IE52066B1 - New naphthimidazole and naphthoxazole derivatives,their preparation,and their use in pharmaceuticals - Google Patents

Description

The present invention relates to new naphth ^l,2-d^ imidazole and naphth [2,1-d] oxazole derivatives, to the process for their preparation, to their use as C.N.S. depressant agents and to the pharmaceutical compositions containing them. More particularly the novel naphthimidazoles and naphthoxazoles of the present invention are represented by the following formula I wherein R and Rp each independently, are selected from the group consisting of hydrogen, halogen, (C,-C,)alkyl and (C.-C,)alkoxy; O X O R2 stands for hydrogen or halogen, and A represents one of the following 10 moieties wherein Rg is (C^-Cglalkyl, (Cg-Cg)cyeloalkyl or a (CH„) -NR.R, group wherein Ζ H J 0 n is 1,2, or 3 Rg stands for hydrogen, or (C^-Cg)alkyl, and - 2 52066 P.g is (C^-Cg)alkyl or R, and R. taken together with the adjacent nitro3 0 gen atom may represent a 4 to 7 membered saturated heteroring which may contain a further heteroatom selected from nitrogen and oxygen, and may optionally bear a substituent selected from the group consisting of (C3_Cg)alkyl, (C2“Cg)alkenyl, (C.-C,)cycloalkyl, aliphatic-(C-C,)acyl, phenyl, o 2 b substituted phenyl (as hereinafter defined), benzyl, halo-benzyl, and pyridyl, represents hydrogen, (C, C )alkyl, (C-C,)4 X·· b 3 0 cycloalkyl or -(CH.) -NR.R- wherein n, R_ and Rr are as 2 n 3 o 3 b defined above; and R_ stands for a group -{CH ) -NR R wherein n, Z 2 n 3 b R, and R, are as defined above; with the proviso that when 5 o the symbol A represents grouping a) or b), one of R3 and R^ is a -(CH ) -NR.R, group and with the further proviso that 2 η ο b when R, stands for a group -(CH.) -NR.R, wherein n is 1, R, 2 n 3 o 3 and R taken together with the adjacent nitrogen atom may 6 not represent a morpholino or piperidino radical.

A preferred group of compounds comprises those compounds of formula I wherein R, R , and Rj are as defined above and the symbol A stands for grouping (a) or (b) wherein R3 and R^ are as defined before, with the proviso that one of R, and R. is a (CH.) -NR.R, group. 4 2 Π 3 b A most preferred group of compounds comprises those compounds of formula I wherein R and R^, each independently are selected from the group consisting of hydrogen, halogen, (C,-C,)alkyl, and (C-C,)alkoxy, R is lb lb 2 hydrogen, and the symbol A represents grouping (a) or (b) wherein R3 is (C^-Cg)alkyl or a -(CH2)2-NRgRg group wherein Rg and Rg taken together with the adjacent nitrogen atom represents a piperazine ring which may optionally bear a substituent selected from the group consisting of phenyl, substituted phenyl(as hereinafter defined), and pyridyl, and R^ represents (C]-Cg)-alkyl or a group -(CH2)n-NRgRg wherein Rg and Rg are as defined above in this preferred group, with the proviso that one of R3 and R^ is a -(CH2)n-NRgRg group.

The term (C-C ) alkyl, as used throughout the disclosu1 b re, comprehends both straight and branched chain hydrocarbon groups containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl. Similarly, the term (C-C ) alkoxy comprehends groups such as methoxy, etho1 b xy, propoxy, isopropoxy, butoxy, tert-butoxy, psntyloxy and hexyloxy.

Also,the term (C-C.)alkenyl comprehends straight or· Ζ O branched unsaturated hydrocarbon groups which may contain one or two double bonds such as allyl, methylallyl, ϊ,3-butadienyl or 1,4-hexadienyl. The expression (C-C )cycloalkyl identifies a cycloalkyl radical □ b containing 5 or 6 carbon atoms i.e. a cyclopentyl or cyclohexyl group.

The term (C-C ) aliphatic acyl refers to an acyl radical 6 derived from an aliphatic carboxylic acid containing 2 to 6 carbon atoms such acetyl, propionyl, butyryl, iso25 butyryl or hexanoyl.

The term substituted phenyl designates phenyl radicals substituted with one to three groups independently selected from (C C )alkyl, (C-C )alkoxy, hydroxy, benX— b lb zyloxy, halogen, trifluoromethyl, amino, mono-and di-al30 kylamino and nitro.

The term halogen is intended to encompass all the four forms thereof, i.e., chlorine, bromine, fluorine and iodine. Representative of 4 to 7-membered saturated heterorings are azetidine, oxazine, pyrrolidine, piperidine, pipera5 zine, morpholine and lH-hexahydro-azepine.

Naphth/1,2-d7imidazoles substituted in the 2-position with a piperidinomethyl, morpholinomethyl, u-hydroxy-&-piperidino ethyl, and a-hydroxy- β-morpholinoethyl group, are known from J.A.C.S. 70, 2415-17 (1948). These compounds were studied because of possible interest as antimalarial agents and their syntheses were investigated and reported in the above cited literature reference.

Several benzimidazoles and naphth [l,2-d] imidazoles having anti15 histaminic properties are known from Chem. Abst. 47 (1953) column 2752c to 2753f.

The compounds of the present invention can be prepared according to known methods: the easiest and most convenient one is the nucleophilic displacement reaction of the alkyl derivatives of the formulae la', lb', and lc'. wherein R, , and R2 have the same meanings as before, R^ is (Cj-CgJalkyl, (Ο^-σθ)cycloalkyl or a -<CH2^n X 9rouP wherein ή is as defined before and X stands for the residue of a reactive ester especially a halogen atom such as chlorine or bromine or the residue of a sul5 furic acid ester or sulfonic acid ester such as methansulfonate, benzenesulfonate, or p-toluenesulfonate, Ri is hydrogen, (C, -C.) alkyl, (C-C,.) cycloalkyl or 4 lo □ d a -(CH.)- X group wherein n and X are as defined above, Π with the proviso that one of R'. and R', is a -(CH.)-X r - 3 4 2 n group, R'7 represents a group X' ~ This nucleophilic displacement involves the attack at carbon by a suitably selected nucleophile HNR.R, and 3 O the replacement of the leaving group -X by the group -NR R . In the actual practice the reaction is carried 3 0 out refluxing a solution of the two reactants in a polar organic solvent such as methanol, ethanol, acetonitrile, acetone, or a mixture thereof, . under inert atmosphere for several hours. In order to remove the.hydrohalic, sulfuric or sulfonic acid which forms during the reaction, at least a molar amount of an acid acceptor agent is employed; according to a preferred embodiment, the reaction is carried out using a double molar amount of the amine; however, alternative! or in addition, other basic agents, such as alkali or alkaline earth metal carbonates, hydroxides or lower alkoxides, or organic nitrogen bases such as pyridine, collidine or aliphatic tertiary amines, can be employed. The end products of formula I are then recovered by evaporating the solvent and are roughly purified by washing with water.

