GB2177689A - Tricyclic dihydropyridazinones and pharmaceutical compositions containing them - Google Patents

Abstract

New tricyclic dihydropyridazinones with cardiovascular protective properties derivatives have the formula I <IMAGE> wherein: n is sero, 1 or 2; R is hydrogen, C1-C6 lower alkyl, -CH2CH=CH2, -CH2C IDENTICAL CH and (CH2)m-C6H5 where m is zero or an integer from 1 to 3; R1 and R2 are independently selected from the group consisting of hydrogen, C1-C6 loweralkyl, <IMAGE> where R3 is selected from the group consisting of C1-C16 branched or linear alkyl residue, optionally containing hydroxy, amino, halogen, thiol groups or a free or esterified carboxy group, an heterocyclic ring, a substituted or unsubstituted aromatic ring, a cycloaliphatic ring, a cycloaliphatic alkyl, an aralkyl or heteroalkyl, a lower C1-C6alkoxy, benzyloxy or NHR6 group where R6 is hydrogen, C1-C6 lower alkyl, or CH2-C6H5; or R4SO2 wherein R4 is selected in the group of CH3, C2H5, phenyl, p-methylphenyl groups; both as racemic or optically active enantiomers and salts thereof, with the proviso that the substituent <IMAGE> is not linked to the aromatic ring A through position b.

Description

SPECIFICATION Tricyclic dihydropyridazinones and pharmaceutical compositions containing them The present invention relates to tricyclic dihydropyridazinones, to a process for their preparation and to pharmaceutical and veterinary composition containing them.

The compounds ofthe invention have the general formula I

wherein - n is zero or an integerfrom 1 to 2; - R is a member selected from the group consisting of hydrogen, a C1-C6 lower alkyl,-CH2-CH=CH2,

being m zero oran integerfrom 1 to3; - R1 and R9 are independently selected from the group consisting of hydrogen, aL'1 - L's loweraiKyl,

wherein m is as above defined, CH2-CH=CH2,-CH2-C-CH, R3-CO- or R4SO2- where R3CO is the acyl part of a carboxylic acid R3CO2H selected from the group consisting of:: a C1-C16 unbranched and branched aliphatic fatty acid and derivativesthereofcontaining hydroxy,amino, halogen, orthiol groups such as formic, acetic, propionic, butirric, isobutirric, stearic, lactic, cystein, alanine, leucine, valine,thioglycolic, glycolic, E-aminocapronic, chloroacetic, 2-chloropropionic; an aromatic acid such as benzoic, o,m,p -toluic; 3,4,5-trimethoxybenzoic, p-hydroxy-3,5-dimethoxy-benzoic, p-fluoro-benzoic, p-chloro-benzoic, p-aminobenzoic, salicyclic, p-hydroxybenzoic; an heterocyclic acid such as nicotinic acid, isonicotinic, pyrazol-3-carboxylic acid, isoxazol-3-carboxylic and 5-carboxylic, 2-thiophencarboxylic, 2-furylcarboxylic acids; a C4-C8 cycloaliphatic acid such as cyclopropylcarboxylic, cyclopentane carboxylic, cyclohexane carboxylic acid; a C5rC16 cycloaliphatic alkyl, aralkyl, heteroalkyl acid such as cyclopentyl acetic, cyclopentyl propionic, cyclopentoxyacetic, cyclohexyl propionic, phenoxyacetic, phenyl propionic, 1 -imidazolylacetic, 2-furylpropionic, 2-tetrahydrofuryl propionic, cinnamic, 2-fluoro-cinnamic, caffeic acids; a dicarboxylic fatty acid such as oxalic, succinic, g lutaric, fumaric having the other carboxylic group free or salified or esterified with a lower C1-C6 alkyl; a carbonic acid wherein R3 is a lower C1-C6 alkoxy, benzyloxy or NHRcwhere Rc is hydrogen, a C1-C6 lower alkyl, or benzyl;; R4SO2 is the sulphonyl part of a sulphonic acid preferably selected from the group consisting of methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluensulphonic and canfosulphonic.

Intheformula l,the

substituent, may be linked to each ofthe possible a, c, d positions of the aromatic ring A but not to the position b.

The compounds offormula I having n = 0 are referred to as: 4,4a-dihydro-5H-indeno-[1 ,2-c]-pyridazin-3-one and the amino substituent in the ring A is therefore referred to as a 6-amino, 8-amino- or9-amino-substituent.

The compounds of formula I having n = 1 are referred to as: 4,4a,5,6-tetrahydro-2H-benzo-(h)cinnoline-3-one and the substituent in the ring A is therefore referred to as a 7-amino, 9-amino or 1 0-amino substituent.

