SE448629B - Pyrido / 1,4 / BENZODIAZEPINES - Google Patents

Description

10 448 629 2 where R represents hydrogen, lower alkyl, -alkl-NR 1 R 2 or -alkl-N = öH-oc2n5; H 1 and R 2 represent hydrogen, lower alkyl, -C (O) O-lower alkyl or R1 and R2 together with a nearby nitrogen atom can form a heterocyclic residue constituting 1-phthalimido, 1-pyrrolidinyl, N-morpholino, 1-piperazino or U-substituent erad piperazin-1-yl; Ar represents 2, 3 or β-pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted with 1-3 halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro and which substituents enter is the same or different; Alkl denotes a straight or branched hydrocarbon chain containing containing 1-8 carbon atoms; Z represents hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or nitro; IN Y represents hydrogen or 1-2 groups consisting of lower alkyl, lower alkoxy or hydroxy which groups are the same or different; n denotes 0 or 1 and when n denotes zero it the dotted line is a double bond, as well as acid addition salts thereof.

The compounds of formula I have use as antidepressants agents for the treatment of depression or as an intermediate in the preparation of other compounds of formula I. -the intermediates (or precursors) which are formed in one reaction mixture prior to cyclization to diazepines and which have further use as antidepressants for the treatment of depression is represented by the formula The new 1-2 - [(amino-pyridinyl) amino] phenyl_7arylmethanone 0 \ ky-Ar v! hrs N Formula II ÄO 448 629 where Ar, Z and Y have been previously defined.

For further definitions of the symbols in the formulas above and where they otherwise appear in the requirements, the terms have the following meanings.

The term alkl denotes straight and branched hydrocarbon chains containing 1-8 carbon atoms exemplified by methylene (-CH2-), ethylene (-CH2-CH2-), propylene (-CHECHECHZ-), ethylene- the L -CH -_ /, ÖHB H ._ 1 __. _ 1,2-propylene L -CH-CH 2 - or -CH 2 -C 1-4 isopropylidene I I CH CH CH 3 3 3 ¿F> Ö-_7 or 1,3-bunylene ¿"-ou-eng-CH2-_7 een similar. f | c H3 CH3 The term "lower alkyl" means straight and branched chain hydrocarbons. chains with up to 8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl and the like.

The term "halogen" denotes chlorine, bromine, fluorine and iodine, preferably chlorine, bromine and fluorine.

The term "U-substituted piperazin-1-yl" denotes piperazine substituted in the M-position with lower alkyl or alkyl-carbonyl blocking group which can then be removed to form unsubstituted piperazine.

Pharmaceutically acceptable acid addition salts are such salts of pyridobenzodiazepines of the present invention pimple with any acid, which is physiologically useful in warm-blooded animals, such salts are formed either by strong or weak acids. Examples of strong acids are salt acid, sulfuric acid and phosphoric acid. Examples of weak acids are fumaric acid, maleic acid, succinic acid, oxalic acid, cyclo- hexamic acid and the like. 6-aryl-11H-pyrido [2,3-b] 7, β-benzodiazepines and their , 6-dihydro derivatives fall within the scope of formula I with the formula 50 448 629 H Ål '-N / (P fl n ”Ïíà z åh Y L 6-aryl-11H-pyrido [3], H-§7¿_1, H_7benzodiazepines and their , 6-dihydro derivatives fall within the scope of formula I with the formula v) Iw AI / u fi n _ ïšu (Hin gl Y L: x -aryl-5H-pyrido [4,3-b_7Z_1, U_7benzodiazepines and their , 11-dihydro derivatives fall within the scope of formula I with the formula ïy -aryl-5H-pyrido [}}, 2-b_7Zf1, U_7benzodiazepines and their , 11-dihydroderivate falls within the scope of formula I with the formula HO 448 629 In the above formulas Iw-Iz, the symbols have R, Ar, Z and Y previously stated meaning.

For the determination of the antidepressant activity of The present inventions have used a method described by Englehardt, E. L., and co-workers J. Med. Chem. 11 (2): 325 (1968) which is considered to be an indication of usefulness of the compounds for the treatment of depression in humans and which process is performed as follows: 20 mg / kg of the compound to be tested is administered to five adults female mice (ICR-DUB strain), intraperitoneally 30 minutes before administration of a ptotic dose (52 mg / kg IP) of tetrabenazine (as methanesulfonate salt). 30 minutes later, attendance was determined or absence of complete eyelid closure (ptosis) in each animal. An EDSO (effective median dose) can be set up for each compound tested for blocking tetrabenazine called depression in mice according to the procedure set forth by Litchfield and co-worker J. Pharmacol. Exp. Therap. go: 99-113 (19H9).

Compounds of the present invention within the scope of formula I which have antidepressant activity in the foregoing procedure has the formula Ip Is __ Nr (H) fl n of 114 Y R IN where R represents hydrogen, lower elkyl or -elk1-N-Rïnz; H1 een n? denotes hydrogen, lower elkyl or where H1 een H2 together with the nearby nitrogen atom forms a heterocyclic residue consisting of 1-pyrrolidinyl, 4-morpholinyl, 1- -piperazinyl or U-lower alkyl-piperazin-1-yl; Ar represents 2, 3 or N-pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted with 1-3 halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro and where the substituent are the same or different; 448 629 alkl denotes a straight or branched hydrocarbon chain containing containing 1-B carbon atoms; Z represents hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or nitro; ß dotted line means a double bond as well as pharmaceutically acceptable acid addition salts thereof.

The compounds of formula Ip wherein R represents -alk1-NR1R2 and where H1 and R2 represent lower alkyl or hydrogen have been found have low antihistamine, anticholinergic and cardiotoxic side effects tested on animals.

The preferred pyridobenzodiazepines, useful for action of depression is the following: Example gray ____ Active compound (free base) _ _ _ _ 9 N, N-dimethyl-6-phenyl-11H-pyridol 2,3-b_ [1,4] / benzodiazepine-11-propanamine. 23 6- (u-fluorophenyl) -ILN-dimethylin 1fl-pyridophz, 3-b_7 1-1, U_7benzodiazepine-11-propanamine. 6-phenyl-11H-pyrido [2,3-b_71_1, Q_7benzodiazepine- -11-propanamine. 28 N-methyl-6-phenyl-1H-pyrido [2,3-b_7Z_1, Q_7benzo- diazepine-11-propanamine. 52b 6- (z-chlorophenyl) -N, N-dimethyl-1111-pyrid® [2,3-b_7 1-1, H_7benzodiazepine-11-propanamine. chloro, carbamoyl or imidate are intermediates rather than antidepressants.

An object of the present invention is thus to provide hand holding new 6-aryl-11H-pyridoβ, β-benzodiazepines, which have antidepressant activity. w 55 448 629 Another purpose is to provide new intermediaries products for the preparation of aryl-substituted 11H-pyrido ¿_1, H_7benzodiazepines which are antidepressants, av some of which are at the same time intermediate products and have depressive activity.

Special description.

The present invention provides novel pyridobenzodiazepines and methanone intermediates of formulas I and II and which can be used as antidepressants and in some cases as intermediates for the production of others antidepressants.

Preparation of the compounds. One reaction scheme for the preparation of the compounds The present invention is set forth in Reaction Scheme 1.

Alternative procedures for the manufacture of certain compounds of formula I are given in Reaction Schemes 2, 3 and N.

Methanones, formula II, see Reaction Scheme 1.

The methanone intermediates are prepared by heating a mixture of halo-aminopyridine and an aminobenzophenone for a shorter period of time than required for cyclization to pyridobenzodiazepines resulting from a chemical ionization mass spectrographic analysis. For ¿_2-¿_ (3-amino-2- -pyridinyl) aminškeny fl methanones are required for about 1-1.5 hours at 170-200 ° C. The methanones can be isolated as the dominant one the product if desired by cooling cmh addition of a suitable organic solvent, such as methylene chloride, which dissolves unreacted starting material and some cyclized (Ia) followed by standard methods of isolation and between solvent and alkaline aqueous solution or methanolic aqueous solution, followed by washing, drying evaporation of the solvent layer and recrystallization from a suitable solvent.

H0 448 629 8 Unsubstituted pyridobenzodiazepines, formulas Ia and Ia-1 (R = H), see Reaction Scheme 1.

The purified compounds of formula II or the crude compounds the compounds of formula II can be further heated in one aprotic solvent for cyclization to compounds of formula Ia, removal of water from the reaction mixture in a conventional manner, for example by reflux boiling using a Dean-Stark water trap. It is however, not necessary to interrupt the heating in it intermediate step in general, it is sufficient to continue heating the original reaction mixture ningen, e.g. III + IV for a longer period of time at which call to the association Ia occurs. In the cyclization step the temperature-time ratio will vary to some extent regardless of the method used, depending on the ones used the reactants. The only requirement is that the heating must take place for a sufficient time to give the desired product as shown by chemical ionization mass spectrophotometry.

The unsubstituted pyridobenzodiazepines are purified by partitioning between suitable solvents such as methylene chloride and basic aqueous solution, the solvent phase is washed and dried, evaporated and chromatographed in a suitable solution such as acetone-benzene. The corresponding dihydro- diazepine can be prepared by reaction with sodium boron cyanohydrin.

Substituted pyridobenzodiazepines. Formulas Ib and Ib (R = lower alkyl), see Reaction Scheme 1.

The compounds of formula Ia (or Ia-1) wherein R represents hydrogen is alkylaminated or groups are introduced which lead to alkylamination by first reacting with sodium hydride and then with a suitable reagent represented of halo-alk1Q where "alk" is previously defined, where Q is defined in Reaction Scheme 1. The compounds are added in a suitable solvent such as dimethylformamide to a stirred suspension of sodium hydride in the same solvent.

The haloalkyl Q reagent (alkylaminating agent or agents leading to alkylamination) is added at about (n 50 H0 9 448 629 room temperature and the reaction mixture was stirred for one time period until the reaction is complete, which for example, determined by thin layer chromatography. Non reacted sodium hydride is decomposed by the addition of water and the product is extracted with a suitable solvent, such as methylene chloride, followed by extraction with an aqueous solution acidification of the solvent phase and isolation of the product from the aqueous phase by neutralization and extraction with methylene chloride followed by evaporation and evaporation precipitate, preferably as an acid addition salt, such as the fumarate, the hydrochloride, the oxalate, the maleate and the like.

Once obtained and purified the acid addition salt can generally the free base is regenerated by distribution of the salt between an alkaline aqueous solution and a suitable solution agents such as methylene chloride and evaporation of methylene the chloride phase. Corresponding dihydrodiazepines can be prepared by reaction with sodium borocyanohydrin. Alternatively can compounds of formula Ib, wherein Q represents halogen, converted to compounds where Q represents -N- (lower alkyl) 2 by reaction with an appropriate dialkylamine as indicated in reaction scheme 2. 2 denotes The primary amines of formula Ic; i.e. R1 and R. both hydrogen, are prepared from -alkl-u »- (1-phthalimido) derivatives, shown in Reaction Scheme 1, by reaction with hydrazine hydrate using the methods set forth in Org. Sight.

Coll. Vol. III, p. 151-153. Generally, 2-5 hours is re- flow boiling sufficient after which an aqueous solution of a acid is added to the mixture and it is filtered. The pri- but the ealclamines are isolated from suitable solvents, such as isopropyl alcohol. The hydrochlorides and hydrochlorides the hydrates are preferred salts in the isolation step. The mot- the corresponding dihydrodiazepines can be obtained by reaction with sodium borocyanohydrin. the alk1-ua-monoalkylamines (formula Ie); for example R1 = methyl, R2 = hydrogen, can be prepared in the manner shown in the reaction. Scheme 1 by reaction between primary -alk1-NH2- derivatives of the formula Ic or Ic-1 with refluxing boiling triethyl orthoformate for a sufficiently long period of time 448 629 10 to form methanimidic acid ester (I-d) which is then obtained react with sodium borohydride. The unreacted boron the hydride is decomposed with water and the product is extracted from a suitable solvent, such as ethyl acetate and can purified by column chromatography and partitioning with a basic solvent. The hydrochlorides are the preferred ones the salts in the isolation step. The method is carefully exemplified neighbors in Examples 27 and 28. The corresponding dihydrobenzodi- azepines can then be prepared by reduction with sodium borocyanohydrin. -alkl-ul monomethylamines can also be prepared by reacting between the primary amine and ethyl chloroformate as is given in Example 29 and then reduction with lithium aluminum hydride, as exemplified in Reaction Scheme 3.

A further more generalized alternative method of conducting of -alkl-uz mono-lower alkylamine groups is via the group; 0 -alkl-N-8-O-lower alkyl. See Reaction Scheme 1. íägrealkyl All formulas Ia, Ia-1, Ib, Ib-1, Ib-2, Ib-3, Ib-U, Ic, Ic-1, Ic-2, Id, Ie, Ie-1 fall within the scope of formula I.

The compounds of formula I wherein the -NRIR2 moiety is unsubstituted 1-Piperazinyl was obtained by hydrolyzing a compound of formula I wherein -NR 1 R 2 represents piperazino substituted in the H-position with an alkylcarbonyl, such as t-butoxycarbonyl. : 1 448 629 Reaction Scheme 1 / - '\ _ "A1" .- "\ _ \ Q \ _ : fw ß + NH2 KÜF 'g v' * 'rme /' HAíII '/ \ Z / f I '\ “. ~~ Y __ (1',. .. \ ', 2 l X \\, - NH2 hal _ // kort per og¿: _àx¿N, ¿S§ /, \ Y III gen IV \ II à // heat Is 5 longer \, / further \ T_ñ period Of uf heat -H O: N -H O (, ¿/ H \ (__ m_ (§š \ /: \ 2 Z / N 'ÄN f NaBH3CN ”/ É" N / l ÉN.' »'_ * \\ /, ~ - acid Z, \\, / J Y H Ia _ _ * ° "_“ “" '”_ NaH + solvent Ia à v lhalogen-alkl-Q Ar, Ar ,(HRS) »AA» HM / ß * i- âärl; 2 'ïgš ¥' ”í§E; lY §§E: 3CN ° z / flik '¥ f \ {Tf> Y Ib alul-Q * \\ alkl-Q * Lí - U- ~ - Ib-1 when Q is (1-phthalimide) Alcohol / hydrazine Ar, hydrate, acid when n = 0 N hrs . N Ar z N; ZÉšš; \ Y syša) k = ålkl-NH É \ ~ \\\\ * “\ ~ (/ \ ï> fH) 2 z »1fšg N Ic-1 hrs ! a Ie-1 ï & rNÄH) (HRS) ZQM, hrs ålxl-N Ie H-substituted pi O -N-É-o-camp alkyl íägrealkyl gíšššl Naß fi u Y NaBH CN, IÄH) N n \ f / ”\ Y ålkl-NH Ar 2 N <::: íš l H-c (øc2H5) 5 \ C) Ar (H) z ”'Ü 1 Y> =='“ lk - -CH3 ann T when n = O Z A 41 Y Nasa cn, alu -N = cn-oc H -CH3 * Q represents -N- (lower alkyl) 2,1-pyrrolidinyl, 1-piperidinyl, perazin-1-yl, A-morpholino, 1-phthalimido, , or halogen. sd- ßsf 448 629 12 Ic Reaction Scheme 2 AI / 1H> n .N - (H) + NH_ (1ägrea1ky1) 2 D 2 f 4 ::! 'Y l Ib-2 alkl-hala Af (H) n "N / (HRS",&::!, z N Y- _ | hrs Ib-3 a1k1-å- (1ägrea1ky1) 2 Reaction Scheme 3 alkl-NH2_ solution means' + N (C2H5) 8_ | ncoc (o) c1 - \\\; Ar _ (H) IN alk-NH-c (o) -oc2H¿ Ic-2 Li AIH | 1 É B lk -N * C113 Ie-l 'IX '25 } 0 U 448 629 Reaction scheme U Are “Re / Unn (Ed z rfY 0 alkl-§7ë-O-lower-alkyl camp cold Ib-H Water mixture of acid or base, I -. alkyl-NH lower alkyl Ie-1 The preparation of the new 1f (aminopyridinyl) aminophenylaryl_7- methanones which are intermediates in the preparation of phenyl-substituted pyridoβ, β-benzodiazepines are shown further of the following intermediate 1-16. The structures of the intermediates are illustrated in Table 1.

Preparation of methanone intermediates Intermediate 1 [2- (3-amino-2-pyridinyl) amino] phenyl] phenylmethanone.

A stirred mixture of 39.0 g (0.20 mol) of 2-aminobenzophenone and 28.3 g (0.2 mol) of 5-amino-2-chloropyridine were heated to 18,000 in a nitrogen atmosphere for 1.5 hours. The mixture n HO 448 629 H allowed to cool slightly and 200 ml of methylene chloride was added slowly. After stirring for 3 hours, the mixture was allowed to stand overnight at room temperature after which U0.1 g solids was filtered off and recrystallized twice from methanol. isopropyl ether to give H, 3 g, probably hydro- chloride site, m.p. 187-90 ° C. This rust material dissolved in a mixture of water-methanol, made basic with BN sodium hydroxide and extracted with methylene chloride.

