NZ191960A - Tricyclic or thofused nitrogen containing heterocycles - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 91 960 Priority Datefs): . ?P. JP ".7f Coro^-ste Specification Filed: *??: 19. J ^.h-s, sV 0 6 Jul I9f PubJication Dacs P.O. Js»ar<i&!r Mo: ./£?7L w bsfij' ii If® Patents Form No. 5 NEW ZEALAND PATENTS ACT 195 3 COMPLETE SPECIFICATION NEW TRICYCLIC ORTHO-FUSED pttPftOGEN CONTAINING COMPOUNDS /WE GRUPPO LEPETIT s.p.a., an Italian Body Corporate, of Via Roberto Lepetit 8, Milan 2 012 4, Italy hereby declare the invention, for which f/we pray that a patent may be granted to p/us, and the method by which it is to be performed, to be particularly described in and by the following statement 191960 Rackyround of the invention 1, 2 , 4 -Tr ia zolo/5, l-a/i soindo] es , 1, 2, 4 -1:ria zolo^/5 , l-a/i so-quinolines and the corresponding 5,6-dihydro derivatives, all of them bearing a phenyl group at the 2-position, are known from New Zealand Patent Specifications Nos. 174 364 and 174365. /Irnidazo /I,2-a/isoquinolines bearing a phenyl group at the 2-position are known from New Zealand Patent Specification No. 179317 the phenyl groups at the 2-position of the above mentioned heterocyclic structures. may be also various substituted (e.g. by alkoxy, allyloxy, halo, alkyl and so on). The biphenylyl substitution, however, has never been described. 191960 Summary of the invention The present invention relates to certain new tricyclic ortho-fused nitrogen containing compounds having anti-reproduc-tive utility, to the processes for their manufacture and to their use as antireproductive agents. More particularly, the present invention relates to new tricyclic ortho-fused nitrogen containing compounds of the following formula: wherein R and R^ are independently selected from hydrogen, fluoro, chloro,*bromo and (C^ ^)alkoxy; A may be -CH -, -CH=CH- or and X represents a nitrogen atom or the group CH; and salts therewith of pharmaceutical^ acceptable acids.

Wherif in the formula I above, X represents the nitrogen atom, the following four structures may be identified: 19 1960 a) l,2,4^-triazolo/5,l-a/ isoindole R b) 5,6-dihydro-l,2,4-triazo-lo/5,1-a/isoquinoline R c) l,2,4-tr±azolo/5,l-a/ isoquinoline d) 6,7-dihydro-5H_-l, 2,4-tria-zolo/5,1-a/ /2/benzazepine Wheiif in the formula I above, X represents the group CH, the following four structures may be identified: 1 9 19 6 C e) imidazo/2,1-a/isoindole f) 5, 6-dihydro-imidazo/2,1-a/ isoquinoline g) imidazo/2,1-a/isoquino*-' h) 6,7- dihydro-5H-imidazo line /2,l-a//2/benzazepine A preferred group of compounds comprises those compounds of formula I wherein A is -CH -CH^- or -CH=CH-, X represents a nitrogen atom or the group CH and R and both represent hydrogen; and salts therewith of pharmaceutical^-ly acceptable acids.

A most preferred group of compounds comprises those compounds of formula I wherein A is -CH -CH^- or -CH=CH-, X represents a nitrogen atom and R and R^ both represent 191960 hydrogen; and salts therewith of pharmaceutically acceptable acids.

Another most preferred group of compounds comprises those compounds of formula I wherein A is -CH^-CH^- or -CH=CH-, 5 X is the group CH and R and R^.both represent hydrogen; and salts therewith of pharmaceutically acceptable acids. Pharmacologically-acceptable salts include those derived from mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid as well as those derived from organic 10 acids such as lactic, maleic, succinic, fumaric, oxalic, glutaric, citric, malic, tartaric, p-toluenesulfonic, ben-zenesulfonic, methanesulfonic/Cyclohexanesulfonic acid and the like. They are prepared according to conventional methods. ; The compounds of the invention can be prepared by different methods which essentially depend on the nature of the symbol X and the reacting substrates. As an example, the compounds a) through d) ie., those of formula I wherein X is the nitrogen atom, can be prepared following substan-20 tially the same procedure described in New Zealand Patent specification No. ]74365 by condensing a compound of formula: N—NH.

II wherein R, R^ and A are defined as above, with a biphenylyl derivative of formula 30 *pTpATBNT QFfiCS 16FEB!9S2^ received 191960 III wherein represents one of the following groups: -CN, -CONH , -C * NH \ OR.

\ -C NH, \ / or -C ^NH NH.

SR. in which R^ is an alkyl group from 1 to 3 carbon atoms.

Both reactants may also be employed in the form of their corresponding acid salts..

