GB2186570A

GB2186570A - 9,10-dihydro-phenanthrene derivatives

Info

Publication number: GB2186570A
Application number: GB08603955A
Authority: GB
Inventors: Gianfederico Doria; Carlo Banzatti; Anna Maria Isetta
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1986-02-18
Filing date: 1986-02-18
Publication date: 1987-08-19
Anticipated expiration: 2006-02-18
Also published as: IT8719371A0; GB2186570B; IT1204912B; DE3705149A1; GB8603955D0; JPS62205043A

Abstract

9,10-Dihydro-phenanthrene derivatives of the formula (I> <IMAGE> wherein R1 represents a) carboxy; b) esterified carboxy; <IMAGE> group, wherein each of Ra and Rb is hydrogen or C1-C6 alkyl, or Ra and Rb, taken together with the nitrogen atom to which they are linked, form a saturated heteromonocyclic ring, optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen to which additional nitrogen atom a hydrogen atom or a C1-C6alkyl, pyridyl or phenyl group is bonded; or <IMAGE> group, wherein R6 is hydrogen or C1-C6alkyl, A is a C2-C6alkylene group; each of R2, R3, R4 and R5, which may be the same or different, is hydrogen, halogen, C1-C6alkyl, C3-C4alkenyloxy or C1-C6alkoxy, and the pharmaceutically acceptable salts thereof; are useful in treating diseases characterised by an immunological imbalance and bacterial and viral infections in mammals.

Description

SPECIFICATION 9,1 0-Dihydro-phenanthrene derivatives and process for their preparation The present invention relates to new 9,1 O-dihydro-phenanthrene derivatives, in particularto neM19- substituted 9,10-dihydro-phenanthrene derivatives,to a process for their preparation and pharmaceutical compositions containing them.The compounds of the invention have the general formula (I)

wherein R1 represents a) carboxy; b) esterified carboxy;

group, wherein each of Ra and Rb, being the same or different, is hydrogen or C1-C6 alkyl or Ra and Rb,taken together with the nitrogen atom to which they are linked,form a saturated heteromonocyclic ring, optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen to which additional nitrogen atom a hydrogen atom ora C1 -Ce alkyl, pyridyl or phenyl group is bonded; or

group,wherein Re is hydrogen orCi-Ce alkyl,A is a C2-C6alkylene group Rbare as defined above; each of R2, R3, R4 and R & which may be the same or different, is hydrogen, halogen, C,-C6 alkyl, C3-C4 alkenyloxy orC,-C6 alkoxy; and the pharmaceutically acceptable salts thereof; and wherein, when R1 is-COOH,-COOCH3, -COOC2H5,-CONH2 or-CON(CH3)2, then at least one of R2, R3, R4 and Rg is otherthan hydrogen.

The present invention also provides pharmaceutical compositions containing a suitable carrier and/or diluent, and, as an active principle, a compound offormula (I), or a pharmaceutically acceptable saltthereof, wherein: R1 represents a) carboxy; b) esterified ca rboxy;

group, wherein each of Ra and Rb, being the same or different, is hydrogen or C1 -Ce alkyl, or Ra and Rb,taken together with the nitrogen atom to which they are linked,form a saturated heteromonocyclic ring, optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen to which additional nitrogen atom a hydrogen atom or a C1-C6 alkyl, pyridyl or phenyl group is bonded; or

group, wherein Re is hydrogen or C1-Cealkyl,Ais a C2-C6alkylene group and Ra and Rb are as defined above; each of R2, R3, R4 and R5, which may be the same or different, is hydrogen, halogen, Ci-Ce alkyl, C3-C4 alkenyloxy or C,-C6 alkoxy.

The invention also includes within its scope all the possible isomers, stereoisomers and optical isomers and their mixtures, and the metabolites and the metabolic precursors or bio-precursors of the compounds of formula (I).

A halogen atom is preferably chlorine or bromine.

The alkyl, alkylene, alkenyloxy and alkoxy groups may be branched or straight chain groups.

A Ci-Ce alkyl group is e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl ortert.butyl, preferably methyl or ethyl. A C3-C4 alkenyloxy group is preferably allyloxy.

A Ci-Ce alkoxy group is e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy orter.butoxy, preferably it is methoxy, ethoxy or propoxy. The alkylene group A includes C2-C6 alkylidene and is preferably a C2-C4 alkylene chain.

When Ra and Rb, taken together with the nitrogen atom to which they are linked, form a saturated heteromonocyclic ring, this may be for example a saturated, 5-or 6-membered heteromonocyclic ring chosen from the group including pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine; when the heteromonocyclic ring is piperazine, it may be unsubstituted or substituted as defined above; preferably it is substituted by C1-C4alkyl, pyridyl or by phenyl.

When R1 is an esterified carboxy group, it is preferably a-COXR7 group, where X is-O- or-S- and R7 is Ci-Ce alkyl u nsubstituted or substituted by pyridyl or by

wherein Ra and Rb are as defined above; more preferably it is a -COXR'7 group, wherein Xis as defined above and R'7 is a C1-C4 alkyl group unsubstituted or substituted by pyridyl or by a

group,wherein each of R'a and R'b is independently hydrogen or C1-C4 alkyl, or R'a and R'btaken togetherwith the nitrogen atom to which they are linked, form a pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine ring, wherein the piperazine ring may be unsubstituted or substituted by C1-C4 alkyl, pyridyl or by phenyl.