The compounds offormula I having n = 2 are referred to as 2,4,4a,5,6,7-hexahydro-3H-benzo-[6,7]cycloheptene-[1 ,2-c]-pyridazin-3-one and the amino substituent in the ring A is accordingly referred as an 8-amino, 10-amino and 11-amino substituent. The present invention refers to the non toxic salts, suitable for pharmaceutical or veterinary use, as well as the optical antipodes, i.e. the enantiomers, the racemic mixture thereof and of the diastereoisomeric mixture.

In the formulae of this specification, when the absolute configuration of the CH bond at the junction ofthe ring B/C is defined, the heavy solid line indicatesthata substituentatthejunction ofthe ring B/C is inthe '3-configuration, i.e. above the planeformed bythe ring A/B (exo-configuration); the dotted line (....)indicates thata substituentatthejunction ofthe ring B/C in the configuration, i.e. below the plane formed by the ring A/B (endo configuration).

The wavy line bond (t) indicates that the stereo-chemistry of the substituent atthe junction ofthe ring B/C is not defined as in the case of racemic mixture ofthe compounds offormula When R, R1, R2 are achiral substituents,the compounds ofthe formula I are a 1:1 mixture ofthe compounds ofthefollowingformulae:

Consequently when R, R1, R2 are chiral substituents the compounds ofthe invention are mixtures ofracemic diastereoisomers which are also included in the scope of the present invention.

Specific examples of preferred compounds ofthe invention are racemic or optically active: -9-acetylamino-4,4a,5,6-tetrahydro-2H-benzo(h)cinnoline-3-one; - 7-acetylamino-4,4a,5,6-tetrahydro-2H-benzo(h)cinnoline-3-one; - 7-amino-4,4a,5,6-tetrahydro-2H-benzo(h)cinnoline-3-one; - 6-amino-4Aa-dihydrn-5H-indeno-[1 ,2-c]-pyridazin-3-one; - 6-acetyla mino-4,4a-dihydro-5H-indeno-[1 ,2-c]-pyridazin-3-one; - 8-acetylamino-4,4a-dihydro-5H-indeno-[1 ,2-c]-pyridazin-3-one; - 1 0-acetylamino-2,4,4a,5,6,7-hexahydro-3H-benzo [6,7]cyclohepten-[1 ,2-cj-pyridazin-3-one.

The compounds ofthe invention are prepared by reacting a racemic and/or optically active compound ofthe general formula II

wherein n, R1 and R2 are as above defined and Rd is hydrogen or a C1-C6 lower alkyl, with a hydrazine compound offormula III H2N-NH-R' (III) wherein R' is hydrogen, lowerC1-C6 alkyl or phenyl,to give a compound of the general formula la

wherein n, R1, R2 and R' are as above defined.

The compounds offormula la, wherein either R1 or R. is hvdroaen and the other one is a C.-G lower alkyl

-CH2-CH=CH2 or-C CH, may be optionally reacted with a convenient activated form of a carboxylic acid of formula R3CO2H and/orwith a convenient activated form of a sulphonic acid offormula R4SO3 wherein R3 and R4 have the above defined meanings.

The compounds offormula la wherein both R1 and R2 are hydrogen, are optionally alkylated so asto obtain a compound wherein either R1 or R2 is hvdroaen and the other one is a C.-CR lower alkvl. a aroun offormula

CH2=CH-CH2 or CH2-C=CH; then,the alkylated compounds can be optionally acylated by an activated acid of formula R3CO2H or R4SO3H.

The compou nds of formula la wherein R' is hydrogen can be optionally transformed into the compou nds wherein R' has the other above defined meaninas bv reaction with an halocompound such as lowerC1-C6

wherein X may be C1, Bror landis preferably iodine, in the presence of a base.

Said alkylation reaction may also be optionally carried out on compounds wherein R' is hydrogen and either R1 or R2 are hydrogen and the other one is a group offormula R3-CO or R4SO2, obtaining therebythe double-alkylated products offormula I wherein Rand either R, or R2 are a C-C6 lower alkyl, allyl, propargyl,or a group offormula

wherein mis 1, 2 or3.

In the process for the preparation of the compounds of the present invention, the final compounds ofthe invention are racemic substances ifthe starting material of general formula lisa racemic substance.

In this case, the compounds offormula la or I may be optionally submitted to optical resolution to their optical antipodes Therefore for example, the compounds of formula la wherein R1 and R2 are indenendently hydrogen, C1-C6 lower alkyl,

may be submitted to optical resolution by crystallization ofthe salts with optically active acids such as, for example, d-tartaric, t-tartaric, e- and d-dibenzoyltartaric acid, d- and t-canfosulphonic acid, d- and e-6-exo-chloro-7-sin-carboxy-bicyclo [2,2,1 ]-heptan-3-one, 3,3-ethylenedioxy, d- and t-ma ndelic acid, d- and t-malic. Otherwise, for example, when one of R1 and R2 is a R3CO acyl substituentwherein R3 is an #-free carboxylic group such as HO2C(CH2)q-wherein q is zero or an integer from 1 to 6 or a group offormula

The optional optical resolution may be carried out by fractional crystallization otthe salts with optical active bases such as for example d- and t-ephedrine; d- and t-a-phenylethylamine, dihydroabiethylamine and so on.