However, according to one aspect of this invention, the condensation is carried out simply by contacting a molar proportion of the intermediate compound of formula II with at least one molar equivalent of the derivative of formula III for a period of time varying from 5 to hours, optionally but not preferably in an organic solvent which may be selected from (C^_^)alkanols, (C^_^)alkoxy - (C^_^)alkanols, ethylene glycol, propylene glycol and mixtures thereof. The temperature at which the condensation takes place may vary from 60°C to the reflux temperature of the reaction mixture.

The desired end compounds are finally recovered and purified by means of techniques which are entirely familiar ~ to a person skilled in the art. These techniques comprise removing the solvent by evaporation, cooling the reaction mixture until a precipitate crystallize^! yracting • 5FEBI982 191960 the final product by means of a suitable solvent which'' is subsequently evaporated. If necessary, the further purification is obtained, by column chromatography or re-crystallization .

A useful method for preparing'compounds of formula I wherein X is the nitrogen atom and A is the group -CH=CH-comprises contacting a 2-amino-isoquinoline-l(2H)-one of formula RW /-V.

N—NH, IV wherein R and R^ are defined as above, with a nitrile of formula V The reaction between compound IV and compound V can be carried out in a suitable solvent system but it can also be carried out in the absence of solvent by simply mixing the two reactants, preferably together with a catalyst. When the reaction is carried out in large batches, it is however desirable to add some solvent" to lower the viscosity of the reaction mass and to facilitate the mixing of the reactants. A wide variety of solvents may be used. • 9 191960 . ♦ I » t~ V Suitable solvents are for instances the alkanols such a's methanol, ethanol, propanol and butanol, the lower aLkoxy-alkanols having 1 to 6 carbon atoms,such as 2-nisthoxy-ethanol, 2-ethoxy-ethanol and 2-propoxy- ethanol, chlorinated-lower hydrocarbons having 1 to 6 carbon atoms, ethyle-^ ne glycol, benzene, chlorobenzene, toluene, nitrobenzene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and mixtures thereof. The temperature of the reaction inay range between the room temperature and the boiling temperature of the reaction mixture when it is carried out in a solvent. In general, temperatures between 60 and 160^C are preferred since under these conditions the reaction rate is sufficiently rapid and the formation of undesired side product is prevented. -*-5 The two reactants are generally used in about equimole- cular amounts, although in some cases an 1 to 20 per cent molar excess of the nitrile may be added, in particular, to facilitate the mixing when the reaction is carried out in the absence of solvents. The reaction is generally carried out in -the presence of a catalyst. Basic catalysts such as alkali metal hydroxides, alkoxides and hydrides were found to give satisfactory results. Tertiary organic amines may also be suitable employed as the catalyst, as well as transition metal salts and elemental sulfur.

Among transition metal, salts ferric chloride and zinc acetate are particularly preferred. The obtained end products are recovered by means of known procedures. The reactants-of formula IV may be. prepared through several methods. | 25 FEB 1982 njl patent 0fhcs' 4 19 19 6 0 The most convenient procedures involve as the final step the reaction between hydrazine and an isocoumarin of formula wherein R and R^ have the same meanings as before. The preparation of the compounds VI is well docximented in the literature and may be conveniently performed through bromination with Br^ of the corresponding 1-isochromano-ne followed by dehydrobromination with triethylamine in 1,2-dichloroethane.

The reaction between hydrazine and the selected isocoumarin is carried out at room temperature by utilizing aqueous hydrazine hydrate in ethanol, as the solvent. Subsequent addition of acids to the reaction mixture allow the transformation of the intermediate 2-amino-3,4-dihydro-3-hydroxy-iso-quinoline-1(2H)-ones into the desired 2-amino-isoquinoli-ne-1(2H)-one.

According to another aspect of the invention, the compounds e) through h) above, i.e., those of formula I wherein X is the group CH, are conveniently prepared by reacting a biphenylyl-halomethyl ketone of formula 191960 with a compound of formula R NH.

R.

N VII (halo — CI or Br) VIII wherein A, R and R^ are defined as above.

This reaction is carried out essentially according to the scheme outlined by F. Kr&hnke et al, Chem. Ber., .95.* 1128, 1962. In the actual practice, the reactants of formulas VII and VIII are contacted in about equimolecular proportions at a temperature comprised between the room temperature and the reflux temperature of the reaction mixture, preferably in the presence of an organic solvent such as, for instance, chlorinated (C^_^)hydrocarbons, dioxane, te-trahydrofuran, benzene, toluene or mixtures thereof. The product which is obtained is the hydrohalide of the compound IV" of formula I wherein X is the group CH and thus the corresponding free base is obtained by treatment with" aqueous bases, such as diluted alkali hydroxides, carbonates or ammonium hydroxide. The recovery of the final products is achieved substantially by means of the methods illustrated for the recovery of the substances of structures aJ through d) ■ 5FEBV582 1919 6 0 It is finally to be noted that the compounds of formulae I above wherein A is -CH -CI^- can be prepared by catalytic hydrogenation with palladium on charcoal of the corresponding compounds where A is -CH=CH-. They, in turn, may be prepared by catalytically dehydrogenating the corresponding compounds wherein A is Among the several useful dehydrogenating agents which may be employed are sulfur, N-bromoacetamide, bromine, lead tetraacetate, chloranil and manganese dioxide.

