FI77232C - SOM MELLANPRODUKT VID FRAMSTAELLNING AV 6-PHENYL-11H-PYRIDO / 2,3-B // 1,4 / BENZODIAZEPINER ANVAENDBARA 2 - / (3-AMINO-2-PYRIDINYL) AMINO / PHENYLARYLMETHANONDERDERAT. TRANSFERRED PAEIVAEMAEAERAE-FOERSKJUTET DATUM PL 14 ç 10.06.82. - Google Patents

Description

1,77232 2- (3-Amino-2-pyridinyl) amino] phenylarylmethanone derivatives useful as intermediates in the preparation of 6-phenyl-1H-pyrido [2,3-b7β,] benzodiazepines

Separated from application 813976 (patent 71935)

The present invention relates to novel 2- ([3-amino-2-pyridinyl) amino] phenylarylmethanone compounds which can be used as intermediates in the preparation of 6-phenyl-11H-pyrido [2,3-b] (1 H) -benzodiazepines having antidepressant activity. with the formula

Ar (H) \ _ / n

R

in which formula:

112 1 2 R is hydrogen, lower alkyl or -alk * ^ NR R, where R and R

1 2 are each hydrogen or lower alkyl, or R and R together with the adjacent nitrogen atom form a heterocyclic group which is 1-piperidinyl or 4-morpholino,

Ar is phenyl which may be substituted by halogen, lower alkyl, lower alkoxy or nitro, alk '*' is lower alkylene, preferably ethylene or propylene, Z is hydrogen or halogen, n is 0 or 1, and when n is 0, a dotted line is a double bond, and their acid addition salts.

GB Patent 907,646 discloses the preparation of certain dibenzazazepines having phenyl radicals substituted on carbon and having alkyl or aminoalkyl radicals on the nitrogen atom between the phenyl rings.

Greig, M.E. et al., J. Med. Chem. 14 ^, No. 2, page 153 (1971), has disclosed dibenzodiazepines similar to those disclosed in GB-Datent 907,646, which compounds are useful in the treatment of anaphylactic seizures.

JP Patent 73/43 520 (CA 8 (): 133501η) 77232 discloses 6-phenyl-2,3,4,4a-tetrahydro-11H-pyrido [2,3-b] [1,47] benzodiazepines, having anti-edematous activity and which can be prepared from e.g. 2-aminobenzophenones and ornithine.

The 2 - [(3-amino-2-pyridinyl) amino] phenylaryl] methanone compounds of the invention have the formula -Ar

/ H-N H

where

Ar is phenyl which may be substituted by halogen, lower alkyl, lower alkoxy or nitro; and Z is hydrogen or halogen.

Acid addition salts of the compounds of formula II are also included within the scope of the invention.

In the above formulas, the term "lower alkyl" means a straight or branched alkyl group containing 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, and octyl.

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

The term "alk" means a straight or branched alkylene containing from 1 to 8 carbon atoms, such as methylene (-Cl 2 Cl 2), ethylene (-Cl 2 Cl 2), propylene (-Cl 2 Cl 2 Cl 2). -), ethylidene

B

/ -CH- /, 1,2-propylene / -CH-CH9- or -CH9-C-7, isopropylidene-I Δ Δ \ ~ CH3 ch3 CH3 JH1 / -C- / and 1,3-butylene / -CH -CH9-CH9- /, preferably ethylene CH3 ch3 and propylene.

3,77232

By acid addition salts are meant salts formed with an acid which is preferably physiologically acceptable, such as salts formed using either strong or weak acids. Typical strong acids are hydrochloric, sulfuric and phosphoric acids. Typical weak acids are fumaric, maleic, succinic, oxalic, cyclohexamine and the like.

The pharmacological properties of the final products of formula I are disclosed in parent application 813976 (patent 71935).

Description of the preparation of the compounds

The reaction sequence for the preparation of intermediates of the invention and their conversion to the final products of formula I is shown in Scheme 1. Alternative methods for the preparation of certain compounds of formula I are shown in Schemes 2, 3 and 4.