On the other hand, for example when in the comnounds offormula la or one of R1 and R9 is a RCO-acvl substituent comprising an free basic group such ac

ora basic heterocvclic nrnu n such as, for example,

tne optional optical resolution may ue performed uy crystaiiization ottne saits witn tne above opticaiiy active acids In addition to these conventional methods, if desired, the optional optical resolution may be performed by chromatographic separation on optically active phases.

Preferably, the optional optical resolution is carried out on the racemic compounds of formula la, i.e. after the reaction of a racemic compound of formula II with a hydrazine compound offormula Ill, taking into account the racemizations due to enolization of the ketogroup ofthe optically active compounds offormula II.

The reaction of a compound of formula II with a hydrazine compound offormula Ill can be carried out in a solvent selected in the group consisting of C1-C4 alcohols, glycols, such as ethylene glycol, propylenglycol; ethers such as dimethoxy ethane, dioxane, tetrahydrofuran; water; formic and acetic acids, and mixture thereof using equimolecular amounts and/or an excess ofthe hydrazine compounds and/or salts thereof which are soluble in the solvents attemperatures ranging from the room temperature to the boiling point of the mixture, for reaction times from a few minutes to twentyfourhours.

The preferred solvent is ethanol, the preferred temperature isthe refluxtemperature fora time of 30 minutes.

The optional acylation of a compound ofthe general formula la where either R1 orR2 are hydrogen, maybe carried out in the presence of a inorganic and/or organic base in an inert solvent such asdichloromethane, 1,2-dichloroethane,benzene,toluene,chlorobenzene,dimethoxyethane,tetrahydrofuran, dimethylformamide, dimethylsulphoxyde, pyridine, dimethylaniline, N-N-diethylacetamide with known activated forms of carboxylic acid R3-CO2H or a sulphonic acid R4-SO3H.

The preferred activated forms are the acid chlorides, anhydrides and their mixed anhydrides.

The inorganic bases are alkali and alkali-earth bicarbonates and carbonates.

The organic bases are selected in the group consisting oftertiaryamines such astriethylamine, tributylamine, pyridine, collidine, dimethylaniline, diethylaniline. The reaction can be carried out using equimolecularamounts and/or an excess ofthe acylating reagent at temperatures ranging from zerotothe solvent refluxtemperature. The room temperature is preferably used.

The optional alkylation of a compound of general formula la is carried out with methods known in the art: for example a preferred method is the reductive amination by reaction with an aldehyde and/or ketone and NaCNBH3. The alkylamino derivative so obtained, if desired, can then be acylated as above described.

The optional alkylation ofthe dihydropyridazinone ring wherein R' is hydrogen, is carried out by reacting the compound with a suitable halocompound in an inert solvent such as acetone,dimethylformamide, dimethylsulfoxide, dimethoxyethane, tetrahydrofuran, benzene, diethylacetamide and their mixtures in the presence of a base such as potassium hydroxyde, potassium ter-butoxyde, potassium carbonate, CH3SOCH2Na, CH3SOCH2K, sodium hydride, diisopropyldithioamide. The reaction temperature is from -60 to 80 C, the time from few minutes to twentyfour hours using equimolecular amounts of the reagents and/or an excess thereof.

The compoundsofthe general formula II are new; and, therefore, they also are objectofthe invention.

Compounds II are obtained by a multistep process, by reacting a compund of the general formula IV

wherein n is as above defined and Re is a lower C1-C3 alkyl, preferably methyl, CF3, phenyl or benzyloxy group, with "in situ" formed glyoxylic acid or an esterthereofto give an alkylidene compound of the general formula V

wherein Re, Rd, n are as above defined.

Compound V is then reduced to give a compound of general formul VI

wherein Rd is as above defined and R'2 is a member selected in the group of hydrogen, lower acyl, preferably acetyl, trifluoroacetyl, benzoyl, benzyloxycarbonyl, which is then optionally hydrolyzed and hence, using methods known in the art, the obtained free amino group is optionally converted into a substituted aminogroup for example by reductive alkylation with aliphatic aromatic, heterocyclic aralkyl, heteroalkyl aldehydes and ketones; the obtained compounds are optionally submitted to acylation with an activated form ofthe R3CO2H and R4SO3H acids and these compounds are optionally subjected to optical resolution, in their racemic or optically active forms.

