IE52494B1 - (2-((amino-pyridinyl)amino))phenyl derivatives - Google Patents

Description

The present invention relates to certain novel pyrido Cl,43 benzodiazepines and more particularly to certain novel {2-C(amino-pyridinyl) amino]} phenyl derivatives used as intermediates in their preparation. The invention also relates to pharmaceutical compositions for treating depression in humans.

The novel pyrido £l,4] benzodiazepines are described in our copending Patent Application No. 2769/81 dated November 25 1981 (Specification No. ) from which the present application has been divided from. The numerals given to the formulae of the present specification correspond, for ease of reference, to the numerals of the formulae of the parent specification.

The novel £2-C(amino-pyridinyl) amino] phenyl) arylmethanone intermediates of the present application which form in the reaction mixture prior to cyclization to diazepines and which have additional utility as anti-depressants for treating depression are represented by the formula Formula II wherein; R represents a hydrogen atom, a loweralkyl, an -alk^-NR^R^ or an -alk^-N=CH-OC,H- group; - 3 R and R each represent a hydrogen atom, or a 2 loweralkyl, or a -C(0)O-loweralkyl group, or R and R taken together with the adjacent nitrogen atom may form a 1-phthalimido, 1-piperidinyl, 1-pyrrolidinyl, 4-morpholino, 1-piperazino, or 4-substituted piperazin1-yl heterocyclic residue; Ar represents a 2, 3 or 4-pyridinyl, a 2 or 3thienyl, or a phenyl or a substituted phenyl group, the said substituted phenyl group Being substituted with. 1 to 3 halo, loweralkyl, loweralkoxy, trifluoromethyl or nitro radicals which may be the same or different; Alx represents a straight or branched hydrocarbon chain containing 1-8 carbon atoms; Z represents a hydrogen atom, or a halogen atom or a loweralkyl, a loweralkoxy, a hydroxy, a nitro or a trifluoromethyl group; X represents a hydrogen atom or 1 or 2 loweralkyl, loweralkoxy' or hydroxy radicals which may be the same or different; and S3 and S4 represent groups which may be the same or different and which do not interfere with the cyclization of compounds of Formula II to pyrido [l,4] diazepines for example R3 and R4 may each represent a hydrogen atom; and ' in which X represents Ό or Q1 where Q1 represents a group, or an atom which does not interfere in the cyclization of compounds of Formula II to pyrido Cl, 4] diazepines and which can either be split off before or during the cyclization reaction to give a -OO group or a carbonyl equivalent Csuch as a katal, thio-ketal or . gem dihalldeL; and represents a pyridine ring whose nitrogen atom is at any of the four positions not substituted with a nitrogen atom; and acid addition salts thereof.

In a preferred class of compounds of Formula II, R3 and R4 and R each, represent a hydrogen atom and X represents “0. in a further modification R3 and R4 may each represent groups which can Be split off, Before or during the cyclization reaction, to leaye groups (which may he the same or differentl which do not interfere in the cyclization of- ccn$ouncl3 of Formula n 'to phenyl substituted pyrldo £Χ,φ: benzodiazepines.

In the further definition of symbols in the 10 formulas hereof and where they appear elsewhere throughout this specification and claims, the following terms have the following significance.

The alk1 straight or branched connecting hydrocarbon chain containing 1-8 carbons Is exemplified by methylene t-CHj-l, ethylene propylene C-CHjCHjCHj-I , H ethylidene [-CH-], 1,2-propyIene [-CH-CHj- or -CHj-C-], ch3 ch3 ch3 ?H3 isopropylidine [-C- ], and l,3.-butylene £-CH-CH2-CH2-]. - 5 The term loweralkyl means straight and branched chain hydrocarbon radicals of up to eight carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, and octyl. The term loweralkoxy means O-loweralkyl.

The term halogen means chlorine, bromine, fluorine, and iodine, preferably chlorine, bromine and fluorine.

The term 4-substituted-piperazin-l-yl means piperazine substituted in the 4-position by a loweralkyl group or an alkyl-carbonyl blocking group which may . subseqently be removed to give the unsubstituted piperazine.