. The combined methylene chloride extracts were dried over magnesium sulphate and evaporated under reduced pressure. The residue was recrystallized from isopropyl ether (activated carbon) 2.1 g of product with a melting point of 91-9300 were obtained.

Drying before analysis overnight at room temperature / 0.02 mm Hg.

Analysis: Calculated for C 18 H 15 N 3 O: C 7U, 72; H 5.23; N 1ü, 52 Obtained 74.9H 5.23 1H, 69 Intermediate 2 1-2-N- (3-amino-2-pyridinyl) amino_7-U-chlorophenyl_7phenyl- methanone.

A stirred mixture of 23.2 g (0.1 mol) of 2-amino-1'-chloro- benzophenone and 1H, 2 g (0.11 mol) of 3-amino-2-chloropyridine heated to 18,000 in a nitrogen atmosphere for 2.5 hours.

The mixture was allowed to solidify while cooling to room temperature and then smashed with a spatula. The solid material was suspended in 100 ml of methylene chloride and collected by filtration. The filter cake was dissolved in a mixture of aqueous methanol, acidified with BN sodium hydroxide and extracted. twice with methylene chloride. The combined methylene- The chloride extracts were dried over magnesium sulphate and evaporated. under reduced pressure. The rest, which had crystallized, triturated in isopropyl ether and it the solid (16.7 g) was collected by filtration.

A 3 g sample was recrystallized from isopropyl ether to 1.6 g of product with a melting point of 153-15500 were obtained.

Analysis; Calculated for c18H1uc1N3o = c 66.77; H 4.36; N 12.98 Obtained 67.06 4.36 13.17 Intermediate 3 1-2 - [(5-amino-2- (pyridinyl) amino) phenyl] (N-methylphenyl) - methanone. f: ÄO 448 629 A stirred mixture of 20.0 g (0.095 mol) of 2-amino-H'-methyl- benzophenone and 13.95 g of 0.10 (mol) 3-amino-2-chloropyridine (96%) was heated in a nitrogen atmosphere at 18,000 for 2.0 hours. mar. The mixture was cooled to a glassy solid which was taken up, triturated in methylene chloride and then the mixture was allowed to stand overnight. The solid material was collected by filtration and dissolved in hot methanol.

The solution was basified with 3N sodium hydroxide diluted with 500 ml of water and extracted three times with 250 ml methylene chloride. The combined methylene chloride extracts are dried. was added over magnesium sulphate and evaporated under reduced pressure print. The residue, which crystallized after receiving was recrystallized twice from the benzene isooctane, at, 0.2 g of product with a melting point of 126-127.5 ° C were obtained.

Analysis: Calculated for O 19 H 17 N 3 O: C 75.23; H 5.65; N 13.85 Received. 75.81 5.69 13.96 Intermediate U 1-2 - [(3-amino-2-pyridinyl) amino] -7-5-chlorophenyl_7- (2-chloro- phenyl) methanone.

A mixture of 20.0 g (0.156 mol) of 3-amino-2-chloropyridine and 37.3 g (0.1 H mol) of 2-amino-2 ', 5-dichlorobenzophenone heated was taken to 19,000 in a nitrogen atmosphere for 5.5 hours. Thin- layer chromatography (5% methyl alcohol-benzene on silica gel) using indicated that the reaction was not completely complete. The mixture was stirred overnight at 19,000, cooled slightly after which 100 ml methylene chloride was added carefully. The suspension was stirred 2 hours and the black solid which formed was separated by filtration. The solid material sus- was diluted in 500 ml of methylene chloride and 300 ml of dilute sodium hydroxide was added. An emulsion was formed and mixed the filtrate was filtered, allowing separation of the phases.

The methylene chloride phase was washed with two 250 ml batches of water by extraction, dried over magnesium sulphate and evaporated. under reduced pressure. The residue was dissolved in benzene and was filtered through a 300 g column with florisil for removal those of materials with a low Rf value. All fractions combined was evaporated and evaporated under reduced pressure. Thin layer chromatography showed the presence of two main components with it dominant spot that had lower Rf value. The remainder 50 448 629. lb was dissolved in benzene and chromatographed on a 600 g column with florisil packed in benzene. The material with it the higher Rf value was eluted with 1% acetone-benzene. When inhaling The residue was triturated in benzene and recrystallized from benzene-isooctane varvid obtained 2 ,? g product with a melting point of 162-14 ° C.

Analysis: Calculated for C 18 H 13 Cl 2 N 5 O: C 60.35; H 3.66; N 11.73 obtained 60.67 3.67 11.77 Intermediates Sa-5u The procedure of intermediate 3 was followed and instead equimolar amounts of the following 2-amino-U'-methylbenzo phenones: 2-amino-U'-ethylbenzophenone, 2-amino-H'-isopropylbenzophenone, 2-amino-H'-bromobenzophenone, 2-amino-3'-fluorobenzophenone, 2-amino-U'-ethoxybenzophenone, 2-amino-H'-nitrobenzophenone, 2-amino-U'-trifluoromethylbenzophenone, 2-amino-3'-methylbenzophenone, 2-amino-3'-ethylbenzophenone, 2-amino-3'-methoxybenzophenone, 2-amino-3'-ethoxybenzophenone, 2-amino-2'-nitrobenzophenone, 2-amino-3'-trifluoromethylbenzophenone, 2-amino-2'-methylbenzophenone, 2-amino-2'-ethylbenzophenone, 2-amino-2'-methoxybenzophenone, 2-amino-2 ', 4'-dichlorobenzophenone, 2-amino-3 ', 4', 5'-trimethoxybenzophenone, 2-amino-2'-fluorobenzophenone, 2-amino-2'-chlorobenzophenone and 2-amino-2'-bromobenzophenone, whereby obtained: a) 1-2-L_ (3-amino-2-pyridinyl) amino_7phenyl_7- (U-ethylphenyl) methanone, b) ¿(2-β- (3-amino-2-pyridinyl) amino] phenyl] - (β-isopropyl) phenyl) methanone, 1.1 c) d) .HRS f) s) hrs) J) R) 1) m) n) 0) P) q) r) S) t) u) 17 448 629 1-2 - [(3-amino-2-pyridinyl) amino] phenyl] 7- (4-bromophenyl) methanone, 1-2-L_ (3-amino-2-pyridinyl) amino-7-phenyl-7- (3-fluoro- phenyl) methanone, 1-2 - [(3-amino-2-pyridinyl) amino] phenyl] 7- (U-ethoxyphenyl) methanone, [2- (3-amino-2-pyridinyl) amino] -7-phenyl_7- (M-nitr-phenyl) methanone, 2-L (3-amino-2-pyridinyl) amino-7-phenyl-7- (U-trifluoro- methylphenyl) methanone, 1-2 - [(3-amino-2-pyridinyl) amino] phenyl] 7- (3-methylphenyl) methanone, 1-2 - [(3-amino-2-pyridinyl) amino] phenyl] 7- (5-ethylphenyl) methanone, [2- (3-amino-2-pyridinyl) amino] -phenyl] -7- (3-methoxy- phenyl) methanone, 1-2 - [(3-amino-2-pyridinyl) amino] phenyl] 7- (3-ethoxyphenyl) methanone, _ [-2- [(3-amino-2-pyridinyl) amino] phenyl] 7- (2-nitrophenyl) methanone, 1-2-[(3-amino-2-pyridinyl) amino] -phenyl] -7- (3-trifluoro- methylphenyl) methanone, 1f2-1f (3-amino-2-pyridinyl) amino; 7phenyl-7- (2-methylphenyl) methanone, [2,2-L] (3-amino-2-pyridinyl) amino; 7-phenyl-7- (2-ethylphenyl) methanone, [2- (3-amino-2-pyridinyl) amino] -phenyl] -7- (2-methoxy- phenyl) methanone, F (2-β- (3-amino-2-pyridinyl) amino] phenyl; 7- (2,3-dichloro- phenyl) methanone, [2- (3-amino-2-pyridinyl) amino] -phenyl] -7- (3,5-tri-tri- methoxyphenyl) methanone, ¿F2-1f (Bjamino-2-pyridinyl) amino_7phenyl_7- (2-fluoro- phenyl) methanone, 1-2-N- (3-amino-2-pyridinyl) amino-7phenyl_7- (2-chlorophenyl) methanone, and 1-2-N- (3-amino-2-pyridinyl) amino] phenyl_7- (2-bromophenyl) methanone. 50 H0 448 629 18 Mgllan product 6a-601 The procedure of intermediate 2 was followed but instead equimolar amounts of the following compounds were reversed instead for 2-amino-U-chlorobenzophenone: 2-amino-5-chlorobenzophenone, 2-amino-6-chlorobenzophenone, 2-amino-N-fluorobenzophenone, 2-amino-4-bromobenzophenone, 2-amino-H-trifluoromethylbenzophenone, 2-amino-N-methylbenzophenone, 2-amino-5-methylbenzophenone, 2-amino-6-methylbenzophenone, 2-amino4U-ethylbenzophenone, 2-amino-H-methoxybenzophenone, 2-amino-U-ethoxybenzophenone, 2-amino-U-nitrobenzophenone, 2-amino-5-nitrobenzophenone, 2-amino-3-methylbenzophenone and 2-amino-3-chlorobenzophenone, whereby obtained: a) β-2- (3-amino-2-pyridinyl) amino; 7-5-chlorophenyl-7-phenyl- methanone, b) 1- [2- (3-amino-2-pyridinyl) amino]; 7-6-chlorophenyl-7-phenyl- methanone, c) [2- (3-amino-2-pyridinyl) amino] -7-U-fluorophenyl_7phenyl- methanone, d) L_2- [(3-amino-2-pyridinyl) amino] -7-4-bromophenyl_7phenyl- methanone, e) [fα-L_ (3-amino-2-pyridinyl) amino] -7-H-trifluoromethyl- phenyl_7phenylmethanone, f) β (2- (3-amino-2-pyridinyl) amino] -7-methylphenyl_7phenyl- methanone, g) 1f2-1f (β-amino-2-pyridinyl) amino-7-5-methylphenyl_7phenyl- methanone, h) 1-2-N- (3-amino-2-pyridinyl) amino-7-6-methylphenyl_7phenyl- methanone, i) 1f2 - [(3-amino-2-pyridinyl) amino] -7-U-ethylphenyl_7phenyl- methanone, j) β (2- (3-amino-2-pyridinyl) amino] -7-H-methoxyphenyl_7phenyl- methanone, 50 H0 19 448 629 k) β (2-amino-2-pyridinyl) amino-7-H-ethoxyphenyl-7-phenyl- methanone, 1) β- [(3-amino-2-pyridinyl) amino] -7-N-nitrophenyl_7phenyl- methanone, m) β-2- (3-amino-2-pyridinyl) amino-7-5-nitrophenyl-7-phenyl- methanone, n) 1-2 - [(3-amino-2-pyridinyl) amino] -7-3-methylphenyl_7phenyl- methanone and o) β (2-amino) (3-amino-2-pyridinyl) amino-7-5-chlorophenyl-7-phenyl- methanone.

Intermediate 7a-7c The procedure of Preparation 1 was followed and essentially equimolar amounts of the following compounds were used instead for 3-amino-2-chloropyridine: Amino-amino-3-chloropyridine, 3-amino-H-chloropyridine and 2-amino-3-chloropyridine, whereby obtained: a) ¿f2-β- (U-amino-3-pyridinyl) amino_7phenyl_7phenylmethanone, b) 1-2 - ((3-amino-U-pyridinyl) amino-7phenyl_7phenylmethanone and c) 1-2 - [(2-amino-3-pyridinyl) amino] phenyl_7phenylmethanone.

Intermediate 8 ¿F2-Å_ (3-amino-2-pyridinyl) amino_7phenyl_7 (3-chlorophenyl) imethanone.

A stirred mixture of 35 g (0.152 mol) of 2-amino-3'-chloro- benzophenone and 23.1 g (0.182 mol) of 3-amino-2-chloropyridine was heated to 18,000 for 2 hours. The hot melt allowed to cool to 11 ° C, after which 100 g of hot toluene were added. was added dropwise with vigorous stirring. The mixture was allowed cool while stirring to 3000 and 50 ml of methylene chloride After stirring for an additional hour, it was filtered the mixture and the filter cake were suspended in methylene chloride with stirring for one hour and the methylene chloride is separated. by filtration. The filter cake containing the product .. (25, H g) was partially dissolved in hot methanol (total volume) 150 ml) and an aqueous solution of 50% sodium hydroxide was added until the mixture was basic. Ice water was added and the solution was extracted with methylene chloride. This methylene- HO 448 629 20 chloride extracts were washed with water and dried over magnetic sodium sulfate and evaporated to dryness. The remainder was dissolved in isopropyl alcohol and boiled with activated carbon. Among- The filtrate was filtered and the volume was reduced to give a first crop of crystals weighing 16 g (33%). Part of the the crystals were recrystallized from isopropyl alcohol to a red lump of solid material was obtained which melted at 119- -12 ° C.

Analysis: Calculated for Received C 66.77; H u, 36; N 12.98 66.78 u, u2 12.9u ell ellanprodukt 9 1f2-ff (3-amino-2-pyridinyl) amino_7phenyl_7 (H-fluorophenyl) methanone.

A stirred mixture of 55 g (0.65 mol) of 2-amino-N'-fluoro- benzophenone and 27 g (0.2 mol) of 3-amino-2-chloropyridine heated to 175-18000 for 2.5 hours. The mixture allowed to cool to 11000 after which 100 ml of hot toluene sat. After cooling to 50 ° C, 50 ml of methylene chloride. The solvent phase was decanted to give a solid black mass which was dissolved in hot methanol. Solution the average volume was reduced by half and the mixture allowed to stand overnight at room temperature. the mixture was filtered and the filter cake was washed twice by pension in methylene chloride. The weight of the impure solids which was obtained was 22.5 g. The solid was dissolved in methanol and acidified with an aqueous solution of 50% sodium hydroxide. The mixture was extracted with methylene chloride and the extract was dried and concentrated. The remainder was crystallized twice from isopropyl alcohol, decolorized by boiling with activated carbon for the second time, 1H g (28%) of solid orange was kept color and had a melting point of 121.5-122.5 ° C.

Analysis: Calculated for C 18 H 11 N 5 OF: C 70¿§5; H Ä, 59; N 13.67 Obtained 70.25 H, 59 13.6u Intermediate 10 1-2-α (3-amino-2-pyridinyl) amino_7phenyl_7 (2-thienyl) methanone.

In accordance with the procedure of intermediate 9, (2-amino- HO 21,448,629 phenyl) (2-thienyl) methanone, prepared by the process as described in Steinkopf & Gunther, Ann. eggs, 28 ~ 3Ä (1935), react with 3-amino-2-chloropyridine, the title compound was obtained.

Intermediate 11 1-2 - [(3-amino-2-pyridinyl) amino] phenyl (3-thienyl) methanone.

In accordance with the procedure of intermediate 9, (2-amino- phenyl) (3-thienyl) methanone react with 3-amino-2-chloropyridine whereby the title compound was obtained.

Intermediate 12 (1-amino-2-pyridinyl) amino-7-phenyl-7 (2-pyridinyl) methanone.

The title compound was prepared by reaction between (2-amino- phenyl) (2-pyridinyl) methanone prepared according to Schofield, K., J. Chem. Soc. lg fl g, 2ÄO8-12 with 3-amino ~ 2-chloropyridine.

Intermediate 13 [1- (3-amino-2-pyridinyl) amino] -7-phenyl_7 (3-pyridinyl) methanone.

The title compound is prepared by reaction between (2-amino- phenyl) (3-pyridinyl) methanone, prepared according to Abramovitch R. A. & Tertzakian, G., Tetrahedron Letters, 1963, 1511-15 and Abramovitch, R. A. and co-workers, Can. J. Chem. fl åíïl, 725-31 (1965) with 3-amino-2-chloropyridine.

Medium-grown 14. 1f2-Å_ (5-amino-2-pyridinyl) amino_7phenyl_7 (U-pyridinyl) methanone.

The title compound is prepared by reaction between (2-amino- phenyl) (U-pyridinyl) methanone, prepared according to Nann, A.J. and Schofield, K., J. Chem. Soc. 1223, 585-9 with 3-amino-2- -chloropyridine.