The glyoxylic acid esters are known substances, which may be formed "in situ" by treating tartaric acid or tartaric esters with an alkaline periodate in acidic medium.

The reaction ofthe compound offormula IV with a glyoxylic acid derivative (free acid or ester) is carried out in water or in a water-miscible solvent such as lower alcohols, preferably the same alcohol esterifying the glyoxylic acid, dimethoxyethane,tetrahydrofuran, dioxane or mixture thereof in the presence of a basic catalyst such as alkaline hydroxydes, alkaline bicarbonates or carbonates or in the presence of strong organic bases such as Triton A, tetrabutylammonium hydroxide, piperidine, morpholine, pyrrolidine.

The reaction is preferably carried out at temperatures ranging from -5"to the refluxtemperature, preferably at room temperature.

The reaction times range from few minutes to several days, but usually do not exceed eight hours and three hours are often sufficient to complete the reaction. Glyoxylic acid or its aqueous solutions are preferably used.

The reduction ofthe double bond ofthe compounds offormula V is simply carried out by treatment in t aqueous acetic acid with zinc dust, heating the mixture attemperatures from 80"C to 1 00'C for 30 minutes.

Otherwise, the reduction can be carried out by catalytic hydrogenation at the room temperature and pressure in the presence of an Adam's platinum and/or palladium on charcoal, particularly when the acylating group ofthe aminogroup is a benzyloxycarbonyi, so obtaining atthe same time reduction of exocyclicdouble bond and removal oftheamino protecting group.

The reduction ofthe exocyclic double bond can be optionally obtained by transfer reduction of aqueous solutions ofthe salts ofthe acids Vwith sodium hypophosphite in the presence of Pd on charcoal.

The removal of the acyl protective group ofthe amino group is carried out by refluxing a solution ofthe compound offormula VI wherein R'2 is a lower acyl, trifluoroacetyl or benzoyl with a concentrated mineral acid solution, such as HC1, HBr or 6N H2SO4, for few minutes; the free amine is recovered after alkalinework-up.

The optional optical resolution of the compound offormula VI may be performed both starting from the amino compounds offormula VI (R'2 = hydrogen, lower alkyl) orfrom the carboxylic acids offormula VI (Rd = hydrogen) according to known methods and, respectively, known optically active acids and amines.

The compounds ofthe general formula IV are known compounds orthey are obtained by a multistep process starting from known compounds. Forexample, using methods well known in the art, the optional acyiation of a bicyclic amine ofthe general formula IVa

where n is as above defined, by treatment with a C1-C4fatty acid anhydride ortrifluoroacetic anhydride or benzoyl chloride or benzyloxycarbonyl chloride, gives a compound of general formula IV.

The bicyclic amines of general formula IVa and the acetylamino derivatives of general formula IV (Re = CH3) are known compounds whose preparation is described for example by C.R. Ingold etal.,J. Chem. Soc. 123, 1469,1923; K. Nakarmura, J. Pharm. Soc. Jap. 61,292,1941; ibid. 62,236,1942; P.A. Smith etal.,J. Org. Chem.

26,27,1961; N.L. Allingeretal.,J. Org. Chem. 27,70,1962; R. Caputo et al., Chim. Ind. (It.) 50, 1008m 1968; and by D.E. Biggs et al.,J. Med. Chem. 19,472,1976.

Preferred starting materials for the amines of the general formula IVa are the nitro-bicyclic ketones of the genera

where n is as above defined. The nitro bicyclic ketones are known compounds, too (see for example the above cited references, Beilstein E 117 pag. 294, Hasbun et al., J. Chem. Soc., 183,1969).

Alternative, the compounds of the general formulae IV, IVa can be obtained by cyclization of a substituted phenylalkanoicacid ofthe general formula Vll

wherein Z is NH-CO-Re and Re and n are as above defined.

The cyclization reaction is carried out in polyphosphoric acid or in Friedel-Crafts conditions, in presence of an excess of a catalyst such as SnCI4 and AlCI3, starting from the corresponding acyl chloride (seeforexample D.F. Biggs petal., J. Med. Chem. 19,472,1976).

The compounds of the present invention are characterized by a low acute toxicity and, therefore, by a very favourable therapeutic index.

Table I shows, for example, the results of experiments of acutetoxicity in mice with some of the most representative compounds of the invention : BBR 1728 dl-9-acetylamino-4,5a,5,6-tetrahydro-2H-benzo(h)-cinnoline-3-one; BBR 1741 dl-7-acetyl-4,4a,5,6-tetrahydro-2H-benzo(h)cinnoline-3-one.