For the purpose of testing antidepressant activity of the compounds of the present invention, the procedure given by Englehardt, E.L., et al., J. Med. Chem. 11(2): 325 (1968) which has been indicative in the past of usefulness of compounds for treating human depression was used as follows: 20mg/kg of the compound to be tested was administered to five adult female mice (ICR-DUB strain), intraperitoneally 30 minutes prior to the administration of a ptotic dose (32 mg/kg IP) of tetrabenazine (as the methane sulphonate salt). Thirty minutes later, the presence or absence of complete eyelid closure (ptosis) was assessed in each animal. An EDgQ (Median Effective Dose) may be established for each tested compound in blocking tetrabenazine induced depression in mice following the procedure given by Litchfield et al., J. Pharmacol. Exp. Therap. 96: 99-113 (1949).

It is an object of the present invention to provide novel intermediates for preparing aryl substituted-llHpyrido [l,4) benzodiazepines which are antidepressants, certain of which intermediates also have antidepressant activity.

The present invention encompasses the novel methanone intermediates as set forth herein in Formula II as compositions of matter and utilization of these intermediates in the preparation of other antidepressants.

Description of Compound Preparation. A reaction sequence set out as chemical equations for the preparation of the compounds of the invention is given below.

Methanones, Formula II The methanone intermediates are prepared by heating a mixture of the halo-amino pyridine (iv) and an aminobenzophenone (ill) for a shorter period of time than that required for cyclization to the pyridobenzodiazepine as indicated by chemical ionization mass spec, analysis. For the 2-C(3-amino-2-pyridinyl) amino]phenylmethanones, the conditions required are about 1 to 1.5 hr at 17O-2OO°C. The methanones may be Isolated as the predominant product, if desired, by cooling and adding a suitable organic solvent such as, for example, methylene chloride which will dissolve unreacted starting materials and some cyclized compound followed by usual methods of isolating such as partitioning between the solvent and aqueous base or methanolic aqueous base followed by washing, drying, evaporating the solvent 25 layer and recrystallizing from a suitable solvent. 82404 - 7 The preparation of the novel [(amino-pyridinyl) amino-phenylaryfl methanones which are intermediates in the preparation of the phenyl substituted-pyrido (l,j benzodiazepines are illustrated more fully in the 5 following Examples 1 to 16. Structures of the intermediates are illustrated in Table* 1.

EXAMPLE 1 [2- [ (3-Amino-2-pyridlnyl) amino]phenylmethanone.

A stirred mixture of 39.4 g (0.20 mole) of 2-aminobenzophenone and 28.3 g (0.22 mole) of 3-amino-2-chloropyridine was heated at 180 °C under a nitrogen atmosphere for 1.5 hr. The mixture was allowed to cool somewhat and 200ml of methylene chloride was added slowly. After stirring for 3 hr and standing overnight at room temperature, 40.1 g of X5 solid was filtered off. and recrystallized twice from methanolisopropyl ether giving 4.3 g, presumably the hydrochloride salt; m.p. 187-90*C. This solid was dissolved in a mixture of water-methanol, made basic with 3H sodium hydroxide and extracted with methylene chloride. The combined methylene 2q chloride extracts were dried over magnesium sulphate and evaporated under reduced pressure. The residue was recrystallized from isopropyl ether (charcoal) to give 2.1 g of product; m.p. 91-3’C. Drying prior to analysis was overnight at room temperature and 0.02 mm Hg pressure.

· Analysis: Calculated for C^H^NjO: C,74.72; 11,5.23; N,14.52 Found : C,74.94; H,5.23; N,14.69 EXAMPLE 2. [2- [ (3-Amlno-2-pyrldlnyl) amino] -4-chlorophenyl] phenylmethanone.

A stirred mixture of 23.2 g (0.1 mole) of 2-amino-4‘chlorobenzophenone and 14.2 g (0.11 mole) of 3-amino-2 chloropyridine was heated at 180 °C under a nitrogen atmosphere for 2.5 hr. The mixture solidified upon cooling to room temperature and was broken up with a spatula. The solid was suspended in 100 ml of methylene chloride and collected by filtration. The filter cake was dissolved in a mixture of - 8 water-methanol, made basic with. 3N sodium hydroxide and extracted twice with methylene chloride. The combined methylene chloride extracts were dried over magnesium sulphate and evaporated under reduced pressure. The residue which had crystallized was triturated in isopropyl ether and the solid (16.7 g) collected by filtration. A 3g sample was recrystallized from isopropyl ether to give .1.6 g of product; m.p. 153-155’C.

