LU83865A1 - PYRIDO (1,4) BENZODIAZEPINES PHENYL-SUBSTITUTED AND INTERMEDIATES THEREOF, USEFUL AS ANTIDEPRESSANT MEDICINAL PRODUCTS - Google Patents

Description

✓ i * - *. The present invention relates to new phenyl-substituted pyrido [1,4] -benzodiazepines and their intermediates, useful as antidepressant drugs.

British Patent No. 907,646 describes the preparation of certain dibenzodiazepines substituted by phenyl radicals on the carbon and by alkyl or aminoalkyl radicals on the nitrogen atom bridging between the phenyl rings.

Greig, M.E. et al., In J. Med. Chem. 14, No. 2, page Λ 153 (1971) describe dibenzodiazepines similar to those described in the aforementioned patent useful against anaphylactic shock.

Japanese Patent No. 73/43,520 (CA 80: 133501η) describes 6-phenyl-2,3,4,4a-tetrahydro-11H-pyrido [2,3-b] [1,4] benzo-h diazepines having an anticonvulsant activity which is prepared for example from 2-aminobenzophenones and ornithine.

The new pyrido [1,4] benzodiazepines of the invention correspond to the formula:

Ar / (H) n

R

where: R represents a hydrogen atom or a lower alkyl radical, -alk1-NR1R2 or -alk1-N = CH-0C H; "12 1 25 R and R are chosen from the group consisting of a hydrogen atom, a lower alkyl radical or -C (O) 0-lower alkyl, ^ 4 12 'or R and R form together with the atom d adjacent nitrogen a heterocyclic radical chosen from the radicals 1-phthalimido, 1-pyrrolidinyl, 4-morpholino, 1-piperazino and piperazine-1-yl 4-substituted; Ar is chosen from the group consisting of radicals 2-, 3- and 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl substituted by 1 to 3 radicals chosen from halo, lower alkyl, lower alkoxy, trifluoromethyl or nitro radicals which may be similar or different; 2 f! - · alk ^ - represents a straight or branched hydrocarbon chain having 1 to 8 carbon atoms; Z is chosen from a hydrogen atom and the halo, lower alkyl, lower alkoxy, hydroxy or nitro radicals; 5 Y is chosen from the group consisting of a hydrogen atom or one or two radicals chosen from lower alkyl radicals, lower alkoxy or hydroxy which may be the same or different; n is zero or one, and when it is zero the dashed line is a double bond. ’10 and their acid addition salts, j The compounds of formula I are useful as antidepressants for treating depression or as intermediates for the preparation of other compounds of formula I.

The new [2 - [(aminopyridinyl) amino] phenyl] aryl-methanones intermediates (or precursors) which form in the reaction mixture before cyclization into diazepines and which are moreover useful as antidepressants for the treatment of depressions are represented by the formula: 20

Γ ^ "· Formula II

H

Where Ar, Z and Y have the same definition as above, and their pharmaceutically acceptable acid addition salts.

In the complementary definition of the symbols of the above formulas and wherever they appear in the present description and claims, certain expressions correspond to the following definitions.

The straight or branched hydrocarbon chain of connection "alk" containing 1 to 8 carbon atoms is for example a methylene (-CH ^ -), ethylene (-CH ^ -CH ^ -), propylene (-CH ^ CH ^ CH) radical ^ -),

H

* 35 ethylidene [-CH-], 1,2-propylene [-CH-CI ^ or -CH ^ -C-], isopropylidene ch3 <5h3 ch3 * i 3 r: · CH, '* »3 [-C- ] or 1,3-butylene [-CH-CH - CH_-] and the like.

t x L L

CH3 CH3

The term "lower alkyl" embraces straight or branched chain hydrocarbon radicals having up to 8 carbon atoms inclusive such as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl radicals , hexyl, heptyle, octyl and the like.

The term "halo" embraces chloro, bromo, fluoro and iodo and preferably chloro, bromo and fluoro.

The term "4-substituted piperazine-1-yl" refers to a piperazine substituted in position 4 with a lower alkyl or alkylcarbonyl blocking group which can then be removed to obtain the unsubstituted piperazine.

The pharmaceutically acceptable acid addition salts are the salts formed by the pyridobenzodiazepines of the invention with any acid compatible with the physiology of warm-blooded animals, these salts being formed with strong or weak acids.

Examples of strong acids that may be mentioned include hydrochloric, sulfuric and phosphoric acids. Examples of weak acids that may be mentioned include fumaric, maleic, succinic, oxalic, cyclohexamic acids and the like.

The 6-aryl-11H-pyrido [2,3-b] [1,4] benzodiazepines and their 5,6-dihydro derivatives encompassed by formula I correspond to the formula: i Ar / (H) \ / n Æf "'5 \ z ÎAfr-t

30 R

The 6-aryl-11H-pyrido [3,4-b] [1,4] benzodiazepines and their 5,6-dihydro derivatives encompassed by formula I correspond to the formula: f 4 Λ J ^% VN / <H> n ZN AjJ ^ y / „7 '

5 R

•he'

The 10-aryl-5H-pyrido [4,3-b] [lj4] benzodiazepines and their 10,11-dihydro derivatives encompassed by formula I correspond to the formula: \ r / H> - 10 ΛηΓ ^ \

R

The 10-aryl-5H-pyrido [3j2-b] [l} 4] benzodiazepines and their 10,11-dihydro derivatives encompassed by the formula I correspond to the formula: \ T ✓ <»> s \ / n 20 ZN ^ N ^ JT ^ y

R

In all the formulas Iw to Iz, the symbols R, Ar, Z and Y have the same definition as before.

"* _" 5, To evaluate the antidepressant activity of the compounds of the invention, the following procedure was used, described by Englehardt, E, L. et al., J. Med. Chem. 11 (2): 325 (1968) which previously demonstrated the usefulness of compounds for the treatment of depression in humans: five adult female mice are administered 200 rag / kg of the test compound ( strain ICR-DUB) intraperitoneally 30 min before the administration of a dose causing ptosis (32 mg / kg ip) of tetrabenazine (in the form of j, methanesulfonate). 30 min later, the presence or absence of complete closure of the eyelids (ptosis) is evaluated on each animal. One can establish a median effective dose (ED ^ q) for each compound studied relative to the inhibition of depression caused by tetra-benazine in mice, according to the technique described by Litchfield et al., J, Pharmacol. Exp. Therap. 96: 99-113 (1949).

The compounds of the invention encompassed by the formula I

who have antidepressant activity in the previous test correspond to the formula Ip: ζ / ”.

R

in which: R represents a hydrogen atom or a lower alkyl radical or - 112 25 alk -N-R R; 1 2 R "and R represent a hydrogen atom or a lower alkyl radical, 12 or R and R form together with the adjacent nitrogen atom * a heterocyclic radical chosen from the radicals 1-pyrrolidinyl, 4-morpholinyl, 1 -piperazinyl or 4-lower alkyl-piperazine-1-yl; Ar represents a 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl radical substituted by 1 to 3 radicals chosen from halo radicals , lower alkyl, lower alkoxy, trifluoromethyl or nitro which may be similar or different; / 6 _> alk represents a straight or branched hydrocarbon chain having 1 to 8 carbon atoms; Z represents a hydrogen atom or a halogen radical, lower alkyl, lower alkoxy, hydroxy or nitro; 5 Y represents a hydrogen atom or one or two radicals chosen from the lower alkyl, lower alkoxy or hydroxy radicals which may be similar or different; n is zero or one and, when n is zero, the broken line e is a double bond, J-3 10 and their pharmaceutically acceptable acid addition salts.

1 12

The compounds of formula Ip where R represents -alk -NR R

31 1 2 and R and R represent a lower alkyl radical or a hydrogen atom have been shown to have few antihistamine, anti-holinergic and cardiotoxic side effects when studied in animals.

The preferred pyridobenzodiazepines useful in the method of treating depression are:

Example Active ingredient (free base) No. ______ 20 9 N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodia zé pine-11-propana mine 23 6- (4-fluorophenyl) -N, N-dime thyl-11H-pyrido [2,3-b] - [1,4] benzodiazepine-ll-propanamine 25 6-phenyl-11H-pyrido [2,3-b] [ 1,4] benzodiazepine-11-propanamine 28 N-methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine s 52b 6- (2-chlorophenyl) -N , N-dimethyl-11H-pyrido [2,3-b] [1,4] - benzodiazepine-11-propanamine.

£ 30 Some of the compounds of formula I in which the symbol R contains a phthalimido, chloro, carbamoyl or imidate moiety are intermediates rather than antidepressants.

i 7 - "• The subject of the invention is therefore: new 6-aryl-11H-pyrido [1,4] benzodiazepines having antidepressant activity; methods of treating depression and pharmaceutical compositions useful therefor; and new intermediates to prepare aryl-substituted HH-pyrido- [1,4] benzodiazepines which are antidepressants, some of these intermediates also having anti-A depressive activity.

Other features and advantages of the invention will become apparent from the following description of the best mode of practicing the invention and the appended claims.

.4- The invention will now be described in detail.

The invention relates to novel pyridobenzodiazepines and methanone intermediates represented by formulas I and II, as well as compositions containing them and the use of these compounds as antidepressants or as intermediates in the preparation of other antidepressant compounds.

Description of the preparation of the compounds The reaction sequence for the preparation of the compounds of the invention is illustrated by scheme 1. Other processes for the preparation of certain compounds of formula I are represented by schemes 2, 3 and 4.

Methanones, Formula II, see Scheme 1 The intermediate methanones are prepared by heating a mixture of haloaminopyridine and an aminobenzophenone for a shorter time than that necessary for cyclization to pyridobenzodiazepine as indicated by the analysis of chemical ionization mass spectroscopy. For [2 - [(3-amino-2-pyridinyl) -30 amino] phenyl] methanones, the necessary conditions are approximately 1 to 1.5 h at 170-200 ° C. The methanones constituting the main product can be isolated, if desired, by cooling and adding an appropriate organic solvent, such as, for example, methylene chloride, which dissolves unreacted starting materials. and certain cyclized compounds (la) followed by usual isolation techniques, such as partitioning between the solvent and an aqueous base or a methanolic aqueous base followed by washing, drying, evaporation of the layer solvent and recrystallization from a suitable solvent.

Unsubstituted pyridobenzodiazepines, formulas la and Ia-1 (R = H), i see diagram 1

It can also be heated in an aprotic solvent. s * 10 the purified compounds XI or the crude compounds II to cyclize them into compounds of formula la and remove the water from the reaction mixture in a conventional manner, for example at reflux with a Dean-Stark water trap. However, it is not necessary to stop the heating at the intermediate stage; generally, it is sufficient to continue heating the original reaction mixture, ie III + IV, for a longer period during which the cyclization of the is carried out. In the cyclization stage, regardless of how one operates, the relationship between temperature and time varies to some extent depending on the reactants used and it suffices to heat for a sufficient time to obtain the desired product as indicated by mass spectrometry-by chemical ionization. The unsubstituted pyridobenzodiazepines are purified by partitioning between an appropriate solvent such as methylene chloride and an aqueous base, washing and drying of the solvent layer, evaporation and chromatography in an appropriate solvent system such as a mixture of acetone-benzene. . The corresponding dihydrodiazepine can be prepared by reduction with sodium borocyanhydrin.

#

Substituted pyridobenzodiazepines. Formulas Ib and Ib-1 (R = lower alkyl), see diagram 1 30 The compounds of formula la (or Ia-1) are alkylamine where R represents a hydrogen atom or radicals are introduced which lead to alkylamination by reaction first with sodium hydride 9 - * then with a suitable reactive compound represented by the formula halo-alk ^ -Q where "alk ^" has the meaning previously indicated and Q has the same definition as in scheme 1 .

Compounds suspended in a suitable solvent such as dimethylformamide are added to a stirred suspension of sodium hydride in the same solvent. The halo-alk ^ -Q reactant compound (alkylamination agent or agent leading to alkylamination) is added near room temperature and the reaction mixture is stirred for a time such that the reaction is completed, as determined for example by thin layer chromatography. Decom-v 10 put the unreacted sodium hydride by adding water and extract the product with a suitable solvent, such as methylene chloride and then extract the solvent layer with an aqueous acid and isolates the product from the aqueous layer by neutralization and re-extraction with methylene chloride, followed by evaporation and precipitation, preferably in the form of an addition salt, such as fumarate, hydrochloride, l 'oxalate, maleate and the like. Generally, after having obtained and purified an acid addition salt, the free base can be regenerated by partitioning the salt between an aqueous base and an appropriate solvent such as methylene chloride and evaporation of the methylene chloride layer. . The corresponding dihydrodiazepines can be prepared by reduction with sodium borocyanhydrin. Alternatively, the compounds of formula Ib where Q represents a halo radical can be transformed into compounds where Q represents -N- (lower alkyl) by reaction with an appropriate dialkylamine as shown in scheme 2.

The primary amines of formula le are prepared (R and - * 2 R both represent a hydrogen atom) from derivatives of the type -alk1-U) - (l-phthalimido), as indicated by scheme 1, by Reaction with hydrazine hydrate according to the method described in Org. Syn. Coll. Flight. III, pages 151-153. Generally, a reflux period of approximately 2 to 3 hours is sufficient, then an aqueous acid is added and the mixture is filtered. The derivatives of the -alk-primary amines type are isolated with suitable solvents, such as isopropyl alcohol. * 10 lique. The sels which are preferred in this isolation stage are the hydrochlorides and the hydrochlorides hydrates. The corresponding dihydrodiazepines can be obtained by reduction with borocyan hydrine sodium.

5 -alk ^ - ^ - monoalkylamines (formula 1 2 le) can be prepared; for example R = methyl, R = hydrogen, as indicated in scheme 1 by reaction of the primary -alk ^ -NE ^ derivatives Ic or Ic-1 with triethyl orthoformate at reflux for a sufficient period of time to form a methanimidic acid ester (Id) which is then reacted with sodium borohydride. The unreacted boro-hydride is decomposed with water and the product is extracted with an appropriate solvent such as ethyl acetate and can be purified by column chromatography and partitioning with basic solvent.

In the isolation stage, the hydrochlorides constitute the preferred salts. The process is illustrated in more detail by Examples 27 and 28. The corresponding dihydrobenzodiazepines can then be prepared by reduction with sodium borocyanhydrin.

The -alk * -W-monomethylamines' can also be prepared by reaction of the primary amine with ethyl chloroformate as in Example 29, then reduction with lithium aluminum hydride as illustrated by figure 3.

Another more general possibility of introducing lower -alk * -1 ^ -monoalkylamine radicals consists in passing through 0 1 "25 the -alk -N-C-O-lower alkyl radical. See diagram 1.

! lower alkyl

All formulas la, Ia-1, Ib, Ib-1, Ib-2, Ib-3, Ib-4, le, Ic-1, Ic-2, Id, le, Ie-1 are encompassed by formula I .

The compounds of formula I are obtained in which the fragment 1 2 v 30 -NR R is a 1-piperazinyl radical unsubstituted by hydrolysis 2 of a compound of formula I in which -NR R is a piperazino radical substituted in position 4 by a radical alkylcarbonyl, such as tert-butoxy-carbonyl.

S, 11 DIAGRAM 1 0

Nc — Ar Period of ov + heating, 5 'VA * ,, .wWv ^ brief

Heating N. Il H / „extended \ / heating I Ar / 10> c: N -HeO> i ^ additional

z ^ gCj @ LY

H __ \ l ^ *

Ia_1 "“ j NaH + solvent

J if halo-alk ^ -Q

5 \ L '* r / (H) «

A ~ N,> F - N

/ "- V H V— \ when η - 0 / ^ ν / ΓΗι V -" \ 2jgx; Â »on i acid i

Ib-1 1 "'......" \ when Q is (1- phthalimido) i hydrazine hydrate when n = O y, ,, alcoholic 25 (OL HBBHaCB, Ar (h) NY ^^ acid \ ïrsN ^ n

• al ^ -NHa (H) n // ~ \ S

here \ LAW 700-1 the V z— ti ^ --— alk1- ^

Ar ".............

30 H-c (0C £ tt5) 3 V M ^ (H) n - Ie-1 al * l-N-CHa

35 when η = o ζ-Aj ^ / ^ N '^ S ^ T''Y

- '% rx' {n acid Id "Uc" - ". cB-0CaH3 <? S \) (¾ 2- ^ VT /" I u 40 alk ^ ÎJ-CHs le * Q Is chosen from the radicals N- ( lower alkyl) 1-pyrridininyl, 1-piperidinyl, substituted piperazine-1-yl 4, 0

It 4-morpholino, 1-phthalimido, -N-C-O-lower alkyl, bu 45 lower alkyl halo.

