PT99831A - METHOD FOR PREPARING BENZOIC ACID DERIVATIVES CONTAINING A DI AZACYLIC OR AZABICYLIC SIDE CHAIN - Google Patents

Description

The present invention relates to novel compounds having pharmacological activity, a process for their preparation and their use as pharmaceutical products. EP-A-220011 (Beecham Group p.l.c.) discloses the use of a benzamide derivative with 5-HT 3 receptor antagonist activity

A group of novel compounds have now been discovered, which compounds are antagonists of 5-HT3 receptors.

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

(I) in which it represents hydrogen or alkoxy of 1 to 6 carbon atoms, R2 is halo, R3 is halo, L is O or NH and

Z represents a di-azacyclic or azabicyclic side chain, with 5-HT 3 receptor antagonist activity

Suitable examples of alkyl moieties in R1 include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and t-butyl.

Suitable examples of halo moieties include fluoro, chloro and bromo.

In particular, R 1 represents hydrogen, R 2 represents chloro and R 2 represents chloro; or R representa is methoxy, R representa is fluoro and R representa is chloro.

Suitable examples of Z are described in the art with regard to 5-HT 3 receptor antagonists, i.e.,: i) GB 2125398A (Sandoz Limited) ii) GB 2152049A (Sandoz Limited) iii) EP-A-215545 (Beecham Group plc) iv) EP-A-214772 (Beecham Group plc) v) EP-A-377967 (Beecham Group plc) vi) PCT / GB91 / 01629 (Beecham Group plc) vii) EP-A-358903 (Dianippon )

Certain side chains of particular interest have the following configuration:

Trooano

Granatano ·

Oxa / 1a-crranatan

Ouirmidine

Isoaminuclidine 6

• Λ * / ^ L /

Isocrranatan

(I.e.

Oxa / thia-isogranatan Ν

Isotrooan

Or

in which R represents hydrogen or methyl; and X represents oxygen, sulfur or nitrogen optionally substituted with alkyl, C a to cycloalkyl, C 0 ciclo ciclo cycloalkylC, alkyl, phenyl, naphthyl, or a phenyl-4-4-alkyl wherein a phenyl or naphthyl moiety is?

C 1-6 alkyl optionally substituted with one or more halo, C 1-6 alkoxy or 1-6 C 1-6 alkyl.

Z-chains of particular interest include tropane, oxagranatane and azagranatane, wherein R represents methyl. Suitable values for N substituents when X is N are described in PCT / GB91 / 01629, for example iso-propyl or ethyl. L is preferably NH.

Alternatively, COL in formula (I) may be substituted with a bioisostereomer, for example 1,2,4-oxadiazole and the other groups of structure h) described in EP-A-377967 (Beecham Group p.l.c.).

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with conventional salts, such as hydrochloric, hydrobromic, boronic, phosphoric, sulfuric and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic , benzoic, ascorbic, methasulfonic, α-ketoglutaric, α-glycero-phosphoric and glucose-1-phosphoric acids. Exemplary pharmaceutically acceptable salts are quaternary derivatives of the compounds of formula (I), such as the compounds quaternized by compounds wherein Rx is alkyl, phenyl-1-6 alkyl or C5 -cycloalkyl, and T is a radical corresponding to anion of an acid. Suitable examples of R1 are methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples of T include halides such as chloride, bromide and iodide. \ y acceptable

Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.

The compounds of formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof.

It will of course be appreciated that some of the compounds of formula (I) have chiral or pro-chiral centers and are therefore capable of existing in a number of stereoisomeric forms, including enantiomers. The invention extends to each of these stereoisomeric forms (including enantiomers), and to mixtures thereof (including racemates). The various stereoisomeric forms can be separated from each other by the usual methods. The invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II):

(II) with a compound of formula (III): (III) HLZ '

I

in which R 2 ', R 3' and / or Z 'are R 2, R 3 and / or Z respectively, or groups or atoms therein convertible, R 4 represents hydrogen or a nitrogen protecting group, Q 1 represents a leaving group and the variables and R 2 ', R 3' and / or Z 'are further and optionally converted to other groups or atoms R 1, R 2, R 3 and / or Z and optionally preparing a pharmaceutically acceptable salt of compound of the formula I resulting. )

Examples of R4 when it is other than hydrogen include C1-4 acyl such as C1-4 alkanoyl, wherein the alkyl may be as stated for R1, preferably acetyl. R4 is generally hydrogen.

