_ayd_Onaphth-2-yl )me thylene7-2-oxindole ;

3- [ l-hydroxy-5 ,6,7, 3-tetrahydrcr_φhth-2-yl )methylene7-2-oxindole ;

3-_T 3-hydrσxy-5 , 6 , 7, 8-tetrahydronaøτth-2-yl )πethylene7-2-oxindole ;

3-ZT 4-hydroxy-5 ,6,7, 8-tetr*ahydronaphth-2-yl )methylene7-2-oxindole ;

3-_ quinolin-5-yl )methylene7-2-oxindole ;

3-£(6-hydroxyquinolin-5-yl)niethylenej|-2-oxindole; 3- (7-hydroxyquinolin-5-yl)methylene^-2-oxindole; 3-f(8-hydroxyquinolin-5-yl)methylene3-2-oxindole; 3- ( uinolin-6-yl)methyleneJ-2-oxindole; 3-[(5-hydroxyquinolin-6-yl)methylenej-2-oxindole; 3- I(7-hydroxyquinolin-6-yl)methylene|-2-oxindole; 3- (8-hydroxyquinolin-6-yl)methylenej-2-oxindole; 3-T(1 _» -dihydroxy-5,6,7,8-te rahydronaphth-2-yl)methylene] -2-oxindole, ^C ι _q ^H _i 7 ^N0 ^Quires: C 74.25 H 5.58 N 4.56 found : C 74.01 H 5.74 N 4.48 MS m/z : 307

IR cm ^"1 (KBr) : 3500-3100 (OH.NH), 1670 (CO),

1605 (C=C); 3-[(quinolin-2-yl)methyleneJ-2-oxindole, ^c , _r> ^H , „N_0 requires C 79.39 H 4.44 N 10.29 18 12 2 found C 79.29 H 4.45 N 10.25 MS m/z 272

IR cm ^"1 (KBr) 3180 (NH), 1710 (CO), 1620-1595- 1505 (C=-C, C=N);

3-f(4-hydroxyquinolin-2-yl)methyleneJ-2-oxindole

^C 1 _I 8 _Q ^H 1 _I 2 ^N 2° 2 requires : C 74.98 H 4.20 N 9.72 found : C 74.66 H 4.25 N 9.38 MS m/z : 288 IR cm ^"1 (KBr) : 3430 (OH.NH) , 1675 (CO), 1630 (C=C)

1595-1580-1530-1515 (arom); 3-_1(quinoliu-4-yl)methyleneJ-2-oxindole, C H N 0 requires : C 79.39 H 4.44 N 10.29;

3-f(quinolin-3-yl)methyleneJ-2-oxindole,

C..„H_ _N„0 requires C 79.39 H 4.44 N 10.29 found C 79.20 H 4.71 N 10.14 MS m/z 272 IR cm ^"1 (KBr) 3500-3100 (NH), 1695 (CO), 1620-1580-1500 (C=C, C=N) ; 4- (indol-3-yl )methylene] -l-phenyl-pyrazolidin-3 , 5-dione ,

^C 18 ^H 13 ^N 3°2 ^rec * ^uires C 71.27 H 4.32 N 13.85 found C 71.05 H 4.33 N 13.64

MS m/z 303

IR cm ^-1 (KBr) 3600-3100 (NH), 1705-1650 (CONH) , 1600-1580-1500 (arom), and 5- C( indol-3-yl )methylene^| -hydantoin,

C _H_N_0_ requires C 63.43 H 3.99 N 18.49 12 9 3 2 found C 63.20 H 3.71 N 18.31 MS m/z 227 IR cm ^"1 (KBr) 3600-3100 (NH), 1740-1700-1650 (CONH),

1620-1580-1530 (C=C).