Finally, crystallization from a suitable solvent or column chromatography, or both, afford the purified end products. Both starting compounds may be employed as free bases or as the corresponding acid addition salts, typically as the hydrochlorides; in this case a further amount of basic agent has obviously to be employed.

For practical reasons when compounds of formula I are prepared wherein the symbol A represents grouping a) or b) wherein R, stands for -(CH_)-NRcR, and R is hydrogen 3 2 n a o 4 (C,-C,)alkyl, or (C,-C,)cycloalkyl, starting compounds 1 o □ o of the above formulas la' and Ib’are preferably employed wherein the symbol X represents a halogen atom, such as chlorine or bromine, since they may be easily prepared from the corresponding diaminonaphthalene derivatives of formulas Ila and lib respectively through condensation with a suitably selected acyl chloride of the formula Cl-^-CCH^J-Halo, wherein Halo stands for chlorine, or bromine, followed by cyclization.

If desired, the cyclization reaction may be carried out 2G in the presence of at least the molar amount of the amine HNR^Rg and a hydrogen halide acceptor, as defined before, yielding directly the desired end products of formulas la and lb wherein R is hydrogen, (C,-C,)alkyl, or (Cr-C.)cyclo4 1 o to alkyl,and R, is a group -(CH.)-NR_R,. w 2 Jl 5 o The diamino derivatives Ila and Ub are known or may be prepared by reducing the corresponding nitro compounds, Ilia and Illb respectively which in their turn may be prepared by conventional procedures well known in organic chemistry.

Another method for preparing the diamino derivatives Ila is represented by the reduction of the corresponding 1-nitroso-N-substituted-naphthaleneamines obtained,according to the method described by S.T. Morgan and F.P. Evens in J. Chem. Soc. 115, 1140 (1919), through acid-catalyzed rearrangement of a 2-(N-nitroso-N-substituted)naphthyl10 amine or more conveniently through reaction of primary amines with l-nitroso-2-naphthol according to E.W. Malmberg and C.S. Hamilton, J. Am. Chem. Soc. 70, 2415 (1948).

A different route for preparing starting compounds of formulas la' and lb' wherein R'g is a -(CHg)-Halo group and R' is hydrogen, alkyl, or cyeloalkyl, involves the condensation of the acyl chloride Cl-C-(CHg)-Halo with the derivatives IIIa and Illb followed by reduction of the nitro group to amino and simultaneous cyclization. Depending on the meanings of the radical Rg, different reducing agents may be employed. As an example, when Rg is hydrogen, .the nitro group may be reduced through catalytic hydrogenation with hydrogen - in the presence of a catalyst, such as Platinum or Palladium, preferably adsorbed on charcoal, or Nikel Raney.

Milder agents and conditions, such as for instance iron in acetic acid, have to be employed when Rg is a halogen atom in order to avoid hydrogenolysis of this group.

Also in this case when preparing starting compounds of formula la' the condensation may also be carried out between the acyl chloride Cl-g-(CH2)-Halo and the suitably selected l-nitroso-N-substituted-2-naphthaleneamine derivative. When compounds of formula Ib are desired wherein R^ is alkyl or cyeloalkyl and R, is a -(CH.)-NR,R, group, z n □ ο starting compounds of formula Ib' are preferably employed wherein the symbol X stands for a sulfonate group. In fact, the process for preparing the starting compounds Ib', which is described in the following scheme, leads to the formation of the corresponding alcohols which are conveniently activated by conversion to sulfonate esters through reaction with a sulphonyl chloride as known in the art. cyclization Η + X Analogously starting from a compound of formula IVa and following the same process, the starting compounds of formula la* are obtained. Finally, starting compounds of formula Ic' wherein Xis a halogen atom are prepared from the corresponding 2-amino-1-hydroxy-naphthalene derivatives through condensation with Cl-g-(CH^)-Halo followed or accompanied by ring closure to naphthoxazole.

Another method for preparing conpounds of formula I wherein independently from the meanings of R, R^ and A, R^is a hydrogen atom, is represented by the hydrogenolysis of the corresponding compounds wherein R2 is halogen. Said hydrogenolysis can be carried out by means of hydrogen in the presence of a catalyst or by means of alkali metal aluminium hydrides. The catalytic reduction with hydrogen is preferably performed at ambient temperature, and at a pressure ranging from the atmospheric pressure to about 10 atmospheres. The catalysts employed are selected from the usual hydrogenation catalysts such as Pt, Pd, Ru, Rh, preferably adsorbed on a carrier. Representative of the alkali metal aluminium hydrides which may suitably be employed are LiAl H4, NaAl-(OC^-CH^OCH^2H2 and LiAl H(OCHjThe novel naphthimidazoles and naphthoxazoles of formula I form acid addition salts. These acid addition salts are obtained by treating compounds of formula I above with pharmaceutically acceptable acids. As acids suitable for formation of therapeutically acceptable salts SKere may be Π mentioned, for example, hydrohalic, sulfuric and phosphoric acids, and nitric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, aspartic, glvco5 lie, gluconic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic acid; phenylacetic, benzoic, paraaminobenzoic, anthranilic, para-hydroxybenzoic, salicylic, para-aminosalicylic or' embonic acid, methanesulfonic, ethanesulfonic, hydroxyethane-sulfonic or ethylenesulfonic acid; halobenzensulfonic, toluenesulfonic, naphthalenesulfonic acids or sulfanilic acid. These or other salts of the new compounds may also be used for purifying the resulting compounds by converting them into salts, isolating the latter and liberating the free compound from them. In view of the close relationship between the new compounds in the free form and in the form of their salts what has been said above and hereinafter with reference to the free compounds concerns also the corresponding salts.

The novel naphthimidazoles and naphthoxazoles of the present 2o invention are valuable medicinal agents and in particular they are useful as CNS-depressant agents. This activity has been assessed by observing the behavioural and neurological changes they induce in normal mice,by means of a multifactorial observational technique similar to that originally developed by Irwin and described in Psychopharmacologia (Berl.) 13, 222-257 (1968). The general procedure used in said tests however is a simplified one wherein the number of parameters evaluated and scored is reduced with respect to the original method. (See C.

Morpurgo - Arzneim-Porsh. (Drug Res.) 21, 1727 (1971).

In particular, the test compounds are administered intraperitoneally in increasing doses to groups of three mice each and the animals are observed over 8 hours following the treatment, for the assessment of potential CNS-activity; the signs which are noted and scored are a diminution of the spontaneous exploratory activity, a diminution of the spontaneous locomotor activity, disturbances in the motor coordination (Ataxia) and relaxation. A range of 0 to 4 scoring is arbitrarily employed which is intended to represent the average intensity of the phenomenon observed (score 0 expresses the normal behaviour in respect to controls and an increase in score is used to quantify the observed depressant activity). The animals are also observed twice a day for 5 days following the treatment to evaluate toxicity, and the approximate LD,. values, i’.e. the dosages which are lethal to 50 percent of the mice, are calculated from the mortality within 120 hours after administration. The results obtained in these screening tests showed that doses ranging from 1/10 to 1/5 of the corresponding IDjqS of the conpounds of examples 1, 4, 5, 6,9, 10, 11, 12, 14, 15,24, 27, 31, 32, 33, 34, and 35 are fully ef. fective in depressing the Central Nervous System producing a marked increase in the scores for all the above four signs of CNS-depression.