Analysis: Calculated for C.aH.,ClN.O : 0,66.77; H,4.36; 14 3 N,12.98 Found ! C,67.06; H,4.36; 11,13.17 EXAMPLE 3 [2- [ (3-Amino-2- (pyrldinyl) amino) phenyl] (4-methylphenyl) 15 methanone.

A stirred mixture of 20.0 g (0.095 mole) of 2-amino4*-methjlbenzophenone and 13.95 g (0.104 mole) of 3-amino2-chloropyridine (96%) was heated under a nitrogen atmosphere at 180°C for. 2.0 hr. The mixture cooled to a glassy solid which was broken up,' triturated in methylene chloride and the mixture stirred overnight. The solid was collected by filtration and dissolved in warm methanol. The solution was made basic with 3N sodium hydroxide, diluted with 500 ml of water and extracted 3 times with 250 ml of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulphate and evaporated under reduced pressure. The residue which crystallized on standing was recrystallized twice from benzene-isooctane to give 4.2 g of product, m.p. 126-127.5°C.

Analysis : Calculated for C.-H.-N.O: 0,75.23; H,5.65; 19 17 3 11,13..85 : C,75.81; H,5.69; 11,13.96 Found S2494 - 9 EXAMPLE 4 [2 -[ (3-Amino-2-pyridinyl)amino]-5-chlorophenyl]-(2chlorophenyl)methanone.

A stirred mixture of 20.0 g (0.155 mole) of 3-amino-25 chloropyridine and 37·3 9 (0.14 mole) of 2-amino-2',5dichlorobenzophenone was heated at 190°C uofer a nitrogen atmosphere for 5.5 hr. Thin layer chromatography (5% methyl alcohol-benzene on silica gel) indicated reaction had not substantially occurred. The mixture was stirred overnight at 190°C cooled somewhat, and 100 ml methylene chloride was added cautiously. The suspension was stirred for two hr and the black solid which formed was separated by filtration. The solid was suspended is 500 1 of methylene chloride and 300 ml of dilute sodium hydroxide was added.

An emulsion formed and the mixture was filtered which allowed separation of layers. The methylene chloride layer was washed with two' 250 ml portions of water by extraction, dried over magnesium sulphate and evaporated under reduced pressure. The residue was dissolved in benzene and filtered through a 300 g column of Florisil (trade marie) to remove low R^ material. All fractions were combined and evaporated under reduced pressure. Thin layer chromatography showed *8® presence of two major components with the lower Rf· spot predominating. The residue was dissolved in benzene and chromatographed on a 600 g column of Florisil packed in benzene. The higher Rf material was eluted with 1% acetone-benzene. On evaporation, the residue was triturated in benzene and recrystallized from benzene-isooctane to give 2.7 g of product; m.p. 162-4°C.