Examples of displaceable Q1 # groups displaceable through a nucleophile include a halogen such as chlorine or bromine, hydroxy, C1-4 alkoxy, such as, CH3 and C2 H50 -, PhO-, activated hydrocarbyl-oxy, such as C1 -C20 - or C130-; or COOH forms a mixed anhydride such that it is acyloxy carboxylic; or a nitrogen linked heterocycle, such as imidazole. 1

If a group Q is a halide, or if CO 2 forms a mixed anhydride, then the reaction is preferably carried out at non-extreme temperatures in an inert non-hydroxylic solvent such as benzene, dichloromethane, toluene, diethyl ether, tetrahydrofuran (THF) or dimethylformamide DMF). It will also preferably be carried out in the presence of an acid acceptor, such as an organic base, in particular a tertiary amine, such as triethylamine, trimethylamine, pyridine or picoline, some of which may also function as a solvent. Alternatively, the acid acceptor may be inorganic, such as Λ X * carbonate. / calcium, sodium carbonate or potassium carbonate. Temperatures of 0 ° -100 °, in particular of 10 ° -80 ° are suitable. 1

If a Q group is C1-4 alkoxy, phenoxy or hydrocarbyl-xi the reaction is preferably carried out in an inert polar solvent, such as toluene or dimethylformamide. It is also preferred that the group Q 1 is C 13 CO- and that the reaction is carried out in toluene at the reflux temperature. 1

If a group Q is hydroxy, then the reaction is generally carried out in an inert non-hydroxylic solvent, such as dichloromethane, THF or DMF, optionally in the presence of a dehydrating agent, such as carbodiimide, for example dicyclohexylcarbodiimide. The reaction may be carried out at any non-extreme temperature, such as 0 ° -100 °, for example, 0 ° -80 °. In general, higher reaction temperatures are employed with less active compounds while lower temperatures are employed with the more active compounds. 1

If a group Q is acyloxy carboxylic, then the reaction is generally carried out essentially in the same manner as the reaction if it is halide. Suitable examples of acyloxy dissociable groups include C. alkanoyloxy and C1-4 alkoxy. alkoxycarbonyloxy, in which case the reaction is preferably carried out in an inert solvent, such as dichloromethane, at a non-extreme temperature, for example at room temperature, in the presence of an acid acceptor, such as triethylamine. The C 1-4 alkoxycarbonyloxy groups may be generated in situ by treatment of the corresponding compound wherein Q 1 is hydroxy with a C 1-4 alkyl chloroformate.

If a group Q 1 is activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as

X as well as dimethylformamide. It is also preferred that the activated hydrocarbyloxy group is a pentachlorophenyl ester and that the reaction is carried out at ambient temperature.

When Y is O, the compound of formula (III) may be in the form of a reactive derivative thereof, which is often a salt, such as the lithium, sodium or potassium salt.

A group or which is convertible to R2 or R3 includes a hydrogen substituent which is convertible to a halogen substituent by halogenation using conventional halogenating agents.

When Z 'is other than Z may be R when it is replaced by R' which is a hydrogenolizable protecting group, which is benzyl optionally substituted with one or two groups selected from halo, alkoxy and C 1-4 alkyl. These benzyl groups may, for example, be removed when R1 / R2 is not halogen, by a conventional catalyzed transition metal hydrogenolysis, to give compounds of formula (I) wherein R is hydrogen. The present invention further provides a process for the preparation of a compound of formula (I) wherein R is methyl or a pharmaceutically acceptable salt thereof, which comprises N-methylating a compound of formula (I) wherein R is hydrogen, and optionally forming a pharmaceutically acceptable salt of the resulting compound of formula (I). In this other process of the invention 'N-methylation' can be effected by reaction with a CH 3 Q 2 compound wherein Q 2 is a leaving group.

Suitable values for Q 2 include groups displaced by nucleophiles such as Cl, Br, I, SO-CHO or OSO-C-H. p CHL, preferably Z is Cl, Br, I. The reaction may be carried out under conditions of conventional alkylation, for example in an inert solvent such as dimethylformamide, in the presence of an acid acceptor such as potassium carbonate. In general the reaction is carried out at non-extreme temperatures, such as ambient temperature, or slightly higher.

Alternatively, 'N-methylation' may be effected under conventional reductive alkylation conditions.

Interconverting R in the compound of formula (III) before joining the compound of formula (II) is also possible. These interconversions are conveniently performed under the above conditions. It is desirable to protect any amine function with a readily removable group by acidolysis, such as a C2-7 alkanoyl group, prior to the R / Z interconversion. It is often convenient in the preparation of such a compound of formula (III) to prepare the corresponding compound wherein the methyl group is substituted with alkoxycarbonyl. These compounds may then be reduced, using a strong reductant such as lithium aluminum hydride, into the corresponding compound of formula (II).