Moreover, the activity of some of the compounds of the present invention has been tested also upon conditioned responses in rats according to the method described by Cook and Weidley in Ann. N.Y.· Acad. Sci. 1957, 66, 740 and subsequently modified by Maffii (J.Pharm. and Pharmacol., 1959, 11, 129-139). In this procedure a rat is placed in a chamber with a grid floor through which electric shocks may be delivered. This chamber is also equipped with a buzzer and with a wooden pole, electrically isolated, which is suspended from the top of the experimental chamber. The animal soon learns to escape the shock by climbing the pole (unconditioned response - U.R.) and by climbing the pole in response to the buzzar alone (conditioned avoidance response - CR). After further exposure to the situation, the rat becomes conditioned and climbs the pole before the buzzer is activated; when this response becomes stable the rat is considered to have developed a secondary conditioned response (CR2).

The drug to be studied is then administered to these long-trained animals and its deconditioning effect is evaluated! In our experiments male rats of the CFHB Wister strain, weighing 200-450 g were used, and it was found that doses of between about 1/20 and 1/,10 of the corresponding LD50s of the compounds of examples 1 and 10 when administered intraperitoneally, are effective in inhibiting completely the secondary conditioned and the conditioned responses (CRg and CR) without influencing the unconditioned response.

A further specific object of the present invention resides in the novel compounds of the present invention when presented or packaged for use as CNS-depressant agents, thus including the pharmaceutical compositions containing the novel compounds or their pharmaceutically acceptable acid addition salts. Suitable pharmaceutical preparations contain the novel compounds or their pharmaceutically acceptable acid addition salts in admixture or conjunction with organic or inorganic, solid or liquid pharmaceutical excipients and may be employed for enteral and parenteral administration. Suitable excipients are substances that do not react with the new compounds e.g. water, gelatin, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohols, polyalkyleneglycols or other known medicinal excipients. The new compounds may be administered by various routes; orally, subcutaneously, intramuscularly or intravenously, for example. For oral administration the substances are compounded in such forms as tablets, dispersible powders, capsules, granules, syrups, elixirs and solutions. For intravenous or intramuscular administration the active ingredients are embodied into injectable dosage forms. Such compositions are formulated as known in the art. The following examples describe in detail some compounds of formula I and illustrate the process for preparing them.

Example 1 - 1-methy1-2-/7-(4-phenvl-l-pipera2inyl)ethyl? -lH-naphth/ΐ,2-d?imidazole 4.22 g (0.017 mole) of 2-(2-chloroethyl)-1-methyl-lHnaphth/ΐ,2-d?imidazole and 5.44 cc (0.035 mole) of 97% 1-phenylpiperazine are dissolved in 90 cc of anhydrous acetonitrile and the obtained reaction mixture is refluxed with stirring under nitrogen atmosphere. After 26 hours 1 cc (0.006 mole) of 1-phenylpiperazine is added and refluxing is prolonged, for 8 additional hours. After evaporating the solvent, the resulting residue is taken up with a small amount of water, filtered and dried. Crystallization from ethyl acetate affords 5.06 g (79% yield) of the compound of the title which melts at 139-141 C. 6.6 g (0.0 178 mole) of the compound of the title are dissolved in 300 cc of hot methanol and treated with a solution of 3.74 g (0.0178 mole) of citric acid monohydrate in 50 cc of methanol. Upon cooling to 0°C, 9.30 g of 1-methyl 2-/2-(4-phenyl-l-piperazinyl)ethyl?-lH-naphth/1,2-d?imidazole citrate crystallizes out. (Yield 93%).

M.p. 190c with decomposition.

Treatment of eguimolecular amount of the compound of the title and methanesulfonic acid affords the l-methyl-2-/2-(4-phenyl-l-piperazinyl)ethyl7-lH-naphthZl,2-d?imidazole mesylate which melts at 175-177°C.

Examples 2 to 8 With the same procedures employed for preparing the compound of example 1 the following compounds are obtained (the starting materials are indicated between brackets): - 1-methy1-2-/2-(4-morpholinyl)ethyl7-lH_naPhth/i,2-d/ imidazole. M.p. 161-163θΟ /from 2-(2-chloroethyl)-1-methyl-lH-naphth/ϊ,2-d?imidazole and morpholing/ - 2-/2-(diethylamino)ethy1/-1-methyl—lH-naphth/ΐ,2-d/imidazole. M.p. 81-82 C /from 2-(2-chloroethyl)-1-methy1-lH-naphth/l,2-d/imidazole and diethylamine/ - 5-bromo-1-butyl-2-/2-(4-phenyl-l-piperazinyl)ethyl/-lH-naphth/l,2-d/imidazole. M.p. 132-134°C. (from 5-bromo-l-butyl-2-(2-chloroethyl)-lH-naphth/ϊ,2-d/imidazole and 1-phenylpiperazine] - 2-/5-(4-phenyl-l-piperazinyl)ethyI7naphth/2,l-d7oxazole. M.p. 12O-121°C (EtOH) (from 2-chloroethyl-naphth/2,l-d7oxazole and 1-phenylpiperazine) - 1-methyl 2-/3-(4-phenyl-l-piperazinyl)propyl/-lH-naphth/1,2-d/imidazole. M.p. 140-141°C (ethyl acetate) (from 2-(3-chloropropyl)-1-methy1-lH-naphth/I,2-d/imidazole and 1-phenylpiperazine) - 2-/2- (4-acetyl -1-piperazinylJethyT^ -5-bromo-l-methyl-IHnaphth/ΐ,2-g/ imidazole (from 5-bromo-2-(2-chloroethyl)-1-methyl-lH-naphth/ΐ,2-d/imidazole hydrochloride and 1-acetylpiperazine hydrochloride) - 2-/(4-phenyl-l-piperazinyl) methy 17-1-methyHH-naphth-/1,2-d7imidazole M.p. 197-198°C(EtOH) (from 2-chloromethyl-l-methyl-lH-naphth/ΐ,2~d7imidazole hydrochloride and 1-phenylpiperazine?. (6 Example 9 - 1-Methyl-2-f 2-f 4-(2-methoxyphenyl)plperazlnyl J -ethylJ -1Hnaphth £l,2-dj Imidazole hydrate 2.6 g (0.013 mole) of 97* l-(2-methoxy phenyl)-piperazine and 1.3 g (0.013 mole) of ground KHCOg are added to a solution of 2.93 g (0.012 mole) of 2-(2-chloroethyl)-l-methyl-lH-naphthfl,2-iJ Imidazole in 100 cc of anhydrous alcohol, maintained under argon atmosphere. The obtained reaction mixture ia refluxed with stirring under argon, and three 1.3 g portions of 97% 1-(2-methoxyphenyl)-piperazine are added at the 23r<\ 30^ and xd hour. After 50 hours, the solvent is evaporated and the residue taken up with a small amount of water, filtered and dried yielding 5.1 g of raw material. Crystallization from a mixture of 160 cc of water and 140 cc of ethanol affords 4.55 g of pure compound melting at 154-55°C (Yield 90%).