12 DIAGRAM 2

Ar (h) n UN '"\ ^ \ + NH- (lower alkyl), i

Xb-2 âlk1-halo V

I? j ·. 10 Ib-3 alk1 ~ N- (lower alkyl) 2 'DIAGRAM 3 vL κ (Η) "» 1 i-- alk-NHa IC \

Solvent + \ Ar (H \ N (C £ H5) 3, \; n 20 EtOC (O) Cl alk1-NH-C (0) -0C2H5

Ic-2

25 Ar H / LiA1H

y \ 4 J&M «

| H

30 Ie-1 alk1-N-CH3 13 DIAGRAM 4

Ar (h). jgé, I. Il j âlk -N-C-O-lower alkyl lower alkyl

Hydrolysis with an acid x or aqueous base

W

AL SB) ° 15 alk1- NH-lower alkyl

Ie-1

The preparation of new [(aminopyridyl) arainophenyl-aryl] methanones which are intermediates in the preparation of phenyl-substituted pyrido [1,4] benzodiazepines is illustrated relative to intermediaries 1 to 16 below. The structures of the intermediaries are illustrated in Table 1 below.

4 Preparation of intermediate methanones

Intermediate 1 [2 - [(3-Amino-2-pyridinyl) amino] phenyl] phenylmethanone 25 ° n heats at 180 ° C under nitrogen atmosphere for 1.5 h a stirred mixture of 39.4 g (0.020 mole) of 2-aminobenzophenone and 28.3 g (0.22 mole) of 3-amino-2-chloropyridine. The mixture is allowed to cool slightly and 200 ml of methylene chloride is added slowly. After 3 h of stirring and a night of rest at room temperature, 40.1 g of solid are separated by filtration which are recrystallized twice from a mixture of methanol and isopropyl ether to obtain 4.3 g of a product which is presumably hydrochloride; Mp 187 ~ 90 ° C. This solid is dissolved in a mixture of water and methanol, basified with 3 N sodium hydroxide and extracted with methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from isopropyl ether (charcoal) to obtain 2.1 g of product; Mp 91-3 ° C. Before the analysis, it is dried overnight at ordinary temperature / 0.026 mbar.

Analysis: Theoretical for ^ gH ^ N ^ O; C 74.72; H 5.23; N 14.52 Found; C 74.94; H 5.23; N 14.69 15 Intermediate 2 [2 - [(3-Amino-2-pyrid iny1) amino] -4-chlorophenyl] phenylme thanone Heated mixture is heated to 180 ° C under nitrogen for 2.5 h 23.2 g (0.1 mole) of 2-amino-4'-chloro-benzophenone and 14.2 g (0.11 mole) of 3-amino-2-chloropyridine. The mixture 20. solidifies by cooling to room temperature and is divided with a spatula. The solid is suspended in 100 ml of methylene chloride and collected by filtration.

The filter cake is dissolved in a mixture of water and methanol, basified with 3 N sodium hydroxide and extracted twice with methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure. The residue which has crystallized is triturated in isopropyl ether * * and the solid is collected (16.7 g) by filtration. A 3 g sample is recrystallized from isopropyl ether to give 1.6 g of product; Mp 153-155 ° C.

Analysis; Theoretical for C ^ gH ^ ClN ^ O: C 66.77; H 4.36; N 12.98 Found: C 67.06 H 4.36; N 13.17 15

Intermediate 3 [2 - [(3-Amino-2 - pyridinyl) amino] phenyl] - (4-me thylpheny 1) me thanone

A stirred mixture of 20.0 g (0.095 mole) of 2-amino-4'-methylbenzophen-5 none and 13.95 g (0.104 mole) of 3-amino-2-chloropyridine (96%). The mixture is cooled to form a glassy solid which is divided and triturated in methylene chloride and then the mixture is stirred overnight. The solid is collected by filtration and Λ dissolved in hot methanol. The solution was basified with 3 N sodium hydroxide, diluted with 500 ml of water and extracted three times with 250 ml of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure. The residue, which crystallizes on standing, is recrystallized twice from a mixture of benzene and isooctane to give 4.2 g of product; Mp 126-127.5 ° C.

Analysis: Theoretical for C ^ H ^ N ^ O: C 75.23; H 5.65; N 13.85 Found: C 75.81; H 5.69; N 13.96

Intermediate 4 [2 - [(3-Amino-2-pyridinyl) amino] -5-chlorophenyl] - (2-chlorophenyl) methanone 20 A stirred mixture is heated to 190 ° C. under nitrogen 20.0 g (0.156 mole) of 3-amino-2-chloropy-ridin and 37.3 g (0.14 mole) of 2-amino-2 ', 5-dichlorobenzophenone.

Thin layer chromatography (5% methyl alcohol in benzene on silica gel) indicates that almost no reaction has occurred. The mixture is stirred overnight at 190 ° C, cooled slightly and 100 ml of methylene chloride are carefully added. The suspension is stirred for 2 h and the black solid formed is filtered off. The solid is suspended in 500 ml of methylene chloride and 300 ml of dilute sodium hydroxide are added. An emulsion is formed and the mixture is filtered and the layers are allowed to separate. The methylene chloride layer is washed with two 250 ml portions of water to extract it, dried over magnesium sulfate and evaporated under reduced pressure.

The residue is dissolved in benzene and filtered through a column of 35,300 g of Florisil to remove material having a low Rf. All the fractions are combined and evaporated under reduced pressure.

r 16

Thin layer chromagography shows the presence of two main components including the one with the weakest Rf spot. The residue is dissolved in benzene and chromatographed on a column packed with 600 g of Florisil in benzene. The material with the highest Rf is eluted with 1% acetone in benzene. After evaporation, the residue is triturated in benzene and recrystallized from a mixture of benzene and isooctane to obtain 2.7 g of product; Mp 162-4 ° C.

Analysis: Theoretical for ^ gH ^ C ^ NgO: C 60.35; H 3.66; N 11.73 10 Found: C 60.67; H 3.67; N 11.77

Intermediaries 5a to 5u - According to the procedures described for intermediate 3 and replacing 2-amino-4'-methylbenzophenone with equal molar amounts of the following compounds: 2-amino-4'-ethylbenzophenone, 2- amino-4'-isopropylbenzophenone, 2-amino-4'-bromobenzophenone, 2-amino-3'-fluorobenzophenone, 2-amino-4'-ethoxybenzophenone, 2-amino-4'-nitrobenzophenone, 2 -araino-4'-trifluoromethylbenzophenone, 2-amino-3'-methylbenzophenone, 2-amino-3'-ethylbenzophenone, 2-amino-3'-me thoxybenzophenone, 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, 17 we obtain a) [2 - [(3-amino-2-py ridinyl) amino] phenyl] - (4-ethylphenyl) methanone, b) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (4-isopropylphenyl) methanone, c) la [2 - [( 3-amino-2-pyridinyl) araino] phenyl] - (4-bromophenyl) me thanone, 5 d) la [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (3-fluorophenyl) methanone, e) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (4-ethoxyphenyl) methanone, £) la [2 - [(3-amino-2-pyridinyl) amino] phenyl] - ( 4-nitrophenyl) methanone, g) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (4-trifluoromethylphenyl) -me thanone.

J 9 10 h) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (3-methylphenyl) methanone, i) [2 - [(3-amino-2-pyridinyl) amino] phenyl ] - (3-ethylphenyl) methanone, j) [2 - [(3-amino-2-pyridinyl) amino Iphenyl] - (3-methoxyphenyl) me thanone, - k) [2 - [(3-amino- 2-pyridinyl) amino] phenyl] - (3-ethoxyphenyl) methanone, 1) la [2 - [(3 -amino-2-pyridinyl) amino] phenyl] - (2-nitrophenyl) methanone, 15 m) la [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (3-trifluoromethylphenyl) -me thanone, n) la [2 - [(3-amino-2-pyridinyl) amino] phenyl] “(2-methylphenyl ) methanone, o) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-ethylphenyl) methanone, p) [2-C (3-amino-2-pyridinyl) amino] phenyl ] - (2-methoxyphenyl) methanone, 20 q) la [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2,4-dichlorophenyl) - methanone, r) la [2 - [(3 -amino-2-pyridinyl) aminoIphenyl] - (3,4,5-trimethoxyphenyl) -me thanone, s) la [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-fluorophenyl) methanone , 25 t) [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-chlorophenyl) methanone, and 'u) [2 - [( 3-amino-2-pyridinyl) amino] phenyl] - (2-bromophenyl) methanone.

^ * Intermediaries 6a to 6o

According to the procedures described for intermediate 2 and replacing 2-amino-4-chlorobenzophenone with equal molar amounts of the following compounds: 2-amino-5-chlorobenzophenone, 2-amino-6-chlorobenzophenone, 2-amino-4-fluorobenzophenone, 35 2-amino-4-bromobenzophenone, i 18 2-amino-4-ftrifluoromethylbenzophenone3 2-amino-4-methylbenzophenone, 2-amino-5-methylbenzophenone, 2-amino -6-methylbenzophenone, 5 2-amino-4-ethylbenzophenone, 2-amino-4-mesthoxybenzophenone, 2-amino-4-ethoxybenzophenone, 2-amino-4-nitrobenzophenone3 * 2-amino-5- nitrobenzophenone3 10 2-amino-3-methylbenzophenone, and 2-amino-3-'chlorobenzophenone3 we obtain: * a) [2 - [(3 -amino-2-pyridinyl) amino] -5-chlorophenyl] phenylme 3 b) [2 - [(3-amino-2 “pyridinyl) amino] -6-chlorophenyl] phenylraethanone, 15 c) [2 - [(3-amino-2-pyridinyl) amino] -4-fluorophenyl] phenylmethanone, d) [2 - [(3-amino-2-pyridinyl) amino] -4-bromophenyl] phenylmethanone, e) la [ 2 - [(3-amino-2-pyridinyl) amino] -4-trifluoromethylphenyl] phenyl-me thanone, £) la [2 - [(3-amino-2-pyridinyl) amino] “4-methylphenyl] phenylmethanone, 20 g) [2 - [(3-amino-2-pyridinyl) amino] -5-methylphenyl] phenylmethanone, h) [2 - [(3 ~ amino-2-pyridinyl) amino] -6-methylphenyl] phenylmethanone, i) [2 - [(3-amino-2-pyridinyl) amino] -4-ethylphenyl] phenylmethanone, j) [2 - [(3-amino-2-pyridinyl) amino] -4-methoxyphenyl] phenylmethanone, k) [2 - [(3-amino-2-pyridinyl) amino] -4-ethoxyphenyl] phenylmethanone, 1) la [2 - [(3-amino-2-pyrid inyl) amino] -4-nitrophenyl] phenylmethanone, m) [2 - [(3-amino-2 ~ pyridinyl) amino] -5-nitrophenyl] phenylmethanone, n) la [2 - [(3-amino-2-pyridinyl) amino] -3-methylphenyl] phenylmethanone, and o) [2 - [(3-amino-2-pyridinyl) amino] -3-chlorophenyl] phenylmethanone.

__ *

Intermediaries 7a to 7c 30 According to the procedure of Preparation 1 and replacing 3-amino-2-chloropyridine with equal molar amounts of the following compounds: 4-amino-3-chloropyridine, 3-amino-4-chloropyridine , and 35 2-amino-3-chloropyridine, * 19:

a) [2 - [(4-amino-3-pyridinyl) amino jphenyl] phenylmethanone, b) [2 - [(3-amino-4-pyridinyl) amino] phenyl] phenylmethanone, and c) [2- [(2-amino-3-pyridinyl) amino] phenyl] phenylmethanone.

5 Intermediate 8 [2 - [(3-Amino-2-pyr idinyl) amino] phenyl] - (3-chlorophenyl) methanone

A stirred mixture of 35 g * (0.152 mole) of 2-amino-3'-chlorobenzophenone and 23.4 g (0.182 mole) of 3-amino-2-chloropyridine is heated at 180 ° C. for 2 h. The hot melt is allowed to cool 10 to 110 ° C. and then 100 ml of hot toluene is added dropwise with vigorous stirring. The mixture is allowed to cool with stirring to * 30 ° C and 50 ml of methylene chloride are added. After another 0.5 h of stirring, the mixture is filtered and the filter cake is suspended in methylene chloride with stirring for 0.5 h and the methylene chloride is separated by filtration. The filter cake containing the product (25.4 g) is partially dissolved in. hot methanol (total volume 150 ml) and 50% aqueous sodium hydroxide is added until the mixture is alkaline. Ice water is added and the solution is extracted with methylene chloride.

This extract is washed in methylene chloride with water and dried over magnesium sulfate and then evaporated to dryness. The residue is dissolved in isopropyl alcohol and boiled with charcoal.

The mixture is filtered and concentrated to obtain a first crop of crystals weighing 16 g (33%). A portion of the crystals is recrystallized from isopropyl alcohol to obtain a brick-red solid melting at 119-120 ° C.

Analysis: Theoretical for CjgH ^ N ^ OCl: C 66.77; H 4.36; N 12.98

Found: C 66.78; H 4.42; N 12.94

Intermediate 9 30 [2 - [(3-amino-2-pyrid inyl) amino] phenyl] - (4-fluorophenyl) me thanone

A stirred mixture of 35 g (0.163 mole) of 2-amino-4'-fluorobenzophenone and 27 g (0.21 mole) of 3-amino-2-chloropyridine is heated at 175-180 ° C. for 2.5 h. The mixture is allowed to cool to 110 ° C. and then 100 ml of hot toluene are added. After cooling to 50 ° C, Λ 20 50 ml of methylene chloride are added. The solvent layer is decanted to leave a black solid mass which is dissolved in hot methanol. The volume of the solution is reduced by half and allowed to stand overnight at room temperature. The mixture is filtered and the filter cake is washed twice by suspending it in methylene chloride. The crude solid produced weighs 22.5 g. The solid is dissolved in methanol and basified with a 50% aqueous solution of sodium hydroxide. The mixture is extracted with methylene chloride and the extract is dried and then concentrated.

* 10 The residue is crystallized twice from isopropyl alcohol, bleaching with charcoal the second time to obtain 14 g (28%) of an orange-red solid; Mp 121.5-122.5 ° C.

Analysis: Theoretical for C ^ gH ^ N ^ OF: C 70.35; H 4.59; N 13.67 "Found: C 70.23; H 4.59; N 13.64 15 Intermediate 10 C 2 - [(3-Amino-2-pyridinyl) amino1phenyl] - (2-thienyl) methanone

According to the procedure described for intermediate 9, the (2-aminophenyl) (2-thienyl) methanone is reacted, prepared according to the method of Steinkopf & Günther, Ann. 522, 28-34 (1936) with 3-amino-2-chloropyridine to obtain the desired compound.

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

According to the procedure described for intermediate 9, the (2-aminophenyl) (3-thienyl) methanone is reacted with the 3-amino-2-chloropyridine to obtain the desired compound.

* Intermediate 12 [2 - [(3-amino-2-pyridinyl) amino3 phenyl] - (2-pyridinyl) methanone

The desired compound is prepared by reaction of (2-amino-phenyl) (2-pyridinyl) methanone prepared as described by Schofield, K.

J. Chem. Soc. 1949. 2408-12, with 3-amino-2-chloropyridine.

21

Intermediate 13 [2 - [(3-a mino-2-pyr idinyl) amino] phenyl] - (3-pyrid iny1) me thanone

The desired compound is prepared by reaction of (2-amino-phenyl) (3-pyridinyl) methanone prepared as described by Abramovitch 5 RA & Tertzakian, G. Tetrahedron Letters, 1963, 1511-15 and Abramovitch, RA and coli., Can. J. Chem. 43 (4), 725-31 (1965) with 3-amino-2-chloropyridine ..

* Intermediate 14 [2 - [(3-amino-2-pyrid inyl) amino] phenylH 4-pyridinyl) me thanone 10 The desired compound is prepared by reaction of the (2-amino-phenyl) (4-pyridinyl) methanone as described by Nann, AJ and Schofield, K., J. Chem. Soc. 1952, 583-9 with 3-amino-2-chloro-pyridine.

Intermediates 15a to 15g 15 According to the procedure described for preparation 1 and replacing 3-amino-2-chloropyridine with equimolar amounts of the following compounds: 3-amino-2-chloro-4-methylpyridine, 3-amino -2-chloro-5-methylpyridine, 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 3-amino-2-chloro-5-raethoxypyridine, - 25 we obtain: a) [2 - [(3-amino-4-methyl-2 -pyridinyl) amino] phenyl] phenylmethanone, - 'b) [2 - [(3-amino-5-methyl-2-pyridinyl) amino] phenyl] phenylmethanone, c) [2 - [(3-amino-6 -methyl-2-pyridinyl) amino] phenylphenylmethanone, d) la [2 - [(3-amino-5,6-dimethyl-2-pyridinyl) amino] phenyl] phenyl-30 me thanone e) la [2 - [( 3-amino-6-methoxy-2-pyridinyl) amino] phenyl] phenylmethanone, f) la [2 - [(3-amino-2-methyl-4-pyridinyl) amino] phenyl] phenylmethanone, and g) [2 - [(3-amino-5-methoxy-2-pyrid inyl) aminojphenyl] phenylme thanone.