Intermediates of benzoic acid derivatives of formula (II) are known or are preparable analogously to, or customarily from, known compounds. When R 2 is fluoro, the intermediate which can be prepared by fluorination of the corresponding R 2 is a hydrogen compound using a suitable fluorination catalyst, for example trifluoro-methylhyfluoride, as described in Description 1 below.

The compounds of formula (III) are generally prepared from the corresponding exocyclic keto derivatives of the azabicyclic side chain by condensation methods, often using a substituted pyridine. They may be prepared by processes described in the above-mentioned Patent Publications relating to Z-side chain values.

It should be noted that in the compounds of formula (I) containing a tropane, granatane or oxa / aza-granatane side chain, the -COL- bond has an endo orientation to the ring of the bicyclic moiety to which the connected. The mixture of the endo and exo isomers of the compound of formula (I) may be synthesized non-stereospecifically and the desired isomer conventionally separated therefrom, for example by chromatography; or alternatively the endo isomer may, if desired, be synthesized from the corresponding endo form of the compound of formula (II). Geometric isomeric pairs for the side chains of isoquinuclidine, isogranatan, oxa / thia-iso-granatane and isotropane are possible.

The pharmaceutically acceptable salts of the compounds of the present invention may be conventionally prepared.

The salts may be prepared, for example, by reacting the base compound of formula (I) with a pharmaceutically acceptable organic or inorganic acid.

The compounds of the present invention are antagonists of 5-HT 3 receptors and are therefore believed to be useful in the treatment or prophylaxis of pain, vomiting, central nervous system (CNS) disorders and gastrointestinal disorders. The pains include migraines, histamine cephalgias, trigeminal neuralgias and visceral pains; emesis includes, in particular, the situation of preventing vomiting and nausea associated with cancer therapies, postoperative emesis and migraine-associated nausea. Examples of the cancer therapies include cytotoxic agents such as platinum complexes including cisplatin, as well as doxorubicin and cyclophosphamide, more particularly cisplatin; and also radiation treatment. Central nervous system disorders include anxiety, psychosis, cognitive disorders such as senile dementia and age-related memory impairment (DMAI), as well as drug dependence. Gastrointestinal disorders include intestinal irritation syndrome and diarrhea.

5-HT 3 receptor antagonists may also be potentially used in the treatment of obesity, arrhythmia and / or disorders associated with myocardial instability. The invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

These compositions are prepared by mixing and are as a rule adapted to oral and parenteral administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, solutions or suspensions for injection or for use in infusions, or suppositories. Orally administrable compositions are preferred as they are more convenient for general use. -Ν.

Tablets and capsules for oral administration are generally presented in unit doses and contain conventional excipients such as binders, fillers, diluents, long forming agents, lubricants, disintegrants, colorants, flavoring and wetting agents. The tablets may be coated according to methods well known in the art, for example with an enteric coating.

The fillers used include cellulose, mannitol, lactose and the like. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium glycolate. Suitable lubricants include, for example, magnesium stearate.

Acceptable, pharmaceutically suitable wetting agents include sodium and lauryl sulfate. Liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product which may be reconstituted with water or any other suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid and, if desired, conventional flavorings or colorants.

I 16

THE

Oral liquid preparations generally are in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or are presented as a dry product which may be reconstituted with water or any other suitable carrier prior to use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), conventional preservatives and flavorings or colorants.

Oral compositions may be prepared by conventional methods such as blending, filling or forming tablets. Repeat blending operations may be used to deliver the active agent through such compositions wherein large amounts of fillers are employed. These operations are, of course, conventional operations within the art.

In the case of parenteral administration, the unit dosage forms are prepared containing a compound of the present invention and a sterile vehicle. Depending on the compound and the concentration, the vehicle can thus be either suspended or dissolved. Parenteral solutions are usually prepared by dissolving the compound in a vehicle and sterilizing by filtration before being introduced into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents are also dissolved in the carrier. In order to increase stability, the composition may be frozen after being introduced into the vial, the water being removed under vacuum.

Parenteral suspensions are prepared in essentially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilized by exposure to ethylene oxide before being suspended in the sterile vehicle. A surfactant or wetting agent is advantageously included in the composition to facilitate uniform distribution of the compound of the invention. The invention further provides a method for the treatment or prophylaxis of the disease, emesis or disorders of the CNS and / or gastrointestinal disorders in mammals, for example in humans, which comprises administering an effective amount of a compound of formula formula (I) or a pharmaceutically acceptable salt thereof. The amount effective to treat the disorders described above depends upon the relative efficacies of the compounds of the invention, the nature and severity of the disorder to be treated and the weight of the mammal.