Intermediates 15a-low The process according to intermediate 1 and substantially equimolar amounts of the following instead of 3-amino-2-chloropyridine: -amino-2-chloro-H-methylpyridine, 3-amino-2-chloro-5-methylpyridine, BD H0 448 629 2 Tu) 3-amino-2-chloro-6-methylpyridine, 3-amino-2-chloro-5,6-dimethylpyridine, 3-amino-2-chloro-6-methoxypyridine, 3-amino-4-chloro-2-methylpyridine and 5-amino-2-chloro-5-methoxypyridine, whereby obtained: a) β-2- (3-amino-H-methyl-2-pyridinyl) amino-7phenyl_7phenyl- methanone, b) β-2- (5-amino-5-methyl-2-pyridinyl) amino-7phenyl_7phenyl- methanone, c) 1-2 - [(5-amino-6-methyl-2-pyridinyl) amino] -phenyl_7-phenyl- methanone, d) 1-2 - [(3-amino-5,6-dimethyl-2-pyridinyl) amino] phenyl_7 phenylmethanone, e) [2- (3-amino-6-methoxy-2-pyridinyl) amino] phenyl_7phenyl- methanone, f) 1-2-Å_ (3-amino-2-methyl-U-pyridinyl) amino_7phenyl_7phenyl- methanone and g) 1-2-Å_ (3-amino-5-methoxy-2-pyridinyl) amino_7phenyl_7phenyl- methanone.

Intermediate 16a-16f The procedure of intermediate 1 was followed and replaced for 3-amino-2-chloropyridine, equimolar amounts of were used following: 2-amino-3-chloro-5-methylpyridine, 2-amino-3-chloro-4,6-dimethylpyridine, 2-amino-3-chloro-5-ethylpyridine, H-amino-3-chloro-5-methylpyridine, U-amino-3-chloro-2,6-dimethylpyridine and 4-amino-3-chloro-2-methylpyridine, whereby obtained: a) β-2- (β-amino-5-methyl-3-pyridinyl) amino; 7-phenyl-7-phenyl- methanone, b) 1-2 - [(2-amino-1,6-dimethyl-3-pyridinyl) amino] phenyl] phenylmethanone, c) -2- [(2-amino-5-ethyl-5-pyridinyl) amino] phenyl_7phenyl] methanone, ' d) 1-2-L_ (4-amino-5-methyl-3-Pyridinyl) amino_7phenyl_7phenyl- methanone, '41 448 629 e) 1-2-L_ (H-amino-6-methyl-3-pyridinyl) amino-7-phenyl-7-phenyl- methanone and f) L_2-L_ (H-amino-2-methyl-3-pyridinyl) amino_7phenyl_7phenyl- methanone. product Is 448 629 u Eêbell 1 %_Are H2 N __ Between; [N Ce's' cens- M-cH3-c6H4- 2-c1-c6H, - ß-c2H5-c6H4- α-i-c3H7-c6H4- u-Br-Cg fl q. 3-F-ceH4- H-oc2H5-c6H4- h-NO2 -C5H4- 4-cF3-ceH4- 3'CH3'CeH4- 3 ~ C2Hs "CeH4 ' 3-0CHa “CeH4- 3-0C2Hs ”CsH4 ~ 2-No2-cBH4- 3-CFs “CeH4- 2 -C 5 g -C 5 H 4 - 2-c2H5-ceH4- 2-ocH3-c6H.- 2, M-cl -can - 3, u, 5 „0CHs a“ CaH2- 2¿F-c6H.- 2-cl-cen, 2 -BI-CQH4 Ceas- IN O F ' u1¿ \ fl nJH mi flfl åm fiflfl åmï flflfifl! fl U1Z2ml fl b2m! fl B1m! fl ï1N fl í fl f) hrs -Cl 6-cl M-F 3-Br -CF3 U-Me -Me 6 -CH3 lf -Cg H5 M-ocns u “OCZ H5 H-Noah * N02 3-CH: 3-Cl (continued) O fl E! P'wuhH-äunrnm mrïtrm crfm HJIW 0:15 Hvru-wt fi nfmm mr10'm EIIIEECISIIImmNmmmt fl i fl mwEmmmmNml fl mmmmEBlt fl mmå⁇ N Table 1 (continued) Between- grodukt 8 9 ll 12 13 14 15a l5b l5c 156 l5e 159 Take l6d 7b 15f Tea lßa Ar Y 3-Cl-CBH4- H N-F7ceH.- H 2-Ghienyl H 3-š fl íenyl H 2- yridinyl H 3-pyridinyl H Α-pyridinyl H ce fl s- H-c fl a Ce fi s ”5“ CHa CSHS- 6-ca - Ce fi s '5 »6'? CHs) 2 Cans- 6-ocna ceH5- 5-ocna Q C ~ ÅI Hey Z N <:) Y IN hrs cens- H Ce * s * 5-C33 C5H5- 6-CH3 CeHs “2-CH3 O Q; _Ar Hg - Z [fi y hrs CBH5- H Cans * 2 “CHa 0 %_Are æ fl N hrs C5H5- H CeHs “5 * CHs CGHS- 4.6 (CH 3) 2 C655 "5-C235 448 629 Sim N E Hibïäim E E fl l fl im E mi! I IN E H üï flfi m N STAY H0 448 629 26 The preparation of the new phenyl-substituted pyrido [1], the benzodiazepine compounds of the present invention and the new procedures are exemplified more fully by the following example. The structure of the compounds according to the examples are illustrated in Table 2. However, the invention is limited time not with the information given there.

Example 1 6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine.

A mixture of 19.7 g (0.1 mol) of 2-aminobenzophenone and .0 g (0.12 mol) of 3-amino-2-chloropyridine were heated nitrogen atmosphere to 19,000 for 1.75 hours. The mixture cooled to room temperature and partitioned between solution of sodium hydroxide and methylene chloride. The combined The beaten methylene chloride extracts were washed with water, dried was added over magnesium sulphate and evaporated under reduced pressure print. The residue, 32.7 g, was dissolved in benzene and chromatographed. graphed on a florisil column packed in benzene, eluted with benzene and 1-2% acetone-benzene mixtures. After inhalation The solid material was crystallized from benzene 7.3 3 of a product with a melting point of 106-108 ° C were obtained.

Analysis: Calculated for C 18 H 15 N 3: C 79.68; H U, 83; N 15, U9 Obtained 79.70 U, 81 15, Ä2 Example 2 8-chloro-6-phenyl-11H-pyrido [2,3-b] 71_1, H_7benzodiazepine.

A mixture of 15.0 g (0.06U7 mol) of 2-amino-5-chlorobenzo- phenone and 9.1 g (0.068 mol) of 3-amino-2-chloropyridine heated m 2 20 ° C (on an oil bath) for 0.75 hours in nitrogen atmosphere. The mixture was cooled and methylene chloride was added.

The mixture was stirred for 1 hour and allowed to stand at night. Brown solid precipitate weighing 8.7 g was separated by filtration. The filtrate was evaporated under reduced pressure print. The residue was combined with the brown solid the material and distributed between an aqueous solution of sodium hydroxide and methylene chloride and the crude product was isolated as in Example 1 with the exception that the the lysis solvent was ethanol. Recrystallization from ethanol and drying overnight at 82 ° C / 0.1 mm Hg gave .0 g product; melting point 156.5-158.5 ° C.

HO 27,448,629 Analysis: Calculated for C 18 H 12 ClN 5: C 70.71; H 3.96; N 13.74 Obtained 70.2Ä ü, 01 13.76 Example 3 9-chloro-6-phenyl-11H-pyrido [2,3-b] 71 [1,1] benzodiazepine.

A suspension of 6.6 g (0.02 mol) of [2- (3-amino-2-pyridyl) - amino_7-U-chlorophenyl_7- (phenyl) methanone (intermediate 2) i 200 ml of toluene were heated under reflux overnight in nitrogen atmosphere. The reaction mixture was filtered hot and the filtrate was reheated to reflux temperature. The wide cooling to room temperature formed the precipitate was separated by filtration and recrystallized from benzene and dried H hours at 97-9800 / 0.1 mm Hg and overnight at room temperature. temperature / 0.1 mm Hg to give 5.7 U with a melting point at 250.5-25200. Elemental analysis for carbon was high and the cloth was re-dried at 13900 (xylenes in a drying gun) for 8 hours hours. Although carbon analysis remained high, proton nuclei were magnetic resonance spectrum and mass spectrum in accordance accordance with the adopted structure.

Analysis: Calculated for C 16 H 12 ClN 3: C 70.71; H 3.96; N 13.7U Obtained 71, ü6 U, 06 13, U6 Example H S-chloro-- (2-chlorophenyl) -5,6-dinyl-chloro-11H-pyrido [2,3-b] -7- ¿_1, H_7benzodiazepine.

Further elution of the florisil column during preparation of intermediate U with 10-15% acetone in benzene and 5-25% methanol in benzene gave two fractions of the title compound according to this example, 6, g and 5.7 wherein the other was completely unclean. The 6.0 g fraction was recrystallized from benzene. isooctane to give 3.7 g of solid with a melt point of 203-600 (decomposition) which was identified by chemical ionization mass spectroscopic analysis, 1H and 130 nuclear spin resonance as 8-chloro-6- (2-chlorophenyl) -5,6-dihydro-11H- -pyrido¿_2,3-b_71_1, Ä_7benzodiazepine. 0 Example 5 6- (H-chlorophenyl) -11H-pyridol-2,3-b_7Zf1, H_7benzodiazepine.

A mixture of 23.2 g (0.1O mol) of 2-amino-U'-chlorobenzophenone and 1U, 7 g (0.11 mol) of 3-amino-2-chloropyridine (96%) were heated 55 40 448 629 28 for 1.5 hours to 18,000 in a nitrogen atmosphere. The mixture cooled to room temperature and methylene chloride was added.

After stirring for 30 minutes, solids were separated filtration and triturated in hot 95% ethanol. Re- standing insoluble matter was collected by filtration and recrystallized from benzene-octane to give 2.7 g product with a melting point of 203 ~ 20U, 5 ° C. Drying conditions for the assay was: overnight at 97-9800 / 0.1 mm Hg.

Analysis: Calculated for C 18 H 12 ClN 3: C 70.71; H 3.96; H 13.7M Obtained 70.76 3.92 13.95 Example 6 6- (4-methylphenyl) -11H-pyrido [2,3-b] 71,1,17benzodiazepine.

A solution of 3.6 g (0.012 mol) of 1-2 (3-amino-2-pyridyl) - amino_7phenyl_7 (M-methylphenyl) mecanone in 100 ml of anhydrous toluene was treated with a catalytic amount of paratoluenesulfonic acid. acid and refluxed overnight under water separation. tion with a Dean-Stark trap. The reaction mixture is filtered. des varm. The product precipitated when the filtrate cooled room temperature and collected by filtration. Fixed material weighed after solvent evaporation 2.5 g and a melting point of 2o3.5-1o5 ° C (decomposition).

Analysis: Calculated for C 19 H 15 N 5: C 79.98; H 5.30; N 1H, 73 Obtained 79.95 5.27 1, 76 Example 7 6- (4-Methoxyphenyl) -11H-pyrido [2,3-b] [1,4] Tbenzodiazepine.

A stirred mixture of 20.0 g (0.088 mol) of 2-amino-N'-methoxy- benzophenone and 13.0 g (0.097 mol) of 3-amino-2-chloropyridine (96%) was heated to 180 ° C in a nitrogen atmosphere for 2 hours.

The reaction mixture was cooled to about 7000 and 100 ml of methylene chloride was added slowly. After the mixture has cooled room temperature, an additional 50 ml of methylene chloride was added and the mixture was stirred overnight. Its suspended solids the material was collected by filtration, air dried, collected dissolved in methanol and basified with 3N sodium hydroxide.

The suspension was diluted with 500 ml of water and extracted with three batches of 250 ml of methylene chloride. The merged the methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. Analysis of mass spectra H0 29 448 629 (E1 and CI) indicated that the residue was a mixture of Β * 2- (3-amino-2-pyridyl) amino-7phenyl_7 (U-methoxyphenyl) meta- non and the title association. The residue mixture was dissolved in 250 ml of toluene with a catalytic amount of paratoluenesulfonic acid and the solution was boiled overnight in a nitrogen atmosphere separation of water in a Dean-Stark trap. Reactional the mixture was filtered while hot. The product precipitates after the filtrate had been allowed to cool to room temperature and collected by filtration. After recrystallization from benzene the product weighed 1.8 g and had a melting point of 198.5-200.5 ° C (decomposition). _ Analysis: Calculated for C 19 H 15 N 5 O: C 75.73; H 5.02; N 13.9H Obtained 75.65 ü, 98 1ü, 03 Example 8 B-chloro-N benzodiazepine-11-propanamine oxalate (1: 1).

To a stirred suspension of 1.05 g (0.0UU mol) of sodium hydride 6.1 g (0.02 mol) were added portionwise under a nitrogen atmosphere. (in mineral oil) in 50 ml of anhydrous dimethylformamide 8-chloro-6-phenyl-11H-pyrido [2,3-b] [7,1] benzodiazepine.

The reaction mixture was stirred at room temperature below 1.5 hours during which the evolution of hydrogen stopped. For mixed 5.5 g (0.022 mol) of 3-dimethylamino- propyl chloride hydrochloride. After stirring overnight at at room temperature, the reaction mixture was poured into 1600 ml of water and the resulting solution was extracted three times with 250 ml batches of methylene chloride. The combined methylene chloride the extracts were washed with two 250 ml batches of water, dried over magnesium sulphate and evaporated under reduced pressure. The residue was dissolved in benzene and chromatographed with acetone-benzene on a 300 g column of florisil packed in benzene.

The starting material, 1.6 g, was recovered in the benzene elution and 3.6 g containing the product as a free base were obtained from the acetone -benzene elution by evaporation of the solvent. Batch of the crude free base, 2.5 g, is dissolved in hot isopropyl alcohol and reacted with 0.8 g (0.006H mol) of oxalic acid hydrate. The oxalate salt, which precipitated on cooling, was was collected by filtration and recrystallized from ethanol whereby 2.2 g of a product with a melting point of were obtained NO 448 629 30 206-20800. The drying conditions before the analysis were 5 hours at 97-98 ° C / 0.02 mm Hg; overnight at room temperature / 0.02 mm Hg.

Analysis: Calculated for C 25 H 25 ClNuOu: C 62.15; H 5.2ü; N 11.65 Obtained 62.52 5.23 11.76.

Example 9 Nm-dimethyl---phenyl-nn-pyriaofz, 3-b_7 [1] pin-11-propanamine fumarate (1: 1).

To a stirred suspension of 1.68 g (0.070 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide was added in a nitrogen atmosphere portionwise a suspension of 8.0 g (o, o29 moi) δ-phenyl-ina-pyridofz, 3-b_7 [1Jajbenso- diazepine in 20 ml of anhydrous dimethylformamide. The mixture stirred for 30 minutes until the addition was complete heated to 65 ° C for 15 minutes and cooled again to room temperature. To the mixture was added 5.6 g (0.035) mol) 3-dimethylaminepropyl chloride hydrochloride. After stirring overnight at room temperature indicated thin layer chromatography that the reaction was almost complete. The reaction mixture was washed in 1500 ml of water and extracted with 250 ml of methylene chloride. The methylene chloride extract was washed with three batches 250 ml of water, dried over magnesium sulphate and evaporated under reduced pressure. The residue was dissolved in methylene chloride and extracted with 100 ml and 150 ml portions of SN hydrochloric acid. Unreacted 6-phenyl-11H-pyridyl_2,3-b_71_1,4_7- benzodiazepine (starting material) precipitated from the acidic water solution and separated by gentle decanting of the liquid from the solid material. The aqueous solution was made basic with ONE sodium hydroxide and extracted with three 100 ml charges methylene chloride. The combined methylene chloride extracts dried over magnesium sulphate and evaporated to dryness reduced pressure to give 7.7 g of residue, which was made by the free base of the title association. A solution of 6.6 g of this residue were reacted in hot isopropyl alcohol with 2.15 g of fumaric acid and the mixture was heated until then the resolution was complete. After it has been allowed to stand for H8 hours the precipitated salt was collected by filtration. After crystallization from isopropyl alcohol-isopropyl ether was obtained .9 g of a product with a melting point of 171-17300. Dryer- 50 H0 M 448 629 conditions before analysis were U hours at 9000 / 0.1 mm Hg above overnight at room temperature / 0.1 mm Hg.

Analysis: Calculated for C 27 H 28 H 10 O: C 68.63; H 5.97; N 11.86 Obtained 68.37 6.05 11.73.

Example 10 N; N-dimethyl-6-phenyl-11H-pyrido [2,5-b] 7 ', 1,7-benzodiazepine- -11-ethanamine fumarate L_1: 1_7.