Examples 10 to 13 By following essentially the same procedure described in the foregoing example which comprises condensation of 2-(2-chloroethyl)-l-methyl-lR-naphth [l,2-&J imidazole with a suitably selected amine in the presence of potassium bicarbonate as the hydrogen halide acceptor, the following compounds are obtained: - 2-f 2-f 4-(3-methoxyphenyl)piperazinylJ ethylj-1-methy 1-ΙΗ-naphth fl,2-df Imidazole hemihydrate. M.p. 134-136°C (EtOH/HjO). The corresponding citrate melts at 154-56°C (from methanol) 11- 2- /2-f 4-(4-methoxyphenyl)piperazinylJ ethyl J -1-methyl-lH-naphthfl,2-df imidazole. M.p. 201-202°C (EtOH). The corresponding citrate melts at 192°C with decomposition (from ethanol). 12- 2-f 2-f4-(2-chlorophenyl)piperazinylJ ethylj -1-methyl - 17 52066 -- 0 -lB-naphth/l,2-d/imidazole. ίΐ.ρ. 159-161 C (EtOAc) 13- l-methyl-2-/2-(4-(2-pyridinyl)piperazinyl/ethyl/-lH-naphth/ΐ,2-d/imidazole. M.p. 15Ο-151θΟ. (EtOAc) Example 14 - 2-/2-/4-(3-chlorophenyl)piperaziny17ethyl7-l-methyl-lH-naphth/ϊ,2-d7imidazole 6.5 g (0.024 mole) of 1-(3-chlorophenyl)piperazine dihydro5 chloride and 8.43 cc (0.06 mole) of triethylamine are added to a solution of 2.93 g (0.012 mole) of 2-(2-chloroethyl)-l-methyl-lH-naphth/l,2-d7imidazole in 100 cc of 95% ethanol. The obtained reaction mixture is refluxed under argon atmosphere for 34 hours, then the solvent is evaporated, the 10 residue is taken up with a small amount of water and filtered yielding 5.04 g of raw product.

Purification, achieved by Silicagel column chromatography using CHC13 : MeOB 99:1 as the eluting system,and recrystallization from ethyl acetate,yields 3.91 g of pure compound χ5 melting at 146-148°C. By adding a solution of hydrogen chloride in ethyl ether to a solution of the free base in the same solvent, the corresponding dihydrochloride crystallizes out M.p. 185-187°C. 2o Example 15 - 2-/2-/3-(4-chlorophenyl)piperazlnyl7ethyl7-l-methyl-lH-naphth/I,2-d7imldazole 6.5 g (0.024 mole) of 1-(4-chlorophenyl)-piperazine dihydrochloride and 8.43 cc (0.06 mole) of triethylamine are added to a solution of 2.93 g (0.012 mole) of 2-(2-chloroethyl)25 -1-raethy1-lH-naphth/1,2-^7imidazole in 100 cc of ethanol.

The reaction mixture is then heated at reflux temperature and maintained under argon atmosphere for 23 hours. -By evaporating the solvent, grinding the residue with water and filtering, a raw product is obtained which is recrystallized from methylisopropylketone yielding'4.36 g (90% yield) of pure compound M.p. 213-215°C.

Example 16 - 5-Bromo-2-/2-(4-ben2yl-l-piperazinyl)ethy17 -l-methyl-lH-naphth/l,2-d7imidazole cc (0.022 mole) of 1-benzylpiperazine is added to a solution of 7.2 g (0.02 mole) of 5-bromo-2-(2-chloroethyl)-l-methyl-lH-naphth/l,2-d7irnidazole hydrochloride and 40 cc (0.04 mole) of IN NaOH in 100 cc of hot methanol, and the obtained reaction mixture is heated under argon atmosphere at reflux temperature for several hours. When the reaction, which is followed by thin layer chromatography, is completed, the solvent is boiled off and the obtained residue is taken up with a small amount of water, filtered and dried. Yield 8.87 g. M.p. 155-157°C.

Example 17 - 5-Bromo-l-methy1-2-/2-(4-phenylplperidino ethyl?-.lH-naphth/l, 2-d7imidazole The compound of the title is prepared by condensing 5-bromo-2-{2-chloroethyl)-l-methy1-lH-naphth/l,2-d7imidazole hydrochloride with 4-phenylpiperidine according to the method described in the foregoing example. M.p. 182-W°C· Example 18 - 5-Bromo-l-methyl-2-/2-(4-methyl-l-piperazlnyl) ethy!7-lH-naphth/l,2-d7imidazole By following the procedure described in example 16 but using l-methylpiperazine instead of 1-benzylpiperazine, the compound of the title is obtained. M.p. 151-157 C (from acetone) Example 19 - 5-Bromo-l-methyl-2-/2-/4-(3-methylphenyl)-1-.piperazinyl/ethylZ-lH-naphth/l,2-d/imidazole By following the procedure described in example 16 but using 1-(3-methylphenyl)piperazine instead of 1-benzylpiperazine, the compound of the title is obtained. M.p. 155-157^C (from ethyl acetate). -ie0« Example 20 - 5-Bromo-l-methy1-2-/2-/4-(3-trifluoromethylphenyl ) -1-piperazinyl/ethy 1/- lH-naphth/1, 2-d/imi dazole The compound of the title is prepared by condensing 5-bromo-2-(2-chloroethyl)-1-methyl-lH-naphth/ϊ,2-d/imidazole hydrochloride with 1-(3-trifluoromethyl)piperazine according to the method described in example 16. M.p. 165-166% (from ethanol). 1° Example 21 - 5-Bromo-l-(1-methylethyl)-2-/2-(4-phenyl-l-piperazinyl)ethyl/-lH-naphth/l,2-d/imidazole By following the procedure described in example 16 but condensing 5-bromo-2-(2-chloroethyl)-1-(1-methylethyl)-lH-naphth/ϊ,2-d/imidazole hydrochloride with 1-phenylpi15 perazine, the compound of the title is obtained. M.p. 2110 -213 C (from ethyl .acetate). The corresponding citrate 0 melts at 169-171 C with decomposition.

Example 22 - 5-Bromo-l-(1-methylethyl)-2-/2-/4-(3-methoxy20 phenyl)-l-piperazinyl/ethyl/-lH-naphth/l,2-d/imidazole The compound of the title is obtained by condensing 5-bromo -2-(2-chloroethyl)-1-(1-methylethyl)-lH-naphth/ΐ,2-d/imidazole hydrochloride with 1-(3-methoxyphenyl)piperazine accor ding to the procedure described in example 16. M.p. 1440 · -147 C (from methanol).

Example 23 - 5-Bromo-l-(1-methylethyl)-2-/2-/4-(3-trifluoromethylphenyl)-1-piperazinyl/ethy1/-1H30 -naphth/1,2-d/lmldazole The compound of the title is prepared by condensing 5-brorao-2-(2-chloroethyl) -l-(l-methylethyl)-lH-naphth ^1,2-dJ Imidazole hydrochloride with l-(3-trifluoromethylphenyDpiperazine. M.p. 161-62°C (from ethanol).