A particularly preferred value of R1 as esterified carboxy group is

wherein n is 2 or3, each of Ra and R"b are independently hydrogen orC,-C4alkyl ortaken togetherwiththe nitrogen atom to which they are linked form a pyrrolidine, morpholine or piperazine ring, wherein the latter is optionally substituted by C1-C4 alkyl or pyridyl.

The pyridyl substituent, which may be bound either to a piperazine ring orto an alkyl chain, may be a 2-, 3or4-pyridyl ring, preferably it is a 2-pyridyl ring.

The pharmaceutically acceptable salts ofthe compounds offormula (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, maleic, mandelic, fumaric or methanesulphonic acid, orwith an inorganic base, e.g. sodium, potassium, calcium or aluminium hydroxide oran alkali metal oralkaline earth metal carbonate or bicarbonate, orwith an organic base, typically an organic amine, e.g. lysine,triethylamine, procaine, dibenzylamine, N-benzyl-ss- phenethylamine, N,N'-dibenzyl-ethylenediamine, dehydroabietylamine, N-ethyl-piperidine, diethanolamine, N-methyl-glucamine, ortris-hydroxymethyl-aminomethane.

As stated above the present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds offormula (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 offormula (I).

Preferred compounds ofthe invention are compounds offormula (I),wherein: R1 represents a') an esterified carboxy group of formula-COXR'7, wherein X is-O- or-S- and R'7 is C1-C4 alkyl u nsubstituted or substituted by pyridyl or by a

group, wherein each of R'a and R'b is independently hydrogen or C1-C4 alkyl, or R'a and R'b, taken together with the nitrogen atom to which they are linked, form a pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine ring, wherein the piperazine ring may be unsubstituted or substituted by C1-C4 alkyl, pyridyl or byphenyl;; or

group, wherein R'e is hydrogen orC1-C4alkyl and A, R'aand R'arn as defined above; each of R2, R3, R4and R5 is independently hydrogen, chlorine, bromine, C1-C4 alkyl or C1-C4 alkoxy; and the pharmaceutically accept- able salts thereof; and wherein, when R1 represents -COOCH3 or-COOC2H5, then at least one of R2, R3, R4 and R5 is other than hydrogen.

Specific examples of compounds of the invention, or respectively, ofthe active ingredients of the pharmac eutical compositions of the invention, are the following: 9,1 0-dihydro-phenanthrene-9-carboxylic acid; 9,1 0-dihydro-phenanthrene-9-carboxyl ic acid, 2-N,N-dimethylamino-ethyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-N,N-dimethylamino-ethylthio ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 3-N,N-dimethylamino-propyl ester; 9,1 0-dihydro-phenanthrene-9-carboxyl ic acid, 2-N,N-diethylamino-ethyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-morpholino-ethyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-(pyrrolidin-1 -yl)-ethyl ester;; 9,1 0-dihydro-phenanthrene-9-N-(2-N,N-dimethylamino-ethyl)-carboxamide; 9,1 0-dihydro-phenanthrene-9-N-methyl-N-(2-N,N-dimethylamino-ethyl)-carboxamide; 9,1 0-dihydro-phenanthrene-9-N-(3-N,N-dimethylamino-propyl)-carboxamide; 9,1 0-dihydro-phenanth rene-9-carboxylic acid, 2-(2-pyridyl)-ethyl ester; 9,1 0-dihydrn-9-[4(2-pyridyl)-pipernzin-1-yli-carbonyl-phenanthrene; and the pharmaceutically acceptable salts thereof.

The compounds offormula (I) and the pharmaceutically acceptable salts thereof can be prepared by a process comprising: A) reducing a compound offormula (II), or a saltthereof,

wherein R1, R2, R3, R4 and R5are as defined above; or B) cyclizing a compound offormula (III)

wherein R1, R2, R3, R4 and R5 are as defined above; or C) reacting a compound offormula (IV)

wherein R2, R3, R4 and R5 are as defined above, with Ci-Ce alkyl alcohol or a Ci-Ce alkylthiol, so obtaining a compound offormula (I), wherein R1 is C1 -Ce alkoxy-carbonyl or Ci-Ce alkylthio-carbonyl;; or D) hydrolyzing a compound offormula (IV), as defined above, so obtaining a compound offormula (I) wherein R1, depending on the reaction conditions, is either carbamoyl or a free carboxy group, and/or, if desired, converting a compound offormula (I) into another compound offormula (I), and/or, if desired, converting a compound offormula (I) into a pharmaceutically acceptable salt thereof, and/or, if desired, converting a salt of a compound offormula (I) into a free compound, and/or, if desired, separating a mixture ofisomers of compounds offormula (I), into the single isomers.

The preparation in this way of compounds offormula (I) and their salts, exceptthose compounds and salts wherein R1 is-COOH,-COOCH3,-COOC2H5,-CONH2or-CON(CH3)2and R2, R3, R4 and R5are all hydrogen, forms part of the invention.

Asaltofa compound offormula (II) may be, for example, an alkali metal salt oran alkaline earth metal salt.

Preferably it is a sodium or potassium salt.

The reduction of a compound offormula (II), or a salt thereof, may be carried out, for example, by treatment with sodium amalgam or aluminium amalgam, at a temperature ranging from 0 Cto about 30 C, in a solvent such as aqueous lower alkyl alcohol, moist dioxane, moisttetrahydrofuran or moist ether. In particular, the reduction of a compound offormula (II), wherein R1 is carboxy, may be carried out by treatment with sodium amalgam in aqueous NaOH or KOH at room temperature.