ί 22

Intermediaries 16a to 16f

According to the procedure described for preparation 1 and replacing 3-amino-2-chloropyridine with equimolar amounts of the following compounds: 2-amino-3-chloro-5-methylpyridine, 2-amino-3-chloro -4,6-dimethylpyridine 2-amino-3-chloro-5-ethylpyridine} 4-amino-3-chloro-5-methylpyridine, 4-amino-3-chloro-2,6 ~ dimethylpyridine, and 10 la 4-amino-3-chloro-2-methylpyridine, we obtain: a) the [2- [(2-amino-5-methyl-3-pyridinyl) amino] phenyl Iphenylme thanone., B) the [2 - [( 2-amino-4,6-dimethyl-3-pyridinyl) amino] phenyl] phenyl-methanone, 15 c) [2 - [(2-amino-5-ethyl-3-pyridinyl) amino] phenyl] phenylmethane, d) [2 - [(4-amino-5-methyl-3-pyridinyl) amino] phenyl] phenylmethanone, e) [2 - [(4-amino-6-methyl-3-pyridinyl) amino] phenyl] phenylmethanone, and £) [2 - [(4-amino-2-methyl-3-pyridinyl) amino] phenylIphenylmethanone,

The preparation of the new phenyl-substituted pyrido [1,4] benzodiazepines of the invention and the new process are further illustrated by the following examples. The structures of the compounds of the examples are illustrated in Table 2 below. These examples in no way limit the scope of the invention.

EXAMPLE 1 6-Phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine 'A mixture of 19.7 g (0, 3) is heated under a nitrogen atmosphere at 190 ° C. 1 mole) of 2-aminobenzophenone and 15.0 g "* (0.12 mole) of 3-amino-2-chloropyridine. The mixture is cooled to room temperature and partitioned between 3N aqueous sodium hydroxide and methylene chloride. The combined methylene chloride extracts are washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue, 32.7 g, is dissolved in benzene and chromatographed on a column packed with Florisil in benzene, eluting with benzene and mixtures of 1 to 2% acetone in benzene. After evapora- * / 23 tions the solid is crystallized from benzene to obtain 7.3 g of product; Mp 106-108 ° C.

Analysis: Theoretical for C18H13N3: C 79> 68 · H M3 î N 15.49 Found: C 79.70; H 4.81; N 15.42 5 EXAMPLE 2 8- Chloro-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine

A mixture of 15.0 g (0.0647 mol) of 2-amino-5-chlorobenzophenone and 9.1 g (200 g) is heated at 200 ° C. (in an oil bath) under a nitrogen atmosphere. 0.068 mol) of 3-amino-2-chloropyridine. The mixture is cooled and methylene chloride is added. The mixture is stirred for 1 h and then left to stand overnight.

The brown solid precipitate weighing 8.7 g is separated by filtration. The filtrate is evaporated under reduced pressure. The residue is combined with the brown solid and partitioned between aqueous sodium hydroxide and methylene chloride and the crude product is isolated as in Example 1 except that the crystallization solvent is ethanol. After recrystallization from ethanol and drying overnight at 82 ° G / 0.13 mbar, 3.0 g of product are obtained; Mp 156.5-158.5 ° C.

Analysis: Theoretical for ClgH12ClN3: C 70.71; H 3.96: N 13.74

Found: C 70.24; H 4.01; N 13.76 EXAMPLE 3 9- Chloro-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine

A 6.6 g (0.02 mole) suspension of [2 - [(3-amino-2-pyridyl) -amino] -4-chlorophenyl] phenylmethanone (reflux) is heated overnight under reflux under a nitrogen atmosphere. intermediate 2) in 200 ml. "Of toluene. The reaction mixture is filtered hot and the filtrate is again heated to reflux temperature. The precipitate formed is filtered off by cooling to room temperature and recrystallized from benzene and then dried for 4 h at 97-98 ° C / 0.13 mbar and overnight at room temperature / 0, 13 mbar to obtain 3.7 g of product; M.p. 250.5-252 ° C. Elemental analysis of carbon is high and the product is dried again at 139 ° C (xylenes in a drying gun) for 8 h.

î 24

Although the carbon analysis remains high, the proton nuclear magnetic resonance spectrum and the mass spectrum correspond to the proposed structure.

Analysis: Theoretical for: c 70.71; H 3.96; N 13.74 5 Found: C 71.46; H 4.06; N 13.46 EXAMPLE 4 8-Chloro-6- (2-chlorophenyl) -5,6-dihydro-11H-pyrido [2,3-b] [1,4] benzodiazepine * · Ι ·. · Ι · ι.ιι -

The Florisil column is again eluted in the preparation of intermediate 4 with 10-15% acetone in benzene and 5-25% methanol in benzene to obtain two fractions of the desired compound in the present example, weighing 6.4 g and 5.7 g respectively, the second being clearly impure. The 6.4 g fraction is recrystallized from a mixture of benzene and isooctane to obtain 3.7 g of solid; F. 203-6 ° C (decomposition) which is identified by chemical ionization mass spectrometry 1 13 as well as nuclear magnetic resonance- H and - C like 8-chloro-6- (2-chlorophenyl) - 5,6-dihydro-11H-pyrido [2,3-b] [1,4] benzodiazepine.

EXAMPLE 5 6- (4-Chlorophenyl) IIIH-pyrido [2,3-b] [1,4] benzodiazepine

A mixture of 23.2 g (0.10 mole) of 2-amino-4'-chlorobenzophenone and 14.7 g (0.11 mole) is heated for 1.5 h at 180 ° C. under a nitrogen atmosphere. 3-amino-2-chloropyridine (96%). The mixture is cooled to room temperature and methylene chloride is added. After 30 min of stirring, the solid material is separated by filtration and triturated in ethanol at 95% by volume, hot.

The residual insoluble material is collected by filtration and recrystallized from a mixture of benzene and isooctane to obtain 2.7 g of product; Mp 203-204.5 ° C. Before analysis, the mixture is heated overnight at 97-98 ° C / 0.13 mbar.

Analysis: Theoretical for ClgH12ClN3: C 70.71; H 3.96; N 13.74 Found: C 70.76; H 3.92; N 13.95 EXAMPLE 6 6- (4-Methylphenyl) IIIH-pyrido [2,3-b] [1,4] benzodiazepine

A solution of 3.6 g (0.012 mole) of [2 - [(3-amino-2-pyridyl) -5 amino] phenyl] - (4-methylphenyl) is treated with a catalytic amount of p-toluenesulfonic acid. ) methanone in 100 ml of anhydrous toluene and the mixture is brought to reflux overnight, separating the water with a Dean-Stark trap. The reaction mixture is filtered hot. The product precipitates out of the filtrate when it is cooled to normal temperature and is collected by filtration. After evaporation of the solvent, the solid weighs 2.5 g; F. 2Û3,5-2056C (decomposition).

Analysis: Theoretical for Ο ^ Η ^, - Ν ^: C 79.98; H 5.30; N 14.73 Found: C 79.95; H 5.27; N 14.76 EXAMPLE 7 6- (4-Mefhoxyphenyl) IIIH-pyrido [2,3-b] [1,4] benzodiazepine 15 A stirred mixture is heated at 180 ° C. under a nitrogen atmosphere for 2.0 h 20.0 g (0.088 mole) of 2-amino-4'-methoxybenzo-phenone and 13.0 g (0.097 mole) of 3-amino-2-chloropyridine (96%). The reaction mixture is cooled to about 70 ° C and 100 ml of methylene chloride is added slowly. After cooling the mixture to room temperature, 50 ml of methylene chloride are added and the mixture is stirred overnight. The solid in suspension is collected by filtration, dried in air, dissolved in methanol and made basic with 3 N sodium hydroxide. The suspension is diluted • with 500 ml of water and extracted with three 250 ml portions of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure. Analysis by mass spectrometry ς * (electronic impact and chemical ionization) indicates that the residue is a mixture of [2 - [(3-amino-2-pyridyl) amino] phenyl] - (4-methoxy-30 phenyl) methanone and the desired compound. The compound residue is dissolved in 250 ml of toluene with a catalytic amount of p-toluene sulfonic acid and the solution is refluxed overnight under a nitrogen atmosphere, separating the water in a Dean-Stark trap. The reaction mixture is filtered hot. The product precipitates out of the filtrate when cooled to room temperature and collected by filtration. After recrystallization from benzene, the product weighs 1.8 g; M.p. 198.5-200.5 ° C (decomposition).

Analysis: Theoretical for ^ - ^ Η ^, - Ν ^ Ο: C 75.73; H 5.02; N 13.94 Found: C 75.65: H 4.98; N 14.03 5 EXAMPLE 8 8-Chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4-b] benzodiazepine-ll-propanamine, oxalate [1/13 To a suspension stirred with 1.05 g (0.044 mole) of sodium hydride (in mineral oil) in 50 ml of anhydrous dimethylformamide 10, 6.1 g (0.02 mole) are added in portions under a nitrogen atmosphere. 8-chloro-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine. The reaction mixture is stirred at room temperature for 1.5 h and the evolution of nitrogen ceases during this period. 3.5 g (0.022 mol) of 3-dimethylaminopropyl chloride hydrochloride are added to the mixture in portions. After stirring overnight at room temperature, the reaction mixture is poured into 1600 ml of water and extracted with three 250 ml portions of methylene chloride. The combined methylene chloride extracts are washed with two 250 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in benzene and chromatographed with a mixture of acetone and benzene on a column packed with 300 g of Florisil in benzene. 1.6 g of starting material are recovered in the benzene eluate and 3.6 g containing the product in the form of the free base is obtained after evaporating the solvent from the elution product by the mixture of acetone and benzene. A portion (2.5 g) of the crude free base is dissolved in hot isopropyl alcohol and reacted with 0.8 g (0.0064 mole) „* of oxalic acid dihydrate. The precipitated oxalate is collected by filtration and recrystallized from ethanol to give 2.2 g of product; Mp 206-208 ° C. The drying conditions before the analysis are as follows: 5 h at 97-98 ° C / 0.026 mbar; overnight at room temperature / 0.026 mbar.

Analysis: Theoretical for C ^ H ^ CIN ^ O ^: C 62.43; H 5.24; N 11.65 Found: C 62.52; H 5.23; N 11.76 i 27 EXAMPLE 9 M, N-Dimethyl ~ 6-phenyl-11H-pyrido [2,3-bl [l.4] benzodiazepine-ll-propa-namine, fumarate [l / l] To a stirred suspension of 1.68 g (0.070 mole) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylforrnamide, a suspension of 8.0 g (0.029 mole) of 6-phenyl-11H-pyrido [2,3-b] Cl, 4] benzodiazepine in 20 ml of anhydrous dimethylforrnamide. The mixture was stirred for 30 min after completion of the addition, heated to 65 ° C for 10 min and cooled again to room temperature. 5.6 g (0.035 mol) of 3-dimethylaminopropyl chloride hydrochloride are added to the mixture. After stirring overnight at room temperature, thin layer chromatography indicates that the reaction is almost complete. The reaction mixture is poured into 1500 ml of water and extracted with 250 ml of methylene chloride. The extract in methylene chloride is washed with three 250 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in methylene chloride and extracted with 100 ml and 150 ml portions of 3 N hydrochloric acid. 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine unreacted starting material precipitates from the aqueous acid solution and is separated by carefully decanting the liquid. The aqueous solution is made alkaline with 3 N sodium hydroxide and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure to obtain 7.7 g of a residue which consists of the free base of the desired compound.

A solution of 6.6 g of the residue in hot isopropyl alcohol is reacted with 2.15 g of fumaric acid and the mixture is heated until complete dissolution. After standing for 48 hours, the precipitated salt is collected by filtration. After recrystallization from a mixture of isopropyl alcohol and isopropyl ether, 5.9 g of product are obtained; Mp, 171-173 ° C. The drying conditions before the analysis are as follows: 4 h at 90 ° C / 0.13 mbar; overnight at room temperature / 0.13 mbar.

Analysis: Theoretical for ^ 27Η28Η4 ° 4: C 68.63; H 5.97; N 11.86 Found: C 68.37; H 6.05; N 11.73 28 EXAMPLE 10 N, N-Dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-ethanamine, fumarate [l / l] To a stirred suspension of 1 , 48 g (0.062 mole) of sodium hydride (in mineral oil) in 35 ml of anhydrous dimethylformamide under nitrogen, 7.0 g (0.026 mole) of 6-phenyl-11H are added in portions -pyrido [2,3-b] [1,4] benzodiazepine.

After the reaction mixture has cooled to room temperature, 4.46 g (0.031 mole) of 2-dimethylaminoethyl chloride hydrochloride is added in portions and stirring is continued overnight. The reaction mixture is poured into 1500 ml of water and the mixture obtained is extracted with 250 ml of methylene chloride. The methylene chloride extract is washed with three 500 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure to obtain 8.6 g of an oil which is the free base of the compound longed for. Part of the oil (6.9 g) is reacted with an equimolecular amount of fumaric acid in isopropyl alcohol. By addition of isopropyl ether, an oily solid is obtained. The mixture is evaporated under reduced pressure and the residue crystallizes on standing. The crystals are triturated with acetone and recrystallized from a mixture of acetone and isopropyl ether to obtain 4.3 g of the fumarate; Mp 175-177.5 ° C. Analysis: Theoretical for C26H26N4 ° 4: G H 5.72; N 12.22

Found: C 67.88; H 5.72; N 12.17 EXAMPLE 11 11- [3- (4-Morpholinyl) propyl] -6-phenyl-11H-pyrido [2,3-b] [1,4] benzodia-zepine, fumarate [l / l] A a stirred suspension of 1.10 g (0.046 mole) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide 30 under a nitrogen atmosphere, 5.0 g (0.0184 mole) are added in portions ) of 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine. The reaction mixture is stirred at room temperature for 15 min, heated to 65-70 ° C for 10 min and allowed to cool to room temperature. 4.1 g (0.02 mole) of 4- (3-chloropropyl) morpholine hydrochloride are added in portions. The reaction mixture is stirred at room temperature for 16 h and then poured into 800 ml of water. This mixture is extracted twice with 200 ml portions of methylene chloride. The extracts in methylene chloride combined are extracted with 150 ml and 75 ml of 3N 5-chloric acid and the combined aqueous extracts are made alkaline with 3N sodium hydroxide. The suspension obtained is extracted with two portions 150 ml of methylene chloride and the two extracts are then combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue which is the free base of the desired compound is reacted with an equimolecular amount of fumaric acid in hot isopropyl alcohol and the mixture is treated with isopropyl ether. The fumarate is collected by filtration and is recrystallized from a mixture of ethanol and ethyl acetate to obtain 5.6 g of product; Mp 154-7 ° C. The drying conditions before analysis are as follows: 4 h at 97-98 ° C / 0.13 mbar; overnight at room temperature / 0.13 mbar.

Analysis: Theoretical for ^ 29 ^ 30 ^ 4 ^ 5 * ^ ^ 7.69; H 5.88; N 10.88 Found: C 67.52; H 5.84; N 10.90 EXAMPLE 12 20 N, N-Diethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-propa ~ namine, oxalate [1/1] To a stirred suspension 1.10 g (0.0461 mole) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide under a nitrogen atmosphere, 5.0 g (0.0184 mole) are added in portions of 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine. The reaction mixture is stirred at room temperature for 0.5 h, heated to 65-70 ° C and slowly cooled to room temperature. 3.77 g (0.020 mole) of 3-diethylaminopropyl chloride hydrochloride is added portionwise to the mixture and the reaction mixture is stirred at room temperature for 16 h. The mixture is poured into 750 ml of water and extracted with three 150 ml portions of methylene chloride. The combined extracts are extracted into methylene chloride with 150 ml and 75 ml of 3N hydrochloric acid. The combined aqueous extracts are made alkaline with 3N sodium hydroxide and then extracted with three 100 ml portions of chloride. methylene. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure to obtain 7.5 g of the free base of the desired compound. One portion, 5.6 g, is reacted with an equimolecular amount of oxalic acid dihydrate in hot isopropyl alcohol. The oxalate is collected by filtration to obtain 5.5 g of product; Mp 196-199 ° C. The drying conditions before the analysis are: 1 h at 97-98 ° C / 0.13 mbar.