Methanones, formula II, see flow chart 1

Methanone intermediates are prepared by heating a mixture of haloaminopyridine and aminobenzophenone for less than the time required to effect cyclization to pyridobenzodiazepine, as determined by mass spectral analysis based on chemical ionization. For the preparation of (2- [3-amino-2-pyridinyl) amino] phenyl} methanones, the conditions required are about 1-1.5 h at 170-200 ° C.

Methanones can be separated as the main product, if desired, by cooling and adding a suitable organic solvent, such as methylene chloride, which dissolves the unreacted starting materials and some cyclized compound (Ia), followed by separation by conventional methods such as partitioning between solvent and aqueous methanol or aqueous base. between the base followed by washing, drying, evaporation of the solvent layer and recrystallization from a suitable solvent.

4,77232

Unsubstituted pyridobenzodiazepines, formulas Ia and Ia-1 (R = H), see Scheme 1____

The purified compounds II or the compounds II in the reaction mixture can be further heated in an aprotic solvent to cyclize the compounds of formula Ia by removing water from the reaction mixture in a conventional manner, for example by heating under reflux using a Dean-Stark trap.

However, it is not necessary to stop heating in the intermediate stage, but it is usually sufficient to continue heating the initial reaction mixture, i. III + IV, a longer time during which cyclization to compound Ia occurs. In the cyclization step, whichever option is used, the temperature and time ratios will vary to some extent depending on the reactants used, in which case it is only necessary to heat for a sufficiently long time. to form the desired product, which can be determined by a mass spectrum based on chemical ionization. Unsubstituted pyridobenzodiazepines are purified by partitioning between a suitable solvent such as methylene chloride and aqueous base, washing and drying the solvent layer, evaporating and chromatographing in a suitable solvent system such as acetone-Toni-benzene. The corresponding dihydrodiazepine can be prepared by reduction with sodium borocyanide hydride.

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

Compounds of formula Ia (or Ia-1) wherein R is hydrogen are alkylated or radicals are added which provide: alkylation by reaction first with sodium hydride and then with a suitable reagent which may be represented by the formula halo-alk · "Has the same meaning as above and Q is as defined 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 haloalkyl-Q reagent (alkyl-aminated substance or substance which results in alkylamination) is added at about room temperature and the reaction mixture is stirred for some time until the reaction is complete, as can be seen, for example, by thin-layer chromatography. The unreacted sodium hydride is decomposed by adding it to water and the product is extracted as a suitable solvent such as methylene chloride followed by extraction of the solvent layer with aqueous acid and separation of the product from the aqueous layer by neutralization and re-extraction with methylene chloride followed by evaporation and precipitation. na, maleate, etc. Once the acid addition salt has been obtained and purified, the free base can generally be regenerated by partitioning the salt between an aqueous base and a suitable solvent such as methylene chloride and evaporating the methylene chloride layer. The corresponding dihydrodiazepines can be prepared by reduction with sodium borocyanohydrin. Alternatively, compounds of formula Ib wherein Q is halogen may be converted to compounds wherein Q is -N- (lower alkyl) 2 · by reaction with a suitable dialkylamine, as shown in Reaction Scheme 2.

1 2

Primary amines of formula Ie, i.e. R and R are both hydrogen, prepared from -alkyl-β- (1-phthalimido) derivatives as shown in Scheme 1 by reaction with hydrazine hydrate using the method disclosed in Org. Syn. Coll. Butter. III, pp. 151-153. Generally, a reflux-cooling time of about 2-3 hours is sufficient, after which an aqueous acid solution is added and the mixture is filtered. Primary β-amines are separated from suitable solvents such as isopropyl alcohol. Hydrochlorides and hydrochloride hydrates are preferred salts in the separation step. The corresponding dihydrodiazepines can be obtained by reduction with sodium borocyanohydrin.

6 77232

According to Scheme 1, -alkyl-co-mono-12 alkylamines (Formula Ie), e.g., R = methyl and R = hydrogen, can be prepared by reacting the primary -alkyl-Ni-Derivative Ie or Ic-1 with a refluxed triethyl orthoform. with the matate for a time sufficient to form the methane imido acid ester (Id), which is then reacted with sodium borohydride. The unreacted borohydride is decomposed with water and the product is isolated by extraction as a suitable solvent such as ethyl acetate and can be purified by column chromatography and partitioning with a basic solvent. The hydrochlorides are the most preferred salts in the separation step. The process is described in more detail in Examples 24 and 25. The corresponding dihydrobenzodiazepines can then be prepared by reduction with sodium borocyanohydrin.