Alternatively, the reduction of a compound offormula (II) may be carried out by treatment with lithium or sodium in refluxing liquid ammonia.

The compounds offormula (III) may be inthecisortransconfiguration or may be a mixturethereof.

The cyclization of a compound offormula (III) may be carried out, for example, at a temperature ranging from 0 C to about 30"C, under inert atmosphere, in a solvent such as benzene, lower alkyl alcohol, water and their mixtures, by irradiation with 300 nm lamps.

The reaction of a compound offormula (IV) with a C1-C6 alkyl alcohol or a C1 -Ce alkylthiol may be carried out in a conventional way, for example in the presence ofan acid catalyst, such as H2SO4, HCI or p-toluenesulfonic acid at a temperature ranging from about 30 C to the reflux temperature.The hydrolysis of a com pound offormula (lV) to afford a compound offormula (I), wherein R1 represents carbamoyl may be carried out according to well known methods, for example, by treatment with 85% H2SO4 at a temperature varying between about 50 C and about 1 00 C or by heating with water in the presence of copper powder as catalyst under inert atmosphere at a temperature varying from about 60 C to about 1 00 C.

Also the hydrolysis of a compound offormula (IV) to afford a compound offormula (I), wherein R1 represents a free carboxy group, may be carried out according to known procedures, for example bytreatment with a basic agent, preferably aqueous NaOH or KOH, in a suitable solvent, e.g. water, dioxane, C1-C2 alkoxyethanol , C1-C4alkyl alcohols, ortheir mixtures, at a temperature offrom about30 Cto the refluxtemperature, followed by acidification.

A compound offormula (I) may be converted, as stated above, into another compound offormula (I) by known methods. For example, a compound offormula (I), wherein R1 is an esterified carboxy group may be converted into another compound offormula (I) wherein R1 is a free carboxy group, by basic hydrolysis, which is carried out by using e.g. sodium or potassium hydroxide, in a solvent, such as, e.g., water or a lower aliphatic alcohol, and operating at a temperature ranging from room temperature to about 1 50"C and then acidifying.Or by an acid hydrolysis, for example, in a solvent, such as, water, or mixtures of aliphatic alcohol or dioxane with water, operating at a temperature ranging from the room temperature to the refluxtemperature; the same reaction may be also carried out e.g. by treatment with a lithium halide, preferably lithium bromide in a suitable solvent, e.g. dimethylsulphoxide, hexamethylphosphorotriamide ordim- ethylformamide, preferably in dimethylformamide at atemperature higherthan 50"C.Further,for example, a compound offormula (I) wherein R1 is a free carboxy group, may be converted into another compound of formula (I) wherein R1 is an esterified carboxy group offormula -COXR7, wherein X and R7 are as defined above, for example: a) by converting the carboxylic acid into the corresponding halocarbonyl, preferably chlorocarbonyl, derivative, by reaction; e.g., with the desired acid halide, for example oxalyl chloride, thionyl chloride, PC13, PC15 or POCI3, either in the absence of a solvent or in an inert organic solvent, e.g., benzene,toluene,xylene, dioxane, dichloroethane, methylene chloride, ortetrahydrofuran, at a temperature preferably from about O"C toaboutl20"C;andthen b) reacting the obtained halocarbonyl derivative with the suitable compound offormula R7-XH, wherein R7 and X are as defined above, in a solvent which may be the same alcohol or in an inert solvent, e.g., benzene, toluene, xylene, dioxane, dichloroethane, methylene chloride, ortetrahydrofuran, at a temperature ranging from about 0 C to about 60"C, if desired in the presence of a base, e.g. triethylamine.

Furthermore, for example, a compound offormula (I) wherein R1 is a free carboxy group may be converted into another compound of formula (I) wherein R1 is a-CONR1Rb or-CONR6-A-NRaRb group, wherein A, Ra, Rb and Rye are as defined above, by reacting a reactive derivative of such carboxylicacid, e.g. an acyl halide, preferably chloride, or a mixed anhydride, with an amine offormula HNRaRb or HN(Ra)-A-NRaRb, wherein A, Ra, Rb and Rg are as defined above, respectively.The reaction may be performed in an organic solvent, such as dioxane, tetrahydrofuran, dichloromethane, chloroform or benzene, at a temperature ranging from about O"C to about 100"C, if desired in the presence of a su itable basic agent. e.g.triethylamine.

Also the optional salification of a compound offormula (I) as well as the conversion of a salt intothefree compounds and the separation of a mixture of isomers into the single isomers may be carried out byconventional methods.

For example, the separation of optical isomers may be carried out by salification with an optically active base or acid and by subsequent fractional crystallization of the diastereoisomeric salts followed by recovering of the optically active isomeric acids or, respectively, bases.

The compounds offormula (II) may be prepared, for example, by Pschorrcyclization of a compound of formula (V)

wherein R1, R2, R3, R4 and Rg are as defined above.

The cyclization of a compound offormula (V) may be carried out, for example, following the method described in J. Med. Chew.,21, 395(1978).

The compounds offormula (Ill) wherein R1 is carboxy may be prepared, for example, by condensation between an aldehyde of formula (VI)

wherein R2 and R3 are as defined above, and an arylacetic acid of formula (VII)

wherein R4and R5are as defined above.

The rection between an aldehyde offormula (VI) and a compound offormula (VII) may be carried out, for example, by heating under reflux in acetic anhydride in the presence oftriethylamine according, for example, to J. Med. Chem.21,395 (9178).