To a stirred suspension of 1.0 g (0.062 mol) of sodium hydride (in mineral oil) in 55 ml of anhydrous dimethylformamide in nitrogen atmosphere was added portionwise 7.0 g (0.026 mol) 6-phenyl-11H-pyrido [2,5,5-b] 7,1-benzodiazepine. After cooling adding the reaction mixture to room temperature was added H, H6 g (0.031 mol) of 2-dimethylaminoethyl chloride hydrochloride portionwise and stirring was continued overnight. Reactive The reaction mixture was poured into 1500 ml of water and the resulting mixture the mixture was extracted with 250 ml of methylene chloride. Methylene- the chloride extract was washed with three batches of 500 ml of water, dried over magnesium sulphate and evaporated to dryness reduced pressure to give 8.6 g of an oil, which was made of the free base of the title association. Part of the the oil, 6.9 g, was reacted with an equimolar amount of acid in isopropyl alcohol. Addition of isopropyl ether gave one oily solid material. The mixture was evaporated under reduced pressure and the residue was then crystallized allowed to stand; The crystals were triturated with acetone and was crystallized from acetone-isopropyl ether to give 4.3 g of the fumarate salt, m.p. 175-177.5 ° C.

Analysis: Calculated for C 26 H 26 NO 2 O: C 68.11; H 5.72; N 12.22 Reached 67.88 5.72 -12.17 Example 11 11-β "3- (β-propylene) propyl] 7-6-phenyl-11H-pyrido [2,5-b] ¿_1,4_7benzodiazepine fumarate ¿_1: 1_7.

To a stirred suspension of 1.10 g (0.0H6 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide in nitrogen atmosphere was added portionwise 5.0 g (0.0184 mol) 6- -phenyl-11H-pyrido¿_2,3-b_7¿_1, ü_7benzodiazepine. Reactional the mixture was stirred at room temperature for 15 minutes, was heated to 65-70 ° C for 10 minutes and allowed H0 448 629 '32 cool to room temperature. To the mixture was added portion- vis H, 1 g (0.02 mol) of 4- (3-chloropropyl) morpholine hydroxide.

The reaction mixture was stirred at room temperature for 16 h hours and then beaten in 800 ml of water. This mixture was extracted twice with 200 ml batches of methylene chloride.

The combined methylene chloride extracts were extracted with 150 ml and 75 ml batches of 5N hydrochloric acid and the combined the aqueous extracts were basified with BN sodium hydroxide. The the resulting suspension was extracted with two batches of 150 ml of methylene chloride and the latter two extracts combined beaten, dried over magnesium sulphate and evaporated reduced pressure. The remainder, the free base of the title was reacted with an equimolar amount of fumaric acid in hot isopropyl alcohol and the mixture was treated with iso- propyl ether. The fumarate salt was collected by filtration and recrystallized from ethanol-ethyl acetate to give 5.6 g, with a melting point of 15u-7 ° c. Torx conditions before the assay was H hours at 97-9800 / 0.1 mm Hg, overnight at room temperature / 0.1 mm Hg. 29H30Nuo5 = c 67.69; H 5.88; N 10.88 67.52 5.84 10.90 Analysis: Calculated for C Received Example 12 N, N-diethyl-6-phenyl-11H-pyrido [2,3-b] 7L_1, H_7benzodiazepine- -11-propanamine oxalate ¿_1: 1_7.

To a stirred suspension of 1.10 g (0.0H61 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide in nitrogen atmosphere 5.0 g (0.018H mol) were added portionwise 6-phenyl-11H-pyrido [2,3-b] -7, 1,7-benzodiazepine. Reactional the mixture was stirred at room temperature for 0.5 hour, was heated to 65-7000 and cooled slowly to room temperature. lucky. To the mixture was added portionwise 3.77 g (0.020 mol) 3-Diethylaminopropyl chloride hydrochloride and reaction mixture The mixture was stirred at room temperature for 16 hours. Among- The mixture was beaten in 750 ml of water and extracted with three rates of 150 ml of methylene chloride. The combined methylene- the chloride extracts were extracted with 150 ml and 75 ml batches BN hydrochloric acid. The combined water extracts were acidified with BN sodium hydroxide and extracted with three 100 ml batches methylene chloride. The combined methylene chloride extracts 40 , 448 629 LU dried over magnesium sulphate and evaporated to give reduced pressure to give 7.5 g of the free base of the title association. One batch, 5.6 g, was allowed to react with an molar amount of oxalic acid dihydrate in hot isopropyl alcohol.

The oxalate salt was collected by filtration to give , 5 g product with a melting point of 196-19900. Drying conditions before analysis was 1 hour at 97-9800 / 0.1 mm Hg.

Analysis: Calculated for C C 68.3U; H 6.37; N 11.81 Erhåiiet 68.31 6, M3 11.86 27H3oNu ° u * Example 15 9-xicro-N, N-dimethyl-6-phenyl-11n-pyrido [2,3-b] 7,1, H_7 benzodiazepine-11-propanamine fumarate L_1: 1_7.

To a stirred suspension of 0.98 g (0.0U1 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide in nitrogen atmosphere was added portionwise 5.0 g (0.016 mol) of 9-chloro- -6-phenyl-11H-pyrido [2,2-b] 7,1, benzodiazepine under 45 minutes. The reaction mixture was stirred at room temperature for 1 hour, heated to 70 ° C and then cooled slowly to room temperature. To the mixture was added portionwise for 30 minutes 2.8H g (0.018 mol) of 3-dimethylaminopropyl- chloride hydrochloride and the reaction mixture was stirred at room temperature for 17 hours. The mixture was beaten into 750 ml water and extracted with 150 ml and two 100 ml batches methylene chloride. The combined methylene chloride extracts was washed with two 100 ml batches of water followed by extraction with 100 ml and 75 ml of BN hydrochloric acid. The acidic extracts combined and filtered to remove precipitate which is formed and then the filtrates were basified with BN sodium hydroxide and extracted with three 100 ml batches methylene chloride. The combined methylene chloride extracts dried over magnesium sulphate and evaporated to dryness reduced pressure. The residue was dissolved in methylene chloride and was filtered through a 50-60 g bed of florisil on a sintered glass funnel. The bed was washed successively with 1%, 2%, 3% and % methanol-methylene chloride mixtures after which the filtrates was evaporated and evaporated under reduced pressure to held the free base of the title association. The free base was reacted with an equimolar amount of fumaric acid in hot iso- propanol to give 3.3 g of fumarate, m.p. ä! HO 448 629 iL- 199-22 ° C.

Analysis: Calculated for C 27 H 27 N 2 O 3 Cl: C 63.96; H 5.37; N 11.05 Erhàllec 63.63 5.56 11.00 Example lü 6-phenyl-11-1-3- (1-piperidinyl) propyl_7-11H-pyrido [2,3-b_7 1-1, U_7benzodiazepine fumarate ¿_1: 1_7.

To a stirred suspension of 1.10 g (0.0U61 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide in nitrogen atmosphere was added portionwise 5.0 g (0.018 mol) of 6-phenyl- -11H-pyrido [2,3-b_7Zf1, H_7benzodiazepine. Reaction mixture The mixture was stirred for 30 minutes, warmed to 7000 and cooled to room temperature. To the mixture was added portionwise H, 1H g (0.0203 mol) of N- (3-chloropropyl) piperidine hydrochloride and the reaction mixture was stirred at room temperature 16 hours. The mixture was beaten in 750 ml of water, extracted with 150 ml of methylene chloride and stirred for 15 minutes. Water- the phase was extracted with two additional batches of 100 ml methylene chloride. The combined methylene chloride extracts was extracted with 150 ml and 75 ml batches of 3N hydrochloric acid and the combined acidic extracts were basified with 3N sodium hydroxide and then extracted with three 100 ml portions of methylene chloride. The methylene chloride extracts were combined, dried over magnesium sulphate and evaporated to dryness reduced pressure. The residue was dissolved in a minimum of methylene ~ chloride and filtered through a 100 g bed of florisil in one sintered glass funnel. The bed was washed one after the other methylene chloride, 1%, 2%, 3% and 5% methanol-methylene chloride mixtures nings. All the filtrates were combined and evaporated reduced pressure. The residue was reacted with 1.3 g of fumarate. acid in hot isopropanol and isopropyl ether were added. One amorphous precipitate was formed. The whole mixture was evaporated dryness and the residue was dissolved in 200 ml of ethanol. Solution was heated to reflux, filtered and isopropyl ether was added. the filtrate was added. Crystals which formed overnight was filtered off to give H, 1 g of fumarate salt with a melt point at 153-600. The drying conditions before the analysis were U hours at 97-98 ° C / 0.1 mm Hg.

Analysis: Calculated for CBOHBZNUOH: C 70.29; H 6.29; N 10.93 Obtained 70.38_ 6.32 10.92 H0 55 448 629 Example 15 6- (u-chlororenyl) -N, N-acetyl-1an-pyrido [2,3-b] benzodiazepine-11-propanamine fumarate ¿_1: 1_7.

To a stirred suspension of 1.57 g (0.065 mol) of sodium hydride G mineral oil) in 25 ml of anhydrous dimethylformamide was added in a nitrogen atmosphere 8.0 g (0.026 mol) of 6- (U-chlorophenyl) - -11H-pyrido¿_2,3 ~ b_7¿_1, H_7benzodiazepine. Reaction mixture The mixture was stirred for 1 hour at room temperature, warmed to 80 ° C for 15 minutes and cooled to room temperature. To to the mixture was added portionwise ü, 55 g (0.029 mol) of 3-dimethyl aminopropyl chloride hydrochloride and the mixture was stirred overnight at room temperature. The mixture was beaten into 750 ml water and stirred for 30 minutes with 150 ml of methylene chloride.

The aqueous phase was further extracted with three 100 ml portions methylene chloride. The combined methylene chloride extracts dried over magnesium sulphate and evaporated to dryness reduced pressure to obtain the free base of the title compound. ningen. The free base was allowed to react with an equimolar amount fumaric acid in hot isopropanol. On cooling, 3.6 g precipitated of the fumarar sauce with a melting point of 200.5-2o2.5 ° C. Pro- the product was air dried before analysis.

Analysis: Calculated for C 27 H 27 ClNuOu: C 63.96; H 5.37; N 11.05 Obtained 6ü, 18 5.33 11.07 Example 16 8-Chloro-N, N-methyl-6-phenyl-11H-pyrido [2,3-b] benzodiazepine-11-ethanamine oxalate ¿_1: 1_ /.

To a stirred suspension of 1.05 g (0.0HU mol) of sodium hydride (in mineral oil) in 50 ml of anhydrous dimethylformamide 6.1 g (0.02 mol) of 8-chloro-6-phenyl-11H- -pyrido¿_2,3-b_71_1, H_7benzodiazepine. The reaction mixture was stirred at room temperature for 1.5 hours during which time the evolution of hydrogen stopped. The reaction mixture was cooled to 5 ° C and 3.2 g (0.022 mol) of 2-dimethylaminoethyl chloride hydrochloride was added portionwise, followed by stirring at room temperature for 60 hours. The reaction mixture was beaten in 1600 ml of water and the mixture was extracted three times with 500 ml batches of methylene chloride. The combined extracts washed with two 500 ml batches of water, dried over magnesium sulphate and evaporated under reduced pressure. 55 H0 448 629% Thin layer chromatography (20% methanol / benzene on silica gel) indicated the presence of the free base of the title compound and the starting material. The residue was dissolved in benzene and was chromatographed on a 200 g column of florisil packed in benzene. Starting material, 1.3 g 8-chloro-6-phenyl-11H- -pyrido [2,3-b_71_1, N_7benzodiazepine was eluted with benzene and the free base of the title compound was eluted with mixed acetone in benzene. The free base had to react with an equimolar amount of oxalic acid dihydrate in refluxing isopropyl alcohol and the product was recrystallized from isopropyl propyl alcohol and weighed 1.6 g and had a melting point of 228.5-252 ° C. The drying conditions were 6 hours before the analysis 82 ° C / 0.1 mm Hg; overnight at room temperature.

Analysis: Calculated for C 21 H 25 ClN 4 Ou: C 61.7U; H ü, 96; N 12.00 Obtained 61.62 H, 95 11.98 Example 17 8-Chloro-11-methyl-6-phenyl-11H-pyrido [2,5-b] 7fl, h_7bemso- diazepine To a stirred suspension of 0.25 g (0.01 mol) of sodium hydride (in mineral oil) in 15 ml of anhydrous dimethylformamide 3.05 g (0.01 mol) of 8-chloro-6-phenyl-11H- -pyrido¿_2,3-b_7Zf1, U_7benzodiazepine. The mixture was heated to about 60 ° C for 1 hour. A solution of 1, U2 g (0.01 mol) of methyl iodide in 10 ml of anhydrous dimethylformamide was added dropwise over 0.5 hours and the reaction mixture The mixture was stirred overnight at room temperature it was beaten in 100 ml of water and stirred for 2 hours. The precipitated solid was recrystallized twice from isopropyl alcohol to give 2.0 g of a product having a melting point of 153-600. The drying conditions before the analysis were 1 hour at 82 ° c / 0.1 mm Hg.

Analysis: Calculated for C 19 H 11 ClCl 3: C 71.36; H U, H1; N 13.10 Obtained 71.6u u, u3 13.32 Example 18 N, N-dimethyl- 6- (4-methylphenyl) -11H-pyrido [2,3-b]] [1,1] h benzodiazepine-11-propanamine fumarate ¿_1: 1_7.

To a stirred suspension of 0.51 g (0.022 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide in a nitrogen atmosphere 55 H0 17 "448 629 2 g (0.01fl7 mol) of 6- (--methylphenyl) -11H- -pyrid0¿_2,3-b_7¿_1, U_7benzodiazepines for H5 minutes.

The mixture was stirred for 1 hour at room temperature, warmed to 75-80 ° C for 1 hour, cooled at room temperature after a solution of 0.018 U mol of 3-dimethylaminopropyl chloride in 10 ml of anhydrous dimethylformamide was added dropwise.

The mixture was stirred overnight at room temperature and beaten in 1000 ml of water. The suspension was extracted with three 150 ml batches of methylene chloride and the combined methylene chloride the extracts were extracted with two 150 ml batches of BN hydrochloric acid.

The precipitate formed in the acidic solution was removed by by filtration and discarded. The filtrate was made alkaline BN sodium hydroxide and extracted with three 100 ml batches methylene chloride. The combined methylene chloride extracts dried over magnesium sulfate and evaporated to reduced pressure to give an oil, the free base of the title compound ningen. This oil formed was dissolved in hot isopropyl alcohol and reacted with an equimolar amount of fumaric acid. Fumar- the acid salt crystallized as a solution cooled to room temperature and was recrystallized twice from isopropyl alcohol-isopropyl ether to give 1.7 g of product with a melting point of 187-18900 (decomposition).

Analysis: Calculated for C 20 BHONHOH: C 69.12; H 6.22; N 11.52 Obtained - 68.86 6.32 11.36 Example 19 6- (U-methoxyphenyl) -N, N-dimethyl-11H-pyrido [2,3-b] benzodiazepine-11-propanamine fumarate ¿_1: 1_7 To a stirred suspension of 0.5 g (0.0187 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide in a nitrogen atmosphere was added H, 5 g (0.015 mol) of 6- (H-methoxyphenyl) -11H-pyrido [2,3- -b_7¿_1, Å_7benzodiazepine for 30 minutes. The mixture was stirred for 30 minutes at room temperature followed by a heating to 80-90 ° C for 1 hour, cooling to room temperature and addition of a solution of 0.019 mol of 5-dimethylamino- propyl chloride in 5 ml of anhydrous dimethylformamide dropwise.

The reaction mixture was stirred overnight at room temperature. and beaten in 800 ml of water. The suspension was extracted with two 150 ml batches of methylene chloride. The merged the extracts were washed with 500 ml of water and extracted with 55 ho 448 629 58 two 100 ml portions of BN hydrochloric acid. The solid material as thereby formed from the combined acidic extracts was filtered and discarded. The filtrate was made basic with BN sodium hydroxide and extracted with three 100 ml portions methylene chloride. The combined methylene chloride extracts dried over magnesium sulphate and evaporated to dryness reduced pressure. The remaining oil had partially crystalline and triturated in methylene chloride and filtered, to give a residue of 0.32 g. The filtrate was evaporated under reduced pressure and residual oil was triturated in hot benzene and filtered to give a residue 0.8 g. The benzene filtrate was evaporated under reduced pressure and the residual oil was reacted with 1.02 g of fumaric acid in hot isopropyl alcohol. When cooling, an oil separated solution. The supernatant was decanted and the oil provided with sprouts. After partial crystallization, the the mixture was obtained to give 2.5 g of solid with one melting point of 157-6000. Attempt to recrystallize from isopropyl alcohol isopropyl ether again gave an oil-solid material mixture. The mixture was heated and further isolated. propyl alcohol was solubilized, filtered, provided sprouts and cooled. The fumarate salt precipitated and collected by filtration to give 2.0 g, m.p. at 159-161 ° C.

Analysis: Calculated for CZBHBONHOE: C 66.92; H 6.02; N 11.15 Obtained 66.90 6.08 11.08 Example 20 6- (3-chlorophenyl) -11H-pyrrolo [2,3-b] 7,1-benzodiazepine.