Analysis: calculated for CiaHisCljNaO: C,60.35* Η,3·66; N,11.73 Found : C,60.67? Η,3·δ7? N,11.77 - 10 EXAMPLES to 5u Pollowing the procedures of Example 3 and substituting equal molar amounts of the following for 2amino-4'-methylbenzophenone: 2-amino-4’-ethylbenzophenone, 2-amino-41-isopropylbenzophenone, 2-amino-41-bromobenzophenone, 2-amino-31-fluorobenzophenone, 2-amino-4*-ethoxybenzophenone, 2-amino-4’-nitrobenzophenone, 2-amino-4' -trifluoromethylbenzophenone, 2-amino-3'-methylbenzophenone, 2-amino-31-ethylbenzophenone, 2-amino-3'-methoxybenzophenone, 2-amino-3'-ethoxybenzophenone, 2-amino-2'-nitrobenzophenone, 2-amino-3’—trifluoromethylbenzophenone, 2-amino-2'-methylbenzophenone, 2-amino-2'-ethylbenzophenone, 2-amino-2'-methoxybenzophenone, 2-amino-2',41-dichlorobenzophenone, 2-amino-3',41,5’-trimethoxybenzophenone, 2-amino-2'-fluorobenzophenone, 2-amino-2'-chlorobenzophenone, and 2-amino-21-bromobenzophenone, there were obtained: a) [2-[(3-amino-2-pyridinyl)amino]phenyl]-(4-ethylphenyl) methanone, b) [2-[ (3-amino-2-pyridinyl) aminojphenyl]-(4 -isopropyl·, phenylJmethanone, e) [2-[(3-*nino-2-pyridinyl)amino]phenyl]-(4-bromophenyl) methanone, d) e) f) 5 g) h) i) 3> k) 15 l) m) n) o) p) 25 g) r) s, - 11 [2-[ (3-amino-2-pyridinyl)amino] phenyl] - (3-fluorophenyl) methanone, [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, [2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-methylphenyl) methanone, [2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-ethylphenyl) methanone, [2-((3-amino-2-pyridinyl)amino]phenyl]-(3-methoxyphenyl) methanone, [2-[(3-amino-2-pyridinyl)amino]phenyl]-(3-ethoxyphenyl) methanone, [2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-nitrophenyl) methanone, [2- [ (3-amino-2-pyridinyl) amino ] phenyl]- (3-trifluoromethylphenyl) methanone, [2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-methylphenyl) methanone, [2-[(3-amino-2-pyridinyl)amino]phenyl]-(2-ethylphenyl) methanone, [2-((3-amino-2-pyridinyl)amino]phenyl]-(2-methoxypheny1)methanone, [ 2-( (3-amino-2-pyridinyl) amino] phenyl] -(2,4-dichlorophenyl)methanone, (2- [ (3-amino-2-pyridinyl) amino] phenyl] -(3,4,5-trimethoxyphenyl)methanone, [2-[(3-amino-2-pyridinyl) amino]phenyl]-(2-fluorophenyl, methanone, - 12 t) C2“C t3-amino-2-pyridinyll aminojphenylj- C2-chlorophenyl) methanone, and u) Q2-£ t3-amino-2-pyridinyll aminojphenylj- (2-bromophenyll methanone.

It will he understood that, by analogy, £2-£t3-amino2-pyridinyllamino]phenyl]-C2-fluorophenyllmethanone may be prepared from 2-amino-2'-fluorobenzophenone.

EXAMPLES 6a to So Following the procedure of Example 2 and substituting equal molar amounts of· the following for 2-amino-4chlorobenzophenone: 2-amino-5-chlorobenzophenone, 2-amino-6-chlorobenzophenone, 2-amino-4-fluorobenzophenone, 2-amino-4-bromobenzophenone, 2-amino-4-trifluoromethylbenzophenone, 2-amino-4-methylbenzophenone, 2-amino75~methylbenzophenone, . 2-amino-6-methylbenzophenone, 2-amino-4-ethylbenzophenone, 2-amino-4-methoxybenzophenone, 2-amino-4-ethoxybenzophenone, 2-amino-4-nitrobenzophenone, 2-amino-5-nitrobenzophenone, 2-amino.-3-methylbenzophenone, and 2-amino-3-chlorobenzophenone, there were obtained: a) [2-[(3-amino-2-pyridinyl)amino]-5-chlorophenyl]phenyl methanone, b) [2-[(3-amino-2-pyridinyl)amino]-6-chlorophenyl]phenyl methanone, 82484 - 13 c) [2-[ {3-araino-2-pyridinyl )amino]-'4-fluorophenyl]phenylmethanone, d) [2-[(3-amino-2-pyridinyl)amino]-4-bromophenyl3phenylmethanone, e) [2-[(3-amino-2-pyridinyl)amino]-4-tri£luoromethylphenyljphenylmethanone, £) [2 -[ (j-araino-2-pyridinyl)amino]-4-methylphenylJphenylmethanone, g) [2-((3-amino-2-pyridinyl)amino3-5-methylphenylJphenylmethanone, h) [2-[(3-amino-2-pyridinyl)amino]-6-methylphenyl]phenylmethanone, i) [2-[(3-amino-2-pyridinyl)amino]-4-ethylphenyl]phenyimethanone, j) [2-[(3-amino-2-pyridinyl)amino]-4-methoxyphenyl]phenylmethanone, '' k) [2 -[[3-amino-2-pyridinyl)amino J-4-ethoxyphenylJphenylmethanone, l) [2-[{3-amino-2-pyridinyl)amino]-4-nitrophenylJphenylmethanone, m) [2-[(3-amino-2-pyridinyl)amino]-5-nitrophenyl]phenylmethanone, n) [2 -[’ (J-amino-2 -pyridinyl) amino ]-3-me thylphenyl Jphenylmethanone, and o) [2-[(3-amino-2-pyridinyl)amino]-3-chlorophenyl]phenylEXAMPLES 7a to 7c Following the procedure of ’Example χ md substi-r tuting equal molar amounts of the following for 3-amino-2ebloropyridine: i - 14 4-amino-3-chloropyridine, 3-amino-4-chloropyridine, and 2-amino-3-chloropyridine, there v«reobtained: '5 a) [2-[(4-amino-3-pyridinyl)amino3phenyl]phenylmethanone, b) [2-[(3-amino-4-pyridinyl)amino3phenyl]phenylmethanone, and e) [2-[(2-amino-3-pyridinyl)amino3phenyl3phenyl!nethanone.