This latter may be prepared in a wet state, as described by Pratt et al, J. Org. Chem. , 2973 , 1961 and is employed under the conditions reported by J. Goldman et al. in J. Org. Chem., 34, ,1979, 1969.

The compounds of the present invention display a very interesting anti-reproductive utility. More particularly, they show a remarkable post-coital-post-implantation an-tifertility activity when administered, by different pharmacological routes, to laboratory animals, e.g. rats, 20 hamsters, dogs, monkeys and baboons.

Moreover, the antifertility activity of these new compounds is not associated with other biological effects which are useful with hormonal substances.

The use of the novel tricyclic ortho-fused nitrogen containing 25 compounds as antireproductive agents refers to all industrially applicable aspects and acts of said use, including the embodying of the novel compounds into pharmaceutical compositions. The pharmaceutical compositions containing said active compounds are in fact a further specific object of this 30 invention. 19 i960 Fertility regulation can usually be achieved in a numbe'r of ways through the administration of hormonal substances. These can involve ovulation inhibition, ova transport, fertilization., implantation of the zygote, resorption of the fetus or abortion. Only with ovulation inhibition has there developed a successful method that is clinically useful.

The compounds of this invention allow an entirely new approach to this problem in which a non-hormonal compound can be administered parenterally, orally or by intrava-ginal route once or more times as needed after a "missed" period" or to induce termination of a more advanced pregnancy .

Representative .experiments for•assessing antifertility activity were carried out with female Syrian golden hamsters. weighing 100 to 130 g. The animals were mated and the presence of sperm in the vagina was taken as evidence of mating. The day sperm was detected was considered day one of pregnancy, since in our laboratories and those of other investigators 90 to 100% of animals that mate as evidenced by vaginal sperm are pregnant.

Pregnancy was later confirmed at the time of autopsy by presence of fetuses or implantation sites in the uterus.

Even if an animal aborts the fetus, implantation scars still remain as evidence that the animal has been pregnant. The * compounds of the invention, which possess a high solubility in the commonly employed pharmaceutical vehicles, were dissolved in sesame oil containing 20% by weight of benzyl ben zoate and administered subcutaneously in doses of 10 mg/kg daily for 5 days beginning on day 4 19 19 6 0 The animals were autopsied on day 14 of pregnancy and the uteri were examined for evidence of pregnancy (implantation sites, fetal resorptions or live fetuses), hemorrhage, and evidence of abnormalities of the uterus, placenta or fe-5 tuses. A compound was considered to be active if there was a reduction of live fetuses in at least 60% of the treated animals and the presence of implantation sites proves the animal to have been pregnant. The compounds of the invention proved to be active according to the above mentioned crite-10 ria.

The compounds were then studied for dose-activity relationships and the corresponding ED^0 values i.e., 100% activity (absence of live fetuses) in-50% of the animals, were also determined. The following Table reports the ED^0 values of 15 some representative compounds of the invention: TABLE I Compound of Example EE>50 s-c* hamsters 1 0.015 3 0.05 4 0.7 6 0.02 IK The same criteria and experimental conditions as above were also applied when the anti-reproductive activity of the compounds of the invention was investigated in other animal species such as, for instance, rats, dogs, monkeys 30 and baboons. 191960 In representative experiments, female Sprague-Dawley rats weighing from 200 to 300 g. were treated subcutaneously with a dosage of 20 mg/kg of the compound to be tested, dissolved in sesame oil oontaining 20% by weight of benzyl benzoate, 5 for five consecutive days starting from day 6 of pregnancy. The rats were killed and autopsied on day 16 and the uteri were examined as seen above for hamsters.

Also in this experiment the compounds of the invention caused a reduction of live fetuses in at least 60% of the 10 treated rats. The ed^q value of the compound of Example 1 was determined and is reported in ±he following Table: TABLE II ^ Compound of Example EE>50 s.c. rats 1 0.55 Favorable results were also obtained by administering 20 the compounds of the invention by oral route. The experiments for assessing this property were carried out on hamsters following the same procedures as above, with the obvious exception that the compounds were administered orally instead of subcutaneously.

The reduction of about 60% of live fetuses was observed at an oral dosage of 10 mg/kg.

The ED£q values of the compounds of Examples 1, 3 and 6 were also determined and are reported in the following Table: ' ^ tH2 PATENTO^^ V5FEBM 191960 TABLE III Compound of Example ed^q mg/kg p.o. hamsters 1 3 6 O. 20 O. 50 0. 30 The compounds of the invention proved to be active also . when administered by intravaginal route. In a representa-10 tive experiment on hamsters, the compound of Example 1 displayed an ed^q about 0.20 mg/kg.