A mixture of 1u g (o, ou33 moi) ¿"2-¿" (3-amino-2-pyrimidine) nyl) amino_7phenyl_7 (3-chlorophenyl) -methanone and 0.3 g para- toluenesulfonic acid in 500 ml of toluene was heated under reflux flow overnight using a Dean-Stark trap for collecting water. At the end of reflux boiling time distilled off a certain amount of toluene (about 250 ml) and the hot solution was filtered. Petroleum ether (30-60 ° C) was added to the cloud point. The solution was placed in refrigerator overnight and filtered, after air drying. 10 g / 76%) of gold-colored crystals were obtained. A rate re- was crystallized from isopropyl alcohol-isopropyl ether and had _ H0 448 629 \"IN \O a melting point of 160-160.5 ° C.

Analysis: Calculated for C 18 H 12 N 5 Cl: C 70, Y 1; H 3.96; N 1}, 7Ä Obtained 70, U7 š, 98 13.62 Example 21 6- (3-chlorophenyl) -N, N-dimethyl-11H-pyrido [2,} - b_71_1, ü_7- benzodiazepine-11-propanamine fumarate ¿_1: 1_7.

To a stirred suspension of 3.0 g (0.07 mol) of sodium hydride G mineral oil) in 250 ml of anhydrous dimethylformamide was added in a nitrogen atmosphere in portions of 8.5 g (0.028 mol) of 6- (3-chloro- phenyl) -11H-pyridoL_2,3-b_7¿_1, ü_7benzodiazepine. The mixture stirred for 30 minutes at room temperature. The temperature was raised to 80 ° C for 5 hours after which it was allowed to assume room temperature. To the reaction mixture was added dropwise a solution of 4.9 g (0.051 mol) of 3-dimethylaminopropyl chloride -hydrochloride in 30 ml of dimethylformamide for 20 minutes.

The reaction mixture was allowed to warm to room temperature and stirred the night in a nitrogen atmosphere. Thin layer chromatography showed that a certain amount of starting material was present. Further sodium hydride 1.0 g (0.03 mol) was added and after 15 g minutes, 0.7 g (0.03 mol) of 5-dimethylaminopropyl chloride hydrochloride followed by stirring for one hour.

Water (20 ml) was added dropwise and the reaction mixture was filtered and concentrated on a rotary evaporator. The residue was partitioned between diethyl ether and diluted sodium hydroxide. The ether phase was washed with water three times and extracted with dilute hydrochloric acid. The aqueous phase was done basic with sodium hydroxide tablets and extracted with methylene chloride. The methylene chloride phase was dried and concentrated to give a residue of 7.5 g of product. The free the base was reacted with fumaric acid and the fumarate salt was crystallized from ethyl acetate-ethanol, m.p. 167.5-168.59c.

Analysis: Calculated for C 23 H 23 N 2 Cl 2: C 63.96; H 5, U7; N 11.05 Obtained 65.95 5.39 11.00 Example 22 6- (M-fluorophenyl) -11H-pyrido [2,3-b] 7 / N, benzodiazepine.

A mixture of 11.5 g (0.037 mol) of 2-β '(3-amino-2- -pyridinyl) amino_7phenyl_7 (U-fluorophenyl) methanone and 0.6 g 55 H0 448 629 Hd paratoluenesulfonic acid in toluene was refluxed for 2ü hours using a Dean-Stark trap for collection of water. At the end of the refluxing period, distilled a certain amount of toluene (300 ml) and the hot the solution was filtered. Petroleum ether (30-6000) was added to the cloud point. The solution was stored in the refrigerator over overnight at 0 ° C a filter area yielding 10.7 g crystals. Some of the material was recrystallized from iso- propyl alcohol and dried in vacuo overnight at 65 ° C, melting point 203-25 ° C.

Analysis: Calculated for C 18 H 12 N 3 F: C 7U, 75; H U, 18; N 1H, 52 Obtained 7M, 61 h, 17 1 h, 5 h Example 23 6- (N-fluorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b_7] -1, U_7- benzodiazepine-11-propanamine hydrochloride hemihydrateJ.

To a stirred suspension of 3.6 g (0.075 mol) of sodium hydride In mineral oil) in 250 ml of anhydrous dimethylformamide was added nitrogen atmosphere in portions 8.7 g (0103 mol) 6- (U-fluorophenyl) - -11H-pyrido¿_2,3-b_7¿_1, H_7benzodiazepine. The mixture was stirred for 30 minutes at room temperature. The temperature was raised to 8 ° C for 3.5 hours after which it was allowed cool to U5 ° C. To the reaction mixture was added dropwise a solution of 5.2 g (0.033 mol) of 3-dimethylaminopropyl chloride hydrochloride in 30 ml of dimethylformamide. After stirring over the night at room temperature indicated thin layer chromatography presence of starting materials. Additional sodium hydride, 3.6 g (0.075 mol) was added and after stirring for H5 minutes the reaction mixture was heated to 50-60 ° C for one hour.

A green color developed with the formation of a gas. The mixture stirred at room temperature for 3 hours. A solution of 5.2 g ®, O33 mol) 3-dimethylaminopropyl chloride in 30 ml of dimethylform amide was added dropwise. (About halfway through the addition a green color developed and the addition was temporarily discontinued for about 1 hour). The reaction mixture was stirred over night at room temperature. To the mixture was added 30 ml water under cooling. After gas evolution has ceased to filter the mixture was concentrated on a rotary evaporator. The residue was partitioned between diethyl ether and water and ether. the phase was extracted with dilute hydrochloric acid. The water phase H0 M 448 629 was filtered and after 15 hours solid was removed.

The filtrate was basified with sodium hydroxide tablets and was extracted with methylene chloride. The extract was dried and concentrated. The residue was divided into two equal parts and was purified by dry column chromatography on two 50 m x 5.5 cm columns of silica gel which had been deactivated by cooling solvent (10% methanol, 1% concentrated ammonium hydroxide, 89% methylene chloride). The control part of the column was excised and extracted with the developer.

The combined extracts were concentrated under reduced pressure pressure and the residue was dissolved in ethyl acetate-ethanol mixture. and acidified with concentrated hydrochloric acid. Hydrochloric acid the salt was recrystallized from ethanol-ethyl acetate mixture. The the solid obtained by filtration was dried at 9900 for H8 hours to give the title compound as one monohydrochloride hemihydrate with a melting point of 120-12300.

Analysis: Calculated for Cu 6 H 5 ON 8 F 2 Cl 2 O: C 65.78; H 6.00; N 13.3M Obtained 65.58 5.77 13, U7 Example 2U 11 - [3- (1,3-Dinhydro-1,3-dioxo-2H-isoindol-2-yl) -propyl] -6- -phenyl-11H-pyrido [2,3-b] [7,1] benzodiazepine.

To a stirred suspension of 0.56 g (0.023 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide was added portionwise. vis 5.0 g (o, o18u moi) 6-phenyl-11H-pyrido [2,3-b_7¿f1, u_7- benzodiazepines. The reaction mixture was heated to 801200 for 1 hour and cooled to room temperature. A solution of 5.55 g (0.020 mol) of N- (3-bromopropyl) phthalimide in 10 ml anhydrous dimethylformamide was added dropwise and after stirring for 16 hours, the reaction mixture was beaten in 650 ml of water and stirred for 30 minutes. A yellow solid material collected by filtration and recrystallized three times from isopropyl alcohol to give 3.7 g of a product with melting point 170-172 ° C.

Analysis: Calculated for C 29 H 22 N 2 O 2: C 75.97; H ü, 8H; N 12.22 76.25 H, 87 12, §U Example 25 6-phenyl-11H-pyrido [2,3-b_7L_1,17] benzodiazepine-11-propane- amine dihydrochloride hemihydrate.

H0 448 629 ”2 A mixture of 16.2 g (0.35 mole) of 6-phenyl-β inido) propyl_7-11H-pyrid2'2,3-b; 2.29 g (0.0387 mol) of hydrazine hydrate, 85% in 175 ml of 95% ethyl alcohol was refluxed for 2.5 hours and allowed stand for 72 hours. A solution of 10 ml concentrated hydrochloric acid in 50 ml of water was added to the mixture. The mixture stirred overnight. The solid precipitate was collected by by filtration and discarded. The filtrate was evaporated under reduced pressure. The residue, which was slightly moist, was suspended in 200 ml of water, after which the mixture was stirred for 2 hours and was filtered through celite. The filtrate was evaporated under reduced pressure and the residue was suspended in 100 ml of 100% ethyl alcohol and evaporated under reduced pressure. The later the procedure was repeated. The impure moist recycle the column (M2.1 g) was recrystallized from isopropanol to give stand about 15 hours. The solid material was collected by by filtration and dried at 8200 over phosphorus anhydride at 0.1 mm Hg for 3 hours. melting point 210-22 ° C (Sun. division).

Analysis: Calculated for Cu 2 H 6 Cl 2 N 8 O: C 61.47; H 5.65; N 13.65 Obtained 61.36 5.72 13.90 Example 26 olphenyl-11H-pyrido [2,3-b] 71, 1,7-benzodiazepine-11-propane- amin.

A batch of 6-phenyl-11H-pyrido [2,3-b] [7] [1,1] benzodiazepine-11- -propanamine dihydrochloride hemihydrate, obtained according to Example 25, dissolved in water, made basic with dilute sodium hydroxide and extracted three times with methylene chloride. The combined methylene chloride extracts were filtered through a 50-60 g bed of florisil on a sintered glass funnel.

The bed was washed successively with 1%, 2%, 3% and 5% methanol-methylene chloride mixtures, the filtrates were combined and evaporated under reduced pressure to give the free one the base, the title association.

Example 27 N-1-3-1-6-phenyl-11H-pyridol-2,3-b_7β1, H_7benzodiazepine-11- -yl_7propyl_7methanimidic acid ethyl ester.

A solution of 8.8 g (0.021 mol) of 6-phenyl-11H-pyrido [2,2-b] ÅO Iaf, 448 629 Å-1,7-benzodiazepine-11-propanamine in 150 ml of triethyl ortho- formate was heated to reflux for nine hours and allowed stand overnight. The mixture was concentrated in vacuo and the residue was washed with petroleum ether (30-60 ° C). Chemical ionization mass spectrum indicated that the compound was a mixed containing the title association.

Eziiänsliê N-methyl-6-phenyl-11H-pyrido [2,3-b] -1, H_7-benzodiazepine-11- -propanamine dihydrochloride.

Preparation of imidate tests _ (Method according to Crochet, T.A. & Blanton, C.D., Jr. Synthesis 197U (1) 55-56) - 6-phenyl-11H-pyrido [2,3-b] 7,1, H_7-benzodiazepine-11-propane- amine dihydrochloride hemihydrate, 25 g (0.06 mol) from Example was converted to the free base by partitioning between dilute sodium hydroxide and methylene chloride, drying and concentration of the methylene chloride phase to dryness, addition of dry benzene and again concentration by evaporation of benzene. The resulting free base was dissolved in 300 ml (267 g, 1.8 mol) freshly distilled triethyl orthoformate below reflux for 9 hours. The mixture was concentrated in vacuo and ethanol was added and the mixture was concentrated again.

Conversion of amidate to amine The 23 .mu.g (0.061 mol) of amidate prepared according to was dissolved in 200 ml of ethanol and sodium borohydrate was added. was stirred with stirring at 15-20 ° C until its thin layer chromatography indicated that the reaction was essentially complete. constant and indicated the absence of significant amounts of starting material. 50 ml of water was added slowly with stirring and cooling continued 15 minutes after the addition of water.

The mixture was then rinsed with 2 l of water and extracted with ethyl acetate. The ethyl acetate phase was washed with water its neutral washing liquid was obtained and then saturated with sodium chloride. The resulting ethyl acetate phase was dried and concentrated. Diethyl ether was added and the mixture cooled. A certain amount of insoluble material was filtered off and castades. The ether phase was concentrated and the product chromatographed. graphed on alumina column (neutral, activity 1), H0 448 629 M eluted with ethyl acetate + methanol + traces of triethylamine.

The fractions containing significant amounts (thin-layer chromatography) was partitioned between ethyl acetate and an aqueous solution of sodium hydroxide. Ether solution of hydrogen chloride the ethyl acetate phase was added and crystalline product was recrystallized. was extracted from acetonitrile-water mixture. Melting point for the product was 139-1HO ° C.

Analysis: Calculated for C 22 H 28 N 2 Cl 2: C 63.62; H 5.82; N 13, U9 Obtained 63.81 6.15 13.60 Example 29 N- [3-1-6-phenyl-11H-pyrido [2,3-b] 7L-1,1-benzodiazepine-11- -y1_7propyl_7carbamic acid ethyl ester.

To a solution of 1.6 g (0.00H5 mol) of 6-phenyl-11H-pyrido [2, 3-b_7 ?_1, H_7benzodiazepine-11-propanamine in dry methylene- chloride was added 0.53 g (0.0052 mol) of triethylamine. To this solution was added dropwise under cooling 0.5H g (0.005O mol) ethyl chloroformate. The mixture was stirred at room temperature for 2 hours. The methylene chloride solution of the product (as indicated by chemical ionization mass spectrometry) was washed with dilute sodium hydroxide-sodium chloride saturated aqueous solution and dried and concentrated to dryness. Residual it was triturated with isopropyl ether. The yield was 1.5 g of title Association.

Example 30 ' , e-dinydr-o-N, N-amethyl-e-phenyl: LH-pyridofz, 5-b_7 _ / _ "1, laj- benzodiazepine-11-propanamine dihydrochloride hemihydrate.

A solution of 3.0 g (0.006 μmol) of N, N-dimethyl-6-phenyl-11H- -pyrido [2,2,3-b_71_1, H_7benzodiazepine-11-propanamide i absolute ethanol was adjusted to pH 5.6 with a methanol solution of hydrogen chloride. To this solution was added on one occasion 0.7 g (0.011 mol) of NaBH 3 CN and the reaction the mixture was refluxed for 20 minutes. The ethanol was removed in vacuo and the residue was partitioned between dilute sodium hydroxide and methylene chloride. The methylene chloride phase dried over magnesium sulphate and concentrated to give a residue was retained which was crystallized twice 2-propanol and isopropyl ether. A yellow solid, 1.6 g (57%) was obtained which lost its crystalline structure at UI Ä0 '45 448 629 heating which started at 156-160 ° C and with decomposition at 18 ° C-195 ° C.

Analysis: Calculated for Cu 6 H 58 N 8 OCl · C: C 62.73; H 6.6U; N 12.72 Obtained 62, Å0 6.90 12.61 Examples 31a-31r The procedure of Example 6 was followed, followed by the following methanone compounds: Β-L (3-amino-2-pyridinyl) amino-7phenyl_7- (U-ethylphenyl) - methanone, 2 "- (3-amino-2-pyridinyl) amino-7-phenyl-7- (H-isopropyl- phenyl) methanone, 1-2-L_ (5-amino-2-pyridinyl) amino_7phenyl_7- (N-bromophenyl) - methanone, 1-2 [(3-amino-2-pyridinyl) amino] phenyl] 7- (M-fluoro- phenyl) methanone, 1- [3- (3-amino-2-pyridinyl) amino] phenyl] 7- (H-ethoxy) phenyl) methanone, 1-2-β * (3-amino-2-pyridinyl) amino-7-phenyl-7- (H-nitro- phenyl) methanone, 2f2-ff (3-amino-2-pyridinyl) amino_7phenyl] -7- (U-trifluoro- methylphenyl) methanone, Β-2- (3-amino-2-pyridinyl) amino_7phenyl_7- (3-methyl- phenyl) methanone, 1-2-L_ (5-amino-2-pyridinyl) amino_7phenyl_7- (3-ethylphenyl) - methanone, ¿F2-¿- (5-amino-2-pyridinyl) amino_7phenyl_7- (3-methoxy- phenyl) methanone, 1- [2- (5-amino-2-pyridinyl) amino] -7phenyl] -7- (3-ethoxyphenyl) - methanone, [1- (3-amino-2-pyridinyl) amino] phenyl] -7- (2-nitrophenyl) - methanone, [α-β- (3-amino-2-pyridinyl) amino] -phenyl] -7- (3-trifluoro- methylphenyl) methanone, [2- (3-amino-2-pyridinyl) amino] phenyl] 7- (2-methylphenyl) - methanone, N 2 - [(3-amino-2-pyridinyl) amino] phenyl] 7- (2-ethylphenyl) - methanone, Ff2-β- (3-amino-2-pyridinyl) amino-7phenyl_7- (2-methoxy- phenyl) methanone, 448 629 40 IN: Oß 1-2-N (3-amino-2-pyridinyl) amino-7-phenyl_7% 2,1-dichloro * pheny1) methanone and 1-2-Å_ (3-amino-2-pyridinyl) amino_7phenyl_7- (3,5, 5-tri- methoxyphenyl) methanone, was cyclized to the following pyridobenzodiazepines: a) 6- (H-ethylphenyl) -11H-pyrido [2,3-b] 7,1-benzyldiazepine, b) 6- (H-Isopropylphenyl) -11H-pyrido [2,3-b] diazepine, c) 6- (H-bromophenyl) -11H-pyrido [2,3-b] 71, 1,7-benzodiazepine, d) 6- (N-fluorophenyl) -11H-pyridole, 5-b_7β, β-benzodiazepine, e) 6- (H-ethoxyphenyl) -11H-pyrido [2,3-b] [1,1] benzodia; epine, f) 6- (α-nitrophenyl) 11H-pyrido [2,3-b] 7Zf1, H_7benzodiazepine, g) 6- (U-trifluoromethylphenyl) -11H-pyrido [2,3-b; benzodiazepines, h) 6- (5-methylphenyl) -11H-pyrido [2,3-b_7], i) δ- (z-ecylphenyl] fl-pyridophz, 3-b '' [1] benzodiazepine, j) 6- (z-mecoxyphenyl) -11H-pyrido [2,3-b] [1] diazepine, k) 6- (z-ecoxyphenyl) -1H-pyrrolido [2,3-b] -7 ", 1,1-benzoiazepine, 1) 6- (2-nitrophenyl) -11H-pyrido [2,3-b] 7L_1, __7benzodiazepine, m. benzodiazepines, n) 6- (2-methylphenyl) -11H-pyrido [2,3-b_7Zf1, N_7benzodiazepine, o) 6- (z-ethylphenyl) -11H-pyridine [2,3-b] [[1] benzodiazepine, p) 6- (2-methoxyphenyl) -11H-pyrido [2,3-b] 7,1-benzodi- azepine, q) 6- (2,0-Dichlorophenyl) -11H-pyrido [2,3-p] 71_1, H; diazepine and r) 6- (3,4,5-trimethoxyphenyl) -11H-pyrido [2,3-b_7Å_1, U_7- benzodiazepines.