Analysis: Theoretical for (^ H ^ qN ^ O ^: C 68.34; H 6.37; N 11.81 Found: C 68.31; H 6.43; N 11.86 10 EXAMPLE 13 9-Chloro- N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine, fumarate [1/1] To a stirred suspension of 0.98 g (0.041 mol) sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide 15 under a nitrogen atmosphere, 5.0 g (0.016 mole) of 9-chloro-6-phenyl-11H-pyrido are added in portions [ 2,3-b] [1,4] benzodiazepine-pine in 45 min The reaction mixture is stirred at room temperature for 1 h, heated to 70 ° C. and then slowly cooled to room temperature. in portions over 20 min 2.84 g (0.018 mole) of 3-dimethyl-aminopropyl chloride hydrochloride and the reaction mixture is stirred at room temperature for 17 h. The mixture is poured into 750 ml of water and extract with 150 ml and two 100 ml portions of methylene chloride The extracts are washed in methylene chloride combined with two 100 ml portions of water and then extracted with * 100 ml and 75 ml of 3N hydrochloric acid. The acid extracts are combined and filtered to remove the precipitate which has formed and the base is alkalized. filtrate with 3 N sodium hydroxide and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in methylene chloride and filtered through a 50-60 g bed of Florisil on a sintered glass funnel. The bed is washed successively with mixtures of methanol at 1%, 2%, 3% and 57.

35 in methylene chloride, the filtrates are combined and evaporated 31 under reduced pressure to obtain the free base of the desired compound.

The free base is reacted with an Iquimolecular amount of fumaric acid in hot isopropyl alcohol to obtain 3.3 g of fumarate; M.p. 199-202 ° C.

5 Analysis: Theoretical for ^ 27 ^ 27 ^ 4 ^ 4 ^: C 63.96; H 5.37; N 11.05 Found: C 63.63; H 5.36; N 11.00 EXAMPLE 14 6-Phenyl-11- [3- (1-piperidinyl) propyl] -11H-pyrido [2,3-b] [1, ^ benzodiazepine, fumarate [1/1] 10 A stirred suspension 1.10 g (0.461 mole) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide under nitrogen, 5.0 g (0.018 mole) of 6-phenyl- are added in portions 11H-pyrido [2,3-b] [1,4] benzodiazepine. The reaction mixture is stirred for 30 min, heated to 70 ° C and cooled to room temperature. 4.14 g (0.0203 mol) of N- (3-chloropropyl) piperidine hydrochloride are added in portions to the mixture and the reaction mixture is stirred at room temperature for 16 h.

The mixture is poured into 750 ml of water and extracted with 150 ml of methylene chloride with stirring for 15 min. The aqueous layer is extracted with two additional 100 ml portions of methylene chloride. The extracts in methylene chloride combined are extracted with 150 ml and 75 ml of 3N hydrochloric acid and the combined acid extracts are alkalized with 3N sodium hydroxide and then extracted with three 100 ml portions of methylene chloride.

The extracts are combined in methylene chloride, dried over magnesium sulphate and evaporated under reduced pressure. The residue is dissolved in a minimum of methylene chloride and filtered through a 100 g bed of Florisil in a sintered glass funnel The bed is washed successively with methylene chloride, and mixtures of methanol at 1%, 2%, 3% and 5% in methylene chloride.

All the filtrates are combined and evaporated under reduced pressure. The residue is reacted with 1.3 g of fumaric acid in hot isopropanol and isopropyl ether is added. An amorphous precipitate is formed. The whole mixture is evaporated to dryness and the residue is dissolved in 200 ml of ethanol. The solution is heated to reflux, filtered and isopropyl ether is added to the filtrate. The crystals which form overnight are filtered off to obtain 4.1 g of fumarate; Mp 153-6 ° C. The drying conditions before analysis are as follows: 4 h at 97-98 ° C / 0.13 mbar.

5 Analysis: Theoretical for ’c 70> 29’> H 6.29 î N 10.93

Found: C 70.38; H 6.32; N 10.92 EXAMPLE 15 6- (4-Chlorophenyl) -NN-dimethyl-11H-pyrido [2.3-b] [1,4] benzodiazepine-11-propanamine, fumarate [1/1] 1 ° To a stirred suspension of 1.57 g (0.065 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide, 8.0 g (0.026 mol) of 6- (4-chlorophenyl) are added under a nitrogen atmosphere ) -11H-pyrido [2,3-b] [1,4] benzodiazepine. The reaction mixture is stirred for 1 h at room temperature, heated to 80 ° C for 15 min and cooled to room temperature. 4.55 g (0.029 mole) of 3-dimethylarainopropyl chloride hydrochloride is added in portions to the mixture and the mixture is stirred overnight at room temperature. The mixture is poured into 750 ml of water and stirred for 30 min with 150 ml of methylene chloride. The aqueous phase is extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure to obtain the free base of the desired compound. The free base is reacted with an equimolecular amount of fumaric acid in hot isopropanol. By * cooling, 3.6 g of the fumarate precipitate; Mp 200.5-202.5 ° C.

The product is then air dried before analysis.

, 5 Analysis: Theoretical for C ^ H ^ CIN ^: C 63.96; H 5.37; N 11.05

Found: C 64.18; H 5.33; N 11.07 30 EXAMPLE 16 8-Chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-ethanamine, oxalate [l / l] stirred suspension of 1.05 g (0.044 mol) of sodium hydride (in mineral oil) in 50 ml of anhydrous dimethylformamide 33, 6.1 g (0.02 mol) of 8-chloro are added in portions 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine. The reaction mixture is stirred at room temperature for a period of 1.5 h during which the evolution of hydrogen ceases. The reaction mixture is cooled to 5 ° C and 3.2 g (0.022 mole) of 2-dimethylaminoethyl chloride hydrochloride are added in portions, followed by stirring at room temperature for about 60 h. The reaction mixture is poured into 1600 ml of water and the mixture is extracted three times with 500 ml portions of methylene chloride. The 10 combined extracts are washed with two 500 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure. Thin layer chromatography (20% methanol in benzene / silica gel) indicates the presence of the free base of the desired compound and starting material. The residue is dissolved in benzene and chromatographed on a column packed with 200 g of Florisil in benzene. The starting material consisting of 1.3 g of 8-chloro-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine is eluted with benzene and the free base of the desired compound is eluted with mixtures of acetone in benzene. The free base is reacted with an equimolecular amount of oxalic acid dihydrate in isopropyl alcohol at reflux and the product recrystallized from isopropyl alcohol weighs 1.6 g; Mp 228.5-232 ° C. The drying conditions before the analysis are as follows: 6 h at 82 ° C / 0.13 mbar; overnight at room temperature.

Analysis: Theoretical for C ^ H ^ CIN ^: C 61.74; H 4.96; N 12.00 Found: C 61.62; H 4.95; N 11.98 EXAMPLE 17 5 8-Chloro-11-methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine A a stirred suspension of 0.25 g (0.01 mole) sodium hydride (in mineral oil) in 15 ml of anhydrous dimethylformarnide, 3.05 g (0.01 mole) of 8-chloro-6-phenyl-11H-pyrido are added in portions [2,3 -b] [1,4] benzodiazepine. The mixture is heated to about 60 ° C for 1 h. A solution of 1.42 g (0.01 mole) of methyl iodide in 10 ml of anhydrous dimethylformarnide is added dropwise over 0.5 h and the reaction mixture is stirred at room temperature 34 overnight then pour into 400 ml of water and stir for 2 h. The precipitated solid is recrystallized twice from isopropyl alcohol to obtain 2.0 g of product; Mp 153 ~ 156 ° C. The drying conditions before analysis are: 1 h 5 at 82 ° C / 0.13 mbar.

Analysis: Theoretical for C ^ gH ^ ClN ^: C 71.36; H 4.41; N 13.14 Found: C 71.64; H 4.43; N 13.32 EXAMPLE 18 N, N-Dimethyl-6- (4-methylphenyl) IIIH-pyrido [2,3-b] Cl, 4] henzodiazepine-ll-, ··. ^ propanamine, fumarate [l / l] To a stirred suspension of 0.51 g (0.022 mole) of sodium hydride in 25 ml of anhydrous dimethylformamide under nitrogen, 4.2 g (0, 0147 mole) of 6- (4-methyl-phenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine in 45 min. The mixture is stirred for 1 h at room temperature, heated to 75-80 ° C for 1 h, cooled to room temperature and a solution of 0.0184 mole of 3-dimethyl chloride is added dropwise -aminopropyl in 10 ml of anhydrous dimethylformamide. The mixture is stirred overnight at room temperature and poured into 1000 ml of water. The suspension is extracted with three 150 ml portions of methylene chloride and the extracts in methylene chloride combined are extracted with two 150 ml portions of 3N hydrochloric acid. A precipitate formed in the acid solution is separated by filtration and we reject it. The filtrate was made basic with 3 N sodium hydroxide and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure to obtain an oil which is the free base of the desired compound. This residual oil is dissolved in hot isopropyl alcohol and reacted with an equimolecular amount of fumaric acid. The fumarate crystallizes from the solution cooled to room temperature and is recrystallized twice from a mixture of isopropyl alcohol and isopropyl ether to obtain 1.7 g of product; Mp 187-189 ° C (decomposition).

Analysis: Theoretical for C28H30N4 ° 4: c 69> 12 H 6.22; N 11.52 Found: C 68.86; H 6.32; N 11.36 * 35 EXAMPLE 19 6- (4-Methoxyphenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine, fumarate [l / l] A a stirred suspension of 0.45 g (0.0187 mole) of sodium hydride in 25 ml of anhydrous diraethylformamide under nitrogen, 4.5 g (0.015 mole) of 6- (4-methoxyphenyl) are added -11H-pyrido [2,3-b] [1,4] benzodiazepine in 30 min. The mixture is stirred for 30 min at room temperature and then heated to 80-90 ° C for 4 1 h, cooled to room temperature and a solution of 0.019 mole of 3-dimethylaminopropyl chloride in 5 ml of anhydrous dimethylformamide. The reaction mixture is stirred overnight at room temperature and poured into 800 ml of water. The suspension is extracted with two 150 ml portions of methylene chloride. The combined extracts are washed with 500 ml of water and then extracted with two 100 ml portions of 3N hydrochloric acid. The solid precipitated in the combined acid extracts is filtered off and discarded. The filtrate is made alkaline with 3 N sodium hydroxide and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure. The residual oil partially crystallizes and is triturated in methylene chloride and then filtered to obtain 0.32 g of residue. The filtrate is evaporated under reduced pressure and the residual oil is triturated in hot benzene and filtered to obtain 0.8 g of residue. The benzene filtrate is evaporated under reduced pressure and the residual oil is reacted with 1.02 g of fumaric acid in hot isopropyl alcohol. Upon cooling, an oil separates from the solution. The liquid is decanted; supernatant and the oil is inoculated. After partial crystallization, the mixture is filtered to obtain 2.5 g of solid; Mp 157-60 ° C.

When an attempt is made to recrystallize from a mixture of isopropyl alcohol and isopropyl ether, an oil-solid mixture is obtained.

The mixture is warmed with an additional amount of isopropyl alcohol, solubilized, filtered, seeded and cooled. The fumarate precipitates and 2.0 g is collected by filtration; Mp 159-161 ° C. .

36

Analysis: Theoretical for C ^ H ^ N ^ O ,. : C 66.92; H 6.02; N 11.15 Found: C 66.90; H 6.08; N 11.08 EXAMPLE 20 6- (3-Chlorophenyl) IIIH-pyrido [2,3-b] [1,4] benzodiazepine 5 The mixture is heated at reflux overnight, collecting the water with a Dean-Stark trap. a mixture of 14 g (0.0433 mole) of [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (3-chlorophenyl) methanone .. and 0.3 g of p-toluenesulfonic acid in 500 ml of toluene. After the reflux period, about 250 ml of toluene is distilled off and the hot solution is filtered. Petroleum ether (30-60 ° C) is added to the cloud point. The solution is refrigerated overnight and filtered to obtain 10 g (76%) of golden crystals after air drying. A portion is recrystallized from a mixture of isopropyl alcohol and isopropyl ether; Mp 160-160.5 ° C.

Analysis: Theoretical for C ^ gH ^ N ^ Cl: C 70.71; H 3.96; N 13.74 Found: C 70.47; H 3.98; N 13.62 EXAMPLE 21 6- (3-Chlorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine, fumarate [1/1] 20 Has a stirred suspension of 3.4 g (0.07 mole) of sodium hydride (in mineral oil) in 250 ml of anhydrous dimethylformamide, 8.5 g (0.028 mole) of 6- (3-chlorophenyl) IIIH-pyrido [2,3-b] [1,4] benzodia-zepine. The mixture is stirred for 30 min at room temperature.

The temperature is raised to 80 ° C for 3 h and then allowed to cool to room temperature. A solution of 4.9 g (0.031 mole) of 3-dimethylaminopropyl chloride hydrochloride in 30 ml of dimethylformamide is added dropwise to the reaction mixture over 20 min. The reaction mixture is stirred at room temperature overnight under a nitrogen atmosphere. Thin layer chromatography indicates the presence of a certain amount of starting material. 1.4 g (0.03 mole) of sodium hydride are added and, after 15 min, 4.7 g (0.03 mole) of 3-dimethylaminopropyl chloride hydrochloride are added and then stirred for 4.5 h. - 37 * 20 ml of water are added dropwise and the reaction mixture is filtered and then concentrated with a rotary evaporator. The residue is partitioned between ethyl ether and dilute sodium hydroxide. The ethereal layer is washed three times and extracted with dilute aqueous hydrochloric acid. The aqueous layer is made alkaline with sodium hydroxide tablets and extracted with methylene chloride. The methylene chloride layer is dried and concentrated to obtain a residue consisting of 7.5 g of product. The free base is reacted with fumaric acid and the fumarate is recrystallized from a mixture of ethyl acetate and ethanol; Mp 167.5-168.5 ° C.

Analysis: Theoretical for ^ 23 ^ 23 ^ 4 ^: ^ 63.96; H 5.47; N 11.05 Found: C 63.95; H 5.39; N 11.00 EXAMPLE 22 15 6- (4-Fluorophenyl) IIIH-pyrido [2,3-b] [1,4] benzodiazepine

It is refluxed for 24 h eh using a Dean-Stark trap to collect the water a mixture of 11.5 g (0.037 mole) of [2 - [(3-amino-2-pyridinyl) amind] phenyl] - (4-fluorophenyl) methanone and 0.6 g of p-toluenesulfonic acid in toluene. At the end of reflux, part of the toluene (300 ml) is distilled off and the hot solution is filtered. Petroleum ether (30-60 ° C) is added to the cloud point. The solution is refrigerated overnight (0 ° C) and filtered to obtain 10.7 g of crystals. Part of the material is recrystallized from isopropyl alcohol and dried under vacuum overnight at 65 ° C; F. 203-205 ° G.

Analysis: Theoretical for ^ 28H12N3F: C »H 4.18; N 14.52

Found: C 74.61; H 4.17; N 14.54 EXAMPLE 23 6- (4-Fluorophenyl) -NN-dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine, hydrochloride hemihydrate To a stirred suspension of 3.6 g (0.075 mole) of sodium hydride (in mineral oil) in 250 ml of anhydrous dimethylformamide, 8.7 g (0.03 mole) of 6- (4-fluorophenyl) are added in portions under a nitrogen atmosphere ) -11H-pyrido [2,3-b] [1,4] benzodiazes- 38 pine. The mixture is stirred for 30 min at room temperature.

The temperature is brought to 80 ° C. for 3.5 h and then allowed to cool to 45 ° C. A solution of 5.2 g (0.033 mole) of 3-dimethylamino-propyl chloride hydrochloride in 30 ml of dimethylformamide is added dropwise to the reaction mixture. After stirring overnight at room temperature, thin layer chromatography indicates the presence of starting material. 3.6 g (0.075 mole) of sodium hydride are added and, after 45 min of stirring, the reaction mixture is heated at 50-60 ° C for 0.5 h. A green color is formed with release of gas. The mixture is stirred at room temperature for 3 h. A solution of 5.2 g (0.033 mole) of 3-dimethylaminopropyl chloride in 30 ml of dimethylformamide is added dropwise. (Towards half of the addition, a green color forms and the addition is temporarily stopped for approximately 1 h). The reaction mixture is stirred overnight at room temperature. 30 ml of water are added to the mixture while cooling. When the evolution of gas has ceased, the mixture is filtered and concentrated with a rotary evaporator. The residue is partitioned between ethyl ether and water and the ethereal layer is extracted with a dilute aqueous solution of hydrochloric acid. The aqueous layer is filtered after 1.5 h to remove the solid material.