EXAMPIE 24 - 2-Methyl-l- Z~2-(4-phenyl-l-plperazlnyl)ethyl 5 -ΙΗ-naphth£1,2-dJ Imidazole .85 g ( 0.0356 mole ) of 2-£2-methyl-naphth [ 1,2-dJ imidazole-l-yl ethyl methansulfonate are dissolved in 200 cc of acetonitrile and 13Ί cc (0.078 mole) of 4-phenyl-l-piperazine are added to the obtained solution. After heating the reaction mixture at reflux temperature for one and a half hours, )0 the solvent is boiled and the residue is heated at 130°C for 3 hours.

Then it is taken up with methylene chloride, washed with water dried over MgSO^,filtered on a layer of neutral alumina and concentrated to dryness. After two recrystallizations from ethyl acetate, 7.8 g of the compound of the title which melts at 182-183°C were obtained, )5 6.6 g (0.0178 mole) of the compound thus obtained are dissolved in 300 cc of hot methanol and treated with a solution of 3.74 g of citric acid monohydrate in 50 cc of methanol. Upon cooling to 0°C a solid crystallizes out which is separated by filtration. Yield 9.3 g (92.8%).

M.p. 138°C (dec.).

Example 25 - 2-[ 2-(4-henzyl-l-plperazinyl)ethylJ -1-methyl-1Hfl,2- dj imidazole - 21 53066 3.9 cc of toluene containing 2.62 g (0.013 mole) of (CH^OC^C^O^NaAl^ are added to a solution of 4.13 g (0.0089 mole) of the compound of example 16 in 80 cc of toluene and the obtained mixture is refluxed with stirring under argon atmosphere. After 6 hours, when the reaction, which is followed by thin layer chromatography, is complete, 100 cc of 52 NaOH are added to the mixture and the toluene phase is separated and washed with a saturated NaCl solution. Upon evaporating the solvent a crude product is obtained which is reerystallized from ethyl acetate : hexane 1:1 yielding 2 g of the compound of the title. M.p. 144-146°C.

EXAMPLE 26 - l-Methyl-2- f2-(4-phenyl-l-piperldinyl)ethylJ -ΙΗ-naphth Imidazole A mixture of 8.32 g (0.0185 mole) of the compound of example 16, 0.9 g of 102 Pd-C catalyst, and 150 cc of tetrahydrofuran containing 20 cc of IM NaOH are shaken in a Paar hydrogenator under about 5.4 atm. of hydrogen pressure until hydrogenolysis completed. The catalyst is filtered and the mother liquor is concentrated to remove the solvent. The residue is taken up with methylene chloride, and washed with water. Upon evaporating the solvent 6.1 g of a crude product are obtained which is reerystallized from acetone yielding 4.74 g of the compound of the title. M.p. 181.5-182.5°C. - 22 52066 Examples 27 to 33 By operating according to the procedures described in the foregoing exanples but starting from the corresponding bromo derivatives which are described in examples 4, 7, 18, 19, 20, 22, and 23 respectively, the following compounds are obtained: - l-butyl-2-/2-(4-phenyl-l-piperazinyl)ethyl7-lH-naphth/l,2-d/imidazole. M.p. 93-95°C. - 2-/2-(4-acetyl-l-piperazinyl)ethyl/-l-methyl-lH-naphth/l,2-d/imidazole. M.p. 152-154°C. - l-methyl-2-/2-(4-methyl*-l-piperazinyl)ethy1/-1H-naphth/ΐ,2-d/imidazole. M.p. 118-121°C. - 1-methy1-2-/2-/4-(3-methylphenyl)-1-piperazinyl/ethyl/-lH-naphth/ϊ,2-d/imidazole. M.p. 165-167θ0 with decomposition (from methanol). - l-methyl-2-/2-/4-(3-trifluoromethylphenyl)-1-piperazi- 0 nyl/ethyl-lH-naphth/l,2-d/imidazole. M.p. 144-145 C with decomposition (from methanol). - 1-(1-methylethyl)-2-/2-/4-(3-methoxyphenyl)-1-piperazinyl7ethyl/-lH-naphth/l,2-d7imidazole citrate. M.p. 144-147°C {from methanol). - 1-(1-methylethyl)-2-/2-/4-(3-trifluoromethylphenyl)-1-piperazinyl7ethyl/-lH-naphth/i,2-d/imidazQle citrate. M.p. 144-145θΟ with decomposition (from methanol).

Example 34 - 3-Methyl-2-/2-(4-phenyl-l-piperazinyl)ethyl/-3H-naphth/l,2-d/imidazole A solution of 5.25 g (0.02 mole) of N-(l-amino-2-naphthyl)-3-chloro-N-methyl-propanamide in 150 cc of anhydrous benzene is gradually added to a solution of 9.73 g (0.06 mole) of 1-phenyIpiperazine in 25 cc of anhydrous benzene under argon atmosphere over a period of time of twenty minutes. The reaction mixture is then refluxed for 21 hours.

Further 11.73 g (0.0724 mole) of 1-phenylpiperazine are added and reflux is prolonged for additional 24 hours.

After cooling to room temperature, the mixture is diluted with 350 cc of benzene, poured in a separatory funnel and washed with 100 cc of water containing 7.8 cc of acetic acid. The benzene phase is extracted four times with 40 cc portions of 8% HCl. The pH of the agueous acid phase is brought to 9 by addition of concentrated NH^OH and this agueous solution is extracted with methylene chloride.

The organic extracts are combined,dried over Na^SO^, filtered and evaporated to dryness yielding 4.03 g of raw compound which is recrystallized from 25 cc of ethanol.

M.p. 153-155°C.

Example 35 - 2-/2-(4-phenyl-l-piperazinyl)ethyl7naphthΖΪ,2-d7imidazole cc (0.05. mole) of 97% 1—phenyl-piperazine is added to a solution of 5.21 g (0.0226 mole) of 2-(2-chloroethyl)naphth/l,2-d7imidazole in 60 cc of methanol.

The mixture- is 'heated at reflux temperature (methanol is boiled off) and the obtained residue is maintained at 130°C for Ij hour. The residue is cooled and taken up with water and methylene chloride. The organic layer is separated, dried over MgSC>4, filtered and concentrated to dryness.

The product (9.9 g) is purified by Silicagel column chro5 matography eluting with CHCl^: CH^OH 95:5. The yield of 2-/2-(4-phenyl-l-piperazinyl)ethyl/naphth/ΐ,2-d/imidazole, M.p. 115-117°C, (from ethyl acetate), is 4 g (49.7%).