EXAMPLE 8 [2-Γ(3-Amino-2-pyridinyl)amiho3nhenyl3(3-chlorophenyl) 2_q methanone.

A stirred mixture of 35 5 (0.152 mole) of ?-amino-3 chlorobenzophenone and 23.¾ 9 (0..182 mole) of 3-waino-2chloropyridine was heated at l80°C for 2 hr. The hot melt was allowed to cool to 110°C , after which 100 ml of hot toluene was added dropwise with vigorous stirring. .The ^•5 mixture was allowed to cool while stirring to 30°C and ( 50 ml of methylene chloride was added. After stirring for an additional 1/3 hour, the mixture was filtered and the 'filter cake suspended in methylene chloride with stirring for·1/3 hr and methylene chloride was separated by filtration. 20 The filter cake containing the product (25.¾ g) was partially dissolved in hot methanol (total volume 150 ml) and 50$ aqueous sodium hydroxide was added until the mixture was basic. Ice water was added and the solution was extracted with methylene chloride. This methylene Chloride extract was washed with water and dried over magnesium .sulphate and evaporated to dryness. The residue was dissolved in isopropyl alcohol and boiled with charcoal. The mixture was filtered, and reduced in volume to give a first crop of crystals weighing 16 g (33#)· A portion of the crystals was recrystallized from isopropyl alcohol to give a brick red solid melting at 119-120°C. - 15 Analysis: Calculated for Found C,66.77; H,4.36; N,12.98 C,66.78; H,4.42; N,12.94 EXAMPLE 9 [2-[(3-Amino-2-pyrldinyl)amino]phenyl](4-fluorophenyl) methanone.

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 was heated at 175-180“C for 2.5 hr. The mixture was allowed to cool to 110’C, after which 100 ml of hot toluene was added. On cooling to 50°C, 50 ml of methylene chloride was added. The solvent layer was decanted, leaving a black solid mass which was dissolved in hot methanol. The solution volume was reduced by one half and allowed to stand overnight at room temperature. The mixture was filtered and the filter cake washed twice by suspending it in methylene chloride. The weight of crude solid produced was 22.5g. The solid was dissolved in methanol and madebasic with 50% aqueous sodium hydroxide. The mixture was extracted with methylene chloride and the extract dried and concentrated. The residue was twice crystallized from isopropyl alcohol, decolorizing by boiling with charcoal on the second crystallization, to give 14 g (28%) of solid which was red-orange in colour; m.p. 121.5-122.5eC.

Analysis: Calculated for C1HH.,N,OF: C,70.35; H,4.59; • 0 I* J W 17 M N,13.67 Found C,70.23; H,4.59 N,13.64 EXAMPLE 10 [2-[(3-Amlno-2-pyridlnyl)amino]phenyl)(2-thlenyl) methanone.

In accordance with the procedure of Example 9 - 16 (2-aminophenyl)(2-thienyl)methanone, prepared by the method of Steinkopf S Gunther, Ann. 522, 28-34 (1936), is reacted with 3-amino-2-chloropyridine to give the title compound.

EXAMPLE 11. [2-[(3-Amlno-2-pyridinyl)amino]phenyl](3-thienyl) methanone.

In accordance with the procedure of Example 9, (2-aminophenyl) (3-thienyl, methanone was reacted with 3-amino2-chloropyridine to give the title compound.

EXAMPLE 12 [2-[(3-Amlno-2-pyridlnyl)amino]phenyl](2-pyridinyl) methanone.

The title compound .was prepared by reacting (2-aminophenyl) (2-pyridinyl) methanone, as prepared by Schofield, K., J. Chem. Soc. 1949, 2408-12, with 3-amino-2-chloropyridine.