Finally, the compounds of the invention display a very low toxicity. In fact, their .LD^^-values, determined According to Lichtfield and Wilcoxon, Journ. Pharm. Expt. 15 Ther. , 9^6, 99, 1949, are never lower than 600 mg/kg when administered to mice by.intraperitoneal route.

The facts that the compounds of the invention possess an outstanding antireproductive activity even when administered by oral route and are very soluble in the common 20 pharmaceutical carriers represent undoubtedly further important properties. As an example, the high solubility causes the compounds to be readily absorbable and incorpo-rable into suitable and more tolerable.injectable dosage forms which possess less drawbacks than corresponding forms 25 wherein the active ingredient is suspended in the carrier. On the other hand, also the activity by oral or intravaginal route allows the compounds to be embodied into more acceptable pharmaceutical preparations.

It results, therefore, that the compounds of the invention . .. • - ~ -17 19196 may be administered by various routes: orally, subcutaneously, intramuscularly or intravaginally.

For oral administration the substances are compounded in such forms as tablets, dispersible powders, capsules, 5 granules, syrups, elixirs and solutions.

The compositions for oral use may contain one or more conventional adjuvants, such as, for instance, sweetening agents, flavoring agents, coloring agents, coating and preservative agents, in order to provide an elegant and 10 palatable preparation.

Tablets may contain the active ingredient admixed with conventional, pharmaceutically acceptable excipients, e.g. inert diluents, such as.calcium carbonate, sodium carbonate, lactose and talc, .granulating and disintegra-15 ting agents, such as, for instance, starch, alginic acid and sodium carboxymethylcellulose," binding agents, e.g. starch, gelating, gum-arabic and polyvinylpyrrolidone and lubricating agents, e.g. magnesium stearate, stearic acid and talc.

Syrups, elixirs and solutions are formulated as known in the art. Together with the active compound they may contain suspending agents, such as, for instance, methylcellu-lose, hydroxyethylcellulose, tragacanth and sodium alginate, wetting agents, e.g. lecithin, polyoxyethylene stearates 25 and polyoxyethylene sorbitan monooleate, and the common preservative, sweetening and buffering agents.

A capsule or a tablet may contain the active ingredient alone or admixed with an inert solid diluent, such as, for instance, calcium carbonate, calcium phosphate and 30 kaolin. ~18'- 19 196 Besides the oral route, other useful ways for administering the compounds of the invention may be suitably employed, such as, for instance, the subcutaneous or the intramuscular administration.

The active ingredient is thus embodied into injectable dosage forms, Such compositions are formulated according to the art and may contain appropriate dispersing or wetting agents and suspending or buffering agents identical or similar to those mentioned above.

Sesame oil, benzyl .alcohol, benzyl benzoate, peanut oil and their mixtures may also be suitably employed as vehicles. A vaginal insert may also contain the active ingredient in admixture with the common_carriers, e.g. gelatin, adipic acid, sodium bicarbonate, lactose and analogs. 15 The compounds of the invention may also be administered in the form of their nontoxic, pharmaceutically acceptable acid addition salts. Such salts possess the same degree of activity as the free bases, from which they are readily prepared by reacting the base with an appropriate acid 20 and, accordingly, are included within the scope of the invention. Representative of such salts are the mineral acid salts, such as, for instance, the hydrochloride, hydrobro-mide, sulfate and the like, and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfo-25 nate, benzene sulfonate, maleate, tartrate, methanesulfona-te, cyclohexylsulfonate and the like.

The dosage of active ingredient employed for inhibiting reproduction may vary within wide limits, depending on the nature of the compound.

Generally, good results are obtained when the compounds, of the above formula 1 are administered in a single dosage from 0.1 to 25 mg/kg intramuscularly or in a multiple dosage (for from 5 to 10 days) of 0.5 to 25 mg/kg orally 5 or intravaginally.

The dosage forms useful for this purpose generally contain from 10 to 600 mg of the active ingredient in admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

The following examples illustrate the process of the invention and describe in detail somo compounds of the general formula. I without limiting the scope of the 15 invention.

Example 1: 2-/(1,1'-Biphenyl)-4-yl/-l/2/4-triazolo/5,l-a/iso quinoline a solution prepared from 0.075 g. of sodium dissolved in 20 ml of absolute ethanol was added to a suspension of . 0.640 g. (0.004 mole) of 2-amino-isoquinoline-l(2H)-one and 0.720 g. (0.004 mole), of 4-phenyl-benzonitrile in 20 ml of absolute ethanol. The resulting mixture was re-25 fluxed for 30 minutes on an oil bath/ then 15 ml. of ethylene glycol were added "and the ethanol.was distilled off 0 by adjusting the temperature of the oil bath at about 150 C. After three hours the reaction mixture was cooled to room temperature whereby the title compound crystallized out. 30 it was recovered by filtration and re-crystallized from a fliXPATENTOF^Cg r I-5FEB1982 ! r"' WBCESffiD 19 19 60 mixture of methylene chlori.de/diethyl ether = 1/1. Yield 0 650 mg. M.p. 203«-5 C.