The filtrate is made alkaline with sodium hydroxide tablets and extracted with methylene chloride. The extract is dried and concentrated. The residue is divided into two equal parts and is purified by chromatography on a dry column with two columns (50 x 1.3 cm) of silica gel which has been deactivated with the developing solvent (10¾ of methanol, 1¾ d concentrated ammonium hydroxide, 89% methylene chloride). The central portion of the columns is cut and extracted with the developing solvent. The combined extracts are concentrated under reduced pressure and the residue is dissolved in a mixture of ethyl acetate and ethanol and then acidified with concentrated hydrochloric acid. The hydrochloride is recrystallized from a mixture of ethanol and ethyl acetate. The solid was filtered off and dried at 99 ° C for 48 h to obtain the desired compound as the hydrochloride hemihydrate mp 120-123 ° C. Analysis: Theoretical for C ^^ H ^ NgF ^ Cl ^ O: C 65.78; H 6.00; N 13.34 Found: C 65.58; H 5.77; N 13.47 3 39 EXAMPLE 24 11 “[3- (1,3-Dihydro-1,3-dioxo-2H-isoindole-2-yl) propyl] -6-phenyl-11H-pyrido [2,3-b ] [1,4] benzodiazepine To a stirred suspension of 0.56 g (0.023 mole) of sodium hydride in 25 ml of anhydrous dimethylformamide, 5.0 g (0.0184 mole) of 6- phenyl-11H-pyrido [2,3-b] [1,4] benzo "diazepine. The reaction mixture is heated to 80-2 ° C for 1 h and cooled to room temperature. A solution of 5.55 g (0.020 mole) of N- (3-bromopropyl) phthalimide 10 in 10 ml of anhydrous dimethylformamide is added dropwise and, after 16 h of stirring, the reaction mixture is poured into 650 ml of water and stirred for 30 min. The yellow solid is collected by filtration and recrystallized three times in isopropyl alcohol to obtain 3.7 g of product; M.p. 170-172 ° C.

15 Analysis: Theoretical for ^ 29H22N4 ° 2: C 75 »^ 7> H» N 12.22

Found: C 76.25; H 4.87; N 12.34 EXAMPLE 25 6-Phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine, dihydrochloride hemihydrate 20 'A mixture of 16.2 is brought to reflux for 2.5 h g (0.035 mole) of 6-phenyl-ll- [3 ~ (phthalimido) propyl] -llH-pyrido [2,3-b] - [1,4] benzodiazepine and 2.29 g (0.0387 mole) d hydrazine hydrate at 85% in 175 ml of ethyl alcohol at 95% by volume. A solution of 10 ml of concentrated hydrochloric acid in 50 ml of water is added to the mixture. The mixture is stirred overnight. The precipitated solid is collected by filtration and discarded. The filtrate is evaporated under reduced pressure. The slightly damp residue is suspended in 200 ml of water and the mixture is stirred for 2 h then filtered through celite. The filtrate is evaporated under reduced pressure and the residue is suspended in 100 ml of 100% ethyl alcohol by volume and evaporated under reduced pressure. This last operation is repeated twice. The crude wet residue (42.1 g) is recrystallized from isopropanol, leaving to stand for approximately 15 h. The solid was collected by filtration and dried at 82 ° G over phosphoric anhydride at 0.13 mbar for 3 h; M.p. 210-220 ° C (decomposition).

40

Analysis: Theoretical for C ^ H ^ Cl ^ NgO: C 61.47; H 5.65; N 13.65 Found: C 61.36; H 5.72; N 13.90 EXAMPLE 26 6-Phenyl-11H-pyrido [2,3-b] [1,443 benzodiazepine-ll-propana mine ^ A portion of 6-phenyl-11H-pyrido- [2, is dissolved in water 3-b] [1,4] benzodiazepine-11-propanamine, dihydrochloride hemihydrate obtained in Example 25, basified with dilute sodium hydroxide and extracted with three portions of methylene chloride. The combined methylene chloride extracts are filtered through a 50-60 g Florisil bed in a sintered glass funnel. The bed is washed successively with mixtures of methanol at 1%, 2%, 3% and 5% in methylene chloride, the filtrates are combined and evaporated under reduced pressure to obtain the desired compound in the form of the free base. .

15 EXAMPLE 27

N- [3- [6-phenyl-11H-pyrido [2,3-b] [1,4-benzo-diazepine-ll-yl] propyl1methanimidic acid ethyl ester

A solution of 8.8 g (0.021 mole) of 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-20 propanamine in 150 ml of is heated at reflux for 4.5 h. 'triethyl orthoformate and allowed to stand overnight. The mixture is concentrated in vacuo and the residue is washed with petroleum ether (30-60 ° C). Chemical ionization mass spectrometry indicates that the product is a mixture containing the desired compound.

EXAMPLE 28 N-Methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine. d ichlorhydra te

Preparation of the imidate ester [Crochet Method, TA & Blanton, CD, Jr. Synthesis 1974 (1) 55-56] 30 g (0.06 mole) of 6-phenyl-11H-pyrido- are transformed [2,3-b] [1,4] benzodiazepine-ll-propanamine dihydrochloride hemihydrate from Example 25 into the free base by partitioning between dilute sodium hydroxide and methylene chloride, drying and concentration at 41! dry of the methylene chloride layer, addition of anhydrous benzene then new concentration to drive out the benzene. The free base obtained is dissolved in 300 ml (267 g; 1.8 mole) of freshly distilled triethyl orthoformate, bringing to reflux for 9 h.

The mixture is concentrated in vacuo, ethanol is added and the mixture is concentrated again.

Conversion of the amidate into an amine The 23.4 g (0.061 mole) of amidate prepared above was dissolved in 200 ml of ethanol and sodium borohydride was added with stirring between 15 and 20 ° C until that the thin layer chromatography * shows practically the absence of starting material indicating that the reaction is essentially completed. 50 ml of water are added slowly with stirring and cooling is continued for 15 min after the addition of water. 2 liters of water are added to the mixture and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water until the washing liquid is neutral and then saturated with sodium chloride. The ethyl acetate layer obtained is dried and concentrated. Ethyl ether is added and the mixture is cooled. A certain amount of insoluble material is filtered off and discarded. The ether layer is concentrated and the product is chromatographed on an alumina column (neutral, activity: 1), eluting with a mixture of ethyl acetate, methanol and traces of triethylamine. The fractions containing a non-negligible quantity of product (chroma-tography in a thin layer) are subjected to a partition between ethyl acetate and aqueous sodium hydroxide. Ethereal hydrochloric acid is added to the ethyl acetate layer and the crystalline product is recrystallized from a mixture of acetonitrile and water. The product has a melting point of 139-141 ° C.

30 Analysis: Theoretical for ^ 22 ^ 24 ^ 4 ^^ 2: ^ 63.62; H 5.82; N 13.49 Found: C 63.81; H 6.15; N 13.60 EXAMPLE 29

N- [3 “[6-phenyl-11H-pyrido [2,3-b] [2,3-benzo-diazepine-ll-yl] propyl] carbamic acid ethyl ester 35 A solution of 1.6 g (0.0045 mole) of 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine in anhydrous 42 methylene chloride, 0.53 g is added (0.0052 mole) of triethylamine.

0.54 g (0.0050 mole) of ethyl chloroformate is added dropwise to this solution while cooling. The mixture is stirred at room temperature for 2 h. The methylene chloride solution of the product is washed (as indicated by chemical ionization mass spectrometry) with a dilute aqueous solution of sodium hydroxide saturated with sodium chloride, dried and concentrated in vacuo. The residue is triturated in isopropyl ether.

, 1.5 g of the desired product are obtained.

EXAMPLE 30 5,6-Dihydro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine, dihydrochloride hemihydrate

A solution of 3.0 g (0.0065 mole) of N, N-15 dimethyl-6-phenyl-11H-pyrido [2,3- is adjusted to pH 5.6 with a solution of hydrochloric acid in methanol. b] [1,4] benzodiazepine-ll-propanamine in absolute methanol. 0.7 g (0.011 mole) of NaBH 4 CN is added all at once to this solution and the reaction mixture is brought to reflux for 20 min. The ethanol is removed in vacuo and the residue is partitioned between dilute sodium hydroxide and methylene chloride. The methylene chloride layer is dried over sodium sulfate and concentrated to leave a residue which is crystallized twice from isopropanol and isopropyl ether. 1.6 g (57%) of a yellow solid are obtained which loses its crystalline structure on heating from 156-160 ° C and decomposes at 180-195 ° C.

Analysis: Theoretical for C ^ gH ^ gNgOCl ^: C 62.73; H 6.64; N 12.72 Found: C 62.40; H 6.90; N 12.61 EXAMPLES 31a to 31r

According to the procedure of Example 6, the following methanone derivatives are cyclized: [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (4-ethylphenyl) methanone, [2- [ (3-amino-2-pyridinyl) amino] phenyl] - (4-isopropylphenyl) methanone, the [2 - [(3-amino-2-pyridinyl) amino jphenyl] - (4-bromophenyl) methanone, the [2- [(3-amino-2 (pyridinyl) amino] phenyl] - (4-fluorophenyl) methanone, 43 "la [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (4-ethoxyphenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (4-nitrophenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (4-trifluoromethylphenyl) -methanone, 5 la [2 - [(3-araino-2 “pyridinyl) amino] phenyl]“ (3-methylphenyl) methanone, la [2 - [(3-amino-2-pyridinyl) amino] phenyl] - ( 3-ethylphenyl) methanone, the [2 - [(3-araino-2-pyrid inyl) amino] phenyl] - (3-me thoxyphenyl) me thanone, the [2-t (3-amino-2-pyridinyl) amino ] phenyl] - (3-ethoxyphenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-nitrophenyl) methanone, 10 la [2 - [(3-amino-2- pyridinyl) aminoJphenyl] - (3-trifluorome thylphenyl) - me thanone, the [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-methylphenyl) niethanone, the [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-ethylphenyl) methanone, the [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-methoxyphenyl) methanone, the [2 - [(3-amino-2-pyridinyl) amino ] phenyl] - (2,4-dichlorophenyl) methanone, and [2 - [(3-amino-2-pyridinyl) amino] phenyl- (3,4,5-trimethoxyphenyl) -me thanone, to the following pyridobenzodiazepines: A) 6- (4-ethylphenyl) IIIH-pyrido [2,3-b] [1,4] benzodiazepine, b) 6- (4-isopropylphenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine, c) 6- (4-bromophenyl) IIIH-pyrido [2,3-b] [l4] benzodiazepine, d) 6- (4- £ luorophenyl) IIIH-pyrido [2 , 3-b] [lj4] benzodiazepine, e) 6- (4-ethoxyphenyl) -11H-pyrido [2,3-b] [l> 4] benzodiazepine, 25 £) 6- (4-nitrophenyl) - 11H-pyrido [2,3-b] [1,4] benzodiazepine, g) 6- (4-trifluoromethylphenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine, h) 6- (3-methylphenyl) -11H-pyrido [2,3-b] [l4] benzodiazepine, i) 6- (3-ethylphenyl) -11H-pyrido [2,3-b] [1 ^^ benzo diazepine, j) 6- (3-methoxyphenyl) -llH-pyrido [2,3-b] [2,3}] benzodiazepine, 30 k) 6- (3-ethoxyphenyl) -llH-pyrido [2,3- b] [l} 4] benzodiazepine, l) 6- (2-nitrophenyl) -11H-pyrido [2,3-b] tl, 4] benzodiazepine, m) 6- (3-trifluoromethylphenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine, n) 6- (2-methylphenyl) -11H-pyrido [2,3-b] [1,4Jbenzodiazepine, o) 6- (2-ethylphenyl) -llH-pyridot2,3-b] [lj4] benzodiazepine, 35 p) 6- (2-methoxyphenyl) -llH-pyrido [2,3-b] [lj4] benzodiazepine, q) 6- (2,4 -dichlorophenyl) -llH-pyrido [2,3-b] [1,4] benzodiazepine, and r) 6- (3,4,5-trimethoxyphenyl) -llH-pyrido [2,3-b] [l, 4] benzodiazepine.

44s

T

EXAMPLES 32a to 32o

According to the procedure of Example 3, the following methanone derivatives are cyclized: [2 - [(3-amino-2-pyridinyl) amino] -5-chlorophenyl] (phenyl) methanone, 5 [2- [ (3-amino-2-pyridinyDamino] -6-chlorophenyl] (phenyl) me thanone, la [2 - [(3-amino-2-pyridinyl) amino] -4-bromophenyl] (phenyl) me thanone, la [2 "C (3-amino-2-pyridinyl) amino] -4-fluorophenyl] (phenyl) methanone, la [2 - [(3-amino-2-pyridinyl) amino] -4-trifluorQmethylphenyl] (phenyl) - = methanone ), 10 [2 - [(3-amino-2-pyridinyl) amino] -4-methylphenyl] (phenyDmethanone, [2 - [(3-amino ~ 2-pyridinyDamino] -5-methylphenyl] (phenyl) methanone , Γ2 - [(3-amino-2-pyr idinyl) amino] -6-me thylphenyl] (phenyl) me thanone, [2- [(3-amino-2-pyridinyDamino] -4-é thyl phenyl] (phenyl) methanone, the [2 - [(3-amino-2-pyridinyl) amino] -4-methoxyphenyl] (phenyl) methanone, the [2 - [(3-amino-2-pyridinyl) amino] - 4-ethoxyphenylKphenyl) methanone, the [2 - [(3-amino-2-pyridinyl) amino] -4-nitrophenyl] (phenyl) methanone, the [2 - [(3-amino-2-pyridinyl) amino] -5 -nitrophény!] (phenyl) m ethanone, [2- [(3-amino-2-pyridinyl) amino] -3-methylphenyl KphenyDmé thanone, and [2 - [(3-amino-2-pyridinyl) amino] -3 ~ chlorophenyl KphenyDmé thanone , 20 to obtain the following benzodiazepines: a) 8-chloro-6-phenyl-11H-pyrido [2,3-b] [1,4jbenzodiazepine, b) 7-chloro-6-phenyl-HH-pyrido [2 , 3-b] [1,4] benzodiazepine, c) 9-bromo-6-phenyl-11H-pyrido [2,3-b] [1,4Jbenzodiazepine, d) 9-fluoro-6-phenyl-HH -pyrido [2,3-b] [1,4 jbenzodiazepine, 25 e) 6-phenyl-9-trifluoromethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine, f) 9-methyl -6-phenyl-11H-pyrido [2,3-b] [1 ^ jbenzodiazepine, g) 8-methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine, h) 7-metbyl-6-phenyl-HH-pyrido [2,3-b] [1,4jbenzodiazepine, i) 9 ~ ethyl-6-phenyl-11H-pyrido [2,3 ~ b3 [ij4] 'benzodiazepine, J) 9-methoxy-6-phenyl-11H-pyrido [2,3-b] [1,4, benzodiazepine, k) 9-ethoxy-6-phenyl-11H-pyrido [2,3-b] [ij4] benzodiazepine, D 9-nitro-6-pbenyl ~ llH-pyrido [2,3-b] [1 ^ 4jbenzodiazepine m) 8-nitro-6-phenyl-llH-pyrido [2,3-b] [i ^ jbenzodiazepine, n) 10-methyl-6-phenyl-11H-pyrido [2jS-bjii ^ jbenzodiazepine, and 35 o) 10-chloro-6-phenyl-11H-pyrido [2,3-b] [χ ^ jbenzodiazepine .