The compounds offormula (III) wherein R1 is otherthan carboxy may be prepared, e.g., starting from the corresponding compound offormula (III) wherein R1 is carboxy according to synthetic methods well known in the art, for example, according to the methods described above for the conversion of a compound of formula (I), wherein R1 is carboxy into another compound offormula (I), wherein R1 is as defined as under b), c)andd).

The compounds offormula (IV) may be prepared, for example, by photochemical cyclization of a compound offormula (VIII)

wherein R2, R3, R4and R5 are as defined above, following the same experimental conditions described above forthe cyclization of the compounds offormula (III).

The compounds offormula (V) may be prepared by reduction of a compound offormula (IX)

wherein R1, R2, R3, R4 and R5 are as defined above, for example, bytreatmentwith SnC12.2H20 and 37% HCI in acetic acid at a temperature varying between the room temperature and the refluxtemperature.

The compounds offormula (VIII) may be prepared,forexample, by condensation between an aldehydeof formula (VI) and a compound offormula (X)

wherein R4 and R5 are as defined above, carrying out the reaction in the presence of a basic condensing agent, such as sodium ethoxide, sodium methoxide, sodium hydride, in a solvent, such as ethanol, methanol, dioxane, dimethylformamide, at a temperature varying between the room temperature and about 1 00 C.

The compounds offormula (IX) may be prepared,forexample, by heating an aldehyde offormula (Xl)

wherein R2 and R3 are as defined above, with an acid offormula (VII), as described above and following the methods of synthesis described aboveforthe preparation of the compounds offormula (III).

The compounds offormula (VI), (VII), (X) and (Xl) may be obtained by methods of synthesis well known in the art. When the new compounds ofthe present invention and in the intermediate products thereof, groups ofthe present, which need to be protected before submitting them to the hereabove illustrated reactions, they may be protected before the reactions take place and then deprotected, according to well known methods in organic chemistry. The compounds and the pharmaceutical compositions ofthis invention possess immunomodulating activity and antiviral activity.

Their immunomodulating activity is, for example, proven bttheir capacity to modify the antibody response induced in mice by a suboptimal dose of sheep red blood cells (SRBC) injected by intraperitoneal route (i.p.).

Groups often femal CD-1 mice were injected i.p. with 2 x 1 0e SRBC as antigen. The tested compounds and compositions were administered i.p. at two dosage levels: 50 and 5 mg/kg body weight, two hours beforethe administration of the antigen.

The control groups of mice received SRBC and saline instead of the compounds. Six days later the mice were killed and antibody titres against SRBC determined in their sera, according to Williams C.A.: Methods in Immunology and Immunochemistry, C.A. Williams and M.W. Chase, Eds. Academic Press, New York, Vol.11, page 152,1977.

The antiviral activity of the compounds and of the pharmaceutical compositions of the invention was, for example, evaluated against influenza in mice.

Groups of CD-1 mice were infected intranasally with the strain APR 8 of influenza virus. The tested compounds and compositions were administered through various routes, e.g. intraperitoneally, subcutaneously ororally.

The effect of the tested compounds and compositions against the influenza virus, was evaluated on the basisofthe number of lung lesions in the drug-treated animals and in the control group.

In view of their high therapeutic indexthe compounds and the pharmaceutical compositions of the invention can be safely used in medicine.

For example, the approximate acute toxicity (LD50) in the mouse ofthe compounds ofthe invention and of the active ingredients of the pharmaceutical compositions of the invention, determinedperos with single administration of increasing doses and measured on the seventh day afterthe day of treatment is generally higherthan 800 mg/kg.

The compounds offormula (I) and the pharmaceutical compositions of the invention are useful in the therapy of transplant reactions, for example transplants of kidneys, heart, bone marrow, skin and endocrine glands.

Other areas of pathology, in which the immunomodulating properties of these compounds and pharmaceutical compositions are oftherapeutic benefit: the therapy of neoplastic diseases, acute and chronic infections of both bacterial and viral origin, and of diseases characterized by an immunologic imbalance, like primary or acquired immunodeficiencies and autoimmune disorders. This last category includes rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, vasculitis and blood dyscrasias. The therapeutic regimen for the different clinical syndromes must be adapted to the type of pathology.

In transplantation and infections diseases the time of onset and the clinical course are, as a rule, known; conversely, the onset of immunological disorders is unknown and their clinical course is generally long and complex. Hence the therapeutic dose must be determined for each single clinical case, taking into account also the fact that it depends also on the route of administration.

The oral route is employed, in general, for all conditions requiring such compounds. Preference is given to the parenteral route, e.g. intravenous injection or infusion, for the prevention of rejection and the treatment of acute infections. For maintenance regimesthe oral or parenteral, e.g. intramuscular or subcutaneous, route is preferred.

For these purposes the compounds and the active ingredients of the pharmaceutical compositions ofthe invention can be administered orally at doses ranging e.g. from about 0.5to about 10 mg/kg of bodyweight perday.

Doses of active compounds ranging e.g. from about 0.2 to about 5 mg/kg of body weight can be used for the parenteral administration. Of course, these dosage regimens may be adjusted to provide the optimal therapeutic response.

As stated above, the invention includes a pharmaceutical composition comprising a compound offormula (I) in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent).

The pharmaceutical compositions 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 and potato starch; lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycoles; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents,forinstance, 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 orfilm-coating processes. The liquid dispersionsfororal administration may be e.g. syrups, emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/orsorbitol; in particular a syrup to be administered to diabetic patients can contain as carrieronly products not metabolizable to glucose, or metabolizable in very small amount two glucose, such as sorbitol.