However, a unit dose for an adult of 70 kg should normally contain from 0.05 to 1000 mg, for example from 0.5 to 500 mg, of the compound of the invention. Unit doses may be administered one or more times per day, for example, 2, 3 or 4 times per day, generally 1 to 3 times per day, i.e., in the range of about 0.0001 to 50 mg / kg / day , and more often from 0.0002 to 25 mg / kg / day.

No adverse toxicological effects are known in the above dosage ranges. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance, in particular for use in

treatment of pain, emesis, CNS disorders and / or gastrointestinal disorders.

The following Examples illustrate the preparation of the compounds of formula (I).

Examples

Ex. NS R1 R2 R3 L Z1 H Cl Cl NH2 CH2 Cl3 NH3 Cl CH3 NH2 Cl3 NH ClO NH3 OCH3 F Cl NH Nm T

NmT = N-methyltropane Q = Quinuclidin-3-yl NmO = N-methyloxagranatan

Description therein Methyl-4-acetamido-5-chloro-3-fluoro-2-methoxybenzoate

Methyl-4-acetamido-5-chloro-3-fluoro-2-methoxybenzoate (10.9 g) was dissolved in chloroform (40 ml) and cooled to -10 ° C under nitrogen. A three molar excess of trifluoromethyl hypofluorite was slowly bubbled through the cooled and stirred solution for 6 hours. A slow and positive nitrogen stream was maintained through the reaction. After warming to room temperature and purging completely with nitrogen, the chloroform was removed in vacuo. x '/ · x' / · using eluent. The residue was chromatographed on silica chloroform, with increasing amounts of methanol. The product was isolated as an off-white solid. 1 H NMR (CDCl 3): 250 MHz δ: 7.64 (d, 1H); 7.37 (bs, 1H); 3.98 (bs, 3H); 3.9 (s, 3H); 2.2 (S, 3H) b) 4-Amino-5-chloro-3-fluoro-2-methoxybenzoic acid

5-Chloro-3-fluoro-2-methoxybenzoate (1.89 g) in 25 ml of ethanol was treated with a solution of sodium hydroxide (1.15 g) in 15 ml of water. The mixture was heated at reflux for 16 hours and then cooled. The solvent was removed in vacuo and the residue acidified. The solid precipitate was collected by filtration to give 1.48 g of product. 1 H NMR (DMSO) 250 MHz

Yield 7.49 (d, 1H); 6.19 (bs, 1H); 3.80 (s, 3H)

Example 1 endo-N- (8-Methyl-8-azabicyclo [3.2.0] octan-3-yl) -4-amino-3,5-dichlorobenzamide (EI)

To a stirred solution of 4-amino-3,5-dichlorobenzoic acid (1.1 g) in CH2 Cl2 (50 ml) and Et3 N (0.8 ml) at 0 ° C was added Et2 OCl (0.48 ml. ) After stirring at room temperature for 1 hour, the solution of endo-8-methyl-8-azabicyclo [3.2.1] octan-3-amine (0.7 g) in CH2 Cl2 (10 ml) and the whole was hectic during the night. The reaction mixture was washed with saturated NaHCO 3 solution, dried and evaporated. Recrystallization of the residue (EtOAc / petrol) gave the title compound (0.35 g), m.p. 192.193 ° C. ¹ NMR (CDCl 3) δ 7.55 (s, 2H) 6.25 (brd, 1H) 4.76 (brs, 2H) 4.22 (q, 1H). 3.21 (brs, 2H) 2.33 (s, 3H) 2.35-2.10 (m, 4H) 1.88-1.68 (m, 4H) V '· "

In a similar manner there was prepared: -

Example 2 N- (1-Azabicyclo [2.2.2] octan-3-yl) -4-amino-3,5-dichlorobenzamide 1121 mp 233-235 ° C Example 3 endo-N- (8-Methyl-8-azabicyclo [ -3-yl) -4-amino-3,5-dichloro-2-methoxybenzamide (E3)

A solution of endo-N- (8-methyl-8-azabicyclo [3.2.1] octan-3-yl) -4-amino-3,5-dichloro-2-methoxybenzamide (0.8 g) in CH 2 COOH ( 25 ml) was treated with a solution of Cl 2 (0.18 g) in CH 2 COOH (5 ml). After standing at room temperature overnight, the solvent was removed by rotary evaporation and the residue was partitioned between EtOAc and an aqueous NaHCO3 solution. The organic extract was separated, dried (K 2 CO 3), evaporated and the residue purified by flash chromatography (SiO 3, 5-10% MeOH / CHCl 3) to provide the title compound) (0.065 g), m.p. 148-151 ° C.