Example 2

2-cyano-3- ( 2-hydroxynaphth-l-y 1 ) thioacrylamide [I, Y = A, R = c, R. = R_ = H, n = 1_

A mixture of 2-hydroxy-l-naphthaldehyde (172 mg, 1 mmol), 2-cyanothioacetamide (110 mg, 1.1 mmol), N,N-diethylamino- ethanol (23 mg, 0.2 mmol) and 15 ml ethanol is stirred for so min at reflux under nitrogen. Then the mixttire is chilled, the precipitate filtered ,wasned with ice-cooled ethanol and dried in a vacuum-oven . Thus an almost pure title compound is obtained

in 85% yield (1080 mg ⁾ . Recrystallization from etnanol furnishes very pure samples.

^C 14 ^H 10 ^N 2° ^{S reα} - ^{uires: C 66} -12 H 3.96 N 11.01 S 12.61 found : C 66.05 H 3.85 N 10.95 S 12.55

MS m/z : 254

IR cm ^"1 (KBr) : 3300 ÷ 2500 (NH, OH), 2020 (CN), 1640 (C-N, N-H), 1600-1560-1510 (C = C) According to the above described procedure the following compounds can be prepared:

2-cyano-3- (3-hydroxynaphth-l-yl)thioacrylamide; 2-cyano-3- (4-hydroxynaphth-l-yl )thioacrilamide; 2-cyano-3- ( l-hydroxynaphth-2-yl )thioacrylamide; 2-cyano-3- (3-hydroxynaphth-2-yl)thioacrylamide; 2-cyano-3- (4-hydroxynaphth-2-yl)thioacrylamide; 2-cyano-3- (2-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)thioacrylamide; 2-cyano-3- (3-hydroxy-5,6,7,8-tetrahydronaphth-l-yl)thioacrylamide; 2-cyano-3- ( -hydroxy-5,6,7,8-tetrahydronaphth-l-yl)thioacrylamide; 2-cyano-3- (l-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)thioacrylamide; 2-cyano-3- (3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)thioacrylamide; 2-cyano-3- (4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)thioacrylamide ; 2-cyano-3- (3-hydroxyquinolin-2-yl)thioacrylamide; -cyano-3- (4-hydroxyquinolin-2-yl)thioacrylamide; 2-cyano-3- (2-hydroxyquinolin-3-vl ) thioacrylamide; 2-cyano-3- (4-hydroxyquinolin-3-vl)thioacrylamide; 2-cyano-3- (2-hydroxyquinolin-4-yl)thioacrylamide; 2-cyano-3- (3-hydroxyquinolin-4-yl)thioacrylamide » and

2-cyano-3-(8-hydroxyquinolin-5-yl) hioacrylamide,

C H N OS requires C 61.16 H 3.55 N 16.46 found C 60.99 H 3.59 N 16.26

MS m/z 255

IR cm ^"1 (KBr) 3440 (OH), 3330-3180 (NH) , 2220 (CN), 1650 (NH) , 1610-1570-1510 (C=C, C=N).

- 24 -

Example 3

2-cyano-3-(l-hydroxynaphth-2-yl)acrylic acid

[I, Y = A, R = a, R _χ -= R. = H, R. = OH, n = l]

To a mixture of l-hydroxy-2-naphthaldehyde (172mg,l mmol) and cyanoacetic acid (85 mg, 1 mmol) in dry dioxane (2 ml) piperidine (42 mg, 0.5 mmol) is added dropwise at 0-5°C. The mixture is kept overnight at room temperature. The crystals formed are filtered and recrystallized from chlo form. Thus 200 mg of pure title compoundare obtained correspon to 90% yield.