It is also possible to prepare -alkyl-monomethylamines by reacting the primary amine with ethyl chloroformate, e.g. according to Example 26, and then reducing with lithium aluminum hydride as shown in Scheme 3.

Another more common alternative for the addition of -alkyl-β-mono-lower alkylamine radicals is via the radical: O-1 "-alkyl-N-C-O-lower alkyl. See Scheme 1. lower alkyl.

All formulas Ia, Ia-1, Ib, Ib-1, Ib-2, Ib-3, Ib-4, Ie,

Ic-1, Ic-2, Id, Ie, Ie-1 are included in formula I.

7 77232

Flowchart 1 o 'c — Ar

/ Additional heating -I ^ O

H V happ ° I NN ^

“I

la-1 --- 1 "I NaH + solvent,

1 1 halo-al ^ -Q

W.N / (H) n / ^ Λ E) - \ when n = o JC_j] NaBH3CN, CjTj \] TVl acid Ζ '^ Αρ' ^ Ib al ^ -Q1 alk 1-Q1

Ib_1 ^ When Q is (1-phthalimido)

Ar f-alcohol-hydrazi-) Τ »^ tun .n -.3 1 1 K $ fate (iO) KaBKgCN, Ar (H) n

; ^ acid A ^ NC

all ^ -NHe ΓΤλΝ V - - »Ι ^ -ΝΗ»

Ar H --- 1 K-CfOCsH,) 1 V h ^ H ^ p

Ie-1 1lkl-a-CHs </ r ^) ^ Th T kun n = ..Q Ζ-Αί ^ Λ-Ν f1 K / H'n acid ^ Id alX1-H-CH-OcaHs; N'-1-CH 2 I · Q is -N- (lower alkyl) 21 1-piperidinyl, 4-morpholino, -N-phthalimido, -N-O-O-lower alkyl or halogen.

lower alkyl 8 77232

Scheme 2 H, n + KH- (lower alkyl) 2 alk1-halo (H) n

Ib-2 A * 'K

2 n ^ 'I?

Ib-5 aIk1 - ^ - (lower alkyl) 2 Flow diagram 3 5L / (H) n alk1- ^

Ic \

Solvent + \ Ar (jj \ NIC2H5) s, \ n

EtOC (O) Cl alk1-NH-C (O) -OC2H5 "7

/ Li AlH

v_? /

f NH

Ie-1 alk1-N-CHa 77232

Flowchart 4 T <»>„

· Vt. OF

I 1 n alk-N-C-O-lower alkyl

Ib-4 L lower alkyl hydrolysis with aqueous acid or base.

alk - NH-lower alkyl

Ie-1

The preparation of the new (tamino-pyridinyl) aminophenylaryl / methanones, which are intermediates in the preparation of phenyl-substituted pyrido [1,4] benzodiazepines, is described in more detail in connection with the following intermediates 1-6. The structures of these intermediates are shown in Table 1.

Preparation of methanone intermediates Intermediate 1 {2- (T3-amino-2-pyridinyl) amino / phenyl} phenylmethanone A stirred mixture of 39.4 g (0.20 mol) of 2-aminobenzophenone and 28.3 g (0.22 mol) moles) of 3-amino-2-chloropyridine, heated at 180 ° C under nitrogen for 1.5 h. The mixture was allowed to cool slightly and then 200 mL of methylene chloride was added slowly. After stirring for 3 h and standing overnight at room temperature, 40.1 g of solid were filtered off and recrystallized twice from methanol-isopropyl ether to give 4.3 g of presumably the hydrochloride salt, m.p. 187-190 ° C. This solid was dissolved in a mixture of water and methanol, basified with 3N sodium hydroxide solution and extracted with methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from isopropyl ether (charcoal) to give 2.1 g of product, m.p. 91-93 ° C. Drying before analysis was performed overnight at room temperature / 0.22 mm Hg.