Example 2 : 2-^/ (1,1'-Bipheny3,)-3-yl_/ -1, 2 , 4-triazolo/5 ,1-a/ isoquinoline This compound was prepared according to the procedure of the foregoing Example, starting from 2-amino-isoquinoline--l(2H)-one and „3-phenyl-benzonitrile. Yield 49%. M.p. 167-69(from ethyl acetate).

\ Example 3: 2-/7l,1-Biphenyl)-4-yl/-5>6-dihydro-l,2,4-tria-zolo/5,1-a/isoquinoline A mixture consisting of 1.94'g. (0.0086 mole) of 4-phenyl- -benzimidic acid ethyl ester and 0.972 g. (0.006 mole) of 2-amino-3,4-dihydro~isoquinoline-2(1H)-one was heated on an oil bath at a temperature of 90^C for 5 hours. The tem- 0 perature of the bath was subsequently raised to 200 C and kept as such overnight. Upon cooling, the obtained mass was dissolved in methylene chloride and chromatographed 20 through silicagel by using as the eluting systems firstly light petroleum/diethyl ether = 9/1 and then light petro-leum/diethyl ether - 8/2 (volume/volume) The fractions containing the title product were collected and the resulting * solution was concentrated to small volume. The title pro-25 duct crystallized out and was recovered by filtration.

Yield 1.180 Q. M.p. 143-44(from diethyl ether/hexane).

Example 4: 2<-/(1,1'-Biphenyl)-4-yl/-5H-l,2,4-triazolo/5,l-a7 isoindole This compound was prepared according to the procedure of 19 19 6 0 Example 3, starting from N<-aminophthalimidine and 4-ph$nyl--benzimidic acid ethyl ester. Yield 52%, M.p. 231^C (from ethyl acetate).

Example 5: 2-/(1,11-Biphenyl)-4-yl/-6,7-dihydro-5H-l,2,4--triazolo/5, l-a/ ./2/benzazepine This compound was prepared according to the procedure of Example 3 starting from 2-amino-4,5-dihydro-2-benzazepi-ne-1(2H,3H)-one and 4-phenyl-benzimidic acid ethyl ester. 10 Yield 63%. M.p. 135-37^C (from diethyl ether)'.

Example 6: 2-/(1,1'-Biphenyl)-4-yl/-imidazo/2,1-a/isoqui-noline A solution of 4.32 g. (0.03 mole) of 1-amino-isoquinoline 15 and 8.25 g. (0.03 mole) of /7l,l'-biphenyl)-4-yl/-bromo-methy1-ketone in 100 ml, of chloroform was heated on a boiling water bath for about 10 minutes until a precipitate separated. The solvent was distilled off at atmospheric pressure and the residue was heated under vacuum for 20 30 minutes at 100^C. It was subsequently taken up with 50 ml of water and the resulting solution was made alkaline by means of 70 ml. of aqueous 10% sodium hydroxide. After extracting with 500 ml. of methylene chloride and evaporating the solvent, a residue was obtained which was re-crystalli-25 zed from ethylene glycol monomethy1ether. Yield 3.0 g. M.p. 221-22°C.

Example 7; A sugar coated table is prepared from 2-/7l,1'-Biphenyl)-4-yl/-l,2,4-triazolo- 50 mg. /5,1-a/isoquinoline 191960 Sodium carboxyjnetby] cellulose • 5 mg Kagnesi urn stea,rate 5 mg Gelatin 5 mg Starch ; 5 mg Saccharose " 27 mg gum arabic.) lactose, titanium dioxide, aluminum lac according to conventional procedures, (Aluminium lac is a gelatinous aluminium hydroxide for coating tablets which turns to a lacquer on drying).