By operating according to the procedures described in the Ιθ foregoing examples,the following compounds can be prepared : -2-methyl-3-/2-(4-phenyl-l-piperazinyl)ethyl/-3H-naphth-/l,2-d/imidazoie -l-methyl-2-/5-/Z-(4-methylphenyl)-l-piperazinyl7ethyl7-lH-naphth/ΐ,2-d7imidazole -l-methyl-2-/2-/3-(2-methylphenyl-1-piperaziny17ethyl7-lH-naphth/ΐ,2-d7imidazole • -l-methyl-2- /2-/3-(4-trifluoromethylphenyl)-1-piperaziny17ethylj -lH-naphth/l,2-d7imidazole -l-methyl-2-/2-(4-cyclopentyl-l-piperazinyl7ethyl7“lH-naphth/ϊ,2-d7imidazole -3-methyl-2-/2-/4-(3-trifluoromethylphenyl)-1-piperaziny ij ethyl-3H-naphth/I,2-d/imidazole -l-pentyl-2-/5-(4-phenyl-l-piperazinyl)ethyJ/’-lH-naphth-/1,2-d7imidazole -3-hexyl-2-/2-(4-phenyl-l-piperazinyl)ethyl7“3H“naphth“/Ϊ,2-d7 imidazole Preparation of the starting materials.

Example 36 - 2-(2-Chloroethyl)-1-methyl-lH-naphth/1,2-d7imidazole 1.1 cc (0.012 mole) of a 35% agueous solution of CH^NH^ are gradually dripped into a stirred solution of 2.82 g (0.01 mole) of 4-bromo-l-methoxy-2-nitronaphthalene in 20 cc of dimethylformamide heated to 60%. The reaction mixture is stirred at 60% for 10 minutes then cooled to 0% and filtered yielding 1.81 g of 4-bromo-N-methyl10 -2-nitro-l-naphthylamine.Further 0.79 g of this compound are obtained from the mother liquors by dilution with water. Overall yield 92%.M.p. 187-188% (from Ethanol).

A mixture of 35.3 g (0.1255 mole) of 4-bromo-N-methyl-2-nitro-l-naphtAylamine, 1.8 g of 10% Pd-C catalyst, and 600 cc of methanol containing 17.6 cc (0.1255 mole) of triethylamine are shaken in a Parr hydrogenator under about 5 atm. of hydrogen pressure for one and a half hours-until the theoretical amount of hydrogen is adsorbed, then the catalyst is filtered off under argon atmosphere and the mother liquor is concentrated to dryness. The residue is taken up with 250 cc of benzene and filtered again under argon over celite* and bleaching earth· FF. By evaporating the solvent 19.73 g (0.115 mole) of N^-methyl-1,2-naphthyldiamine are obtained as a dark oil. To a mixture of this compound and 16.1 cc (0.115 mole) of triethylamine in 500 cc of methylene chloride cooled to 0-5 C and kept under argon atmosphere, a solution of 14.55 g (0.115 mole) of 3-chloropropanoyl chloride in 140 cc of anhydrous methylene chloride is added dropwise. When the addition is ter30 minated the reaction mixture is allowed to stand at room temperature for a few hours and then it is heated at reflux * Trade Mark temperature for 1/2 hour. The pH is brought to 7 by the addition of 2 cc of triethylamine and the reaction mixture is warmed to 35θΟ for two hours, washed with water and dried. The raw product (25.5 g) which is obtained by evaporating the solvent is taken up with 160 cc of 5% HCl and stirred at 60°C for 3 hours. The solids which are insoluble at this temperature are separated by filtration and discarded while the solution is decolorized with activated carbon. The clear solution is cooled to 0 C and made alkaline with NH^OH. The product which precipitates is separated by filtration and recrystallized from 95% Ethanol. Yield 57.6%. M.p. 251°C. (dec.).

Example 37 - 5-Bromo-l-buty1-2-(2-chloroethyl)-lH-naphth/1,2-d7imidazole 7.05 g (0.025 mole) of 4-bromo-l-methoxy-2-nitronaphthalene are dissolved in 300 cc of methanol by heating the mixture at reflux temperature, then 5 cc (0.05 mole) of butyiamine are gradually dripped into the obtained solution and when the addition is terminated the reaction mixture is still refluxed for 30 minutes with stirring.

Upon cooling to 0-5 C a precipitate forms which is separated by filtration and dried yielding 5.4 g of 4-bromo-N-butyl-2-nitro-l-naphthylamine. Further 0.92 g are recovered from the mother liquor and the two crops are combined together and recrystallized from methanol. M.p. 65-66.5°C.

A mixture of 17.6 g (0.0544 mole) of this compound and 7.84 cc (0.0816 mole) of 3-chloropropionyl chloride is stirred at 60°c for four hours. When the reaction is com27 pleted the mixture is poured in a separatory funnel and vigorously shaken with methylene chloride and a 5% agueous NaHCO^ solution. The organic layer is separated, washed with water and dried. The residue which is obtained by evaporating off the methylene chloride is dissolved in 180 cc of EtOH and 22 cc of glacial acetic acid. 10.4 g of powdered iron are added to the obtained solution and the resulting mixture is refluxed with stirring for 20 minutes; then it is poured into 720 cc of water and extracted with methylene chloride. The methylene chloride is evaporated off, the residue is dissolved in a mixture of 125 cc of 95% EtOH and 50 cc of 10% HC1 and heated at reflux temperature for lj hour. The solvent is boiled off and the solid residue is triturated with ether, filtered and dried. The yield of 5-bromo-l-butyl-2-(2-chloroethyl)-lH-naphth/ΐ,2-d/imidazole, m.p. 172θΟ (dec.), is 19.4 g (90.8%).

Example 38 - 5-Bromo-l-(1-methylethyl)-2-(2-chloroethyl)-lH-naphth/ΐ,2-d/imidazole The compound of the title is prepared by following the pro20 cedure described in the foregoing example but using (1-methylethyl) amine instead of butylamine. The corresponding hydrochloride melts at 137θΟ with decomposition (fran ethanol) Example 39 - 2-(2-Chloroethyl)-naphth/ϊ,2-d/oxazole 19.5 g (0.1 mole) of l-hydroxy-2-naphthylamine hydrochloride and 10 cc (0.1 mole) of 3-chloro-propionyl chloride in 250 cc of polyphosphoric acid are stirred at room temperature for 3 hours. After standing at room temperature for two days, the reaction mixture is heated to 80θ0 for 7 hours and to 100°C for 1 hour, then it is poured into 2 It of ice-water. The product is extracted with ethyl ether and purified by means of column chromatography (eluent cyclohexanesethyl acetate 8:2). Yield 5,38 g. M.p. 8O-82°C.

Example 40 - 2- (3-Chloropropyl)-l-methyl-lH-naphth/ΐ, 2-d7~ imidazole 11.25 cc (0.08 mole) of triethylamine in 100 cc of anhydrous methylene chloride and 4.48 cc (0.04 mole) of 4-chloro5 butanoyl chloride in 100 cc of methylene chloride are added dropwise to a methylene chloride solution of 8.78 g 1 (0.04 mole) of N-roethyl-1,2-naphthyldiamine hydrochloride, prepared as described in example 3 6, cooled at 0-5°C and maintained under argon atmosphere. When the addition, which takes about 90 minutes,, is terminated the reaction mixture is allowed to stand at room temperature for 1 hour. Further 1.15 cc (0.008 mole) of triethylamine and 0.45 cc (0.004 mole) of 4-chlorobutanoyl chloride are added and the mixture is stirred* at room temperature for 1 hour, washed with water and dried. The residue, obtained by evaporating the solvent, is taken up with 500 cc of 5% HCl and stirred at 60 C for 3 hours and at 90°C for further 30 minutes. By the addition of NH^OH at room temperature a precipitate forms which is separated by filtration and recrystallized from ethyl acetate. 2o Yield 6 g M.p. 246-248°C.