TABLE I Compounds LD50in mglkg os BBR1720 1000 1000 BBR1741 1000 450 As reported in Table II, the compounds ofthe invention BBR 1720 and BBR 1741, when tested in spontaneously hypertensive rats, by oral route, at the dosage of 6.25 mg/kg in comparison with the regional isomer dI-8-acetylamino-4,4a,5,6-tetrahydro-2H-benzo(h)cinnoline-3-one(BBR 1508) seem to induce a clear hypotensive and vasodilatory action which is surprisingly combined with a pronounced heart-rate decrease.

TABLE II Compounds: SMHrats 4,4a,5,6-tetrahydro 2H-benzo(hjcinnoline- A BPsist hours heart-rate 3-one mm Hg 8-acetylamino -55 4.6 ~ 5-10% (BBR 1508) 9-acetylamino -40 6 20% (BBR 1728) 7-acetylamino -22 6 16% (BBR 1741) t increase t decrease In opposition to the 8-actylamino isomers, a hypotensive effect of similar magnitude is combined with an increase ofthe heart-rate particularly evident in the laevorotatory isomers ratherthan in the dextro rotatory ones.

A long-lasting decrease of the heart-rate combined with a hypotensive effect is then a peculiar and unexpected characteristic ofthe novel compounds ofthe invention.

From the chemical point of view, the novel compounds are regional (positional) isomers of tricyclic dihydro pyridazinones described in the British PatentApplication No.8419253 filed on 27th July, 1984, in the Applicant's name, endowed with cardiovascular protective agents fortheirvasodilatory antiaggregant and antithrombotic properties.

The novel compounds differ in the position of the amino substituent on the phenyl ring.

As a consequence of said chemical modification, the novel compounds according to the present invention, seem to be completely devoid of any antiinflammatory, antiagregant, antithrombotic and cytoprotective actions, rendering the above mentioned compounds strictly related tb prostacyclin mimetic substances.

In conclusion,the compounds ofthe invention are characterized by good hypotensive activity and in particular, by the interesting property of decreasing the heart-rate.

Therefore, the novel compounds are particularly useful as cardiovascular protective agents, and in particular, they may be used as antiarrhytmic and antiaginal agents. The negative chronotropic effect combined with the hypotensive effect, in fact, induces a decrease ofthe cardiac work with a consequently reduced need of oxygen consumption on behalf of the myocardium.

The decrease of heart-rate is a particularly advantageous characteristic which make these compounds particularly useful in order to preventtachycardic manifestations of different origin.

The compounds I can be administered by the oral, intravenous, subcutaneous, intramuscular, rectal routes.

In emergency situations, the intravenous administration is preferred.

The dose usually ranges from 0.5to 100 mg/kg/day according to the patient's condition, weight, age and on the administration route.

As previously stated, the compounds ofthe invention can be administered either to humans or animals in a variety of dosage forms, e.g., orally in the form oftablets, capsules or liquids; rectally, intheform of suppositories; parenterally, subcutaneously or intramuscularly or in theform of sterile implantsforprolonged action, the intravenous administration is preferred in emergency situations. The pharmaceutical orveterinary compositions of the invention may be prepared in conventional ways and contain conventional carrier and/or diluents.

For example, for intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For subcutaneous orintramuscular injection, sterile solutions orsuspensions in aqueous or non-aqueous media may be used; fox tissue impiants, a sterile tablet or silicone rubber capsule containing or impregnated with the compound is used.

Conventionai carriers or diluents are, for example, water, gelatine, lactose, dextrose, saccharose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium or magnesium stearate, glycol, starch, arabic gum, tragacanth gum, alginic acid or alginates, lecithin, polysorbate, vegetable oils, etc.

Example 1 A hydrazine acetate solution in ethanol (20 ml) is prepared by mixing hydrazine hydrochloride (1.05 g) and potassium acetate (2 g) and added to a suspension of dl-5-acetyl-amino-l-oxo-l ,2,3,4-tetrahydronapht-2-yl-acetic acid (1.8 g) in ethanol (20 ml). The mixture is refluxed for 1.5 hours and then cooled at 0-5"C for 2 hours.

The crystalline precipitate is filtered out to give 1.72 g of dl-7-acetylamino-4,4a,5,6-tetrahydro-2H-benzo/H/cinnoline-3-one, m.p. 330"C; H-NMR (DMSO-drTMS): :2.2 (s,3H,CH3); 2.4-3.6 (m,7H); 7.4 (m, 2H,Ar); 8.0 (m, 1H,A.r); 9.6(s, 1H, NH); 11.0(s, 1H,NH).

Asample ofthis compound (1.2 g) is treated with 30 ml of 4N HCI at the refluxtemperature until a complete solution is obtained. After 2.5 hours, the mixture is cooled at room temperature and extracted with ethylacetate to remove u n reacted material.