In a similar manner there were prepared:

Example 4 endo-N- (9-Methyl-9-aza-3-azabicyclo [3.3.11nonan-7-yl-4-amino-3,5-dichloro-2-methoxybenzamide (E4) m.p. 170-172Â ° C.

EXAMPLE 5 The title compound was prepared according to the procedure described in Example 1. The title compound was prepared according to the procedure described in Example 1. The title compound was prepared as a white powder prepared from 4-amino-5-chloro-3-fluoro-2-methoxybenzoic acid by a procedure analogous to that described in Example 1. The product was isolated as the hydrochloride salt, m.p. 202-203 ° C. 1 H NMR (free base), (CDCl 3) 250 MHz δ: 8.61 (bd, 1H); 7.81 (d, 1H); 4.34 (bs, 2H); 4.20 (dd, 1H); 3.98 (d, 3H); 3.10 (b, 2H); 1.53-2.21 (m, 11H S inc., 2.21, 3H).

Antagonist activity of 5-HT3 receptor receptors

The compounds were analyzed for their antagonism to the von Bezold-Jarisch reflex raised by 5-HT in the anesthetized rat according to the following method:

Male rats of 250-350 g were anesthetized with urethane (1.25 g / kg interperitoneally) and the rate of blood pressure and pulsations was recorded as described by Fozard J.R. et al., &Quot; J. Cardiovasc, Pharmacol. 2, 229-245 (1980) ". A sub-maximal dose of 5-HT (generally 6 μg / kg) was administered intravenously and heart rate variations were quantified. The compounds were administered intravenously and the concentration required to reduce the

control reaction raised by 5-HT to 50% of the (ED50) reaction was then determined.

I

Claims (1)

24 A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof: wherein: R1 represents hydrogen or alkoxy of 1 to 6 carbon atoms, R1 represents halo; R 3 represents halo; L represents O or NH; e > Z represents a di-azacyclic or azabicyclic side chain; with 5-HT 3 receptor antagonist activity; characterized in that a compound of the formula (II) is reacted: with a compound of the formula (III): HLZ '(III) or a reactive derivative thereof in the cases wherein L represents O; in which: R 1 ', R 2', R 3 'and / or Z' represent R 2, R 3 and / or Z, respectively, or groups or atoms therein convertible; R'4 represents hydrogen or an N-protecting group; represents a leaving group; and the remaining variables have the abovementioned meaning and thereafter optionally converting R 1 ', R 2', R 3 'and / or Z' to other groups or atoms R 1, R 2, R 3 and / or Z; and, optionally, a pharmaceutically acceptable salt of the resulting compound of formula (I) is formed; The process according to claim 1, wherein R 1 is hydrogen, R 2 is chlorine and R 3 is chlorine. T - ν '. The process according to claim 1, characterized in that it is methoxy, R 2 represents fluoro or chloro and R 3 represents chloro. 4. A process according to any one of claims 1 to 3, characterized in that the side chain Z represents tropane, granatane, oxa / thia / azagranatan, quinuclidine, isoquinuclidine, isogranatane, oxa / thiisogranatane or isotropane. 5. A process according to claim 4, characterized in that Z represents tropane, oxagranatane or azagranatane. 6. A process according to any one of claims 1 to 5, wherein L is NH. The process according to claim 1, wherein endo-N- (8-methyl-8-azabicyclo [3.2.1] -octan-3-yl) -4-amino-3,5-dichlorobenzamide . 8. A process as claimed in claim 1 for preparing N- (1-azabicyclo [2.2.2] octan-3-yl) -4-amino-3,5-dichlorobenzamide. (8-methyl-8-azabicyclo [3.2.1] -octan-3-yl) -4-amino-3,5-dichloro- 2-methoxybenzamide. 10. A process according to claim 1 wherein the endo-N- (9-methyl-9-aza-3-azabicyclo [3.3.1] nonan-7-yl) -4-amino- 5-dichloro-2-methoxybenzamide. 11. A process as claimed in claim 1, wherein the endo-4-amino-5-chloro-3-fluoro-2-methoxy-N- (8'-methyl-8-azabicyclo [3,2.1] octan-3-yl) benzamide or a pharmaceutically acceptable salt of this compound . 12. A process for the preparation of a medicament for the treatment and / or prophylaxis of pain, emesis, disorders of the central nervous system (CNS) and / or gastrointestinal disorders, characterized in that a compound of the formula (I), prepared according to claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. Lisbon, December 17, 1991 J. PEREIRA DA CRUZ Official Agent of Industrial Property RUA VICTOR COROON, 10-A 3. " 1200 LISBOA