The suspensions and the emulsions may contain as carrier,forexample, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections may contain together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amountof 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 sorbitan fatty acid ester surfactant or lecithin.

The following examples illustrate but do not limit the invention.

Example 7 To a suspension of phenanthrene-9-carboxylic acid, sodium salt (139), in refluxing liquid ammonia, sodium metal (3.67 g) was added in small pieces over a period of one hour under stirring. The deep red mixture obtained atthis stage was allowed to stirforfurthertwo hours then the ammonia was cautiously evaporated. The residue was heated with ethanol (20 ml) and then dissolved in water (200 ml). The solution was acidified to pH = 1 with 37% HCI and the precipitate was extracted with ether. Evaporation of the organic solution to dryness gave a gummy residue which was crystallized from CH2Cl2/n-hexane to yield 10.4 g of 9,1 0-dihydro-phenanthrene-9-carboxylic acid, m.p. 118-1 20aC.

By proceeding analogously the following compounds were prepared: 9,1 0-dihydro-3-methyl-phenanthrene-9-carboxylic acid; 9,1 0-dihydro-3-methoxy-phenanthrene-9-carboxylic acid; 9,10-dihydro-6-methoxy-phenanthrene-9-carboxylicacid; and 9,1 0-dihydro-3,6-dimethoxy-p henanthrene-9-carboxyl ic acid.

Example 2 a-Phenyl-cinnamic acid (0.5 g) dissolved in methanol (11) was irradiated with a 300 nm lamp underargon at room temperature for 20 hours. After evaporation ofthe solvent in vacuo to dryness the residue was crystallized from CH2C12/n-hexane to give 0.42 g of 9,10-dihydro-phenanthrene-9-carboxylic acid, m.p. 118- 120aC.

By proceeding analogously the following compounds were prepared: 9,1 0-dihydro-3-methyl-phenanthrene-9-carboxylic acid; 9,1 0-dihydro-3-methoxy-phenanthrene-9-carboxylic acid; 9,10-dihydro-6-methoxy-phenanthrene-9-carboxylic acid; and 9,1 0-dihydro-3,6-dimethoxy-phenanthrene-9-carboxylic acid.

Example 3 9-cyano-9,1 0-dihydro-phenanthrene (5 g) in 2-methoxyethanol (20 ml) was treated with potassium hydroxide (5 g) dissolved in water (2 ml) and the solution was heated atthe refluxtemperature under nitrogen for 10 hours. After cooling the solution was diluted with ice water (150 ml) and extracted with ethyl acetate. The organic layerwas eliminated and the aqueous phase was acidified with 37% HCI until pH = 1.

The precipitate was filtered and washed with water until neutral, to give 9,1 0-dihydro-phenanthrene-9- carboxylic acid (4,8 g), m.p. 1 17-1 19"C.

By proceeding analogously, the following compounds were prepared: 9,1 0-dihydro-3-methyl-phenanth rene-9-carboxylic acid; 9,1 0-dihydro-3-methoxy-phenanthrene-9-carboxylic acid.

Example 4 9-cyano-9,1 0-dihydro-phenanthrene (3.03 g), n-propyl alcohol (1.8 ml) and p-toluenesulfonic acid mono- hydrate (2.85 g) were refluxed under argon with stirring for 6 hours. After cooling the reaction mixturewas diluted with ice water (50 ml) and extracted with ethyl acetate. The extracts were washed with 10% Na2CO3 solution then with water and dried over sodium sulfate. Evaporation of the solution in vacuo to dryness gave 2.4 g of 9,1 0-dihydro-phenanthrene-9-carboxylic acid, n-propyl ester as a pale yellow oil.

By proceeding analogously, the following compounds were prepared: 9,1 0-dihydro-phenanthrene-9-carboxylic acid, ethyl ester; and 9,1 0-dihydro-3-methoxy-phenanth rene-9carboxylic acid, ethyl ester.

Example 5 9-cyano-9,10-dihydro-phenanthrene (3.5 g) in 85% H2SO4 (30 ml) was heated under argon at80 Cfor3 hours. The solution was cooled and poured into 300 g of crushed ice. The precipitate 9,1 0-dihydro- phenanthrene-9-carboxamide was filtered and washed with water until neutral (2.8 g), m.p. 226-8"C.

By proceeding analogously the following compounds were obtained: 9,1 0-dihydro-3-methyl-phenanthrene-9-carboxamide; 9,1 0-dihydro-3-methoxy-phenanthrene-9-carboxamide; 9,10-dihydro-6-methoxy-phenanthrene-9-carboxamide; and 9,1 0-dihydro-3,6-dimethoxy-phenanthrene-9-carboxamide.

Example 6 9,1 0-dihydro-phenanthrene-9-carboxylic acid (4.5 g)was suspended in thionyl chloride (50 ml) and kept at room temperature overnight. The solution was evaporated in vacuo. The crude residue was dissolved in 100 ml ofanhydrous dichloromethane and the obtained solution was added dropwise at O/S"Cto a solution of morpholine (4.4 ml) and 100 ml of dichloromethane. After one hourthe solution was washed with water, dried over sodium sulfate and concentrated in vacuo to dryness to give 4.2 g of 9,1 0-dihydro-9- morpholinocarbonyl-phenanthrene.