The aqueous phase is then brought to pH 8.5 and then extracted with ethylacetate to give, after the usual work-up, dl-7-amino-4,4a,5,6-tetrahydro-2H-benzo[h]-cinnoline-3-one (free base), m.p. 255-258"C; (hydrochloride salt) m.p. 305-309"C.

Example2 A solution of 90% hydrazine hydrate (0.52 ml) is added to a solution of dl-1 -oxo-7-acetylamino-indan-2-yl-acetic acid (1.8 g) in ethanol (25 ml).

The mixture is heated at the reflux temperature for 2 hours. After cooling at room temperature, the crystalline precipitate is filtered to give 1.64 g ofdl-9-acetylamino-4, 4a-dihydro-5H-indeno-[1 ,2-c]-pyridazin-3-one, m.p. 233-2350C, H-NMR (DMSO-drTMS) â 2.2 3H, CH3); 2.4-3.0 (m, 5H); 7.0-7.6 (m, 2H,Ar); 8.2 (m, 1 H, Ar); 9.8(s,1 H, NH); 11(s,1 H, NH). After hydrolysis ofthe acetylamino group by 3N HCI acid, according to the procedure of Example 1, the dl-9-amino-4,4a-dihydro-5H indeno-[1 ,2-c]-pyridazin-3-one, m.p. 285-287"C (as hydrochloride salt) is obtained.

Example3 Starting from the following bicyclic acids: - dl-1 -oxo-4-acetylamino-indane-2-yl-acetic; - dl-1 -oxo-6-acetylamino-indane-2-yl-acetic; - dl-1 -oxo-7-actylamino-1,2,3,4-tetrahydro-2-na phtylacetic; - dl-l -oxo-8-acetylamino-l ,2,3,4-tetrahydro-2-naphtylacetic; - dI-1 -oxo-8-acetylamino-benzo-[6,7]-cycloheptan-2-yI-acetic and using the procedures of Examples 1 and 2,thefollowing dihydropyridazinones are obtained:: - dl-6-acetylamino-4,4a-dihydro-5H-indeno-[1,2-c]-pyridazine-3-one, m.p. 278-280"C; - dl-8-acetylamino-4,4a-dihydro-5H-indeno-[1 ,2-cj-pyridazine-3-one, m.p. 300-302"C; - dl-9-acetylamino-4,4a-5,6-tetrahydro-2H-benzo[h]cinnoline-3-one, m.p. 297-298"C; - dl-10-acetylamino-4,4a,5,6-tetrahydro-2H-benzo-[h]cinnoline-3-one, m.p. 242-244 C; - dl-1 0-acetylamino-2,4,4a,5,6,7-hexahydro-3H-benzo-[6,7j-cycloheptene-[1 ,2-c]-pyridazine-3-one, m.p.

258260eC.

The subsequent hydrolysis with 4N HCl acid in water gives the corresponding aminopyridazinones: - dl-6-amino-4,4a-dihydro-5H-indeno-[l ,2-c]-piridazine-3-one; - dl-8-amino-4,4a-dihydro-5H-i ndeno-[l ,2-c]-piridazi ne3-one; - dl-9-amino-4,4a,5,6-tetrahydro-2H-benzo[h]cinnoline-3-one; - dl-10-amino-4,4a,5,6-tetrahydro-2H-benzo[h]-cinnoline-3-one; - dl-1 0-amino-2,4,4a,5,6,7-hexahydro-3H-benzo[6,7]cyclohepten-[1 ,2-c]-piridazine-3-one.

Example 4 dl-9-Amino-4,4a,5,6-tetrahydro-2H-benzo[h]cinnoline-3-one, m.p. 248-250"C (as free base) and m.p.

276-278"C (as hydrochloride) is also obtained starting from the dl-1 -oxo-7-amino-1,2,3, 4-tetrahydro-2naphtyl-acetic acid by reaction with hydrazine hydrate according to the procedure of Example 2 The free base (1.1 g) intoluene (25 ml) is treated with triethylamine (0.65 g) and chloro acetyl chloride (0.7g) and stirred for 2 hours at 50"C.

After cooling, the mixture is partitioned with water, dried on Na2SO4 and evaporated to dryness.

The residue is crystallized from ethanol to give 0.92 g of dl-9-chloroacetylamino-4,4a,5,6-tetrahydro-2H-benzo[h]cinnoline-3-one, m.p. 242-256 C.