45 EXAMPLES 33a to 33r

According to the procedure of Example 15, but using equimolecular quantities of each of the compounds prepared in Example 31, the following pyridobenzodiazepines 5 6-phenyl-substituted are prepared: a) 6 ~ (4-ethylphenyl) “ N} N ~ dimethyl-11H-pyrido [2J3-b] [1 ^ benzodiazepine-11- propana mine, b) N, N-dimethyl-6- [4- (1-methylethyl) phenyl] -llH-pyrido [ 2,3-b] [1,4] -1 benzodiazepine-ll-propanamine, c) 6- (4-bromophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1,4 ] benzodiazepine-ll-propanamine, d) 6- (4 ~ £ luorophenyl) -N, N-dimethyl-llH-pyrido [2,3 ~ b] [l} 4] benzodia- - zepine-ll-propanamine , e) 6- (4 ~ ethoxyphenyl) “N, N-dimethyl-11H-pyrido [2,3-b] [1,4] benzodia-zepine-ll-propanamine, f) N, N-dimefchyl ~ 6- (4-nitrophenyl) -11H-pyrido [2,3-b] [1 ^ benzodiazepine-11-propanamine, g) N, N "dimethyl" 6 "[4- (trifluoromethyl) phenyl] -llH- pyrido [2,3-b] [1,4] - benzodiazepine-ll-propanamine, 20 h) N, N-dimethyl-6- (3 ~ methylphenyl) -llH-pyrido [2,3-b] [l } 4] ben2odia- zepine-ll-propanamine, i) 6- (3-ethylph enyi) -N, N-dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine, j) 6- (3-methoxyphenyl) -N, N-dimethyl-11H -pyrido [2,3 ~ b] [l> 4] benzodia- zepine-ll-propanamine, k) ô- (3-ethoxyphenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [l} 4] benzodiazepine-ll-propanamine, l) N, N-dimethyl-6- (2-nitrophenyl) -11H-pyrido [2,3-b] [i, 4] benzodia-zepine-ll -propanamine, 30 m) NJN-dimetbyl-6-r4- (tri £ luoromethyl) phenyl] -llH-pyrido [2,3-b] ClJ4] - benzodiazepine-ll-propanaraine, n) N, N-di .methyl-6- (2-methylpheny) -llH-pyrido [2,3-b] [l> 4] benzodiaze pine-1X-prûpana mine o) la 6- (2-ethylphenyl) -N, N- dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine, 46 p) 6- (2-methoxyphenyl) -Ν, Ν-dimethyl-11H-pyrido [2, 3-b] [1,4] benzo-diazepine-11-propanamine, q) 6- (2,4-dichlorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1,4 ] benzo-diazëpine-ll-propanamine, and 5 r) N, N-dimathyl-6 ~ (3,4,5-trimethoxyphenyl) -llH-pyrido [2,3-b] [1,4-] -benzadiazepine- ll-propanamine.

EXAMPLES 34a to 34o j According to the procedure of Example 13, but using equimolecular amounts of the compounds prepared in; Example 32 Instead of 9-chloro-6-phenyl-11H-pyrido [2,3-bHl, 4] - benzodiazepine, the following pyridobenzodiazepines are prepared: a) 8-chloro-N3N-dimethyl-6 -phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine, b) 7-chlorQ-N3N-dimethyl-6-phenyl-11H-pyrido [2,3-b ] [1,4] benzodia-zepin-ll-propanamine, c) 9 »broma-N, N-dimethyl-6-phenyl ~ llH-pyrido [2,3-b] [1,4] benzodia-zepine -ll-prapanamine, d) 9 '"£ luoro - N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine, 20 e ) N, N-dimethyl-6-phenyl-9- (trifluoromethyl) IIIH-pyrido [2,3-b] [1,4] - benzodiazepine-ll-propanamine, f) N, N, 9-trimethyl -6-phenyl-nH ~ pyrido [2,3 ~ b] [1,4] benzodiazepine-11-propanamine, g) N1NJ8-trimethyl-6-phenyl-ilH-pyridoC2,3-b] [1,4] benzodiazepine-11-propanaraine, 'h) N, N, 7-triraethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine, i) 9-ethyl ~ N, N-dimethyl-6-phenyl-IIH-pyrido [2,3-b] [l} 4] benzodia-zepine-ll-propanamine, 30 j) 9-methoxy-N, N-dimethyl-6 ~ ph enyl-UH-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine, k) 9-ethoxy-N, N '»dimethyl-6-phenyl-llH-pyrido [2,3 -b] [1,4] benzodiazepine-ll-propanamine, l) Ν, Ν-dimethyl "9-nitro-6 ~ phenyl-llH-pyrido [2,3-b] [1,4] benzodia- 35 zepin-ll-propanamine,! 47 * ra) NjN-dimethyl-e-nitro-ô-phenyl-11H-pyridofëjS-blCl ^ benzodia-zepine-ll-propanamine, n) N, N310-trimethyl-6-phenyl-11H-pyrido [2, 3-b] [1 ^ benzodiazepine-ll-propanamine, and 5 o) 10-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4-benzodiazepine -ll-propanamine EXAMPLES 35a to 35c

According to the procedure of Example 1 and replacing 3-amino-2-chloropyridine by equimolecular amounts of the following compounds: 4-amino * -3-chloropyridine, 3-amino-4-chloropyridine, and 2-amino-3-chloropyridine, we obtain: 15 a) 6-phenyl-11H-pyrido [3,4-b] [1,4] benzodiazepine, b) 10-phenyl-5H-pyrido [4,3 -b] [1,4] benzodiazepine, and c) 10-pbenyl-5H-pyrido [3,2-b] [1,4] benzodiazepine.

EXAMPLES 36a to 36c

According to the procedure of Example 3, the following compounds are transformed: [2 - [(4-amino-3-pyridinyl) amino] phenylmethanone [2 - [(3-amino-4-pyridinyl) amino] phenylmethanone, and [2 - [(2-amino-3-pyridinyl) amino] phenylmethanone, in the following compounds: '25 a) 6-phenyl-11H-pyrido [334 ~ b] [1,4] benzodiazepine, b) 10-phenyl-5H-pyrido [4,3-b] [1,4] benzodiazepine, and c) 10-phenyl-5H-pyrido [3,2-b] [1,4] benzodiazepine.

EXAMPLES 37a to 37c

According to the procedure of Example 9, but replacing 6-ph "nyl-11H-pyrido [2,3-b] [1,4] benzodiazepine with equimolecular amounts of the following compounds' 6-phenyl- llH-pyrido [3} 4-b] [1 ^ benzodiazepine, 10-phenyl-5H “Pyrido [4,3 ~ b] [1,4] benzodiazepine, and 10-phenyl-5H-pyrido [3,2 -b] Γ1.4] benzodiazepine, 48 "the following compounds are obtained: a) N, N-dimethyl-6-phenyl-11H-pyrido [3,4-b] [1,4] benzodiazepine-ll-pro pana mine, fuma rate b) N, N-dimethyl-10-phenyl-5H-pyrido [4,3-b] [1,4] benzodiazepine-5-5 propanamine, fumarate, and c) N, N- dimethyl-10-phenyl-5H-pyrido [3,2-b] [1 ^ Ibenzodiazepine-S-propanamine, fumarate.

EXAMPLE 38 5,6-Dihydro-6-phenyl-N-methyl-tlH-pyrido [2, 3-bl [1,4] benzodiazepine-ll-- 10 propanamine A solution of 1.4 g (0.0035 mol ) methyl ester of N- [3- [6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-yI] -propyl] carbamic acid (from Example 29 ) in tetrahydrofuran, 0.4 g (0.0105 mole) of lithium aluminum hydride is added under a nitrogen atmosphere and a slightly exothermic reaction takes place. The mixture is cooled to avoid overheating.

The mixture is stirred at reflux temperature for 16 h. Thin layer chromatography indicates that only partial conversion has occurred. 0.4 g (0.0105 mole) of lithium aluminum hydride is added and the mixture is brought to reflux overnight. Thin layer chromatography indicates that the product consists mainly of the desired compound.

EXAMPLE 39 6- (2-Thienyl) IIIH-pyrido [2,3-b] [1,4] benzodiazepine ^ According to the procedure of Example 20, the [2 - [(3-amino- 2-pyridinyl) amino] phenyl] (2-thienyl) methanone with p-toluenesulfonic acid as catalyst in an organic solvent by removing water with a Dean-Stark trap to obtain the desired compound.

EXAMPLE 40 6- (3-Thienyl) IIIH-pyrido [2,3-b] [1,4] benzodiazepine

According to the procedure of Example 20, the [2 - [(3-amino-2-pyridinyl) amino] pbenyl] (3-thienyl) methanone is heated with p-toluenesulfonic acid as catalyst in an organic solvent 49 r * while hunting, water with a Dean-Stark trap to obtain the desired compound.

EXAMPLE 41 6- (2-Pyridinyl) IIIH-pyrido [2,3-b] [1,4] benzodiazepine 5 According to the procedure of Example 3, the [2 - [(3-amino-2) is cyclized -pyridinyl) amino] phenyl] (2-pyridinyl) me thanone to obtain the desired compound.

EXAMPLE 42; 6- (3-Pyridinyl) IIIH-pyrido [2.3-b] [1,4] benzodiazepine 10 According to the procedure of Example 3, the [2 - [(3-amino-2-pyrid inyl) is cyclized amino] phenyl] (3-pyridinyl) me thanone to obtain the desired compound.

EXAMPLE 43 6- (4-Pyridinyl) IIIH-pyrido [2,3-b] [1,4] benzodiazepine According to the procedure of Example 3, the [2 - [(3-amino-2) is cyclized -pyr id inyl) amino] phenyl] (4-pyrid iny1) me thanone to obtain the desired compound.

EXAMPLE 44 N.N-Dimethyl-6- (2-thienyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine-ll-20 propanamine

According to the procedure of Example 23, the 6- (2-thienyl) -UH-pyrido [2,3-b] [1,4] benzodiazepine is reacted with sodium hydride and then with sodium chloride. 3-dimethylaminopropyl to obtain the desired compound.

EXAMPLE 45 N, N-Ditethyl-6- (3-thienyl) -1H-pyrido [2.3-b] [1.4] benzodiazepine-ll-propanamine

According to the procedure of Example 23, the 6- (3-thienyl) -IIIH-pyrido [2,3-b] [1,4] benzodiazepine is reacted with sodium hydride and then with sodium chloride. 3-dimethylaminopropyl to obtain the desired compound.

i! Ψ 50 EXAMPLE 46 N, N-Dimethyl-6- (2-pyridinyl) IIIH-pyrido [2,3-b] C1,4] benzodiazepine-ll-propanamine

According to the procedure of Example 23, the 6- (2-pyridinyl) -IIIH-pyrido [2,3-b] [1,4] benzodiazepine is reacted with sodium hydride and then with sodium chloride. 3-dimethylaminopropyl to obtain the desired compound.

EXAMPLE 47 N, N-Dimethyl-6- (3-pyridinyl) IIIH-pyrido [2,3-bHl .43ben.godiazepine-ll-- 10 propanamine

According to the procedure of Example 23, reacting = 6- (3-pyridinyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine with sodium hydride then with chloride 3-dimethylaminopropyl to obtain the desired compound.

EXAMPLE 48 N, N-Dimethyl-6- (4-pyridinyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine-11 “propanamine

According to the procedure of Example 23, the 6- (4-pyridinyl) -IIIH-pyrido [2,3-b] [1,4] benzodiazepine is reacted with sodium hydride and then with sodium chloride. 3-dimethylaminopropyl.

EXAMPLES 49a to 49g

According to the procedure of Example 6, the following methanone derivatives corresponding to intermediates 15a to 15g are transformed: the [2 - [(3-amino-4-methyl-2 ~ pyridinyl) amino] phenylIphenylmethanone, the [ 2 - [(3-amino-5-methyl-2-pyridinyl) amino] phenyl] phenylmethanone, the [2 - [(3-amino-6-methyl-2-pyridinyl) amino] phenyl] phenylmethanone, the [2- [(3-amino-5,6-dimethyl-2-pyridinyl) amino] phenyl] phenylmethanone, la [2 - [(3-amino-6-methoxy-2-pyridinyl) amino] phenyl] phenylmethanone, la [2 - [(3-amino-2-methyl-4-pyridinyl) amino] phenyl] phenylmethanone, and [2 - [(3-amino-5-methoxy-2-pyridinyl) -amino] phenyl] phenylmethanone, in pyridobenzodiazepines following: 4

S

51 a) 4-methyl-6-phenyl-11H-pyrido [2,3-b] Cl, 4] benzodiazepine, b) 3-methyl-6-phenyl-11H-pyrido [2,3-b] [ 1 ^ benzodiazepine, c) 2-methyl-6-phenyl-11H ~ pyrido [2,3-b] [1,4] benzodiazepine, d) 2,3-dimethyl-6-phenyl-11H-pyrido [2 , 3-b] [1,4] benzodiazepine 5 e) 2-methoxy-6-phenyl-11H-pyridoC2,3-b] [14} benzodiazepine, f) l-methyl-10-phenyl-5H -pyrido [4,3-b] [l} 4] benzodiazepine ,. and g) 3-methoxy-6-phenyl-11H-pyrido [2,3 b] [1,4] benzodiazepine.

EXAMPLES 50a to 50p

According to the procedure of Example 23, the pyridobenzodiazepines prepared in Example 49 are reacted with sodium hydride and 3-dimethylaminopropyl chloride to obtain the following compounds: a) N, N, 4- tri.methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine, 15 b) N, N, 3-trimethyl-6-phenyl-11H-pyrido [2 , 3-b] [1,4] benzodiazepine-ll-propanamine, c) N, N, 2-trimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll- propanamine, d) N, N, 2J3-tetramethyl-6-phenyl-11H-pyrido [2,3 ~ b] [1,4] benzodiazepine-20 11-propanamine, e) 2-methoxy-N, N- dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodia-zepine-ll-propanamine, f) N, N, 1-trimethyl thyl-10-phenyl-5H-pyrido [4 , 3-b] Cl, 4 Jbenzodiazepine-5-propanamine, and 25 g) 3-methoxy-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodia- - zepine-ll-propanamine.

EXAMPLES 51a to 51c

According to the procedure of Example 22, but using instead of [2 - [(3-amino-2-pyridinyl) amino] phenyl] (4-fluorophenyl) methanone the following compounds: [2 - - [(3-amino-2-pyridinyl) amino] phenyl] (2-fluorophenyl) methanone, [2 - [(3-amino-2-pyridinyl) amino] phenyl] (2-chlorophenyl) methanone, and [ 2 - [(3-amino-2-pyridinyl) amino] phenyl] (2-bromophenyl) methanone, the following compounds are obtained: - '. 52 sa) 6- (2-fluorophenyl) IIIH-pyrido [2,3-b3 [1,4] benzodiazepine, b) 6- (2-chlorophenyl) IIIH-pyrido [2J3-b] tl, 4 ] ben20diazepineJ and c) 6- (2-bromophenyl) IIIH-pyrido [233-b] [l34] benzodiazepine.

EXAMPLES 52a to 52c According to the procedure of Example 23, replacing 6- (4-fluorophenyl) IIIH-pyrido [233-b] [l34] benzodiazepine with the following pyrido [l} 4] benzodiazepines:

6- (2-fluorophenyl) IIIH-pyrido [233-b] [134] benzodiazepine3 6- (2-chlorophenyl) IIIH-pyrido [2,3-> b] [134] benzodiazepine, and 10 la 6- (2-bromophenyl) -11H-pyrido [233-b] [1J4] benzodiazepineJ

we obtain: a) 6-C2-fluorophenyl) -N, N-dimethyl-11H-pyrido [2i3-b] [1,4] benzo-diazepine-ll-propanamine, mp 92-94 ° C; recrystallization solvent: isopropyl alcohol / isopropyl ether, 15 b) 6- (2-chlorophenyl) -NJN-dimethyl-lUl-pyridol2,3-b] [1,4] benzodia-zepine-ll-propanamine, F. 104 -105 ° C; recrystallization solvent: isopropyl ether} and c) 6- (2-bromophenyl) -N3N-dimethyl-llH-pyrido [233-b] [l} 4] benzodia-zepine-ll-propanamine3 F. 96-9S ° C ; recrystallization solvent: 20 isopropyl ether.

EXAMPLES 53a and 53b

According to the procedure of Example 9, replacing 3-dimethylaminopropyl chloride with 3-dimethyl-amino-2-methylpropyl chloride and 4-diraethylaminobutyl chloride, one obtains: a) N3N, ß-trimethyl -6-phenyl-11H-pyrido [233-b] [l34] benzodxazepine “ll-propanamine3 fumarate, and b) N} N-dimethyl-6“ phenyl “llH-pyrido [233-b] [l34] benzodiazepine- ll- butanamine, fumarate, 3 ° EXAMPLES 54a and 54b

The procedure of Example 11 is repeated, replacing 4- (3'-chlorophenyl) morpholine, hydrochloride with the following compounds: »53 lO-chlpropropyl) -pyrrolidiiie, hydrochloride, and l- (3-chloropropyl) “4-methylpiperazine, hydrochloride to obtain the following compounds: 6-phenyl“ ll- [3- (1 “pyrrolidinyl) propyl3-11H-pyrido [2,3-'b] [1,4]“ 5 benzodiazepine, and 6-phenyl “ll- [3- (4-methyl-1-piperazinyl) propyl]“ llH-pyrido [2,3-b] “[1,4] benzodiazepine.