Analysis: Calculated for C 18 H 18 N 2 O 2: C, 74.72; H 5.23; N 14.52 Found: C 74.94; H 5.23; N 14.69 Intermediate 2 {2- (T3-amino-2-pyridinyl) amino] -4-chlorophenyl} phenylmethanone _: ____

A stirred mixture of 23.2 g (0.1 mol) of 2-amino-4'-chlorobenzophenone and 14.2 g (0.11 mol) of 3-amino-2-chloropyridine was heated at 180 ° C under nitrogen. 2.5 h. The mixture solidified after cooling to room temperature and decomposing with a spatula. The solid was suspended in 100 mL of methylene chloride and collected by filtration. The filter cake was dissolved in water-methanol, basified with 3N sodium hydroxide solution and extracted twice with methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The crystallized residue was triturated with isopropyl ether and the solid residue (16.7 g) was collected by filtration. A 3 g sample was recrystallized from isopropyl ether to give 1.6 g of product, m.p. 153-155 ° C.

Analysis: Calculated for C 18 H 14 ClN 3 O: C, 66.77; H 4.36; N 12.98 Found: C 67.06; H 4.36; N 13.17 11 77232 Intermediate 3 {2- (73-amino-2-pyridinyl) amino] phenyl} (4-methylphenyl) methanone

A stirred mixture of 20.0 g (0.095 mol) of 2-amino-4'-methylbenzophenone and 13.95 g (0.104 mol) of 3-amino-2-chloropyridine (96%) was heated at 180 ° C under nitrogen. 2.0 h. The mixture was cooled to a glassy solid which was crushed, triturated in methylene chloride and stirred overnight. The solid was collected by filtration and dissolved in warm methanol. The solution was basified with 3N sodium hydroxide solution, diluted with 500 ml of water and extracted three times with 250 ml of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate 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 to 127.5 ° C.

Analysis: Calculated for C 75.23; H 5.65; N 13.85: found: C 75.81; H 5.69; N 13.96 Intermediate 4 {2- (T3-amino-2-pyridinyl) amino] -5-chlorophenyl} - (2-chlorophenyl) methanone

A stirred mixture of 20.0 g (0.156 moles) of 3-amino-2-chloropyridine and 37.3 g (0.14 moles) of 2-amino-2 ', 5-dichlorobenzophenone was heated at 190 ° C under nitrogen. 5.5 h. Thin layer chromatography (5% methyl alcohol-benzene on silica gel) showed no substantial reaction. The mixture was stirred overnight at 190 ° C, cooled slightly and 100 ml of methylene chloride was carefully added. The suspension was stirred for 2h and the formed black solid was filtered off. This solid was suspended in 500 ml of methylene chloride and 300 ml of dilute sodium hydroxide solution was added to 12,77232. An emulsion formed and the mixture was filtered and allowed to separate into layers. The methylene chloride layer was washed by extraction with two 250 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in benzene and filtered through a 30 g "fluorisil" column to remove low R material. All fractions were combined and evaporated under reduced pressure. Thin layer chromatography showed the presence of two main components, with a lower R value predominating. The residue was dissolved in benzene and chromatographed on a 600 g column of "fluorosilium" placed in benzene. Material with a higher R value was eluted with 1% acetone-benzene. Upon evaporation, the residue was triturated with benzene and recrystallized from benzene-isooctane to give 2.7 g of product, m.p. 162-164 C.

Analysis: Calculated for C H Cl N 0: C 60.35; H 3.66; N 11.73 18 13 2 3 Found: C 60.67; H 3.67; N 11.77 Intermediate 5 {2 - / (3-amino-2-pyridinyl) amino] phenyl} - (3-chlorophenyl) methanone

A stirred mixture of 35 g (0.152 moles) of 2-amino-3'-chlorobenzophenone and 23.4 g (0.182 moles) of 3-amino-2-chloropyridine was heated at 180 ° C for 2 h. The hot melt was allowed to stand. to cool to 110 ° C, after which 100 ml of hot toluene were added dropwise with vigorous stirring. The mixture was allowed to cool to 30 ° C with stirring and 50 ml of methylene chloride was added. After stirring for an additional 1/2 h, the mixture was filtered

The filter cake was suspended in methylene chloride with stirring for 1/2 h, and the methylene chloride was filtered off. The filter cake containing the product (25.4 g) was partially dissolved in weaving methanol (total volume 150 ml) and 50% aqueous sodium hydroxide solution was added until the mixture was basic. Ice water was then added and the solution was extracted with methylene chloride. This methylene chloride extract was washed with water and dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in isopropyl alcohol and boiled with charcoal. The mixture was filtered, reduced in volume to give a first crop of crystals weighing 16 g (33%). Some of the crystals were recrystallized from isopropyl alcohol to give a brick red solid, m.p. 119-120 ° C.