H 7benzodiazepine, Example 32a-320 The procedure of Example 5 was followed, the following methanone compounds: [2- (3-amino-2-pyridinyl) amino] -75-chlorophenyl; 7 (phenyl) - methanone, 1-2-N- (3-amino-2-pyridinyl) amino-7-6-chlorophenyl-7 (phenyl) - methanone, J [2- (3-amino-2-pyridinyl) amino] -7-U-bromophenyl_7 (phenyl) - methanone, '40 11-7 448 629 1-2-1- 3-amino-2-pyridinyl) amino_7-M-fluorophenyl_7 (phenyl) - methanone, 1-2-1f (3-amino-2-pyridinyl) amino_7-4-trifluoromethylphenyl_7- (phenyl) methanone, 1-2 [(3-amino-2-pyridinyl) amino] -7-H-methylphenyl] (phenyl) - methanone, 1-2 - [(3-amino-2-pyridinyl) amino] -5-methylphenyl_7 (phenyl) - methanone, [2- (3-amino-2-pyridinyl) -amino] -7-6-methylphenyl_7 (phenyl) - methanone, 1- [2- (3-amino-2-pyridinyl) amino] -7-ethylphenyl] (phenyl) - methanone, w [2- (3-amino-2-pyridinyl) amino] -7-methoxyphenyl] (phenyl) - methanone, [2- (3-amino-2-pyridinyl) amino] -7-U-ethoxyphenyl_7 (phenyl) - methanone, 1-2-A (3-Amino-2-pyridinyl) amino-7-H-nitrophenyl-7 (phenyl) - methanone,. 1- [2- (3-amino-2-pyridinyl) amino] -7-5-nitrophenyl_7 (phenyl) - methanone, 1-2 - [(3-amino-2-pyridinyl) amino] -3-methylphenyl_7 (phenyl) - methanone and [α-β- (3-amino-2-pyridinyl) amino] -3-chlorophenyl_7 (phenyl) - methanone, was cyclized to the following benzodiazepines: a) 8-chloro-6-phenyl-11H-pyrido [2,3-b] 71f1, H_7benzodiazepine, b) 7-chloro-6-phenyl-11H-pyrido [72,5,5-b] 7,1-benzodiazepine, c) 9-bromo-6-phenyl-11H-pyrido [2,3-b] 7L_1, H_7benzodiazepine, d) 9-fluoro-6-fepyl-11H-pyrrolo [2,3-b] -7,4; 7-benzodiazepine, e) 6-Phenyl-6-trifluoromethyl-11H-pyrido [2,3-b] diazepine, f) 9-methyl-6-phenyl-11H-pyrido [2,3-b] z-1,4-benzodiazepine, g) 8-methyl-6-phenyl-11H-pyrido [2,2-b] 7,1, 7-benzodiazepine, n) 7-methyl-6-phenyl-11H-pyrrolo "2,5-b_7", 1,1'-benzodiazepine, í) 9-ethyl-6-phenyl-11H-pyridol-2,3-b_71_1, H_7benzodiazepine, j) 9-methoxy-6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine, / k) 9-ethoxy-6-phenyl-1: H-pyrido [2,3-b] [1, 1) 9-nitro-6-phenyl-11H-pyridolpha, 3-b_7-1,7-benzodiazepine, m) 8-nitro-6-phenyl-11H-pyrido [2,3-b] 7,1, H_7benzodiazepine, n) 10-Mecyl-6-phenyl-11H-pyrido [2,3-b] H_7benzodiazepine, H0 448 629 '# 8 diazepine and - 0) 10-Chloro-6-phenyl-11H-pyrido [2,3-b] 7,1-benzodiazepine. §Š§mE @ l_5åë; 22E Using the procedure of Example 15 but using equimolar amounts of each of the compounds prepared according to Example 31, the following 6-phenyl -substituted pyridobenzodiazepines are prepared: a) 6- (M-ecylphenyl) -N, N-methyl-11H-pyrido [2,3-b] [1,1] M_7- benzodiazepine-11-propanamine, b) N, N-dimethyl-6-β- (1-methylethyl) phenyl] -11-11-pyrimino-2 __ , 3-b_7Zf1, H_7benzodiazepine-11-propanamine, c) 6- (H-bromophenyl) -N, N-dimethyl-11H-pyrido [-2,5-b_71_1, U_7- benzodiazepine-11-propanamine, d) 6- (4-fluorophenyl) -N, N-acetyl-11H-pyrido [2,3-b] benzodiazepine-11-propanamine, e) 6- (H-ethoxyphenyl) -N, N-dimethyl-11H-pyrido [2,3-b] benzodiazepine-11-propanamine, f) N, N-dimethyl- 6- (4-nitrophenyl) -11H-pyrido [2,3-b] benzodiazepine-11-propanamine, g) N, N-dimethyl-6-β-H- (trifluoromethyl) phenyl-7-11H-pyrido- 1f2,3-b_7l_1,4_7benzodiazepine-11-propanamine, n) N, N-dimecyl-6-13-methylphenyl) -11H-pyrido [2,5-b_7] 1, M_7- benzodiazepine-11-propanamine, 1) 6- (3-Ezylphenyl) -N, N-dimenyl-11H-pyrrolo [2,5,5-b] benzodiazepine-11-propanamine, j) 6- (3-methoxyphenyl) -N, N-dimethyl-11H-pyrido [2,3-b_7Zf1, N_7- benzodiazepine-11-propanamine, 6- (3-ethoxyphenyl) -N, N-amimecyl-11H-pyrido [2,3-b] [1,4] -7- benzodiazepine-11-propanamine, l) N, N-dimethyl-6- (2-nitrophenyl) 411H-pyrido [2,3-b] 7,1, H_7- benzodiazepine-11-propanamine, m) N, N-dimethyl-6-N- (trifluoromethyl) phenyl- 7-11H-pyrido- ¿F2,3-b_7Zf1, U_7benzodiazepine-11-propanamine, n) N, N-dimethyl-6- (2-methylrenyl) -11H-pyrrolo [2,3-b] 7,1, M_7- benzodiazepine-11-propanamine, 0) 6- (2-Ecylphenyl) -N, N-methylethyl-11H-pyrrolo [2,5-b] [7], 7_7- benzodiazepine-11-propanamine, p) 6- (2-Mecoxyphenyl) -N, N-dimethyl # 11H-pyrido [2,5-b] benzodiazepine-11-propanamine, H0 tg W '448 629 q) 6- (2, H-dichlorophenyl) -N, N-dimethyl-11H-pyrido [2,} - U_7- 1-1, U_7benzodiazepine-11-propanamine and r) N, N-methylethyl- 6- (3, u, 5- @ rimenoxyphenyl) -11H-pyrrolo " [fl, H_7benzodiazepine-11-propanamine.

Example 3Ma ~ 5Uo Using the procedure of Example 13 but using exchange for equimolar amounts of the compounds prepared in Example 32 instead of 9-chloro-6-phenyl-11H-pyrido [2,3-b] L_1, H_7benzodiazepines could contain the following pyridobenzodiazepines produced: _ a) 8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] 7,1, H_7- benzodiazepine-11-propanamine, b) 7-Chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] 71, 1,7 benzodiazepine-11-propanamine, C) 9-bromo-N, N benzodiazepine-11-propanamine, a) 9-fluoro-N, N-dimethyl-6-phenyl-11H-pyrido [2,5-b] benzodiazepine-11-propanamine, e) N, N-dimethyl-6-phenyl-9- (trifluoromethyl) -11H-pyrido [2,3- -b_7Zf1, U_7benzodiazepine-11-propanamine, f) N, N, 9-trimethyl-6-phenyl-11H-pyrido [2,3-b; diazepine-11-propanamine, g) N, N, 8-trimethyl-6-phenyl-11H-pyrido [2,3-b] diazepine-11-propanamine, h) N, N, 7-trimethyl-6-phenyl-11H-pyrido [2,3-b] diazepine-11-propanamine, 1) 9-Ecyl-N, N-methyl-6-phenyl-11H-pyrido [2,3-n] benzodiazepine-11-propanamine, J) 9-Methoxy-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] benzodiazepine-11-propanamine, k) 9-Ecoxy-N, N-dimethyl-6-phenyl-11H-pyrrolo [2,3-b] z ['1, u; 7- benzodiazepine-11-propanamine, 1) N, N-methyl-9-nicro-6-phenyl-11H-pyrrolo [2,3-b; benzodiazepine-11-propanamine, m) N, n-Aimecyl-β-Nuro-6-phenyl-11H-pyrrolo [2,3-b] benzodiazepine-11-propanamine, n) N, N-10, trimeuyl-6-phenyl-11n-pyro [2,5-b_7 ?_1, u_7benzo- diazepine-11-propanamine and 0) 10-chloro-N, N-dimethyl-6-phenyl-11H-pyrrolo [2,3-b] 448 629 50 benzodiazepine-11-propanamine.

Examples 35a-35c The procedure of Example 1 was followed but instead 3-amino-2-chloropyridine used equimolar amounts of following: H-amino-3-chloropyridine, -amino-U-chloropyridine and 2-amino-3-chloropyridine, whereby obtained: a) 6-phenyl-11H-pyridyl_3, H-b_7¿_1, H_7benzodiazepine, b) 10-phenyl ¥ 5H-pyridoyl_H, 3-b_7Zf1, β-benzodiazepines and c) 10-phenyl-S-pyridolepis, 2-b; f [_1, ü_7benzodiazepine.

Examples 56a-36c The procedure of Example 3 was followed with the following: ¿F2 ~ ¿f (U-amino-3-Dyridinyl) amino-7phenylmethanone, 21 (5-amino-H-pyridinyl) amino] phenylmethanone and 1-2 - [(2-amino-3-pyridinyl) amino] phenylmethanone, was converted to: a) 6-phenyl-11H-pyrido [3,4-b] -7,4-benzodiazepine, b) 10-phenyl-5H-pyridolphene, 3-b-7β, 1β-benzodiazepine and c) 10-phenyl-5H-pyrido [3,2-b] [1,1] M] benzoiazepine.

Examples 37a-57c The procedure of Example 9 was followed and instead 6-Phenyl-11H-pyrido [2,3-b] [7,4] 1,7-benzodiazepine was used equimolar amounts of the following: 6-phenyl-11H-pyrido [β], β-β, β-benzodiazepine, -phenyl-5H-pyrido [MM, 5-b_7 ?_1, U_7benzodiazepine and -phenyl-5H-pyridolpha, 2-b; Z [1,1, H_7benzodiazepine, whereby obtained: a) N, N-dimethyl-6-phenyl-11H-pyridolph,--b_7 diazepine-11-propanamine fumarate, b) N, N-Dimethyl-10-phenyl-5H-pyrido [5,5-b] diazepine-5-propanamine fumarate and C) N, N-dimethyl-10-phenyl-sn-pyrido [3,2-b] diazepine-5-propanamine fumarate. 40 51 448 629 Example 38 , δ-ainyaro-δ-renyl-N-methyl fl w-pyriaofz, 3-b_7 [1, u__7- benzodiazepine-11-propanamine.

To a solution of 1.0 g (0.0035 mol) of N-1-3 -6-phenyl) -11H- -pyrido¿_2,3-b_7Z_1, U_7benzodiazepin-11-yl_7propyl_7carb- amino acid ethyl ester (from Example 29) in tetrahydrofuran in nitrogen gas was added with 0 g (0.0105 mol) of lithium aluminum hydride and a slight exothermic reaction occurred. The mixture is cooled. was designed to prevent overheating. The mixture was stirred at reflux temperature 16 hours. Thin layer chromatography indicated that only partial conversion had taken place. Further 0.6 g (0.0105 mol) of lithium aluminum hydride was added and the mixture was boiled under reflux. Thereafter, the thin layer chromatography that the product consisted mainly of the title association.

Example 39 6- (2-thienyl) -11H-pyrido [2,3-b] [1,1] Tbenzodiazepine.

The procedure of Example 20 was followed to give ¿_2-¿_ (3-amino- -2-pyridinyl) amino_7phenyl_7 (2-thienyl) methanone was heated with paratoluenesulfonic acid catalyst in organic solvent while removing water in a Dean-Stark trap wherein the title compound was obtained.

Example HO 6- (3-thienyl) -11H-pyrido [2,3-b] [1,7] benzodiazepine.

The procedure of Example 20 was followed to give β-2- (5-amino- -2-pyridinyl) aminophenyl_7 (3-thienyl) methanone was heated with paratoluenesulfonic acid catalyst in an organic solution means while removing water in a Dean-Stark trap led to the formation of the title association.

Example 41 6- (2-pyridinyl) -11H-pyrido [2,3-b] 1,1,4,4-benzodiazepine.

The procedure of Example 3 was followed to give ¿f2 # ¿_ (3-amino- -2-pyridinyl) amino_7ienyl_7 (2-pyridinyl) methanone cyclization to the title association.

Example H2 6- (5'PyPidinyl) -11H-pyrido [2,3-b] [1,1] benzodiazepine. 55 H0 448 629 se The procedure of Example 3 was followed to give 1f2-_ (3 * amino- -2-pyridinyl) amino_7phenyl_7 (3-pyridinyl) methanone cyclic acid to the title association.

Example H5 6- (H-pyridinyl) -11H-pyrido [2,3-b] [1,1] benzodiazepine.

The procedure of Example 3 was followed to give ¿_2-¿_ (3-amino- -2-pyridinyl) amino_7phenyl_7 (U-pyridinyl) methanone cyclization to the title association.

Example HH _ N, N-dimethyl-6- (2-phenyl) -11H-pyrido [2,3-b] 7,1, M_7benzo- diazepine-11-propanamine.

The procedure of Example 25 was followed to give 6- (2-thienyl) - -11H-pyrido¿_2,3-b; 7¿_1, fl7 benzodiazepine was reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the title compound.

Example H5 N, N-Amethyl-6- (3-ylmethyl) -115-pyrido [2,5-b] diazepine-11-propanamine.

The procedure of Example 23 was followed to give 6- (3-thienyl) - -11H-pyrido1_2,3-b_7¿_1,4_7benzodiazepine was reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the title compound Example H6 N, N-dimethyl-6- (2-pyridinyl) -11H-pyrido [2,3-b_7Z_1,4_7- benzodiazepine-11-propanamine.

The procedure of Example 23 was followed, substituting 6- (2-pyrimidine). dinyl) -11H-pyrido [2,3-b_7], U_7benzodiazepine was reacted with sodium hydride, followed by reaction with 3-dimethylamino- propyl chloride to give the title compound.

Example U? N, N-dime: γ1-6- (3-pyridinyl) -11H-pyrrolo [2,3-b] benzodiazepine-11-propanamine. _ The procedure of Example 25 was followed to give 6- (3-pyridine) dinyl) -11H-pyrido [2,2-b] [7], U_7benzodiazepine was reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl 448 629 LI ' \ _ ~ l chloride to give the title compound. Example ÄB N, N-aim @ ny1-6- (M-pyridinyl) -1nn-pyriao¿ "2,3-b_7¿" 1, u_7- benzodiazepine-11-propanamine.