Example 41 - 5-Bromo-2-(2-Chloroethyl)-1-methyl-lH-naphth/1,2-d7imidazole.

A mixture of 80.3 g (0.286 mole) of 4-bxomo-N-methyl-2-nitro25 -1-naphthylamine, prepared as described in the first part of exanple 36, and 41 cc (0.426 male) of 3-chloxopiopanqyJ. chloride is stir0 0 red for 2 hours at 60 C and for further 2 hours at 80 C.

The excess of acyl chloride is distilled off at 40°C under vacuum and the residue, taken up with methylene chloride, is washed first with a saturated NaHCOj solution and then with uater.

By evaporating the solvent, a residue is obtained whioh is purified by column chromatography (eluent : cyclohexane : ethyl acetate 8:2). The obtained intermediate product is dissolved in 750 cc of absolute alcohol and reduced by means of powdered iron (47.8 g) in glacial acetic acid (98 cc). The mixture is stirred at reflux temperature for 1/2 hour under argon atmosphere then it is poured into 2500 cc of water containing 1000 cc of glacial acetic acid and extracted with methylene chloride.

The organic layer is dried over MgSO^ and the solvent is distilled off. The residue is dissolved in 500 cc of 95% Ethanol and 200 cc of 10% HCl and refluxed for one and a half hours. Upon cooling the reaction mixture to room temperature a precipitate forms (35 g) whioh is separated by filtration.

The water liquors are concentrated to small volume and by the addition of 150 cc of acetone a further crop (38 g) of 5-bromo-2-(2-chloroethyl)-I-methyl-lH-naphth/ΐ,2-57imidazole’hydrochloride precipitates. The two combined crops are dissolved in methanol and the solution is made 2o alkaline by the addition of 10% NaOH. By pouring it in water the free base separates as a crystalline solid.

M.p. 146-148% (CH-30H).

Example 42 - 2-/2-Methyl-naphth/l,2-d7imldazol-1 -yl 1 ethyl methanesulfonate OC 0.67 g (0.011 mole) of 2-aminoethanol is added to a solution of 2.82 g (0.01 mole) of 4-bromo-2-nitro-l-methoxy naphthalene in 20 cc of dimethylformamide and the obtained mixture is heated to 60% with stirring. After 1 hour the reaction mixture is poured into ice-water.

The precipitate which forms is filtered and dried yielding 2.5 g (0.008 mole) of intermediate compound. This intermediate is mixed with 1.71 cc (0.024 mole) of acetyl chloride, and the mixture is refluxed for 30 minutes, and then taken up with 100 cc of ethyl ether. The organic solution, washed with a sodium bicarbonate solution and then with water, is dried over Mg SO^, filtered and concentrated to dryness yielding 3.189· 2·5 9 of the obtained compound is dissolved in 100 cc of methanol andO.Scc of triethylamine and catalytically hydrogenated at room temperature under, about 5.4 atm. of hydrogen pressure in the presence of 0.5 g of 20% Palladium adsorbed on charcoal. After 1 hour the catalyst is filtered off and the solvent evaporated.

The obtained residue taken up with methylene chloride is then washed with water. The organic layer is dried over MgS04, filtered and concentrated to dryness yielding 1.9 g of intermediate product. 10.02 g (0.035 mole) of this intermediate compound and 6.65 g (0.035 mole) of toluenesulfonic acid hydrate are dissolved in 600 cc of toluene and the obtained solution is heated for 30 minutes at reflux temperature. After evaporating the solvent, the residue is taken up with a solution of 185 cc of 5%HC1 in 300 cc of methanol and refluxed for one hour. The solvent is then evaporated to a volume of 250 cc and the solution is diluted with 1000 cc of ice-water and made alkaline with 10% NaOH. The solid which precipitates is separated by filtration and dissolved in 830 cc of methylene chloride containing 6.48 cc of triethylamine.

A solution of 2.78 cc of methanesulfonyl chloride in 30 cc of methylene chloride is added ever a period ef 20 minutes to the methylene chloride solution cooled to ΙΟθΟ.

After stirring for 1 hour at 10 C the reaction mixture is washed twice with 300 cc of water, dried and concentrated to dryness, yielding 8.9 g of the compound of the title. M.p. 169-171°C (95% EtOH). 53066

Claims (11)

1. 53066 CLAIMS 1, A compound of the formula wherein R and R^, each independently, are selected from 5 the group consisting of hydrogen,halogen, (C^-Cg)alkyl and (Cj-Cg)alkoxy? Kj stands for hydrogen, or halogen and A represents one of the following moieties a) b) c) wherein Rj is (C^-Cg) alkyl, (Cg-C g )cycloalkyl or 10 a -(CH.)-NR.R, group wherein n is 1,2, or 3 Rg stands for hydrogen, or (C^-Cg)alkyl, and Rg is (C^-Cg)alkyl or R c and R, taken together with the adjacent nitro□ 0 15 gen atom may represent a 4 to 7 membered saturated heteroring which may contain a further heteroatom selected from nitrogen and oxygen, and may optionally bear a substituent selected from the group consisting of (Cj-Cg)alkyl, (Cj-Cg)-alkenyl, (Cg-Cg)cycloalkyl, 20 aliphatic-iCg-CgJacyl, benzyl, halobenzyl, pyridyl, phenyl, and phenyl substituted with one to three groups independently selected from (C-j-CgJalkyl, (C^-Cg)alkoxy, hydroxy, benzyloxy, halogen, trifluoromethyl, amino, mono- and di-alkyl amino and nitro, R 4 represents hydrogen, (C^-Cg)alkyl, (Cg-Cg)-cyeloalkyl or ~^ CH 2^n NR 5 R 6 w ^ erein n ’ R 5 ar, d R 6 are as defined above and Ry stands for a group (CHgJg-NRgRg wherein n, Rg and Rg are as defined above, with the proviso that when the symbol A represents 5 grouping a) or b), one of Rg and R^ is a _ {CH 2 ) n -NRgRg group, and with the further proviso that when Rg stands for a group ( CH 2^n’ NR 5 R 6 where i n n is b R5 an d Rg taken together with the adjacent nitrogen atom may not represent a morpholino or piperidino radical; or a non-toxic pharmaceutically acceptable acid addition salt 10 thereof.

2. A compound as in claim 1 wherein A represents one of the following moieties a) b) wherein Rg and R^ are as defined in claim 1.

3. A compound as in claim 1 wherein R 2 is hydrogen and A represents one of the following moieties .N / a) or b) wherein Rg is (C 1 -Cg)alkyl, or 5 a -(CHgJg-NRgRg group wherein Rg and Rg taken together with the adjacent nitrogen atom represent a piperazine ring which may optionally bear a substituent selected from the group consisting of phenyl, and pyridyl, and phenyl substituted with one to three groups independently selected from 10 (C^-Cg)alkyl, (C^-Cg)alkoxy, hydroxy, benzyloxy, halogen, trifluoromethyi, amino, mono- and di-alkyl amino and nitro R 4 represents (C^CgJalkyl or -(CHg^-NRgRg wherein Rg and Rg are as defined above; with the proviso that one of R 3 and R^ is a -{CHgJg-NRgRg group; or a non-toxic pharmaceutically 15 acceptable acid addition salt thereof.