EXAMPLE 13 [2-[ (3-Amlno-2-pyridlnyl)amino]phenyl](3-pyrldinyl) methanone.

The title compound was prepared by reacting (2-aminophenyl) (3-pyridinyl)methanone as prepared by Abramovitch R.A. & Tertzaklan, G., Tetrahedron Letters, 1963, 1511-15 and Abramovitch, R.A. et al., Can. J. Chem. 43(4), 725-31 (1965) with 3-amino-2-chloropyridine.

EXAMPLE 14 [2-[ (3-Amino-2-pyridlnyl)amino]phenyl](4-pyrldinyl) methanone, The title compound was prepared by reacting (2-aminophenyl) (4-pyridinyl)methanone as prepared by Nann, A. J. and Schofield, K., J. Chem. Soc. 1952, 583-9 with 3-amino2-chlorpoyridine. - 17 EXAMPLE 15a to 15g Following the procedure of Example 1 and substituting equal molar amounts of the following for 3-amino-2-chloropyridine: 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-methoxypyridine, there were obtained: 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]phenyl]phenylmethanone, d) [2-[(3-amino-5,6-dimethyl-2-pyridinyl)amino]phenyl] phenylemthanone, e) [2-[(3-amino-6-methoxy-2-pyridinyl)amino]phenyl] phenylmethanone, f) (2-((3-amino-2-methyl-4-pyridinyl)amino]phenyl]phenylmethanone, and g) [2-[(3-amino-5-methoxy-2-pyridinyl)amino]phenyl]phenylmethanone .

EXAMPLE 16a to 16f Following the procedure of Example 1 and substituting equal molar amounts of the following for 3-amino2-chloropyridine: 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 4-amino-3-chloro-2-methylpyridine,. there are obtained: a) 12—[(2-amino-5-methyl-3-pyridinyl)amino]phenyl]phenylmethanone, b) [2-[(2-amino-4,6-dimethyl-3-pyridinyl) amino]phenyl] phenylmethanone, c) [2-[2-amino-5-ethyl-3-pyridinyl)amino]phenyl]phenylmethanone, d) [2-((4-amino-5-methyl-3-pyridinyl)amino]phenyl]phenylmethanone, e) (2-((4-amino-6-methyl-3-pyridinyl)amino]phenyl]phenylmethanone, f) [2-[(4-amino-2-methyl-3-pyridinyl)amino]phenyl]phenylmethanone .

Table 1 VI .fcVI MW Ar Y Z a' CeHs- ?β%- 4-CB3-CeB4- 2-Cl-CeH4- 4-C2Hs-CeH4- H H H H H a 4- Cl a 5- C1 a b 4-i-C3H7-CeH4- B a c 4-Br-CeB4 H a a’ ?-E-CeH4- H a e 4-0C2H5-CeH4- H a f 4-N02-CeH4- H a g, Ji-CFa-Ceft»- H a h 3-CHs-CeO,- B a i 3-C2Hs-CeH4- H a 3 ^-OCHa-CelU- H a k 3-OC2 H5 — C®H<- H a r 8-N02-CeB4- H a ro 3-CFs-CeH4- H a n 8-CH3-CeB4- H a o 8-C2a5-CeB4- H a P 2-0CH3-CeH4- H a q 8,4-Cla-CeHs- H a r 3,4,5-{00Η3)3-0βΗ8- B a 8 2-F-CeH4- H a t 2-Cl-CeH* H a u 2-Br-CeH4 H a a CeHs- H 5-Cl b CeHg- H 6-ci c Ce£fe- B 4-f a’ CeHs- H 4-Br e Ce&i- H 4-CF3 f CeHg- H 4-Me g C3Hs- H 5-Me h CeHs- B 6-ca3 i CeHs- B 4-c2Bs 3 CeHs- H 4-OCBs k CeHs- B 4-oc2b5 1 CeHs- H 4-NOa IQ CeHs- H 5-NOe n CeHs- H 3-cb3 0 CeHs- B 3-cl (cont.) - 19 Table 1 (cont.) Example Ar 8 3-Cl-CeH4- 9 4-F-CeH4- 10 2-thienyl 11 3-thienyl 12 2-pyridinyl 13 3-pyridinyl 14 4-pyridinyl 15a CeHs- 15b CeHs- 15c CeHs- 15a CeHs- 15e CeHs- 15g CeH5- 7» l6d e f 7b 15f 7c 16a b fc-Ar ΚΙ H Y z Η H Η H Η H Η H Η H Η H Η H 4- CHa H “CHs H 6-CHa- H ,6-(CHs)a H 6-OCH3 H - OCHs H Formula IIx Ce%Ce%CeHsCeHsH H -CHs H M(CBs)s B 5-CaHs B μ 52484 - 20 Formulation and Administration Effective quantities of the foregoing pharmacologically active compounds ' of Formula II may be administered to humans for therapeutic purposes according to usual modes of administration and in usual forms, such as orally in solutions, emulsions, suspensions, pills, tablets or capsules, in pharmaceutically acceptable carriers or parenterally in the form of sterile solutions.