Example 5 By reaction of an amino-pyridazinone ofthe Examples 1,2 or 3 with an acylating agent selected in the group ofe-chloro-acetylchloride, trifluoroacetylanhydride, oc-(acetylthio)acetylchloride and benzene-sulphonyl chloride, according to the procedure of Example 4,thefollowing compounds are obtained: - dl-7-benzensulphonamido-4,4a,5,6-tetrahydro-2H-benzo[h]-cinnoline-3-one; - dl-8-&alpha;-acetylthioacetylamino-4,4a-dihydro-5H-indeno-[1,2-c]-pyridazine-3-one; - dl-8-trifluoroacetylamino-4,4a-dihydro-5H-indeno[1,2-c]-pyridazine-3-one; - dl-9-chlornacel-4,4a-dihydrn-5H-indeno-[1 ,2-c]-pyridazine-3-one.

Example 6 A solution of n-butyl hydrazine acetate in ethanol (15 ml), obtained from n-butylhydrazine hydrochloride (1 g) and potassium acetate (0.85 g) is added to a solution in ethanol (25 ml) of dl-l -oxo-7-acetylamino-indane-2-yl-acetic acid.

After stirring for 2 hours at room temperature, the mixture is heated at refluxtemperature for 3 hours and then it is evaporated to dryness. The residue is partitioned between ethylacetate and 5% aqueous Na2HPO4.

The organic phases are collected, washed until neutral, dried on Na2SO4 and evaporated to dryness.

The solide material is crystallized from ethylacetate-ethyletherto give: dl-1 -n-butyl-g-acetyla mino-4,4a-di hyd rodl-l-indeno-[l ,2-c]-pyridazine-3-one, m.p. 221-222 C.

Example 7 "Glyoxylic acid" is prepared "in situ" by addition of a cooled solution oftartaric acid (29.6 g) in water (60 ml) to a stirred solution of periodic acid in water (280 ml) from NalO4 (42 g) and H2SO4 (5 ml), cooled to 0-2 C.

7-Acetylamino-1,2,3,4-tetrahydro-1-oxo-naphtalene in ethanol (300 ml) and a solution of NaOH (35.2 g) in water (640 ml) are then added to this m ixture maintaining the tem peratu re at about 20-24"C.

The stirring is continued for4 hours at room temperature and then the mixture is heated for one hour at 70-80"C.

After cooling, the precipitate is removed by filtration and the eluate is acidified with 2N H2SO4to crystallize the 7-acetylamino-1 ,2,3,4-tetrahydro-1 -oxo-2-naphtyliden-acetic acid, m.p. 222-225"C.

Example 8 8N Aqueous sodium hydroxyde (23.5 ml) is added in a period of twenty minutes to a stirred suspension of finely powdered 7-acetylamino-indane-1 -one in a solution of glyoxylic acid monohydrate (16 g) in water(100 ml), cooled atO-5 C.After2 hours at room temperature under stirring, the reaction mixture is acidified with 8N sulphuric acid, with external cooling, to pH 2.5 and further stirred for 30 minutes.

The crystalline precipitate is filtered out, washed with water and dried undervacuum at 600C to give 7-acetylamino-1 -oxo-indane-2-ylidene-acetic acid (10.92 g), m.p. 241 C.

Example 9 Using in the procedure ofthe Examples7 and 8the following bicyclicketones: - 5-acetylamino-1 -oxo-1 ,2,3,4-tetrahydro-naphtalene; - 8-acetylamino-1 -oxo-1 ,2,3,4-tetrahydro-naphtalene; - 4-acetylamino-1 -oxo-indane; - 6-acetylamino-1-oxo-indane; - 8-acetylamino-1 -oxo-benzo-[6,7]-cycloheptane the corresponding alkylidene acids are prepared:: - 5-acetylamino-1 -oxo-1 ,2,3,4-tetrahydro-2-naphtylidene-2-acetic acid, m.p. 210"C; - 8-acetylamino-1 -oxo-1 ,2,3,4-tetrahydro-2-naphtylidene-2-acetic acid, m.p. 21 6"C; - 4-acetylamino-1 -oxo-indane-2-ylidene-acetic acid; - 6-acetylamino-1 -oxo-indane-2-ylidene-acetic acid; - 8-acetylamino-1 -oxo-benzo-[6,7]-cycloheptane-2-yl idene acetic acid, m.p. 224-227"C.

Example 10 2.3 Grams of potassium hydrogen carbonate is added to a suspension of 8-acetylamino-1 -oxo-benzo-[6,7]-cycloheptane-2-yliden acetic acid (5 g) in water (50 ml) and the mixture is stirred till complete dissolution of the reagents.

After addition of 0.4 g of 10% palladium on charchoal, the solution ofthe potassium salts is heated at75-80 C and added with sodium hypophosphite (2 g) in 4 portions (every 15 minutes).

The stirring is continued for additional 30 minutes, then the mixture is cooled at room temperature, filtered and acidified until pH 2.5 with 2N sulphuric acid.