Example'* 8: A vial for injectable use is prepared from 2-/(1,1'-Biphenyl)-4-yl/—1,2,4-triazo- lo/5,1-a/isoquinoline 30 mg - Benzyl benzoate 220 mg Sesame oil q.s. to 2 ml Example 9: A tablet is prepared from 2-/ (1,1 '-Biphenyl) -4-yl/-imidazo/2,1- -a/isoquinoline 100 mg Levilite " 80 mg Starch ■ . 80 mg Magnesium stearate 10 mg (Levilite is a pure precipitated powdered silica) 19 19 60 The "Fol lowing compounds may be prepared according "to -the procedure outl i ned in the -Foregoing Examples: 2-/(l,1' — Bi phenyl ) —3-yj_/-5H-l, 2,4-tr iazol o/5, l-a/i so i ndole 2—/(l, 1' —Bi phenyl ) — 4~y]_/~ 7— chl oro—5H-1, 2, 4-tr iazol o/5, 1—a/ iso-i ndole 2-/(l, 1 '—'Bi phenyl )— 4-yJ_/—8-ch I oro-5H-l ,2, 4-tr i azol o/5,1—a/iso-indole 2-/(1,1'—Biphenyl )-4-yJ_/-8-methoxy-5H-l, 2; 4-tr iazol o/5, l-a/\so- . I * . - - ' i nd o 1 e • 2—/(1, 1' —B i phenyl ) — 4~ yJ_/~"7, 8—d i ch Ioro-5H-l ,2, 4~tr i azol o^5 , 1 ~&J • so i nd oIe 2-/(1, 1 ' — Bi phenyl )— 2-yJ_/—5H-1, 2,4-tr iazol o/5, 1-a/i so i ndol e 2-/(1,1' —Bi phenyl )—3-yJ_/~5, 6-d i hydro-l, 2, 4~tr i azol o/_S, 1—a/i so-qui nol i ne 2-/(1,1'—Bi phenyl )-2-yJJ/~"5, 6-d i hydro-l, 2;4-tr iazol o^5, 1—a./' so-qui nol i ne 2-/(1, 1' —Bi phenyl ) — — chl oro-5, 6-d i hydro-l, 2,4~tr i azol o /5,1-aj i soqu i noI i ne 2—/l, 1' —B i phenyl ) -4-yJ_/— 8-ch I oro-5, 6-d i hydro—1, 2, 4~tr i azol o /5,1—a/i soqu i nol i ne 2-/^(1,1' —Bi phenyl )—4-yj_/~ ® ' ^~d i chl oro—5, 6-d i hydro-l ,2, 4—tr iazo I o /5,l-a/isoquinol i ne . -24- ^ ^ 2-^(1, 1 ' —Bi phe nyl )-4-yJ_/—7-niethoxy-5, 6-d i hydro-l, 2, 4-"tr i azo! o /5,1-a/ i soqui nol i ne * ? ' • enyl )-4-y.L/—9""fI,e~t:hox>"~5, 6-d i hydro-l, 2,4-tr i azol o /5, l-a/ isoquinoline 5 2-^.(1, 1' — Biphenyl )—4-y.L/--8,9 imethoxy-5,6-dihydro—1,2,4-triazolo Z5#l~a/ i soqu i noJ i ne 2-/(l, 1 ' — Biphenyl )-4-yJ_/~7-ethoxy-5/ 6-d i hydro-l, 2,4-tr i azol o /5,l-a/isoquinoI ine 2-/.(l, 1' —Bi phenyl ) -4—yJL/~ ^-ethoxy-5, 6-d i.hydro—1, 2, 4-tr iazol o iO /5,1-a/isoquinol i ne 2-/^(1, l'—Bi phenyl )-2-yJJ/-l, 2,4_tri azol o/5r l~a/i soqut nol i ne 2-/^(1, 1' — Bi phenyl ) — 4—yj_/— ^-chl oro-1,2, 4—tr i azo I o/5 r 1—a/ • soqui nol i ne 2-/^(l, 1Bi phenyl )—4~yJ_/ —8-ch I oro-1,2, 4~"tr iazol o/5 , 1—.a/ i soqui no-15 I i ne .2-/^(1,1 ' — Bi phenyl ) — 4~yJ_/~* 8,9 -d i chl oro-1,2, 4~tr i azo I o/_S , l-a/i soqui nol i ne 2-/^(1, l' — Bi phenyl ) -4-yJ_/-7-methoxy— 1, 2,4-triazol o/S 11*"®./' soqui not i ne ^9 2-/^(1,1' —Bi phenyl )-4-y.L/~" ^-methoxy—1, 2, 4-tr iazol o/5, l-a_/i so-- qui nol i ne '2 1 9 2-/(1,1B i phenyl ) -4-yJ_/- 8/9 -d i methoxy-1,2, 4-tri azol o/5r l-a/' s° qui nol i ne • \ • * 2-/(1,1*—Biphenyl )-4-yJL/-7-ethoxy-l, 2,4~triazol o/5,l-a/'soqui no 1 i ne 2-/(1, 1Bi phenyl )—4-yJ./- 9-ethoxy-l, 2,4-tri azol o/5,l-a/ • soquino-1 i ne « 2-/(l, 1'—Bi phenyl )-3-yl/-6, 7-d i hydro-5H-l, 2, 4-tri azol o/5, l-a/ / 2_/benzazepi ne 2-/(1, 1 ' — Bi phenyl -2-yJ_/-6; 7-d i hydro-5H-l, 2, 4-tri azol 0/5, l-a./ / 2/benzazep i ne ,10 2-/(1,1' —Bi phenyl 2-/(1,1'—Bi phenyl 2-/(1,1'-Bi phenyl 2-/(1,1'—Bi phenyl 2-/(1,1'—Bi phenyl 2-/(l,1' —Bi phenyl 2-/(1,1' — Bi phenyl 2-/(l,1' —Bi phenyl 2-/(ljj 1'—Bi phenyl IC. 2-/(1,1'—Biphenyl -2-yJ_/- i m idazo/2", l-a./i so i ndo I e —3-yJL/-> midazo/2, 1-a/i soi ndol e -4-yjy-i midazo/2, 1-a/i so i ndol e —4-yJ_/~7— chl oro- i midazo/2, l-a/ i so i ndol e —4-yJ_/-8—ch I oro- i midazo/2— 1—a/ i soi ndol e -4-yl/-8-methoxy— i midazo/2, 1—a/i soi ndo 1 e —2—y\J~5, 6-d i hydro—i midazo/2, 1—aj i soqui nol i ne — 3-yJ_/~5# 6-d i hydro— i midazo/2,l-a/i soqu i nol i ne —4-yJL/-5/ 6-d i hydro- i midazo/2, l-a/i soqu i nol i ne -4-yJL/-9-chl oro-5,6-d ihydro-i midazo/2, 1-a/iso qui nol i ne 2-/(l, 1' —B i phenyl )—4-yi/-8-ch I oro-5, 6-d i hydro- i midazo/2, 1-a/iso qui nol i ne • - -2G- ^ 9 2-/(1,1' —Bi phenyl ) —4-yi/~-8, 9 -d i chl oro-5, 6-d i hydro- i m idazo/2,-l-a/ isoquinol i ne V . .