The procedure of Example 23 was followed to give 6- (H-pyridinyl) - -11H-pyrido¿_2,5-b_7¿_1, ü_7benzodiazepine was reacted with sodium hydride, followed by reaction with 5-dimethylaminopropyl chloride to give the title compound.

Example ü9a-H9g The procedure of Example 6 was followed, followed by the following methanone compounds of intermediate 15: [2- (3-amino-N-methyl-2-pyridinyl) amino] phenyl_7- phenylmethanone, ¿F2-¿- (3-amino-5-methyl-2-pyridinyl) amino_7phenyl_7- phenylmethanone, Β-β- (3-amino-6-methyl-2-pyridinyl) amino; phenylmethanone, ¿F2-¿_ (3-amino-5,6-dimethyl-2-pyridinyl) amino_7phenyl_7- phenylmethanone,, 1-2 - β (3-amino-6-methoxy-2-pyridinyl) amino_7phenyl_7- phenylmethanone, Β (2- (3-amino-2-methyl-N-pyridinyl) amino] phenyl; phenylmethanone and (2-Amino-5-methoxy-2-pyridinyl) amino_7phenyl_7- phenylmethanone, was converted to the following pyridobenzodiazepines: a) M-methyl-6-phenyl-11H-pyridine-2,5-b-7β, 1,1-benzodiazepine, b) 3-Mecyl-6-phenyl-11H-pyridol-2,5,5-b-7,1'1, M_7benzoiazepine, c) 2-methyl-6-phenyl-11H-pyrido [2,3-b] L-1,7-benzodiazepine, d) 2,3-dimethyl-6-phenyl-11H-pyrido [2,3-b] 71, H_7benzo- diazepine, e) 2-methoxy-6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine, f) 1-Methyl-10-phenyl-5H-pyridol-3-b-7-benzyl-diazepine and g) 3-methoxy-6-phenyl-11H-pyridolpha, 3-b-7β, N-benzodiazepine. 50 ÄO 448 629 S " Example 50a: äQg The procedure of Example 23 was followed to give pyridobenzo diazepines prepared in Example H9 were reacted with sodium hydride and 3-dimethylaminopropyl chloride to give following: a) N, N, H-trimethyl-6-phenyl-11H-pyrido [2,5,5-b; diazepine-11-propanamine, b) N, N, 3-trimethyl-6-phenyl-11H-pyrido [2,3-b; diazepine-11-propanamine, e) N, N, 2-Crimethyl16-phenyl-1H-pyridophz, 3-b_7 [1] diazepine-11-propanamine, _ d. benzodiazepine-11-propanamine. e) 2-methoxy-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b_7Zf1, U_7- benzodiazepine-11-propanamine, f) N, N, 1-trimethyl-10-phenyl-5H-pyrido [1,3-b] -7, 1,7-benzo- diazepine-5-propanamine and e) fi-methoxy-N, N-amyl-s-phenylH-pyridophz, 3-b_7 [1,14_7- benzodiazepine-11-propanamine.

Examples 51a-51c The procedure of Example 22 was followed but instead Β-2- (3-amino-2-pyridinyl) amino-7-phenyl- 7 (H-fluorophenyl) - methanone was used: 1-2-N- (5-amino-2-pyridinyl) amino_7phenyl_7 (2-flumphenyl) - methanone, ' [2- (3-amino-2-pyridinyl) amino] phenyl_7 (2-chlorophenyl) - methanone and [2- (3-amino-2-pyridinyl) amino] phenyl] (2-bromophenyl) - methanone, whereby obtained: a) 6- (2-fluorophenyl) -11H-pyrido [2,3-b] 7,1-benzodiazene- pin, _ I b) 6- (2-chlorophenyl) -11H-pyrido [2,3-b] 7,1-benzodiazepine and c) 6- (2-bromophenyl) -11H-pyrido [2,3-b_7Zf1, H_7benzo- diazepine. . Example 52a-52c The procedure of Example 25 was followed but instead 55 HO 448 629 \ _r ~ \ _f7 6- (H-fluorophenyl) -11H-pyrido [2,2-b] 71-1,1-benzodiazepine the following pyrido [1], U_7benzodiazepines were used: 6- (2-fluorophenyl) -11H-pyrido [2,3-b] 7,1-benzodiazepine, 6- (2-chlorophenyl) -11H-pyrido [2,3-b] [7,1] benzodiazepine, 6- (2-bromophenyl) -11H-pyrido [2,3-b] 7,1-benzodiazepine, whereby obtained: a) 6- (2-fluorophenyl) -N, N-dimethyl-11H-pyridol-2,5-b-7 benzodiazepine-11-propanamine, m.p. 92-9 ° C, recrystalline isopropyl alcohol-isopropyl ether, b) 6- (2-chlorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] benzodiazepine-11propanamine, m.p. 10H-10500, recrystalline isopropyl ether and c) 6- (2-bromophenyl) -N, N-dimethyl-11H-pyrido [2,2-b] 7,1, H_7- benzodiazepine-11-propanamine, m.p. 96-98 ° C, recrystalline lysing solvent isopropyl ether.

Examples 53a and Sšb The procedure of Example 9 was followed but instead of 5-di methylaminopropyl chloride was used: 3-dimethylamino-2-methylpropyl chloride and 2-dimethylaminobutyl chloride, whereby obtained: a) N, NM6-trimethyl-6-phenyl-11H-pyrido [2,5,5-b] diazepine-11-propanamine fumarate and b) N, N-Dimethyl-6-phenyl-11H-pyrido [2,3-b] diazepine-11-butanamine fumarate.

Exemgel Büa och Säb When in the procedure of Example 11 instead of N- (3- (chloroxyl) morpholine hydrochloride was used: 1- (3-chloropropyl) Pyrrolidine hydrochloride and 1- (3-chloropropyl) -H-methylpiperazine hydrochloride, obtained: _ 6-phenyl-11-1E- (1-pyrrolidinyl) propyl_7-11H-pyrido [2,3-b_7- ¿_1, U_7benzodiazepine and 6-phenyl-11-β- (H-methyl-1-piperazinyl) propyl-7-11H-pyrido- L_2,3-b_7¿_1, H_7benzodiazepine. Example 55a-55c When in the procedure of Example 9 instead of 6-phenyl-11H- H0 448 629 56 2,3-b_7¿_1, ü_7benzodiazepine was used: 8-methyl-6-phenyl-11H-pyrido [3, U-b_71_1, U_7benzodiazepine, 6- (U-chlorophenyl) -11H-pyridol_3, U-b_7¿_1, U_7benzodiazepine and -methoxy-6-phenyl-11H-pyrido [3, U-b_71_1, N_7benzodiazepine, obtained: a) N, N, 8-Trimethyl-6-phenyl-11H-pyrido [5], U-b_7? diazepine-11-propanamine, b) 6- (M-xlofophenyl) -N, N-dimethyl-11H-pyridyl-5, u-b-7'1, H_7- benzodiazepine-11-propanamine and c) 3-Methoxy-N, N-dimecyl-6-phenyl-11H-pyrrolo [5, u-b_7¿ "1, u_7- benzodiazepine-11-propanamine.

Examples 56a-56d When in the procedure of Example 17 instead of 8-chloro-6- -phenyl-11H-pyrido [2,3-b] 7,1, H_7benzodiazepine was used: 6-phenyl-11H-pyrido [2,3-b] [7] [1,1] benzodiazepine, 8-chloro-6- (2-nitrophenyl) -11H-pyrido [2,3-b] diazepine, 8-chloro-6- (2-chlorophenyl) -11H-pyrido [2,3-b] 71, 1,7-benzo- diazepine and « 8-chloro-6- (2-bromophenyl) -11H-pyrido [2,3-b] 71, 1,7-benzo- diazepine, obtained: a) 11-methyl-6-phenyl-11H-pyrido [2,5-b] or 1,4-benzodiazepine, b) 8-Chloro-11-methyl-6- (2-nitrophenyl) -11H-pyrido [2,3-b] -7- F1,4_7benzodiazepine, m.p. 165-16600, recrystallized ionic solvent ethyl alcohol, C) 8-x-chloro-6- (2-chlorophenyl) -11-methyl-11H-pyridine-2,3-b-7- ¿F1, M_7Sensoaiazepine, m.p. 150-152 ° C, omxriscallisa- isopropyl alcohol isopropyl ether and a) 6- (2-bromophenyl) -8-chlora-11-mecyl-11H-pyrrolo [2,3-b] -7- ¿_1, U_7benzpdiazepine with a melting point of 121-12300, crystallization solvent: isopropyl ether.

Example 57 N-methyl-N-β- (11H-pyrido [2,3-b] -7β, β-benzodiazepine-11- -yl) propyl_7carbamic acid methyl ester.

The title compound was prepared by adding 6-phenyl-11H-pyrido- Β _3,3-b_7¿_1, U_7benzodiazepine was reacted with (3-chloro- "of s? 448 629 propyl) methylcarbamic acid methyl ester. ššemgel 58 9-hydroxy-N, N-dimethyl-6-phenyl-1H-pyridol-2,3-b-7L-1, N_7- benzodiazepine-11-propanamine.

The title compound was prepared by reaction between 11 (dimethylamino) propyl-7-9-methoxy-6-phenyl-11H-pyrido [2,5,5-b] -7- ¿_1, U_7benzodiazepine and hydrogen iodide and glacial acetic acid.

Example 59 hydroxy-N, N-dimethyl-6-phenyl-nn-pyridophz, z-b _ "[1, §_7- benzodiazepine-11-propanamine.

The title compound was obtained by reaction between 3-methoxy-N, N- -dimethyl-6-phenyl-11H-pyridolpha, 5-b_7z_1, H_7benzodiazepine-11- -11-propanamine and hydrogen iodide and glacial acetic acid 58 448 629 umnmE: u umnmësu umnmësu um fi mxo umpmësw umnmëzm umamësw nm fl mxo wmnmësm vwnmesw pmnmssw um fi mxo and fi mm O OOOOOOO O O CIOOOHOOOOOOO III fi ? w m E I H a a U? O | | NII æ oxaazn m m 11'- SE3133323122 212 ' 212 NIICIJZIISIZIIEITMIIIZTSIIIJIIE M _ Jmo u m¿ ~ \ L »m @ W @ ^: v \ .z < N H fl wnm fi ) | = mwO «Ho | n - = m @ o «Hu | m | = m @@ | fi moo »= | = m @ u | mmu | # Immwu -mmwu | = mmo | Ho | = -mmwo -mmmo | m: @ 0 | m = wU -mmmo | mm @ U -mmmu - == @ U-mmOo-z - = mwo-nmU- = | = m @ o-Hu | = | :: @ 0 | Ho | ~ mmwu mmwo fmmwo m fl ~ ^ mmuvz-m ^ ~ muv- N ^ mmovz | n ^ muv- ~ ^ nmovz «m ^ movf mao! N ^ m = Ovz- ^ ~ mu, - N ^ nm0Vz «n ^ ~ muV» Hmc fl u fl awm fl m - «| m ^ ~ mov« ~ ^ nm @ vz | n ^ ~ mQv | ~ ^ mm ~ QVz | m ^ ~: uv | æc Loë wwmwmov- ^ fl mov2 | ~ ^ N: @ v1 ^ mmovz | m ^ ~ moV | N N ~ ^ mmUvz | m ^ ~ mov | m m m m m m m m fi m if m fl æ fl æ fi w fi m fl :HRS na N fi we 'r-I O we O\ r-lmr fi rmxowoo fi maëmxm 448 629 59 omm m “o .Hoz N ao: m ON: N .Ho = N om: ~ \ H .Hem »Hmm O 'fl OOOOOOOOOOOOO_OOO O O EIOOO m: c m o m: m m m = :: = = m azzn m m m D! IE Nim m m ïIIUII-IIIECIIIIIZEETIISIIIDSIEZIIIIÉIEZC IC III IIS > '| ZE21.1IIZ | = m @ u | mmuo1 ~ | == @ u «mm ~ o- ~ - «mwo-nmu | ~ «= M @ u- fi mo | n - = mwu-oz- ~ - = m @ Q-m = ~ Qø-n - = m @ 0 | nm0o-m - = mwu | mm ~ u-n | = mw0-nmo- = | = mwu-nmo- = |: mwu- ~ oz- = - = mwU-mm ~ uo |: - = mmo | m- = - = m @ Q | um | = = m @ 0-> mnu | fl | = - == @ u | m = wuW = - = U - = mwu-m-: - = m @ u-m- = w | <.

I fl IEZI-Iï flfl ïšïå fl ïï fi lïlälilil fl ïüïüï fl ilï ~ ^ n = Uvz-n ^ Nm ° v- mmwuo | ^ ovomz | n ^ ~ muv | nmomz | n ^ ~ mov « mmmuo | mouz | n ^ Nmov | ~ mz | n ^ ~ mov | ~: z | n ^ ~ = Qv | fl> 0 @ fl s fi ~ m »@ | fi | n ^ ~: ov | ~ ^ nm0Vz-n ^ ~ = uV- IN m Am Ao AC fi e ñ fi ~ x ^ fi ^ fi As Am ^ « ^ « Au Ao An Am fl n if mw ww »N wm mw : N mm NN wmmammm 448 629 60 Table 2 (continued) p fi mw C | OO OOOOOOOOOOOOOOOOOOOOOQQQO = m'm m m m m m m m m MI; 1; x m m: m m m m m m m m = m m m m m m m = m m m m m m | = m @ 0-nm0o-n - = m @ 0-mm ~ u | n - == @ o-n = o | m | = m @ u | nmo | = | = m @ u | ~ oz- = L = mmu | mm ~ uo | = - = m @ o | m | = «= M @ 0- ~ m- = | = mwo-Amnu | «| = | = mwu | m = @ 0 | = | w -www »Mmwo -mmwu -mmwø -mmwu -mmmo | mm @ Q -m wo | m = @ 0 -m wo -mmwo -m wo -mmwø -mmmo -mmwo ; f fi Anmoov-m. =. n n=@u|~AHuv=.~ m fl ~ An = o, = - nA ~ m ° v- wAwmuvz | wAmmoV | A EOVZI A SQVI ~ A fi movz-nA ~ mov | ~ An = 0v = -nA ~ = Uv- ~ Anmuvz-mA ~ muv- ~ Anm °, z-nA ~ m0v- . ~ Anmovz-nA ~ mov- ~ Anm0Vz-nA ~ mov- ~ AnmU.z-nA ~ = Uv- fl ílï fl ïlï IÉJIZCZIIEIIIIICEZIICIIIBIIIIZIII An A fi As Aw Au Am Of Ao An Am nn AE AE AH Ear AW A.D A: Aw AQ Am Of An Ad Nm Ah AU Hwmsmxm 448 629 61 Table 2 (continued) QIOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO i Mif-II211211ZHIIIIIECCZTIZIIEZIZIIIIIIZEZEIIIIEIISZIIIIIIII3152221333: Hæcwu fl næaan fl ac fl u fl næaam Hacmwann fl æcmwaam | m = mo | m = wQ -mmwu | mm @ o | mmmu | mmwu | mm @ 0 -mmwo | mm @ o | mmmo -mmwo -mmwu -mmwu -mmwo -mmwo | m = @ u ~ mmo-n ^ m = Uov-m. =. n -mm@o-~^HUv|=.~ «: = Wv | nmoo | ~ - == @ 0 | mm ~ o «~ | = m @ o-nmo- ~ a = mmo | nmo | m «= M @ u- ~ oz | ~ | = m @ u-mm ~ vo | fi n < 2113131211 .nmumzn ^ ~ muV- m ^ Wmuvz-W ^ wmuv- ^ muVz | A aug- ~ ^ nmovz »fi ^ ~ = ov- ~ ^ fl møVz | n ^ ~: ov- ~ ^ nm0vz-n ^ N = ° v- ~ ^ nmuvz | n ^ ~: 0v | ~ ^ nmoVz | n ^ ~ = ov- ~ ^ n = ovz-m ^ ~ m0v- ~ ^ nmuvz-n ^ ~ = uv- ~ ^ nmuvz-m ^ ~ mOV- ~ ^ n = ovz | n ^ ~ = Uv- N ^ n = Ov = -n ^ ~ = uv- ~ ^ n = ovz-m ^ ~ = 0v- ~ ^ n = 0Vz-m ^ ~ = ov- ~ ^ fl movz-n ^ Nmuv- ~ ^ nm0vz-n ^ ~ = u, - ~ ^ mmoVz | n ^ ~ mov- ~ ^ “MuV = -n ^ ~ mOv- ~ ^ nmoVz-n ^ ~ mov- ~ ^ nmuvz | fi ^ ~ mo, - ~ ^ nmuvz-n ^ ~ m @ v- ~ ^ nmuVz | m ^ ~ muv- ~ ^ m = uvz-n ^ N = Uv- s N: fl z oz mn æn ñm: M 448 629 62 Table 2 (continued) umnmszm umumesw »Hmm O O CJOOOOOOOOO OOOOOOQQOOOOOOO IL ' N | IIIZIICIIZIIIIISIZECEUIIEZIIEICZIIIIZZJ-ï fl ï fl ïm fl l flämgggm: IN 32 m m m = ::: m m n = 0o-n n = 0o- ~ «AnmoV | n.N mmu- ~ mm0-n A = o- = nmoo-n mmOo- ~ ~ An: 0v-n. ~ rn rxfn m I m 9 “f 9 > q m U: I 21 I 2: -: rn n -mmmo | = m @ 0 | fi m | ~ -Amwu- ~ Q- ~ | = mmu «m | ~ - = mmo | »m | ~ - = mwo | Hø- ~ - = wwo-m-N | mmwu -mmwu -mmwø .-m = mQ -m wo ßmmwo -m mo | mmwu nmmwo -mmwu fl mmwu -mmwu A> = fl @ fifi> @ | = Hmc fi n fi naann fi zcwø fl namuw fi æsw fl uun fi æcm fl uam A> = fi ø fi »> @ | = MQ Hæc fl u flfl ohnæa -fl- mA ~ moV- ~ Anm0vz- = A ~: UV- ~ AnmoV = - ~ m0AnmovmuNmu- NAnmQV = -nA ~ mov- ~ An = uvz-nA ~ m0v « ~ Anm0vz-mA ~ mUv- = = = ~ A¶mQV = -mA ~ = Uv- ~ AnmuVz | nANmuv- ~ An = uv = - »A ~ m0v- ~ AnmoVz | mA ~ = oV | NAn = uvz | mA ~ muv- ~ An = uvz | mA ~ æuv- 3321131211 !! ~ Amm0Vz | mA ~ mov- ~ Anmuvz-nA ~ m0v- ~ Anmovz | mA ~ mUv | ~ Ammuvz | mA ~ m0v | ~ An = ovz-mA ~ = Qv- = m ¿$ _ Am: m An Am mm A0 An Aw Nm Au An Am fl m Am ^ w Au Ao An Am om Aw Am Ao A0 An Am Q: w: ~ = w = m: == M: mmmamww 448 629 63 Table 2 (continued) QNLNESM OOOOOO O CIC OOOOO nm @ -w 31213 moum Honæ fi ouæ Hunæ N12 ï-EZEZISIIIIGCE Wu: znmnzmn: ~ ^ nm0Vz | n ^ ~ mov- ~ ^ n = 0vz | n ^ ~ = Qv | ~ ^ nmuvz- fi ^ ~ = ov- N ^ n = uvz-m ^ ~ = 0v- IN = ~ ^ fi muVz | m ^ ~: uV | ~ ^ nmuvz-n ^ ~ muv- fi moo ^ @ VU | ^ nmuVz | fi ^ Nm0v- mmm- n = o | m = ø | mmo- fl æu fi ucwnmnwm fi a n fl æumënznn fi mmovu x ^ Q An Am mm Am Nm Am wn fi w mn mm mm wm Ao fi u An ^ m wm An fi wmëwxm 448 629 64 Table 2 (continued) pmamszw @ æumE: u and fl mm O c, c> <> o o Q å: N | m E I m m ~ ^ nmuVz-n ^ ~ mov- AU ßn m ^ ° _ @ fi m ^ ° mn n ^ ~ mov | ÄH if m AM m = w ^ n = 0vz-m ^ ~ = vv | An bn m ^ ß om m Än mn M Hmmewwm ~ ^ m = Qv2 | 448 629 65 Example 60 N-methyl-6- (2-fluorophenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine -111-propanamine-fumarate In a nitrogen atmosphere, 3.6 g (0.023 mol) of phenyl chloroformate were added on a batch at room temperature to a stirred solution of 7.5 g (0.020 mol) 6- (2-fluorophenyl) -N, N-dimethyl-11H- -pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine (Example S2a) in 100 ml of dry benzene. The reaction mixture was refluxed. flow 5 hours. cooled to room temperature and filtered.