Exemplary of solid carriers for oral administration are such as lactose, magnesium, stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia.

Exemplary of liquid carriers for oral administration are vegetable oils and water.

For intramuscular administration the carrier or excipient may be a sterile, parenterally acceptable liquid; e.g., water or a parenterally acceptable oil; e.g., arachis oil contained in ampoules.

Although very small quantities of the active materials of the present invention are effective when minor therapy is involved or in cases of -administration to subjects having a relatively low body weight, unit dosages are usually from five milligrams or above and preferably 10,25,50, or 100 milligrams or even higher, perferably administered three or four times per day, depending, of course, upon the emergency of the situation, the compound used, and the particular result desired. Twenty-five to 200 milligrams appears optimum per unit dose or usual broader ranges appear 'to be about 10 to 500 milligrams per unit does. Daily dosaqes usually required should range from about 0.3 to about 20 mg/ kg/day, preferably 0.3 to 10 mg/kg for the more active compounds.

The active ingredients of the invention may be combined with other compatible pharmacologically active agents. It is only necessary that the active ingredient constitute an effective amount; i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several. unit dosage forms may be administered at about the same time. The exact. individual dosages as well as daily dosages will, of course. - 21 be determined according to standard medical principles under the direction of a physician.

The following formulations are representative for the pharmacologically active compounds of this invention.

FORMULATIONS EXAMPLES 17a to 17e Capsules of 10 mg and 50 mg of active ingredient per capsule are prepared. With the higher amounts of active ingredient, reduction may be made in lactose. the amount of EXAMPLE 17a 10 mg 17b 50 Typical blend for Per Per encapsulation Capsule Capsule Active ingredient, as salt .10 50 Lactose 259 219 Starch 126 126 Magnesium stearate _4 Total 399 _4 399 Additional capsule formulations preferably contain a higher dosage of active Ingredient and are as follows: Example 17 c 100 mg.per 17d 250 mg.per 17e 500 mg.per Ingredients Capsule Capsule Capsu Active ingredient, as salt 100 250 500 Lactose 214 163 95 Starch 87 81 47 Magnesium stearate 4 6 8 Total 299 500 650 - 22 In each case, the selected active ingredient was uniformly blended with the lactose, starch, and magnesium stearate and the blend then encapsulated.

EXAMPLE 18 A typical formulation for a tablet containing 5 5.0 mg of active ingredient per tablet follows. The formulation may be used for other strengths of active ingredient by adjustment of the weight of dicalcium phosphate.

Per Tablet, mg. 1. Active Ingredient 10.0 10 2. Corn starch 15.0 3. Corn starch (paste) 12.0 4. Lactose 35.0 5. Dicalcium phosphate 132.0 6. Calcium stearate 2.0 15 Total 202.0 Ingredients 1,2,4 and 5 were first uniformly blended. Ingredient 3 was prepared as a 10% paste In water. The blend was granulated with the starch paste and the wet mass passed through an 8 mesh (U.S. sieve series) screen. The wet granulation was dried and sized through a 12 mesh (U.S. sieve series) screen. The dried granules were blended with the calcium stearate and compressed. 8 mesh has openings of 2.38 mm; 12 mesh of 1.68 mm., EXAMPLE 19 An Injectable sterile 2% solution was made up as follows: - 23 Per cc Active ingredient mg. 20 Preservative, e.g. chlorobutanol, w/vol. precent 0.5 Hater for injection g.s.