"I 2-/(1, 1'—Bi phenyl )—4-yJL/~"^"-me'thoxy-5,6-d i hydro— imidazo/2, l-a/ i soqu i no I i ne " 5 2-/(1,1'—Bi phenyl ) —4-yJ_/"~8-me-thoxy-5, 6-d i hydro- i midazo/2, 1 -a/ isoquinol i ne • 2-/(1, 1' — Bi phenyl ) -4_yJ_/— 8,9 -d i me-thoxy-5, 6-d i hydro- i midazo /2, l-_a/i soqu i nol i ne 2-/(1,1'-Bi phenyl )-2-yJ_/—i m idazo/2, l-a/i soqui nol i ne 2-ZTl,l'-Biphenyl)-3-yl7- i midazo/2, 1—a/i soqu i nol i ne 2-/(1,1 '-Bi phenyl )-4-yJ_/-7-chl oro-i midazo/2, J —a/i soqui nol i ne 2-/(1,1' —Bi phenyl )—4-yj_/~* 8-ch I oro— i m idazo/2, 1 — aj i soqu i no I i ne 2-/(1,1 * —Bi phenyl ) —4-yl )— 7, 8—d i chf oro — i midazo/2, l—a./' soqu i nol i ne 2-/(l, 1*—Bi phenyl — 4-yJ_/~*7— methoxy- i midazo/2, l—a/ i soqu i nol i ne 2-/(1,l'-Bi phenyl -4~yJ_/—8-methoxy- i midazo/2, 1-a/i soqui nol i ne 2-/(l, 1'—Bi phenyl -4-yJ_/— 7,8-d i methoxy- i midazo/2, 1—a/ i soqu i nol ine 2-/(1,1 *—Bi phenyl )— 4-yi/~7-ethoxy- i midazo/2, l-a./i soqui nol i ne 2-/(l,!' — Bi phenyl ) — 4-y_L/~"8-e"kkoxy— ' midazo/2, 1—a/isoqui nol i ne 2-/(1,1-Bi phenyl)-2-yl)-6,7-dihydro-5H-imidazo/2,l-a//2/- IV . - - -benzazepine 2-/(1, l'-Biphenyl)-3-yl/-6,7-dihydro-5H-imidazo/2,l-a//2/--benzazepine 2-/(1, l'-Biphenyl)-4-yl/-6,7-dihydro-5H-imidazo/2,l-a//2/-benzazepine 19 19 6 0 PREPARATION- OF: THE- STARTING MATERIALS :• A) 2- Amino-isoquinoiine--i (2H) -one A solution of isocoumarin (26 g, 0.16 mol) in 95% ethanol (2000 ml) was treated with 25% hydrazine hydrate in water 5 (64 ml, Q*32 mol) and stirred at room temperature for one hour. The precipitate of 2-amino-3,4-dihydro-3-hydroxy- -1H (2H) -isoquinolinone was dissolved and dehydrated by addition of 10% hydrochloric acid (150 ml) at room temperature. After three hours, the mixture was neutralized with sodium ig carbonate and the ethanol recovered by distillation in vacuo. The title compound was isolated by filtration and extraction with chloroform to give 27.92 g (98%) of the product of the title, M.p. 103-4°C. ..... • B) 2-Amino-4,5-dihydro-2-benzazepine-T(2H,3 H)-one Asolution of 2.7 g of 0-amino-sulfonic acid and 1.25 g of a 55% oily suspension of sodium hydride in 30 ml of dime-thylformamide and 30 ml of tetrahydrofuran was gradually added at a temperature of 10^0 to a suspension of 9.66 g 2o (0.017 6 mol) 4,5-dihydro-2-benzazepine-l(2H,,3H)-one. After standing for 1 hour at room temperature the mixture was poured into a saturated aqueous solution of NaCl, then the "■w organic layer was separated and the mother liquors were extracted with 300 ml (3 x 100 ml) of an 1 : 1 (v : v) mixtu-25 re of tetrahydrofuran and dimethylformamide. The organic phases were combined and brought to dryness. The obtained residue was subsequently taken up with 500 ml of ethyl acetate and the resulting organic solution was extracted with 191960 200 ml (5 x 40 ml) of a 3% aqueous solution of HC1. The, acidic extract was made alkaline with 5% aqueous sodium hydroxide and subsequently extracted with, ethyl acetate. After evaporating the solvent, an oily residue was obtained which was distilled under reduced pressure.