By proceeding analogously, the following compounds were prepared: 9,1 0-dihydro-9-(pyrrolidin-1 -yl)-carbonyl-phenanthrene; 9,1 0-dihydro-9-(4-methyl-piperazin-1 -yl)-ca rbonyl-phena nth rene: and 9,1 0-dihydro-9-[4-(2-pyridyl)-piperazin-1 -yl]-carbonyl-phenanthrene.

Example 7 9,1 0-dihydro-phenanthrene-9-carboxylic acid (3.2 g)was suspended in thionyl chloride (30 ml) and after 20 hours at room temperature the solution was evaporated in vacuo. The crude residue was dissolved in 80 ml of benzene and the obtained solution was added dropwise, at room temperature, to a solution of N,N,N'trimethylenediamine (1.4 ml) in 80 ml of benzene. After half and hour the solution was washed with water and dried over sodium sulfate and concentrated in vacuo to dryness to give 9,1 0-dihydro-phenanthrene-9-[N-(2- N,N-dimethylaminoethyl)-N-methyl]-carboxamide as colourless oil.

By proceeding analogously the following compounds were prepared: 9,10-dihydro-phenanthrene-9-N-methyl-carboxamide; 9,1 0-dihydro-phenanthrene-9-N-ethyl-carboxamide; 9,1 0-dihydro-phenanthrene-9-N-(2-N,N-dimethylaminoethyl)-carboxamide; 9,1 0-dihydro-phenanthrene-9-N-(3-N,N-dimethylaminopropyl)-carboxamide; 9,1 0-dihydro-3-methyl-phenanthrene-9-[N-(2-N,N-dimethylamino-ethyl)-N-methyl]-carboxamide; 9,1 O-dihydro-3-methoxy-phenanthrene-9-[N-(2 ide; 9,1 0-dihydro-6-methoxy-phenanthrene-9-[N-(2-N,N-dimethylamino-ethyl)-N-methyl]-carboxamide; and 9,1 0-dihydro-3,6-dimethoxy-phenanthrene-9-[N-(2-N,N-dimethyl-aminoethyl)-N-methyl]-carboxamide.

Example 8 9,1 0-dihydro-phenanthrene-9-carboxylic acid (2 g) was reacted with thionyl chloride (5.3 g) at room temperature for 20 hours then the solution was evaporated in vacuo to dryness. The residue was dissolved in isopropyl ether (40 ml) and reacted with 2-dimethylaminoethanol (2 g) dissolved in isopropyl ether (40 ml) and dioxane (15 ml) at room temperaturefor3 hours. The solution was diluted with water (100 ml) and the organic phase was separated and washed with water then evaporated in vacuo to dryness to give 1.7 g of 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-N,N-dimethylaminoethyl ester as a colourless oil, n21 c= 1.5861.

By proceeding analogously the following compounds were prepared: 9,1 O-dihydro-phenanthrene-9-carboxylic acid, 2-N,N-diethyl-aminoethyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 3-N,N-dimethyl-aminopropyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-morpholino-ethyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-(pyrrolidin-1 -yl)-ethyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-N,N-dimethyl-aminoethylthio ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-(2-pyridyl)-ethyl ester; 9,1 0-dihydro-3-methyl-phenanthrene-9-carboxylic acid, 2-N,N-dimethylaminoethyl ester;; 9,1 0-dihydro-3-methoxy-phenanthrene-9-carboxylic acid, 2-N,N-dimethylaminoethyl ester; 9,1 0-dihydro-6-methoxy-phenanthrene-9-carboxylic acid, 2-N,N-dimethylaminoethyl ester; and 9,1 0-dihydro-3,6-dimethoxy-phenanthrene-9-carboxylic acid, 2-N,N-dimethylaminoethyl ester.

Example 9 9,1 0-dihydro-phenanthrene-9-carboxylic acid (1.6 g) was suspended in thionyl chloride (5 g) and kept at room temperature for 20 hours. The solution was evaporated in vacuo to dryness and the residuewastreated with anhydrous ethanol (20 ml) at 50"Cfor3 hours. The solution was evaporated in vacuo to dryness and the residue was dissolved in ethyl acetate. The organic solution was washed with water until neutral and evaporated in vacuo to dryness to give 1.4 g of 9,1 0-dihydro-phenanthrene-9-carboxylic acid, ethyl ester as an oil.

By proceeding analogously the following compounds were prepared: 9,1 0-dihydro-phenanthrene-9-carboxylic acid, methyl ester; 9,1 0-dihydro-3-methyl-phenanthrene-9-carboxylic acid, ethyl ester; 9,1 0-dihydro-3-methoxy-phenanth rene-9-carboxylic acid, ethyl ester; and 9,1 0-dihydro-6-methoxy-phenanthrene-9-carboxylic acid, ethyl ester.

Example 10 9,1 0-dihydro-phenanthrene-9-carboxylic acid (1.8 g)was dissolved in 0.5 N ethanolic NaOH (16 ml). The solution was evaporated in vacuo to dryness and the residue was diluted with acetone (100 ml). The pre cipitate was filtered to give 1.6 g of 9,1 0-dihydro-phenanthrene-9-carboxylic acid, sodium salt, m.p. 230"C, dec.

By proceeding analogously, the following compounds were obtained: 9,1 0-dihydro-3-methyl-phenanthrene-9-carboxylic acid, sodium salt; 9,1 0-dihydro-3-methoxy-phenanthrene-9-carboxylic acid, sodium salt; 9,1 0-dihydro-6-methoxy-phenanthrene-9-carboxylic acid, sodium salt; and 9,1 0-dihydro-3,6-dimethoxy-phenanthrene-9-carboxylic acid, sodium salt.