C, „H _Λ N0 requires: C 75.33 H 4.06 N 6.28 14 8 2 found : C 75.20 H 3.95 N 6.15

MS m/z : 223

I IRR ccmm ^""11 ((KKBBrr)) :: 333300C0 - 2500 (COOH , OH), 2200 (CN) 1690 (COOH), 1600-1560-1510 (C = C)

Following the above reported procedure and starting from the appropriate aldehyde derivative the following compounds can be prepared:

2-cyano-3-(2-hydroxynaphth-l-yl)acrylic acid; 2-cyano-3-(3-hydroxynaphth-l-yl)acrylic acid;

2-cyano-3-(4-hydroxynaphth-l-yl)acrylic acid;

2-cyano-3-(3-hydroxynaphth-2-y1)acrylic acid;

2-cyano-3-(4-hydroxynaphth-2-y1) crylic acid;

2-cyano-3-(2-hydroxy-5,6,7,8-tetrahydronaphth-1-yl) crylic aci 2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-l-yl)acrylic aci

- 25 -

2-cyano-3- (4-hydroxy-5,6,7,8 -tetrahydronaphth-1-yl)acrylic acid

2-cyano-3-(l-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acryli c acid

2-cyano-3-(3-hydroxy-5,6,7,8*-tetrahydronaphth-2-yl) crylic acid

2-cyano-3-(4-hydroxy-5,6,7,8--tetrahydronaphth-2»-yl)acr ylic acid

2-cyano-3-(3-hydroxyquinolin--2-yl)acrylic acid;

2-cyano-3-(4-hydroxyquinolin--2-yl)acrylic acid;

2-cyano-3-(2-hydroxyquinolin-•3-yl)acrylic acid;

2-cyano-3-(4-hydroxyquinolin-■3-yl)acrylic acid;

2-cyano-3-(2-hydroxyquinolin-•4-yl)acrylic acid; and

2-cyano-3-(3-hydroxyquinolin-•4-yl)acrylic acid.

Example 4

3-(l-hydroxy-5,6,7,8-tetrahydronaphth-2-yl ) acrylic acid tl, Y = B, R = i, R _χ « R _g =H, R ₃ = OH, n = 1 J

A mixture of l-hydroxy-5,6, 7,8-tetrahydro-2-naphthaldehyde (176 mg, 1 mmol), malonic acid (208 mg, 2 mmol) .piperidine (85 mg,

1 ππol ⁾ and pyridine (1 ml ⁾ are heated at 100°C for 3 ^' h and at reflux for

The mixture is then cooled and poured onto ice and hydrochloric acid. The precipitated material is separated by filtration and then recrystallized from ethanol thus giving pure title compoun in 80% yield (174 mg).

C H 0 calc. :C 71.54 H 6.46 found :C 71.35 H 6.30

MS m/z :218

IR cm ^"1 (KBr) :3300 - 2500 (COOH, OH), 1690 (COOH), 1640 (C =

- 26 -

Example 5

2-(4-hydroxyphenyl)-3-(naphth-2-yl)acrylic acid Cl, Y = A, R = i, R. -= H, R ₃ = OH, n = zero/

A mixture of 2-naphthaldehyde(156 mg, 1 mmol), 4-hydroxyphenylacetic acid (152 mg, 1 mmol), triethylamine (101 mg, 1 mmol) and acetic anhydride (510 mg , 5 mmol) are heated for 5 h at 100°C.

After cooling,the mixture is treated with diluted hydrochloric acid and then extracted with ethylacetate. The organic layer is separated and reextracted with diluted sodium hydroxide solution. The aqueous phase is separated and the raw product isolated by precipitation with hydrochloric acid. Pure title compound is obtained by crystallization from isopropanol in 60% yield (174 mg) .

C H 0 calc. : C 78.60 H 4.86 found : C 78.69 H 4.89 MS m/z : 290

IR cm ^"1 (KBr): 3600 - 2500 (OH, COOK) , 1680 (COOH),

1600, 1585, 1510 (C = C) By proceeding analogously the following compounds can be prepared:

2-(4-hydroxyphenyl)-3-(quinolin-3-yl)acrylic acid

C _1C H _N0_calc. : C 74.21 H 4.50 N 4.81 18 13 3 found : C 73.85 H 4.37 N 1.53

27 -

MS m/z : 291 -1 IR cm : 3380 (OH), 3100 - 1800 (COOH), 1670 (COOH) 1605. 1580, 1510 (C = C)

2-(4-hydroxyphenyl)-3-(naphth-l-yl)acrylic acid; -(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-l-yl)acrylic a -(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-2-yl)acrylic a -(4-hydroxyphenyl)-3-(quinolin-2-yl)acrylic acid; and -(4-h droxypheny1)-3-(quinolin-4-yl)acrylic acid.