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

Claims (1)

1. claims 1, A compound having the formula R represents a hydrogen atom, a loweralkyl, an 10 -alk 1 -NR 1 R 2 or an -alk 1 -N=CH-OC 2 H 5 group; 1 2 R and R each reoresenfc a hvdrogen atom, or a 1 2 loweralkyl, or a -C(0)0-loweralkyl group, or R and R taken together with the adjacent nitrogen atom may form 15 a 1-phthalimido, 1-piperidinvl, 1-pyrrolidinyl, 4morpholino, 1-piperazino, or 4-substituted piperazin-1yl heterocyclic residue; Ar represents a 2, 3 or 4-pyridinyl, a 2 or 3thienyl, or a phenyl or a substituted phenyl group, the 20 said substituted phenyl group being substituted with 1 to 3 halo, loweralkyl, loweralkoxy, trifluoromethyl or nitro radicals which may be the same or different; Aik 1 represents a straight or branched hydrocarbon chain containing 1-8 carbon atoms; 25 Z represents a hydrogen atom, or a halogen atom or a loweralkyl, a loweralkoxy, a hydroxy, a nitro or a trifluoromethyl group; Y represents a hydrogen atom or cne or two loweralkyl, loweralkoxy or hydroxy radicals which may be the same or 30 different; and R3 and R4 represent groups which may be the same or different and which do not interfere with the - 25 cyclization of compounds of Formula II to pyrido [1,43 benzodiazepines. X represents =0 or Q1 where Ql represents a group or an atom which does not interfere in the cyclization of compounds of Formula II to pyrido 0.,5 benzodiazepines and which can either be split off before or during the cyclization reaction to give a -C=O group or a carbonyl equivalent; and represents a pyridine ring whose nitrogen atom is at. any of the four positions not substituted with a nitrogen atom; and acid addition salts thereof. wherein Ar, are as defined in Claim 1. - 26 3. The compound of Claim 1 which is [2-[(3-amino 2-pyridinyl)amino]phenyllphenylmethanone. 4. The compound of Claim 1 which is [2-[(3-amino 2-pyridinyl) amino] -4-ohlorophenyl] phenylmethanone. 5 5. The compound of Claim 1 which is[2-[(3-amino2-pyridinyl) amino]phenyl] (4-methylphenyl) -methanone. 6. The compound of Claim 1 which is [2-[(3-amino 2-pyridinyl)amino]-5-ehlorophenyl](2-chlorophenyl,methanone. 10 7. The compound of Claim 1 which is [2-((3-amino 2. -pyridinyl) amino] -3-chlorophenyl] phenylmethanone. 8. The compound of Claim 1 which is [2-[(3-amino 2-pyridinyl)amino]-4-fluorophenyl]phenylmethanone. 9. The compound of Claim 1 which is [2-[(3-amino 15 2-pyridinyl,amino]phenyl] (3-chlorophenyl)methanone. 10. The compound of Claim 1 which is [2-[(3-amino 2-pyridinyl) amino] phenyl] (4-f luorophenyl) methanone. 11. The compound of Claim 1 which is [2-[(3-amino 2-pyridinyl)amino]phenyl]-(3-trifluoromethylphenyl,15 methanone. 12. The compound of Claim 1 which is [2-[(3-amino 2-pyridinyl,amino]phenyl]- (3-fluorophenyl) methanone. 13. ’ The compound of Claim 1 which is [2-[(3-amino 2-pyridinyl) amino] phenyl] - (2-f luorophenyl) methanone. 14. The compound of Claim 1 which ia [2-£t3amino-2-pyridinyll aminojphenylj- C2-chlorophenyll methanone. 15. The compound of Claim 1 which is [2-£U5 amino^-pyridinyl, aminojphenylj-12-bromophenyl) methanone. 16. A compound as claimed in Claim 1 substantially as specifically described herein with, reference to any one of Examples 1 to 16. 10 17. λ compound having antidepressant activity as claimed in any one of Claims 2 to 16 for use in treating depression. 18. A pharmaceutical composition for treating depression in unit dosage form comprising (al an 15 effective amount of a compound having antidepressant activity as claimed in any one of Claims 2 to 17 and (b) a pharmaceutical carrier therefor. 19. A pharmaceutical composition as claimed in Claim 18 substantially as specifically described 20 herein with, reference to any one of Examples '17 to 19.