Example 17 To a solution of 9,1 0-dihydro-phenanthrene-9-[N-(2-dimethyl-aminoethyl)-N-methyl]-carboxamide (1.1 g) in isopropyl ether (25 ml) the stoichiometric amount of gaseous HCI in isopropyl ether solution (50 ml) was added. The precipitate was filtered and washed with isopropyl ether to give 1 g of 9,1 0-dihydro- phenanthrene-9-[N-(2-N,N-dimethylaminoethyl)-N-methyl]-carboxamide hydrochloride, m.p. 175"C dec.By proceeding analogously the following compounds were prepared: 9,1 0-dihydro-phenanthrene-9-N-(2-N,N-dimethylaminoethyl)-carboxamide hydrochloride; 9,1 0-dihydro-3-methyl-phenanthrene-9-[N-methyl-N-(2-N,N-dimethylamininoethyl)]-carboxamide hydrochloride; and 9,1 0-dihydro-3-methoxy-phena nth rene-9-[N-(2-N,N-dimethylaminoethyl)-N-methyl]-carboxamide hydrochloride.

Formulation Examples Formulation 1: Tablet (50 mg) Tablets, each weighing 150 mg and containing 50 mg of the active substance were manufactured asfollows: Compositions (for 10000 tablets) 9,1 0-dihydro-phenanthrene-9-carboxyl ic acid 500 g Lactose 7109 Corn starch 238g Talc powder 369 Magnesium stearate 16g 9,1 0-dihydro-phenanthrene-9-carboxylic acid, lactose and a half of the corn starch were mixed; the mixture was then forced through a sieve of 0.5 mm openings. Corn starch (18 g) was suspensed in warm water (180 ml). The resulting paste was used to granulate the powder. The granules were dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearatewas added, carefully mixed, and processed into tablets using punches of8 mm diameter.

Formulation2: Intramuscular injection An injectable pharmaceutical composition was manufactured by dissolving 50-100 mg of9,10-dihydro- phenanthrene-9-carboxylic acid, 2-N,N-dimethylamino-ethyl ester hydrochloride in sterile water our sterile normal saline solution (2-5 ml).

Analogously, injectable pharmaceutical compositions containing the compounds previously described in the preceding examples were prepared.

Claims

1. Acompound ofthegeneralformula (I)

wherein R1 represents a) carboxy; b) esterified carboxy;

group, wherein each of Ra and Rb, being the same or different, is hydrogen orCi-Ce alkyl orRa and Rb,taken together with the nitrogen atom to which they are linked, form a saturated heteromonocyclic ring, optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen to which additional nitrogen atom a hydrogen atom or a C,-C6 alkyl, pyridyl or phenyl group is bonded; or

group, wherein R5 is hydrogen or C1-C6 alkyl, A is a C2-C6 alkylene group and Ra and Rb are as defined above; each of R2, R3, R4 and R5, which may be the same or different, is hydrogen, halogen, C-C6 alkyl, C3-C4 alkenyloxy or C,-C6 alkoxy and the pharmaceutically acceptable salts thereof and wherein, when R1 is -COOH,-COOCH3,-COOC2H5,-CONH2or-CON(CH3)2,then at least one of R2, R3, R4 and R5 is otherthan hydrogen.

2. Acompound offormula (I), according to claim 1,wherein R1 represents a') an esterified carboxygroup offormula -COXR'7, wherein X is-O- or-S- and R'7 is C1-C4 alkyl unsubstituted or substituted by pyridyl or bya

group, wherein each of R'a and R'b is independently hydrogen orC1-C4alkyl, orR'a and R'b, taken together with the nitrogen atom to which they are linked, form a pyrrolidine, piperidine, morpholine,thiomorpholine or piperazine ring, wherein the piperazine ring may be unsubstituted or substituted by C1-C4 alkyl, pyridyl or by phenyl; or

group, wherein R'e is hydrogen orC1-C4alkyl, A is as defined in claim 1 and R'a and R'b are as defined above; each of R2, R3, R4 and Rg is independently hydrogen, chlorine, bromine, C1-C4 alkyl or C1-C4 alkoxy; and the pharmaceutically acceptable salts thereof; and wherein, when R1 represents-COOCH3 or-COOC2He, then at least one of R2, R3, R4 and R5 is other than hydrogen.

3. A compound selected from the group consisting of: 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-N,N-dimethyl-amino-ethyl ester; 9,1 0-dihydro-phenanth rene-9-ca rboxylic acid, 2-N,N-dimethyl-amino-ethylthio ester; 9,10-dihydro-phenanthrene-9-carboxylic acid, 3-N,N-dimethyl-amino-propyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-N,N-diethyl-amino-ethyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-morpholino-ethyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, acid,2-(pyrrol idi n-1 -yl)-ethyl ester; 9,1 O-dihydro-phenanthrene-9-N-(2-N,N-dimeth )-carboxamide;; 9,10-dihydro-phenanthrene-9-N-methyl-N-(2-N,N-dimethylamino-ethyl)-carboxamide; 9,10-dihydro-phenanthrene-9-N-(3-N,N-dimethylamino-propyl)-carboxamide; 9,1 0-dihydro-phenanth rene-9-carboxylic acid, 2-(2-pyridyl )-ethyl ester; 9,10-dihydro-9-[4-(2-pyridyl)-piperazin-1-yl]-carbonyl-phenanthrene; and the pharrnaceuticallyacceptablesaltsthereof.