EXAMPLES 55a to 55c

The procedure of Example 9 is repeated, replacing; 10 6 “phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine with the following compounds:: 8-methyl-6-phenyl“ llH-pyrido [3,4-b] [l, 4] benzodiazepine, 6- (4 “chlorophenyl)“ llH-pyrido [3,4 “b] [1,4] benzodiazepine, and 3-methoxy-6“ phenyl-llH-pyrido [3,4-b] [1,4] benzodiazepine 15 to obtain the following compounds: a) N, N, 8-trimethyl “6-phenyl-11H-pyrido [3,4-b] [1,4] benzodiazepine-11-propanamine b) 6- (4-chlorophenyl) -N, N-dimethyl “IIH-pyrido [3,4-b] [1,4] benzodiazepine-ll-propanamine, and c) 3-methoxy-N, N -dimethyl “6-phenyl-11H-pyrido [3,4“ b] [1,4}] benzodiaze pine-11-propanamine.

EXAMPLES 56a to 56d

The procedure of Example 17 is repeated, replacing the 8-chloro-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine 25 with the following compounds: 6-phenyl-11H- pyrido [2,3-b] [1,4] benzodiazepine, 8-chloro-6- (2-nitrophenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine, 8-chloro- 6- (2-chlorophenyl) -11H-pyridot2.3-b] [1,4] benzodiazepine, and 8-chloro-6- (2 “bromophenyl) -11H-pyrido [2,3-b] Cl, 4 ] benzodiazepine 30 to obtain the following compounds: a) ll-methyl-6-phenyl-11H-pyrido [2,3-b] [l} 4] benzodiazepine, b) 8-chlorO “ll-methyl-6- (2 “nitrophenyl) ~ llïï-pyrido [2> 3-b] [lJ43- benzodiazepine, mp 165-166 ° C; recrystallization solvent: ethyl alcohol, t * 54 c) 8-chloro-6- (2-chlorophenyl) -ll-methyl-11H-pyrido [2,3-b] [l ^ 4] - benzodiazepine, F. 150 -152 ° C; recrystallization solvent: isopropyl alcohol / isopropyl ether, and d) 6- (2-bromophenyl) -8-chloro-ll-methyl-11H-pyrido [2,3 "b] [l 4] - 5 benzodiazepine, F. 121-123 ° C; recrystallization solvent: isopropyl ether.

EXAMPLE 57 N-methyl-N - [(11H-pyridoi2,3-b] [1,43benzodiazepine-ll-yl) propyl] carbamic acid methyl ester 10 The desired compound is prepared by reaction of 6 -phenyl- HH-pyrido [2,3-b] [1,4] benzodiazepine and the methyl ester of (3-chloropropyl) methylcarbamic acid.

EXAMPLE 58 9-Hydroxy-N, N-dimethyl-6-phenyl-11H-pyrido [2.3-b] [1,4] benzodiazepine-15 11-propanamine

The desired compound is prepared by reaction of 11-C3- (dimethylamino) propyl] -9-methoxy-6-phenyl-11Hpyrido [2,3-b] [1,4] benzo-diazepine with hydroiodic acid and l glacial acetic acid.

EXAMPLE 59 3-Hydroxy-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine

The desired compound is prepared by reaction of 3-methoxy-N, N-dimethyl-6-phenyl-11H-pyrido [2,3 ~ b] [1,4] benzodiazepine-ll-propana- "mine with the acid hydroiodic and glacial acetic acid.

'' 25 Compositions and administration

Effective amounts of the pharmacologically active compounds of formula Ip and / or formula II can be administered to humans for therapeutic purposes according to the usual modes of administration and in usual forms orally, in the form of solutions, emulsions, suspensions, pills, tablets, capsules with vehicles acceptable in pharmacies and parenterally in the form of sterile solutions.

»55

Examples of solid vehicles for oral administration are lactose, magnesium stearate, gypsum, sucrose, talc, stearic acid, gelatin, agar, pectin or gum arabic. Examples of liquid vehicles for oral administration are vegetable oils and water.

For intramuscular administration, the vehicle or excipient may be a sterile liquid suitable for the parenteral route, such as water, or an oil suitable for the parenteral route, such as peanut oil contained in ampoules.

Although very small amounts of the active ingredients of the invention are effective in the case of minor treatment or in the case of administration to subjects having a relatively low body weight, the unit doses are generally 5 mg or more and preferably 10, 25, 50 or 100 mg or even more and they are preferably administered three or four times a day depending, of course, on the urgency of the situation, the compound used and the result particularly desired. Unit doses of 25 to 200 mg appear to be optimal, with a wider range appearing to be approximately 10 to 50 mg. The generally necessary daily doses are between approximately 0.3 and approximately 20 mg / kg and preferably 0.3 to 10 mg / kg for the most active compounds. The active ingredients of the invention can be combined with other agents with compatible pharmacological activity. It suffices that the active ingredient is in an effective amount, that is to say such that an appropriate dosage is obtained in accordance with the form of administration used. Of course, several unit doses can be administered practically simultaneously.

Individual dosages as well as daily dosages must of course be determined according to conventional medical principles under the guidance of a doctor.

Typical compositions containing the pharmacologically active compounds of the invention are set out below.

COMPOSITIONS

1. Capsules

Capsules containing 10 mg to 50 mg of active ingredient are prepared. For larger amounts of active ingredient, the amount of lactose can be reduced.

»56 10 mg by 50 mg per Typical blend for capsule capsule capsule

Active ingredient in the form of a salt 10 50

Lactose 259 219 5 Starch 126 126

Magnesium stearate A 4

Total 399 399 Other compositions for capsules preferably containing a greater amount of active ingredient are the following M: 100 mg per 250 mg per 500 mg per

Ingredients capsule capsule capsule

Active ingredient in the form of a salt 100 250 500

Lactose 214 163 95: 15 Starch 87 81 47

Magnesium stearate 4 6 8

Total 399,500,650

In all cases, the selected active ingredient is uniformly mixed with lactose, starch and magnesium stearate and the mixture is introduced into capsules.

2, Tablets

A typical composition for preparing tablets each containing 5.0 mg of active ingredient is shown below. The composition can be used with other amounts of active ingredient by modifying the weight of the dicalcium phosphate.

Per tablet, mg 1. Active ingredient 10.0 2. Corn starch 15.0 3. Corn starch (poison) 12.0 30 4. Lactose 35.0 5, Dicalcium phosphate 132.0 6, Calcium stearate 2.0

Total 202.0

1, 2, 4 and 5 are mixed uniformly. 3 is prepared in the form of a 10% paste in water. The mixture is granulated with the starch paste and the wet mass is passed through a sieve of 2.38 mm of mesh opening. The wet granules are dried and passed through a sieve of 1.41 mm mesh size. The dried granules are mixed with the calcium stearate and made into tablets.

3. Sterile solution for injection at 2% Far ml

Active ingredient mg 20 5 Preservative, e.g. chlorobutanol% w / v 0.5

Injectable water q.s,

The solution is prepared, clarified by filtration, conditioned in bottles, capped and autoclaved.

Of course, various modifications can be made by those skilled in the art to the devices or methods which have just been described only by way of nonlimiting examples without departing from the scope of the invention.

% 58 TABLE 1 ° C-Ar

H

Intermediate _Ar_ γ Z

10 1 CeH5- H H

2? 6H5 ~ H 4-cl

>? 4-CH3-CeH4- H H

4 2-Cl-C6H4- H 5-Cl

5 a 4-C2H5-CeH4- H H

15 b) 4 “i-C3H7-C6H4- H H

c) 4-Br ~ C6H4 H H

dj 3-f-c6h4- h h e 4-OC2H5-C6H4- h h f 4-no2-c6h4 ~ h h 20 g 4-cf3 ~ c6h4- h h b) 5-CH3-C6H4- h h i)? -C2H5-C6H4- h h

j) 3-0CH3-CeH4- H H

fc) 3-OC2H5-CsH4- h h

25 1 2-N02-CeH4- H H

Π ”) 2-CF3-C6H4- h h n) 2-CH3-C6H4- h h

o) 2-C2H5-C6H4- H H

P) 2-0CH3-C6H4- H H

30 q) 2,4-cl ”-c6h3- h h

r 3, ^ 5- (0CH3) 3-CeH2- H H

S 2-F-CeH4- h h

t) 2-Cl-CeH4 H H

u) 2-Br-CeH4 H H

35 6 a) CeHs- H 5-Cl b) CeH5-- H 6-Cl c) CeH5- H 4-pd C6Hs- H iJ-Br, Λ e CeHs- H 4-CF3 40 f CeHË- H 4-Me g) CeHs- H 5-Me b) CsH5- H O-CHa i CSH5- H 4-CgH5 j) CaH5- H 4-0CH3 45 k.) CeHs- H 4 -OCg Hg 1) CeHs- H 4-Nûg m! CeH5- H 5 ”N0s n) CaH5- H 3-CH3 o) CeH5- H 3-Cl» TABLE 1 (continued) 59!

Intermediate Ar_ Y 2

8 5-Cl-CsH4- H H

5 9 * i-F-C6H4- H H

10 2-thienyl H H

11 5-thienyl H H

12 2-pyridiny] e H H

13 J-pyridinyl H H

10 11} ^ -pyridinyl H H

15a CeHs- i} -CH3 H

15b C6H5- 5-CH3 H

15c C6H5- 6-CH3- H

15 <3 CeH5- 5> δ- (0Η3) 2 H

15 15th CeHs- 6-OCH3 H

15g CeH5- 5-OCH3 H

O

'c ~ Ar

H

7a CeHs ~ H H

l6d CeHs- 5-CH3 H

25 6 CßHs- Ö-CH3 H

f C6H5- 2 ~ CH3 H

H

7b CeH5- H H

15 f CeH5- 2-CH3 .H

O

35 C-Ar

H

7c CeHs- H H

0 loa CeHs- 5-CH3 H

b C6H5- M (CH3) 2 H

c CeH5- 5 ”CsHs H

i,! * 60 TABLE 2 Af_N '(H) n Y * \

R

Example „_, --— £ £ r. X 2n Salt 1 H CeHc- H HO ”2 H C0K5 H D-Cl 0 10? K CeHE H 9-C1 0 * H 2-Cl-CeH4- H 6-C1 1 î "l-Ci ~ CeH4 HH οχ" <ί-0Η3-06Η4- HH 0 - IH, l-0CH3-CeH4- HHQ - 15 8 - CH5Ja - "(CH3ia CeHs- H 8-Cl 0 oxalate 9“ (cHg) 3-N \ CH3 ^ 2 CßU5- H HO fumarate ”" (CHa> a "K; CH3I2 CeHs- H Ho fumarate II" - (CHa} 3 -% - GeH5- HH 0 morphoiinyl fumtrist 20 12 - (^) 3 - ^^ 285) 2 CeHE- H HO oxalate 15 - (082 / 3- ^ 0 ^) 2 CeHs- H 9-C1 û fumarate 1 '- (CHeJ3-1- C8h5- H II 0 piperidinyl fumarate 15 - (082) 3 - ^ (083) 2 ^ -Cl-CeH4- H HO fumarate 1- - (CHa-Kv CHs) z CeH5- H 8-Cl 0 oxalate -CH3 CeH «- H 8-Cl 0 1)? -) 0¾) 3-n (ch3 ^ 2 ^ -CH3-ceH4- h HO fumarate 19 - (CHa) s-in CH3 j2 Ji -0CH3-CeH4- H HO fumarate on | 0 H 5-Cl-CeH4- HH 0 - 21 - (0¾) 3-n (0H3) 2 2-cl ~ c6H4- H HO fumarate 22 H ^ -Γ-0βΗ4- HH 0 - 23 “ICH2; 3-N (CH3) g * tF-CBH4- HHO HCl, OB84 - (0¾) 3.-1- 1 CeH * - H HO 1 * 'Us ° 55 phcalimidoyl 25 - (CHg) 3 — HHg CeHs- HH 02 HCl,

,,, 2 HftO

26 - (cHs) 3-NH2 CeH5- HR 0 "2? - (CH8) aN" CH- C6H5- HHO - 40 oc2h5 28 -jCHeîa-KHCHs CeHe- HH 0 2 HCl 29 - (che) 3-nhc (q ) - C6H5- h H 0 - 0C £ H5 30 - (CHs) 3-N (cH2) 2 CgHg- HH 12 HCl, 45, „. 0.5 8.0 31 a H 4-c2h5-c6h4- hh 0 * - - b] H 4-i-c3H7-CeH4- H 00- c> "* t-Br-CeH4- HHQ - <* H fi-F-CeH4" HH 0 - • "50 e H ^ -0CsH5- CeH4- HH 0 - f H 4-HOa-CeH4- HHG - 2) H ii_CF2-CcK4- HHG - h (H -4-CH3-CeH4- HH 0 - 1 »3-CaH5-CeH4- H 8 0- 55 : h 3-ocH3-ceH4- hhg * H 3-OCaH5-CeH4- HH 0 - 1) H 2-N0g “CeH4- KH 0 - H 3-CFa-Ce, H4- HHO - n 8 8-CH3-CeH4 - HH 0 - 60 o) H 2-CaH5-CeH4- K Ho P) 8 2-OCHs-CeH4 HHO 1 r) H ΪΛ, Μύν.Ίί)} · HHO -

Celig- $ TABLE 2 (continued 1) 61

Example R 'Ar Y z n _Sel 32 aj' H CgHç- H 8-Ci 0 b H CeHs- H 7-Cl 0 5 c H CeHs- H 9-Br 0 d) H CaHs-. H 9-F 0 e) H CaHr- H 9-CF3 0 f) H CBHE- H 9-CHa 0 1n 9) H CgHe- H 8-CH3 0 iü h H CeHs- H 7-CHa 0 i H CeH's - H 9-¾% 0 k D) h CeH5- H 9-0CH3 0 k H Ce% - H 9 “OCaH5 0 H- CeH5- H 9-KO * 0 15 m) H Ce% - H 8-NOg 0

n) H CeHs- H 10-CHa O

o) H CeHs- H 10-Cl O

33 a) - (CHs) 3-N (CH3) 2 Ji-C2H5-CeH4- HH 0 - 20 b) - CHgJa-N; cH3) a J * -i-CaH -, - CeH4- HH 0 - c) - CHgJa-NfCHaÎE 4-Br-CeH4- HHO - d) - CHe) 3-N; CH3 2 * -F-CeH4- HHO - e - CHîis-N CH3 2 *) - 00εΗ3-ΰβΗ4- HH 0 - £ - CHe aN CH3) b ^ -N02-CeH4- HHO - 25 g) - (CHa) 3-N (CH3) 2 J * -CF3-C6H4- HHO - h - CHsla-N CH3U 3-CH3-CeH4- HHO - i - CHa; 3-N CH3) a? -C2H5-CeH4- HHO - D -fCHc 3-N CH3) 2? -0CH3-CeH4- HHO - - (CHa) 3-H (CH3'2 3-0C2Hs- CeH4- HHO - 30 1 - CH2i3-K CH3U 2-NOg -CeH4- HH 0 - ΤΓ, - CHe aN CH3) 2 3-CF3-CeH4- H Ηθη .CHb) SN CH3'2 2-CH3-CaH4- HHO - ° “CHSJ3-N (CH3 g 2-C2H5-CflH4- HH 0 - p“ VCHa 3-N CH3 g 2-0CH3-CeH4- HH 0 35 q] - CHs 3-N CH3U 2, MCl) a-CeH3 - HH 0

r; - (cHBÏa-N (CBa) B 3, *, 5- (θΟΗ3) 8- H H 'O

C6Ha

3 * a) - (CH £) 3-NfCH3) 2 CeHs- H B-Cl O

b (- CHe 3-N (CH3 z CeHE- H 7-Cl O

4U c / - (CHa) 3-N (CH3) a CeHs- H 9-Br O

d) -! CH2 a-N CH3) 8 CeH5- H 9-F O - e; - CH2) 3-N .CH3 g CeH5- H Q-CFa 0

f - CHg 3-N CH3 a CeHs- H 9-CH3 O

S - CHa U-N CH3U CeH5- H 8-CH3 O

45 h - (CHa a-N CH3 2 CeHs- H 7-CH3 0

i) - (CHa) 3-Ki CH3) 2 CeHs- H 9-C2% O

j> - {CHa ia-N-.CHsîa CeHs- H 9-OCH3 O

k) - (CHa) 3-N (CHa) a CeH £ - H 9-00¾¾ O

1 - (CHa) 3-N CH3) 2 Ce% - H 9-NO »0 50 m - CHa s-N CH3 a 0βΗ3- · H 8-N0a 0

n) - (CHa) 3-N (CH3) a CeHs- H 10-CH3 O

o) - (CHa) 3-N (CH3) 2 CeH5- H 10-Cl O

38 - (CHa) 3HHCH3 CeHs- HH 1 39 H 2-thienyl HHO - 55 H 3-thieny 'hho {* £ H 2-pyridinyl HHO - H 3-pyridinyl HHO - 1 * 3 H ** - pyridinyl HHO - ^ - (CH2) 3-N (CHa) a 2-thienyl. HH 0 - 60 1 * 5 - (CHa) 3-N (CHa) a 3-thienyl HHO - "5 - (CHa) 3-N (CH3) a 2-pyridinyl HH 0 - O - (CHa) 3-N (cH3) 2 3-pyridinyl HHO - ** ““ (CHa) 3-N (CH3) 2 4-pyridinyl HHO - 62 TABLE 2 (continued 2) <*