The filtrate was washed with sodium bicarbonate solution (2x) 50 ml). 50 ml of water. IN HCl (2 x 50 mL) and finally 50 mL water. The benzene solution was dried over sodium sulfate and concentrated. was concentrated in vacuo. The residue was dissolved in 300 ml of isopropyl alcohol and to the solution was added 15 g of potassium hydroxide pellet and 50 ml of water. The reaction mixture was boiled with stirring and reflux for 48 hours. The reaction mixture was cooled to room temperature and the isopropyl alcohol was evaporated in vacuum. To the residue were added 200 ml of water and 250 ml of di- ethyl ether. The phases were separated and the ether phase and washed with 50 ml of water. The acidic extracts and the second water wash the liquid was combined and washed with 75 ml of ether. The sour the phase was cooled to 5 to 10 ° C. was made basic with 30 g of rium hydroxide pellets and extracted with methylene chloride (3x) S0 ml). The combined methylene chloride extracts were dried sodium sulfate and concentrated in vacuo. the remainder converted was added to the fumarate salt and crystallized from isopropyl alcohol-ethyl acetate to give 6.4 g (67 2) of a product.

Recrystallizations from isopropyl alcohol-water gave 5.6 g of a light yellow solid with a melting point of 171-174 ° C during decomposition after a phase change at 160-166 ° C.

Analysis: calculated for C H N O F: C 65.54: H 5.29; N 11.76 26 25 4 4 Found: C 65.68; H 5.34; N 12.00 448 629 66 ' Exemgel 6l N, N-beta-trimethyl-6-phenyl-11H-pyrido [2,3-b] [1.4] benzodiazepine-. -ll-propanamine The procedure of Example 9 was followed but instead of 3-di methylaminopropyl chloride, N, N-beta-trimethylaminepropyl chloride was used. chloride to give the title compound as a yellow powder with a melting point of 141-143 ° C. Formula: C24H26N4.

Example 62 6- (2-fluorophenyl) -N, N-beta-trimethyl-11H-pyrido [2,3-b] [1,4] benzo- diazepine-11-propanamine The procedure of Example 9 was followed but instead of 6- -phenyl-11H-pyrido [2,3-b] [1.4] benzodiazepine and dimethylamine pyl chloride used 6- (2-fluorophenyl) -1H-pyrido [2,3-b] [1.4] - benzodiazepine and N, N-beta-trimethylamine propyl chloride to give the compound was kept according to the title which was recrystallized from isopropyl alcohol to give a yellow solid with a melting point of 121-123 ° C. Formula: C2gH25N4F.

Example 63 N, N-Dimethyl-6- (2-fluorophenyl) -11H-pyrido [2,3-b] [1,4] benzodi- azepine-11-propanamine hydrochloride The procedure of Example 9 was followed but instead of 6- -phenyl-11H-pyrido [2,3-b] [1.4] benzodiazepine used 6- (3- -fluorophenyl) -1H-pyrido [2,3-b] [1.4] benzodiazepine wherein the association was held according to the title which was transformed into the hydrochloride salt with an ether solution hydrochloride in isopropyl alcohol-isopropyl ether and was obtained as a yellow solid with a melting point of 214-21S ° C. Formula: C23H24N4FCl.

Example 33-1-1 5 The monohydrochloride salt of Example 33-1 Compound was set and recrystallized from isopropyl alcohol to a solid yellow material with a melting point of 239-240 ° C was obtained.

Formula: C23H24N5O2Cl. 448 629 Example 46-1 The monooxalate salt of Example 46 was prepared from an ethereal hydrogen chloride solution in isopropyl alcohol-isopropyl ether. were separated and recrystallized from isopropyl alcohol-ethyl acetate and dry at 98 ° C vacuum for 36 hours. The product consisted of a yellow solid with a melting point of 176.5-178 ° C (below decomposition). Formula: C24H25N504.

Exemgel 44-1 _ The monohydrochloride hemihydrate salt of Example 44 was prepared from an ethereal hydrochloric acid solution in isopropyl alcohol isopropyl ether mixture and recrystallized from isopropyl alcohol-ethyl acetate. and was obtained as a yellow powder with a melting point of 176 -178 ° C. Formula: C21H2qN4Oo SS.

Exemgel 45-l The monooxalate salt of the compound of Example 45 was prepared and recrystallized from isopropyl alcohol-water to give dark yellow flakes with a melting point of 203-204 ° C were kept.

Formula: C23H24N40qS.

Exemgel 33m-l The monofumarate salt of the compound of Example 33m is prepared and recrystallized from isopropyl alcohol-isopropyl ether to give 1.48 g of a yellow solid with a melt point at 160-162 ° C. Formula: C28H27Nq04F3. 443 629 68 Activity table É Are Example 'rwsza nr z Ar alkl Ring Enso H CeHs - (c112) 2-cnszcns 0.3 9 H CeHs - (CHa) -_ = .- cnaæna 0.02-o.o7 28 H CQHS - (CH @) s- about 0.07 12 H Ce fi s “(CHë) a- CgH57C¿Hg 6.U 11 H Cans -tc fl aa- * få> 1o.o 114 H cens - (cn2) 3- _ Ö> 1o.o 16 8-c1 cens - (cH2) 1 - cnsæna 1 .9 8 8-c1 cens - (cnz) 8- cns: css o .7 13 '9-c1 06116 402193- cH-. Fi c fl a 7.1 u lt-clcen. - (cH2) 8- cnsmns 14.8 23 H ll-Fcßn. - (cH2) 3- C113 fena 0.2 18 H ü-cnacsa., - (cH, -_.) S- c fi a: C213 9 .8 19 H H-cnaoqa., - (CHa) 3- CHa: CI-Ia> 20 -0 21 n 3-c1c, n. - (<: H2) = - CHsæHs 0.7 52: u a-arcßn. - (C212) s- cn,: ens o. 9 521 »a a-clcen, - (cH2), - cnaæns 0.1 52a H 2-rcen4 - (c1z2) 3- caycna 0.o1-o.o3 33 1-1 u a-uozcsa, - (cna) s- cnsæna 0.6 46-1 n e-csnm - (CH =) S- cHsæHs 0-7 60 n a-rcgz. - (CH =). =, Cnsm 0-08 hrs (hus - (cH2), - mn o.3-o.14 u 448 629 69 Example TTBZa 111. ' z AI n Riga Enso v * 51 H CeHs (C212 -cH-crza) etc. wa, 3.3 ffHß ' 52 H 2 -FCGH4 (GHz -cH-cHa) ena maa 1 .u 55 H 3'FC <= H ~ - (CHe) = - ena: ens o .18 “H H SFI - (CH = n- cnaæns 9.91; > === _ ”5-1 H Síl - (CHa) = - cns fl zas 1.85 33m-1H 2-C23-CGH4 - (cH =) s- cH =: cHs Imipramine 0_2-0_ & Clomipramine 0_h Desipramine Q_2 Amitriptyline 0.9 protection against tetrabenazine-induced ptosis, mg / kg, IP av compound calculated on the basis of the free base of active agent. 55 HO 448 '629 70 Preparation and administration.

Effective amounts of the foregoing pharmacologically active compounds of formula Ip or formula II may be administered to humans for therapeutic purposes as usual methods of administration and in common forms, such as orally in the form of solutions, emulsions, suspensions, pills, tablets and capsules, in pharmaceutically acceptable carriers and parenterally in the form of sterile solutions.

Examples of solid carriers for oral administration are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia gum.

Examples of liquid carriers for oral administration are vegetarian tabile oils and water.

For intramuscular administration, the vehicle or diluent the excipient is a sterile, parenterally acceptable form liquid, e.g. water or a parenterally acceptable oil, for example arachidonic oil contained in ampoules.

Although very small amounts of the active material according to the present invention is effective when minor therapies technical results are desired or when administered to patients with relatively low body weight, are usually unitary doses of 5 mg or more, preferably 10, 25, 50 or 100 mg and even higher, preferably administered three or four times daily, depending of course on how pass á fl serious situation is, which compound was used and what result is desired. 25-200 mg seems to be an optimal unit dose or a usually wider range may be about 10-500 mg per unit dose. Daily doses are required usually in the range of 0.3 to about 20 mg / kg / day, preferably 0.3-10 mg / kg for the more active compounds.

The active ingredients of the present invention may combined with other compatible pharmacologically active agents.

The only thing necessary is that the active ingredients constitute an effective amount, i.e. so that an appropriate effective dose can obtained in conjunction with the daily dose utilized.

STAY H0 448 629 71 Obviously, several dosage forms can be administered together. early. The exact individual dose as well as the daily the dose is determined according to standardized medical principles under the guidance of a physician.

The following preparations are representative of pharmacology active compounds of the present invention.

PREPARATIONS 1. Capsules. capsules with 10 mg and 50 mg active ingredient more capsule produced. When higher amounts of active ingredient are required, the amount of lactose is reduced. mg 50 mg Typical mixture for encapsulation per capsule per capsule Active ingredient, such as salt 10 50 Lactose 259 219 Starch 126 126 Magnesium stearate __ï __fl Total 399 399 Additional capsule formulations preferably containing higher doses of active ingredient are as follows: 100 mg 250 mg 500 mg Ingredient per capsule per capsule per capsule Active ingredient, such as salt in 100 250 500 Lactose 2lU 163 95 Starch 87 81 H7 Magnesium stearate __ï __§ __§ A total of 599,500,650 In each case, the selected active ingredients are mixed with lactose, starch and magnesium stearate and the mixture is capsule. 2. Tablets.

A typical preparation for tablets containing 5.0 mg of active ingredient per tablet is as follows. The preparation can be used for other strengths of active ingredients by adjusting the ring by weight dicalcium phosphate. 448 629 72 Per tablet, mc Active ingredient 10.0 2. Corn starch 15.0 3. Corn starch (pasta) 12.0 H. Lactose 35.0 . Dicalcium phosphate 132.0 6. Calcium stearate __§¿Q A total of 202.0 1, 2, U and 5 are mixed evenly. 3 is prepared as a 10% solid in water. The mixture is granulated with starch paste and passed as a wet mass through a sieve with the sieve number 8 mesh. The wet granules are dried and allowed to pass through one visibility with the sight number 12 mesh. The dried granules are mixed with calcium stearate and pressed. Injectable - 2% in sterile solution.

Per ml Active ingredient mg 20 Preservatives, e.g. chlorobutanol calculated as weight% per volume 0.5 Water for injection q.s.

The solution was prepared, clarified by filtration and filled into ampoules, sealed and autoclaved.

Different variations and equivalent solutions are obvious for the person skilled in the art and can be done regarding the associations, the compositions and methods of the present invention without departing from the scope of the invention. It is obvious that the invention is limited only by the appended claims.

Claims (11)

Claim selected from the group of the formula Ar 'J-LN / (l-Ûn \ (mn _ Z? YR where rr 1 1 2 R represents vate, lower alkyl. alk -NR R or H c 1 I -alk -N = C-OCZHS; 1 R and R represent hydrogen, lower alkyl, -C (O) O-lower alkyl or where R 1 and R 2 together with the adjacent nitrogen atom forms a heterocyclic group consisting of l-phthalimido. 1-pyrrolidinyl, 4-morpholinyl. 1-piperazinyl and 4-substituted piperazin-1-yl; Ar denotes 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl substituted with 1,2 or 3 halogen. lower alkyl. lower alkoxy, trifluoromethyl or nitro and may be the same or different: alkl denotes a straight or branched hydrocarbon chain having 1-8 carbon atoms; Z represents hydrogen. halogen. lower alkyl. lower alkoxy, hydroxy or nitro: Y represents hydrogen or 1-2 groups consisting of lower alkyl. lower alkoxy or hydroxy and which groups may be the same or different: n represents 0 or 1 and when n represents 0 the dotted line denotes a double bond and acid addition salts thereof. Compound according to Claim 1, characterized in that it consists of N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine 44 Compound according to Claim 1, characterized in that it is NN-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1.4] benzodiazepine-11-propanamine fumarate [1: 1]. A compound according to claim 1, characterized in that it is 6- (4-fluorophenyl) -N.N-dimethyl-11H-pyrido- [2,3-b] {1,4] benzodiazepine-11-propanamine. A compound according to claim 1, characterized in that it consists of 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine. A compound according to claim 1, characterized in that it is 6-phenyl-11H-pyrido [2,3-b] [1.4] benzodiazepine-11-propanamine dihydrochloride hemihydrate. A compound according to claim 1, characterized in that it is N-methyl-6-phenyl-11H-pyrido [2,3-b] [1.4] benzodiazepine-11-propanamine. A compound according to claim 1, characterized in that it is N-methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine dihydrochloride. A compound according to claim 1, wherein it is 6- (2-fluorophenyl) -N, N-dimeyl-11H-pyrido- [2,3-b] [1,4] benzodiazepine-11-propanamine. A compound according to claim 1, wherein it is 6- (2-chlorophenyl) -N.N-dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine. 11-propanamine. uy. .