Yield: lO g. of the title compound. B.p. 120^C/ _ ^ 0.2 mmHg C) 2-Airtino-3 , 4-d ihydr o-is oqui no1 ine- 2 (1H) -one The preparation of this compound is described, in ■ United Kingdom Patent • 1*377,310.

D) N-Aminophthaiimidine The- preparation of this compound is described by Bellasio 15 et al., Annali di Chimica/ 5J9, 451, 1969.

E) 1-Ami no-i soqui noTine This is a commercial product. „5FEB»82

Claims (12)

WHAT WE CLAIM IS:

1) Tricyclic ortho-fused nitrogen containing compounds of formula 10 15 wherein R and R_L are independently selected from hydrogen, fluoro, chloro', brcxro and (C^Jalkoxy. a may be -CU^-, -CH^-CU^-, -CH=CH- or ~^CH2^3~; and x represents a nitrogen atom or the group CH and salts therewith of pharmaceutically acceptable acids. 20

2) A compound as in claim 1 wherein A is -CH^-CH^- or -CH=CH-f X represents a nitrogen atom or the group CH and R and R^ both represent hydrogen; and.salts therewith of pharmaceutically acceptable acids. 25

3) A compound as in claim 1 wherein A is -CH^-CH^- or -CH=CH-, X represents a nitrogen atom and R and R^. both represent hydrogen, and salts therewith of pharmaceutically acceptable acids. 30

4) A compound as in claim 1 wherein A is -CH^-CH^- or -CH=CH-, X is the group CH and R and R^ both represent hydrogen; and salts therewith of pharmaceutically acceptable 19 19 6 0 "30—

5) A process for preparing compounds of formula wherein A, R and R^ are defined as in claim 1, which comprises contacting a molar proportion of a compound of formula 0- N -NH. 15 II wherein A, R and R^ are defined as in claim 1, or an acid 20 salt thereof, with at least one molar equivalent of a compound of formula R, 25 III or an acid salt thereof, wherein R^ is selected from 30 -31- ~CN, -CONH^ f \ NH NH ■OR. \ NH. V NH. and -C- \ SR. 10 in which R^ is an alkyl group f-xom 1 to 3 carbon atoms, for a period of time varying from .5 to 15 hours, optionally in an organic solvent selected from (C^_^)alkanols, (C^ ^)alkoxy-(C^ ^Jalkanols, ethylene glycol, propylene glycol and mixtures thereof, at a temperature comprised between .60°C and the reflux temperature of the reaction mixture. 15 20

6) A process for preparing 2-;biphenylrs-triazolo/5,1-a/isoquinoline derivatives of "fonrvula wherein R and are defined as in claim 1, which comprises contacting a molar proportion of a 2-amino-isoquinoline--l(2H)-one of formula 25 N NH. IV 3Q wherein R and R^ are defined as in claim 1, with . substan- ^32- 19 19 6 tially a mola,r equivalent of a nitrile of formula V 10 preferably in the presence of a catalyst.

7) A process for preparing compounds*of formula 15 20 wherein A, R and R^ are defined as in claim 1, which comprises contacting a molar proportion of a compound of formula 25 halo-CH2 CO wherein halo represents chlorine or bromine, with an 30 approximate equimolecular proportion of a compound of -33- '91960 formula VXK 10 15 wherein A, R. and R^ are defined as in claim 1 at a temperature comprised between room temperature and the reflux temperature of the reaction mixture, in the presence of an. organic aprotic solvent selected from chlorinated hy drocarbons, dioxane, tetrahydrofuran, benzene, toluene and mixtures thereof, and adding,a suitable amount of an alkaline agent. »

8) An antireproductive pharmaceutical composition containing from 10 to 600 mg. of a compound of formula 20 25 wherein A, R, R^ and X are defined as in claim 1, in admixture with an acceptable pharmaceutical carrier. 30 (frA"TOflM -9 MAR198£ received -34- m 10 i;i?60

9) A method for preventing reproduction in warm-blooded non-human animals, which comprises administering to the animal a dosage varying from 0.1 to 2 5 mg/kg of body weight of a compound of formula wherein A, R, R^ and X are defined as in claim 1.

10) The use of a compound of claim 1 as an antireproductive agenty -h-e<*4 of -

11) Compounds of claim 1 as particularly described herein.

12) A process for producing the compounds of claim 1 substantially as herein described with reference to any one of the examples. BALDWIJ 1 &/CmEY ATTORi r"