4. A process for preparing a compound of formula wherein R and R^, each independently, are selected from the group consisting of hydrogen, halogen, (C -C )alkyl X b and (C-C ) alkoxy; R. stands for hydrogen or halogen, 16 2

5. And A represents one of the following moieties a) b) or c) wherein R is (C-C ) alkyl, (C-C )cycloalkyl or 3 lb 5 o a-(CH 2 ) n -NRjRg group wherein n is 1,2, or 3 10 R. stands for hydrogen, or (C-CJ alkyl and 5 l b R. is (C,-C )alkyl or b lb R and R taken together with the adjacent 5 b nitrogen atom may represent a 4 to 7 membered saturated heteroring which may contain a further heteroatom selected 15 from nitrogen and oxygen, and may optionally bear a substituent selected from the group consisting of (C -C )al1 b kyl, (C 2 ~C g )alkenyl, (C g -C g )cycloalkyl, aliphatic- (C 2 -Cg)acyl, benzyl, halobenzyl, pyridyl, phenyl and phenyl substituted with 1 to 3 groups independently selected from (C-j-Cg)al.kyl, (C-j-Cg)alkoxy, 20 hydroxy, benzyloxy, halogen, tri fluoroniethyl, amino, mono- and di-alkyl-amino, and nitro, R 4 represents hydrogen, (C^CgJalkyl, (Cg-Cg)cycloalkyl or ^^2·η”^^5^6 w ^ ere i n n , R5 a nd Rg are as cte'F'ined above, and 53066 R. stands for a grouD -(CH.) -NR.R, wherein 7 2 n □ 6 n, R and R are as defined above, with the 5 6 proviso that when the symbol A represents grouping a) or b), one of R. and R, is a —(CH_) -NR.R, group and with 3 4 2 n □ o 5 the further proviso that when R^ stands for a group -(CH.) -NRR, wherein n is 1, R, and R, taken together 2 n 5 6 5 6 with the adjacent nitrogen atom may not represent a morpholino or piperidino radical; and its pharmaceutically acceptable acid addition salts; which comprises reacting 10 a compound of formula 1' 1' wherein R, R^ the symbol A' and R? have the same meanings as before and represents one of the following moieties c') wherein RI is (C,-C,)alfcyl, (C.-C,)cycloalkyl, or a 3 X Ο J Ό -(CH 2 )- X «roup wherein n is as defined before and X stands for the residue of a reactive ester R' 4 is hydrogen, (C^CgJalkyl, (C 5 -C g ) cycloalkyl or a - (CH 2 )- X group and R^ represents a -(CHp- X group with the proviso that when the symbol A' represents grouping a 1 ) or b') one of R' 3 and R' 4 is a -(CH 2 )- X group, with an amine of formula HNR^Rg wherein R^ and Rg 5 are as defined before, in the presence of at least the molar amount of an acid acceptor agent; said process being further characterized in that when a compound of formula I is obtained wherein R 2 stands for a halogen atom, it may be transformed into the corresponding compound wherein 10 R^ is hydrogen by hydrogenolysis. 5) A process as in claim 4 for preparing a compound of formula I wherein R and R , each, independently, are selected from 15 the group consisting of hydrogen, halogen, (C^-Cg)alkyl and (C,-c,)alkoxy; R_ stands for hydrogen or halogen, X v 2 and A represents one of the following moieties a) or b) 20 wherein R, is (C-C,)alkyl, (C_-C,)cyeloalkyl or J X O .00 a-iCHjJ-NRgRg group wherein n is 1,2,or 3 Rg stands for hydrogen, or (C^CgJalkyl, and Rg is (C.|-Cg)alkyl or Rg and R g taken together with the adjacent nitrogen atom may represent a 4 to 7 membered saturated heteroring which may contain a 5 further heteroatom selected from nitrogen and oxygen, and may optionally bear a substituent selected from the group consisting of (C^-Cg)-alkyl, (Cg-Cg)alkenyl, (Cg-C g )cycloalkyl, aliphatic-(C 2 -Cg)acyl, benzyl, halobenzyl, pyridyl, phenyl, and phenyl substituted with 1 to 3 groups independently selected from (C^-Cg)alkyl, (C-|-Cg)alkoxy, 10 hydroxy, benzyloxy, halogen, trifluoromethyi, amino, mono- and di-alkylamino and nitro, and R 4 represents hydrogen, (^-Cgjalkyl, (Cg-Cg)cycloalkyl or ”^%^η” Ν % Κ 6 wherein n > r 5 and R 6 are as defined above; with the proviso that one of Rg and R 4 is a (CH 2 ) n -NRgRg group and with the 15 further proviso that when Rg stands for a group (CH 2 ) n -NRgRg wherein n is 1, Rg and R g taken together with the adjacent nitrogen atom may not represent a morpholino or piperidino radical; and its pharmaceutically acceptable acid addition salts.

6. A process as in claim 4 for preparing a compound of formula I wherein R and Rp each independently, are selected from the group consisting of hydrogen, halogen, (CpCg)alkyl and (CpCg) alkoxy, R 2 is hydrogen and A represents one of the following moieties N-- D N a) b) wherein Rg is (CpCg)alkyl, or a -(CH 2 ) 2 ~NRgRg group wherein Rg and R g taken together with the adjacent nitrogen atom represent a piperazine ring which may optionally bear a substituent selected from the group consisting of pyridyl, 10 phenyl, and phenyl substituted with 1 to 3 groups independently selected from (C-j-Cg)alkyl, (C 1 -Cg)alkoxy, hydroxy, benzyloxy, halogen, trifluoromethyl, amino, mono- and di-alkyl-amino, and nitro, and R 4 represents (C^-C g )alkyl, or -(CH 2 ) 2 -NRgRg wherein 15 Rg and R g are as defined above; with the proviso that one of Rg and R 4 is a -(CH 2 ) 2 ~NRgRg group; and its pharmacologically acceptable acid addition salts.

7. The process of claim 4 wherein the residue of a reactive ester is a halogen atom such as chlorine or bromine or the residue of a 20 sulfuric acid ester or sulfonic acid ester such as methanesulfonate, benzenesulfonate, or p-toluenesulfonate.

8. A compound of claim 1 for use as a CNS depressant agent.

9. A pharmaceutical composition suitable for depressing the central nervous system, containing a compound oficlaim 1 as the active ingredient. 5

10. A process for preparing a compound of formula I as claimed in Claim 1, or a pharmaceutically acceptable acid addition salt thereof, substantially as described herein with reference to the Examples.

11. A compound of formula I whenever prepared by a process as claimed in any one of claims 4 to 7 or 10. Dated this 12th day of June 1981 TOMKINS & CO., Applicants 1 Agents (signed) 5 Dartmouth Road,