Example 6

2-(4-hydroxyphenyl)-3-(naphth-2-yl)acrylamide Cl, Y = A, R = i, R_= H _χ R_ = NH_, n = zero?

A mixture of 2-naphthaldehyde (156 mg, 1 mmol),4-hydroxyphenylac acid (152 mg, 1 mmol), triethylamine (101 mg, 1 mmol) and ace anhydride (510 mg, 5 mmol) are heated for 5 h at 100°C. The mixture is treated with diluted hydrochloric acid after cooling and then extracted with ethylacetate. The organic layer is extracted w sodium hydroxide solution. After separation of the aqueous ph the raw carboxilic acid is isolated by precipitation with hydrochloric acid.

The raw carboxylic acid is transformed in its acid chloride b treatment with thionyl chloride (1190 mg, 10 mmol) in boiling benzene (5 ml) for 2 h. After evaporation to dryness under vacuum the raw acid chloride is transformed to the amide by reaction with diluted ammonium hydroxide at room temperature for 1 h. The raw product is obtained by filtration, washing a drying under vacuum. Crystallization from isopropanol furnish pure title compound in 50% yield (145 mg). ^C ₁₉ ^H ₁ 5 ^N °2 ^calc - ^{: 78} - ^{87 H 5} '23 N 4.84 found : C 78.71 H 5.09 N 4.65

MS m/z : 289

IR cm ^"1 (KBr) : 3366000 - 3100 (OH, NH), 1650 (CONH) 1610, 1560, 1510 (C = C)

According to the above described procedure tho following compounds can be prepared:

2- (4-hydroxyphenyl)-3-( uinolin-3-yl)acrylamide

C,_H, NO calc C 74.47 H 4.86 N 9.65 18 1422 found C 74.32 H 4.71 N.9.51

MS m/z : 290 IR cm ^-1 (KBr) : 3450, 3320 (NH), 3500 - 2300 (OH),

1665(C0NH), 1615, 1565, 1510, 1490 (C=C,C=N)

2-(4-hydroxyphenyl)-3-(naphth-1-yl)acrylamide; 2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-1-yl)acrylam ide; 2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-2-yl)acrylam ide; 2-(4-hydroxyphenyl)-3-(quinolin-2-yl)acrylamide; and 2-(4-hydroxyphenyl)-3-(quinolin-4-yl) crylamide.

Example 7

2- ( 4-hydroxyphenyl ) -3- ( naphth-2-yl ) acryloni trile [i , Y •= A, R = j , R ₂ = H , n =- ^* zero7

V a solution of 2-naphthaldehyde ( 156 mg , 1 mmol ) and

4-hydroxybenzylcyanide ( 133 mg , 1 mmol ) in dry ethanol ( 2 ml ) is added portionwise under cooling sodium ethoxide ( 204 mg , is 3 mmol ) and the resulting solution/ maintained for 96 h at room teπperatur

Then the solution is poured onto a mixture of ice and diluted

5

- 30 -

hydrochloric acid. The precipitate formed is filtered off, washed with ice-cooled aqueous ethanol and dried in a vacuum-

Thus, pure title compound is obtained in 80% yield (217 mg).