The crystalline precipitate was filtered out to give 4.2 g of dl-8-acetyla mino-1 -oxo-benzo-[6,7]-cycl oheptane-2-yl-acetic acid. H-N M R (DMSO-dTMS) 3: 2.1(s, 3H, CH3); 7.6 (m, 2H, Ar).

Example 71 Zine dust (1.65 g) is added in portions to a solution ofthe 8-acetylamino-1 -oxo-1 ,2,3,4-tetrahydro-2-naphtylidene-acetic acid (2.24 g) in 80% aqueous acetic acid (25 ml), heated at 1 OO"C, under stirring for 45 minutes.

The inorganic material is removed byfiltration and washed with warm 80% aqueous acetic acid (5 ml). The eluates are collected and diluted with 0.5 N sulphuric acid (30 ml). The crystalline precipitate is filtered outto give dI-8-acetylamino-1 -oxo-1 ,2,3,4-tetrahydro-2-naphtylacetic acid (1.48 g), m.p. 2062080C.

Example 12 The following compounds: - dl-8-acetylamino-1,2,3,4-tetrahydro-1 -oxo-2-naphtylacetic acid (m.p. 185-187"C); - dl-5-acetylamino-l ,2,3,4-tetrahydro-l -oxo-2-naphtylacetic acid (m.p. 1581 600C); - dl-4-acetylamino-1 -oxo-indane-2-yl-acetic acid; - dl-6-acetylamino-1 -oxo-indane-2-yl-acetic acid; - dl-7-acetylamino-1 -oxo-indane-2-yl-acetic acid (m.p. 213-215"C) are prepared starting from the corresponding alkylidene acetic acid obtained according to the procedure of Example 7,8 and 9 when subjected to the reduction of the exocyclic double bond using the procedure described in Examples 10 and 11.

Claims (6)

1. Acompound ofgeneralformuia I

wherein: -nissero,1 or2; - R is hydrogen, C1-C6 lower alkyl,-CH2-CH =CH2, -CH2-C=-CH and (CH2)rnC6H5 where m is zero or an integer from 1 to 3;; - R1 and R2 are independently selected from the group consisting of hydrogen, C1 -C6 lower alkyl,

wherein m is as above defined, CH2-CH=CH2,-CH2-CECH, R3-CO- where R3 is selected from the group consisting of C1-C16 branched or linearalkyl residue, optionally containing hydroxy, amino, halogen,thiol groups or a free or esterified carboxy group, an heterocyclic ring, a substituted or unsubstituted aromatic ring, a cycloaliphatic ring, a cycloaliphaticalkyl, an aralkyl or heteroalkyl, a lower C1-C6 lower alkoxy, benzyloxyor N HR6 group where R6 is hydrogen, C1-C6 lower alkyl, or CH2-C6H5;; R4SO2wherein R4 is selected in the group of CH, C2H5, phenyl, p-methylphenyl groups; both as racemicor optically active enantiomers and saltsthereof, with the proviso thatthesubstituent

is not linked to the aromatic ring Athrough position b.

2. Acompound selected from the group consisting of a racemic and/oroptically active: - 9-acetylamino-4,4a,5,6-tetrahydro-2H-benzo(h)cinnoline-3-one; - 7-acetylamino-4,4a,5,6-tetrahydro-2H-benzo(h)cinnoline-3-one; - 7-amino-4,4a,5,6-tetrahydro-2H-benzo(h)cinnoline-3-one; - 6-amino-4,4a-dihydro-5H-indeno-[1 ,2-c]-pyridazine-3-one; - 8-acetylamino-4,4a-dihydro-5H-indeno-[1 ,2-c]-pyridazine-3-one; - 1 0-acetylam ino-2,4,4a,5,6,7-hexa hydro-3H-benzo-[6,7]-cyclo heptene-[1 ,2-c]-pyridazine-3-one.

3. A pharmaceutical or veterinary composition having hypotensive activity, comprising a therapeutically effective amount of one or more compounds of claim 1 or2 in admixture with a suitable carrierand/ordiluent.

4. A pharmaceutically orveterinary composition, having antianginal activity, comprising atherapeutically effective amountofone or more compounds of claim 1 or2 in admixture with a suitable carrierand/ordiluent.

5. A pharmaceutical or veterinary composition, having antiarrhytmic activity, comprising atherapeutically effective amountofone or more compounds of claim 1 or2 in admixturewith a suitable carrier and/ordiluent.

6. A process for the preparation of compounds offormula I characterized in that a compound offormula II

wherein n, R1 and R2 have the above defined meanings and Rd is hydrogen or a lower c1-C6 alkyl is reacted with an hydrazino compound offormula II H2N-NH-R' (III) wherein R' has the above defined meanings and that the compounds so obtained are optionally alkylated, acylated and subjected to optical resolution.