Example £ ^ χ 2 n Sel ^ 9 *) H CeHs- Ji-CH3 H 0 - C b) H ce% - 3-CHa h Q -

5 c) H CeH5- 2-CHa H θά) H CeHs- S, 3 “(CH3) 8 H

e) H CeHs- 2-OCHs H 0 - 9) H CeH5- 3-0CH3 H 0 50 a) -ÎCH2) 3-N (CH3) 2 CaHs- Ji-CHg H 0 10 b - CHs sN CHa a CeHs- '3-CHs H 0 - "0 - (CHa) sH (CH3) 8 CeHg-? -CH- H- θά - j <% aN CH3U CeHs- 2,3- (CH3) 8 H 0 e - elf sn ( ch3U CeHs- 2-OCHa HQ - g) - (CH2) aN (CH3) 2 CeH5- 3-OCHs H 0 15 51 a) H 2-F-CeH4- HHQ - - b H 2-Cl-C6H4- HH 0 - c) H 2-Br-CeH4 ~ HH 0 52 a) - (CH2) 3-N (CH3) 2 2-F-CeB4- HH 0 - on b - CHe 3-N CH3 a 2-Cl-CeH4- HHO - 20 c) - (cHalâ-KÎCHsls 2-Br-CeH4 HH 0 - 53 ®) -CH2CH (ch3) ch2- CeHg- H Ho fumarate N (ch3) 2 b) - (0¾) 4-n (ch3) 2 ceH5- H Ho fumarate 51 * a) - (CHg) al- CeHs- HH 0 - pyrrolidinyl b) - (CHa) 3 - ^ -, CeH5- H HO- methylpiperazine. 1-yle on ^ 5 a) -CH3 CeH5- HH 0 • 30 b -CH3 2-N02-CeH4- H 8-Cl 0 c -CH3 2-Cl-CeH4- H 8-Cl 0 â) -CHa 2- Br-CeH4- H 8-Cl 0 57 - (0¾) aN (CH3) - C6Hs- HH 0 - C (0) 0CH3 35 58 - (CHeU-NfCHsU CeHs- H 9-OH 0

59 - (0¾ J 3-N (cH3) 2 CeHs- 3-OH H Q

jH) n

ZNY

40 R

35 “) H CeH5- HHQ - 36 a H CeHs- HH 0 - 37 a) - (0¾) sn (ch3) 2 CeHg- HH 0 fumarate 55 a) - (0¾) 3“ N (CH3) 2 CeHs- H 8-CH3 0 45 b - 0¾ aN ch3 2 ceHs- 3-OCH3 H 0 C) - (0¾) sn (cH3) 2 ¢ 8¾. H H 0 -

Ar (H) n

R

50 TABLE 2 (continued 3) '”63 d“

Example r Ar yzn Sel 3 = b 'H CeHr- HH 0 - 3b b) H C0% - HH 0 - 5 37 b) - (cHÈ) sN (CH3) e CeHs ~ HHO fuMrate ^ 9 f) H CeHs- 1 -CH & HO - 50 f) “(CH2) 3-N (CH3) 2 CeHs- 1-CH3 HO - 10

R

35 c) H CeH5- H H 0 - 3b c) H CeHs- H H 0 - 3? c (- (0¾) 3 ~ n {ch3) a ceH £ - H HO fumarate

Claims (65)

9 64 1. New compounds characterized in that they correspond to the formula: Ar \ ^ r / (H) n R where 10. represents a hydrogen atom or a lower alkyl radical, -alk ^ -NR ^ R ^ or -alk ^ -N = C-0C „H .; 12 ^ ^ R and R represent a hydrogen atom or a radical 1 2 lower alkyl or -C (O) 0-lower alkyl, or R and R together with the adjacent nitrogen atom form a heterocyclic radical chosen from the radicals 1-phthalimido, 1-pyrrolidinyl, 4-morpho-linyl, 1-piperazinyl and piperazine-1-yl 4-substituted; Ar represents a 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl radical substituted by one to three radicals chosen from the halo, lower alkyl, lower alkoxy, trifluoromethyl or nitro radicals which may be similar or different; alk represents a straight or branched hydrocarbon chain having 1 to 8 carbon atoms; Z represents a hydrogen atom or a halo, lower alkyl, lower alkoxy, hydroxy or nitro radical; 25. represents a hydrogen atom or one or two radicals chosen from lower alkyl, lower alkoxy or hydroxy radicals which may be similar or different; n is 0 or 1 and when n is zero, the broken line is a double bond; 30 and their acid addition salts. 2. Compound according to claim l, characterized in that it consists of 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine. 3. Compound according to claim 1, characterized in that it consists of 8-chloro-6-phenyl-11H-pyrido [2,3-b] [i, 4] benzodiazepine. 65 J ft Ί * 4. Compound according to claim 1, characterized in that it consists of 9-chloro-6-phenyl-11H-pyrido [2,, 3-b] [l34] benzodia-zepine. 5. A compound according to claim 1, characterized in that it consists of 6- (4-chlorophenyl) IIIH-pyrido [2j3-b] [134] benzodiazepine. 6. Compound according to claim 1, characterized in that it consists of 6- (4-methylphenyl) IIIH-pyrido [233-b] [l34] benzodia-zepine. 7. Compound according to claim 1, characterized in that it consists of 6- (4-methoxyphenyl) IIIH-pyrido [2,3-b] [l34 '] benzodia-zepine. 8. Compound according to claim 1, characterized in that it consists of 8-chloro ~ N3N-dimethyl-6-phenyl-11H-pyrido [233-b] [l34] .. 15 benzodiazepine-11-propanamine. 9. Compound according to claim 1, characterized in that it consists of 8-chlora-N3N-dimethyl-6-phenyl-11H-pyridOL233-b] [l34] -benzodiazepine-ll-propanamine, oxalate [1/1 ]. 10. Compound according to claim 1, characterized in that it consists of NjN-dimethyl-ô-phenyi-11H-pyridof ^^ - b] [l34] benzodia-zepine-ll-ethanamine. 11. Compound according to claim 1, characterized in that it consists of N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzo-diazepine-ll-ethanamine, fumarate [1/1]. 12. Compound according to claim 13 characterized in that it consists of ll- [3- (4-morpholinyl) propyl] -6-phenyl-11H-pyrido [233-b] [1,4] benzodiazepine, 13. Compound according to claim 1, characterized in that it consists of ll- [3- (4-morpholinyl) propyl] -6-phenyl-11H-pyrido [2,3-b] [l34] benzodiazepine3 fumarate [1/1]. 14. A compound according to claim 1, characterized in that it consists of N3N-diethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzo-diazepine-ll-propanamine. 15. Compound according to claim 1, characterized in that it consists of N, N-diethyl-6-phenyl-11H-pyrido [233-b] [l34] benzo "diazepine-11-propanamine, oxalate [1 / 1], 66 i! m 16. Compound according to claim 1, characterized in that it consists of 9-chloro-N, N-dimethyl-6-phenyl ~ llH-pyrido [2,3-b] - [1.4] benzodiazepine-11-propanamine , 17. Compound according to claim 1, characterized in that it consists of 9-chloro-N, N-diraethyl-6-phenyl-11H-pyrido [2,3-b] [1,4]. Benzodiazepine -ll-propanamine, fumarate [1/1.]. 18. Compound according to claim 1, characterized in that it consists of 6-phenyl-ll- [3- (l-piperidinyl) propyl] -llH-pyrido [2,3-tb] [1,4] benzodiazepine . 19. Compound according to claim 1, characterized in that it consists of 6-phenyl-ll- [3- (l-piperidinyl) propyl] -llH-pyrido [2,3-sb] [l, 4] benzodiazepine, fumarate [1/1], 20. Compound according to claim 1, characterized in that it consists of 6- (4-chlorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] - 15 [1,4] benzodiazepine- 11-propanamine, 21. Compound according to claim 1, characterized in that it consists of 6- (4-chlorophenyl) -N, N-dimethyl-llH-pyrido [2,3-b] ~ [1.4] benzodiazepine-ll-propanamine , fumarate [1/1], 22. Compound according to claim 1, characterized in that it consists of 8-chloro-N, N-diraethyl-6-phenyl-11H-pyrido [2,3-b] - [1.4] benzodiazepine-ll- ethanamine. 23. Compound according to claim 1, characterized in that it consists of 8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] - [1.4] benzodiazepine-ll-ethanamine , oxalate [1/1], 24. Compound according to claim 1, characterized in that it consists of 8-chloro-ll-methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] -benzodiazepine. 25. Compound according to claim 1, characterized in that it consists of N, N-dimethyl-6- (4-methylphenyl) IIIH-pyrido [2,3-b] - [1,4] benzodiazepine- 11-propanamine. 26. Compound according to claim 1, characterized in that it consists of N, N-dimethyl-6- (4-raethylphenyl) -llH-pyrido [2,3-b] - [1.4] benzodiazepine-ll-propanamine , fumarate [1/1], 27. Compound according to claim 1, characterized in that it consists of 6- (4-methoxyphenyl) -N, N-dimethyl-11H-pyrido [2,3 ~ b3- [1.4] benzodiazepine-ll-propanamine . 3 67 Λ 28. Compound according to claim 1, characterized in that it consists of 6- (4-methoxyphenyl) -N, N-dimethyl-11H-pyrido [2,3-b] - [1 ^ jbenzodiazepine-ll-propanaminej fumarate [1/1], 29. Compound according to claim 1, characterized in that it consists of 6- (3-chlorophenyl) IIIH-pyrido [233-b] [1,4] benzodiazepine. 30. Compound according to claim 1, characterized in that it consists of 6- (3-chlorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] - [1,4] benzodiazepine-ll -propanamine. - 10 31. Compound according to claim 1, characterized in that it consists of 6- (4-fluorophenyl) IIIH-pyrido [2j3-b] [li4] benzodia-zepine. 32. Compound according to claim 1, characterized in that it consists of 6- (4-fluorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] -15 [1,4] benzodiazepine- ll-propanaraine. 33. Compound according to claim 1, characterized in that it consists of ll- [3- (1,3-dihydro-1,3,3-dioxo-2H-isoindole-2-yl) pro-pyl] 6-phenyl -11H-pyrido [2,3-b] [1,4] benzodiazepine. 34. Compound according to claim 1, characterized in that it consists of 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine. 35. Compound according to claim 1, characterized in that it consists of 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine, dihydrochloride hemihydrate. 36. Compound according to claim 1, characterized in that it consists of the ethyl ester of N- [3- [6-phenyl-11H-pyrido- [2,3-b3 [l> 4] benzodiazepine acid. -ll-yl] propyl] methanimide. 37. Compound according to claim 1, characterized in that it consists of N-methyl-6-phenyl-11H-pyrido [2,3-b] [l; 4] benzodiazé · 30 pine-ll-propanamine. 38. Compound according to claim 1, characterized in that it consists of N-methyl-6-phenyl-11H-pyrido [2,3-b] [l} 4] benzodiazé-pine-ll-propanamine, dihydrochloride. 39. Compound according to claim 1, characterized in that it consists of the ethyl ester of N- [3- [6-phenyl-11H-pyrido- [2,3-b] [lJ4] benzodiazepine acid. -ll-yl] propyl] carbamic. 268 r, 40. Compound according to claim 1, characterized in that it consists of 5,6-dihydro-N, N-dimethyl-6-phenyl-11H-pÿrido [2,3, b] - [1.4] benzodiazepine-ll -propanamine. 41. Compound according to claim 1, characterized in that it consists of 5,6-dihydro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] - [1.4] benzodiazepine- ll-propanamine, dihydrochloride hemihydrate. 42. Compound according to claim 1, characterized in that it consists of 8-chloro-6- (2-chlorophenyl) -5,6-dihydro-11H-pyrido- [2,3-b] [1,4 ] benzodiazepine. 43. Compound according to claim 1, characterized in that it consists of 5,6-dihydro-N-methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] - benzod iazepine- 11-propanamine. 44. Compound according to claim 1, characterized in that it consists of 6- (2-fluorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] -15 [1,4] benzodiazepine- ll-propanamine. 45. Compound according to claim 1, characterized in that it consists of 6- (2-chlorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] - [1.4] benzodiazepine-ll-propanamine . 46. Compound according to claim 1, characterized in that it consists of 6- (2-bromophenyl) -N, N-dimethyl-IIH-pyrido [2,3-b] - [1.4] benzodiazepine-II- propanamine 47. Compound according to claim 1, characterized in that it consists of 8-chloro-ll-methyl-6- (2-nitrophenyl) IIIH-pyrido [2,3- b] [1,4] benzodiazepine. 48. Compound according to claim 1, characterized in that it consists of 8-chloro-6- (2-chlorophenyl )ll-methyl-11H-pyrido [2,3- ^ b] [1,4] benzodiazepine . 49. Compound according to claim 1, characterized in that it consists of 6- (2-bromophenyl) -8-chloro-ll-raethyl-11H-pyrido [2,3- 30 b] [1,4] benzodiazepine . 50. Compound according to claim 1, characterized in that it consists of 6- (3-chlorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] - [1.4] benzodiazepine-ll-propanaraine , fumarate [1/1]. 51. Compound according to claim 1, characterized in that it consists of 6- (4-fluorophenyl) -N, N-dimethyl-11H ~ pyrido [2,3-b] - [1.4] benzodiazepine-ll- propanamine, hydrochloride hemihydrate, "cl 69 52. New drugs useful in particular for the treatment of depression, characterized in that they contain as active product at least one of the compounds according to any one of claims 1 to 51 or their pharmaceutically acceptable salts. 53. Medicines according to claim 52, characterized in that they are packaged for the administration of amounts corresponding to approximately 10 to 500 mg and better still from 25 to 200 mg of active product by oral or parenteral route. - 54. New compounds characterized in that they correspond to the formula 0 · Ar 15. H where Ar represents a 2-, 3- or 4-pyridinyl or 2- or 3-thienyl, phenyl or phenyl radical substituted by one to three radicals chosen from halo, lower alkyl, lower alkoxy, trifluoromethyl or nitro radicals may be similar or different; Z represents a hydrogen atom or a halo, lower alkyl, lower alkoxy, hydroxy or nitro radical; Y represents a hydrogen atom or one or two radicals chosen from lower alkyl, hydroxy or lower alkoxy radicals which may be the same or different; and their pharmaceutically acceptable acid addition salts. _ 55. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2-pyridinyl) amino] phenyl] phenylmetha-30 none. 56. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2-pyridinyl) araino] -4-chiorophenyl3-phenylraethanone, 57. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2-pyridinyl) araino] phenyl] (4-methy1-pheny1) meoneone. \ * 70 58. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2-pyridinyl) amino] -5-chlorophenyl] (2-chlo-rophenyl) methanone. 59. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2-pyridinyl) amino] -3-chlorophenyl] phenyl-methanone. 60. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2-pyridinyl) araino] -4-fluorophenyl] phenyl "^ methanone. * 10 61. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2-pyridinyl) amino] phenyl] (3-chlorophenyl) -methanone. 62. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2-pyridinyl) amino] phenyl] (4 ~ fluorophenyl) - 15 methanone. 63. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2 “pyridinyl) amino] phenyl] - (3-trifluoro-methylphenyl) methanone. 64. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2-pyridinyl) araino] phenyl] - (3-fluorophenyl) -methanone. 65. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2-pyridinyl) araino] phenyl] - (2-fluoro-phenyDmethanone. 66. Compound according to claim 54, characterized in that it consists of [2 - [(3-araino-2-pyridinyl) amino] phenyl] - (2-chloro-phenyl) methanone. - 67. Compound according to claim 54, characterized in that it consists of [2 - [(3-amino-2-pyridinyl) amino] phenyl] - (2-bromophenyl) -30 methanone. 68. New medicaments useful in particular for the treatment of depression, characterized in that they contain as active product at least one of the compounds according to any one of claims 54 to 67 or their pharmaceutically acceptable salts. 71 t: f 69. Medicines according to claim 68a, characterized in that they are packaged for the administration of amounts corresponding to approximately 10 to 500 mg and better still from 25 to 200 mg of active product by oral or parenteral route. (S