Cj»yH•!* NO calc. C 84.11 H 4.83 N 5.16 found C 83.91 H 4.87 N 4.86 MS m/z : 271

IR cm ^"1 (KBr) : 3340 (OH), 2220 (CN), 1605, 1585, 1510 (C=

Example 8

2-cyano-3-(l-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acryla mide [I, Y = B, R = a, R ₂ **- R ₂ = H, R. = NH _£ , n = ij

The starting material for this de-etherification example is 2-cyano-3-(l-methoxy-5,6,7,8-tetrahydronaphth-2-yl) acrylamid which can be obtained according to the procedure described in Example 1. To a stirred solution of 2-cyano-3-(l-methoxy-5,6,7,8- tetrahydronaphth-2-yl)acrylamide (256 mg, 1 mmol) in anhydrou dichloro e'.hane (10 ml) is added at -78°C under nitrogen, ove a period of 10 min, a 1.0 M solution of boron tribromide in dichloromethane (3 ml, 3 mmol). The resulting mixture is sti or another 1 h at -78°C and then allowed to warm to room

- 31 -

temperature. After stirring for 1.5 h at 20-25°C the mixture is cooled to -10°C and then quenched by the dropwise additio of water (10 ml) over a 10-min period. After addition of ethylacetate (10 ml) the organic layer is separated, washed with water, dried with Na.SO and evaporated under vacuum to dryness. The residue is crystallized from ethanol thus givin 169 mg of pure title compound (yield 70%).

^c C 69.40 H 5.82 N 11.56 1,4„ ^H ι14„ ^N 2°2.-, calc. found C 69.30 H 5.85 N 11.41 MS m/z : 242 w

IR cm ^"1 (KBr) : 3500 - 3100 (NAT,OH), 2210 (CN),

1685 (CONH ), 1610, 1590, 1560

According to the above described procedure and starting from the corresponding phenolic methylether,the compounds mention in fxamplesl,2 and 3 can be obtained.

Example 9

2-cyano-3- ( 1-ace toxy-5 , 6, 7, 8-tetrahydronaphth-2-yl ) acrylamid [I-Y = B , R = a, R. = C0CH ₃ , R_ = H, R_ = NH. , n = lj

The starting material for this acylation example is 2-cyano-

-3-( l-hydroxy-5 , 6 , 7, 8-tetrahydronaphth-2-yl ) acrylamide , whi may be obtained according to the procedure described in exam

To a cooled solution of 2-cyano-3-( l-hydroxy-5 , 6 , 7 , 8- ;etrahydr -2-yl )acrylamide ( 242 mg, 1 mmol in dry pyridine (0.5 ml ) is

added acetic anhydride (204 mg, 2 mmol) and the mixture maintained at 0-5° overnight. There upon the mixture is concentrated under vacuum, the residue dissolved in dichloromethane, the organic layer washed with*water and then evaporated under reduced pressure. The crude product is crystallized from chloroform/methanol to yield pure title compound in 90% yield (256 mg).

C,-H,_N O calc: C 67.59 H 5.67 N 9.85 16 16 2 3 found: C 67.41 H 5.45 N 9.71

MS m/z : 284

IR cm~ ¹ (KBr): 3300+3200 (NH), 2200 (CN) , 1750 (CH COO), 1690 (CONH-), 1610, 1590, 1560

According to the above described procedure the phenols obtained in E xamples 1 to 9 can be transformed into the corresponding C -C alkanoyl derivatives. 2 6

Example 10

Tablets each weighing 0.150 g and containing 25 mg of the active substance, can be manufactured as follows: composition (for 10000 tablets):

2-cyano-3-(l-hydroxynaphth-2-yl)acrylamide 250 g Lactose 800 g

Corn starch 415 g

Talc powder 30 g Magnesium stearate 5 g

The 2-cyano-3-(1-hydroxynaphth-2-y1)acrylami e, the lactose and half the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml) and the resulting paste is used to granulate the powder. The granulate is dried, comminuted on a sieve of 1.4 mm mesh size, then the remaining quantity of starch, talc and magnesium stearate are added, carefully mixed and processed into tablets.

Example 11

Capsules, each dosed at 0.200 g and containing 20 mg of the active substance can be prepared. Composition for 500 capsules:

2-cyano-3-(3-hydroxynaphth-2-yl)acrylamide 10 g Lactose 80 g

Corn starch 5 g

Magnesium stearate 5 g

This formulation is encapsulated in two-piece hard gelatin capsules and dosed at 0.200 g for each capsule.