4. A process for the preparation of a compound offormula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 ,the process comprising: A) reducing a compound offormula (II), ora saltthereof,

wherein R1, R2, R3, R4 and R5 are as defined in claim 1; or B) cyclizing a compound offormula (III)

wherein R1, R2, R3, R4 and R5 are as defined in claim 1; or C) reacting a compound offormula (IV)

wherein R2, R3, R4and R5 are as defined in claim 1,with a Ci-Cealkyl alcohol ora Ci-Cealkylthiol, so obtaining a compound offormula (I), wherein R1 is C1-C6 alkoxycarbonyl or Ci-Ce alkylthio-carbonyl; or D) hydrolyzing a compound offormuia (IV), as defined above, so obtaining a compound offormula (I) wherein R1, depending on the reaction conditions, is either carbamoyl or a free carboxy group, and/or, if desired, converting a compound offormula (I) into another compound offormula (I),and/or, if desired, converting a compound offormula (I) into a pharmaceutically acceptable salt thereof, and/or, if desired, converting a salt of a compound offormula (I) into a free compound, and/or, if desired, separating a mixture of isomers of compounds offormula (I), into the single isomers.

5. A pharmaceutical composition containing a suitable carrier and/or diluent, and, as the active principle, a compound offormula (I), or a pharmaceutically acceptable salt thereof, wherein: R, represents a) carboxy; b) esterified carboxy; c)a

group, wherein each of Ra and Rb, being the same or different, is hydrogen or Ci-Ce alkyl, or Ra and Rb,taken together with the nitrogen atom to which they are linked, form a saturated heteromonocyclic ring, optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen to which additional nitrogen atom a hydrogen atom ora Ci-Ce alkyl, pyridyl or phenyl group is bonded; or

group, wherein Re is hydrogen orCi-Ce alkyl,Ais a C2-Cealkylene group and Ra and Rb are as defined above; each of R2, R3, R4 and R5, which may be the same or different is hydrogen, halogen, C1-C6 alkyl, C3-C4 alkenyloxy or C1-C6 alkoxy.

6. A pharmaceutical composition containing a suitable carrier and/or diluent, and, as an active principle, a compound selected from the group comprising: 9,1 0-dihydro-phenanthrene-9-carboxylic acid; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-N,N-dimethyl-amino-ethyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-N,N-dimethyl-amino-ethylthio ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 3-N,N-dimethyl-amino-propyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-N,N-diethyl-amino-ethyl ester; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-morpholinoethyl ester;; 9,1 0-dihydro-phenanthrene-9-carboxylic acid, 2-(pyrrolidin-1 -yl)-ethyl ester; 9,10-dihydro-phenanthrene-9-N-(2-N,N-dimethylamino-ethyl)-carboxamide; 9,10-dihydro-phenanthrene-9-N-methyl-N-(2-N,N-dimethylamino-ethyl)-carboxamide; 9,1 0-dihydro-phenanthrene-9-N-(3-N,N-dimethylamino-propyl)-carboxamide; 9,1 0-dihydro-phenanthrene-9-carboxyl ic acid, 2-(2-pyridyl)-ethyl ester; 9,10-dihydro-9-[4(2-pyridyl)-piperazin-1-yl]-carbonyl-phenanthrene ora pharmaceutically acceptable salt thereof.

7. The use of a compound offormula (I)

wherein R1 represents a) carboxy; b) esterified carboxy;

group, wherein each of Ra and Rb, being the same or different, is hydrogen or C1-C5 alkyl, or Ra and Rb,taken together with the nitrogen atom to which they are linked, form a saturated heteromonocyclic ring, optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen to which additional nitrogen atom a hydrogen atom ora CI-Cs alkyl, pyridyl orphenyl group is bonded; or

group, wherein Re is hydrogen or C,-C6 alkyl, A is a C2-Ce alkylene group and Ra and Rb are as defined above; each of R2, R3, R4 and R5, which may be the same or different, is hydrogen, halogen, Ci-Ce alkyl, C3-C4 alkenyloxy or C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for treating diseases characterized by an immunologic imbalance in mammals.

8. The use of a compound offormula (I)

wherein R1 represents a) carboxy; b) esterified carboxy;

group, wherein each of Ra and Rb, being the same or different, is hydrogen or C,-C6 alkyl, or Ra and Rb,taken together with the nitrogen atom to which they are linked, form a saturated heteromonocyclic ring, optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen to which additional nitrogen atom a hydrogen atom or a Ci-Ce alkyl, pyridyl or phenyl group is bonded; or

group,wherein R6 is hydrogen orC1-Cealkyl,Ais a C2-C6alkylene group and Ra and Rare as defined above; each of R2, R3, R4 and R5, which may be the same or different, is hydrogen, halogen, Ci-Ce alkenyloxy orC-C6 alkoxy, ora pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for treating bacterial and viral infections in mammals.

9. A compound offormula (I) as defined in claim 1,ora pharmaceutically acceptable saltthereof, hereinbefore specified otherthan a compound orsaltclaimed in claim 3,

10. A compound offormula (I) as defined in claim 5, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or anima body by surgery or therapy or of diagnosis practiced on the human or animal body.

11. A compound or salt according to claim 10 for use in treating diseases characterised by an im munologic imbalance in mammals.

12. A compound or salt according to claim 10 for use in treating bacterial and viral infections in mammals.

13. A process for the preparation of a compound offormula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, said process being substantially as hereinbefore described in any one of Examples 1 toll.

14. A pharmaceutical composition substantially as hereinbefore described in Formulation Example 1 or 2.