Analysis: Calculated for <18H14N3OC '*': ^ ^ 'H ^ / 36? N 12.98 Found: C 66.78; H 4.42; N 12.94 Intermediate 6: {2- (T3-amino-2-pyridinyl) amino] phenyl} (4-fluorophenyl) methanone

A stirred mixture of 35 g (0.163 moles) of 2-amino-41-fluorobenzophenone and 27 g (0.21 moles) of 3-amino-2-chloropyridine was heated at 175-180 ° C.

2.5 h. The mixture was allowed to cool to 110 ° C, after which 100 ml of hot toluene was added. After cooling to 50 ° C, 50 ml of methylene chloride was added. The solvent layer was decanted to leave a black solid which was dissolved in hot methanol. The volume of this solution was halved and allowed to stand overnight at room temperature. The mixture was filtered and the filter cake was washed twice by suspending in methylene chloride. The weight of the prepared crude solid was 22.5 g. This solid was dissolved in methanol and basified with 50% aqueous sodium hydroxide.

14 77232

The mixture was extracted with methylene chloride and the extract was dried and concentrated. This residue was crystallized twice from isopropyl alcohol, decolorized by boiling with charcoal a second time to give 14 g (28%) of a solid which was red-orange in color, m.p. 121.5-122.5 C. Analysis: Calculated for C H N OF: C 70.35? H 4.59? N 13.67 18 14 3 found: C 70.23? H 4.59? N 13.64

Table 1 \ / ΑΓ

C H N

B

Intermediate Ar

1 C H - H

6 5 2 C H - 4-C1 6 5

3 4-CH -C H - H

3 6 4 4 2-C1-C H - 5-Cl 6 4

5 3-C1-C H - H

6 4

6 4-F-C H - H

6 4

The following Examples 1-6 describe the preparation of phenyl-substituted Pyrido [1,47] benzodiazepine compounds using the 2- (T3-amino-2-pyridinyl) amino / phenylarylmethanone intermediates of the invention. Examples 7-31 further describe the substitution of phenyl-substituted pyrido [1,4] benzodiazepine compounds. The structures of the compounds shown in the examples are shown in Table 2.

Example 1 9-Chloro-6-phenyl-11H-pyrido [2,3-b] 1,4] benzodiazepine A suspension of 6.6 g (0.02 mol) of {2- [73-amino-2- pyridyl) amino-4--chlorophenyl} - (phenyl) methanone (intermediate 2) in 200 ml of toluene, was heated under reflux overnight under nitrogen. The reaction mixture was filtered hot and the filtrate was heated back to reflux.

is 77232

The precipitate formed on cooling to room temperature was filtered off and recrystallized from benzene and dried for 4 h at 97-98 ° C / 0.1 mm Hg and overnight at room temperature / 0.1 mm Hg to give 3.7 g. product, m.p. 250.5-252 C. Elemental analysis for carbon o was high and the product was re-dried at 139 C (xylene in a spray gun) for 8 hours. Although carbon analysis remained high, the magnetic resonance spectra and mass spectra of the protons corresponded to the assumed structure.

Analysis; Calculated for C H Cl N: C 70.71; H 3.36; N 13.74 16 12 3 Found: C 71.46; H 4.06; N 13.46

Example 2 8-Chloro-6- (2-chlorophenyl) -5,6-dihydro-11H-pyrido [2,3-b] -4H, 4-benzodiazepine

Further elution from the "fluorisil" column, preparation of intermediate 4, with 10-15% acetone in benzene and 5-25% methanol in benzene gave two fractions of the title product of this example, 6.4 g and 5.7 g, of which the latter was very impure. The 6.4 g fraction was recrystallized from benzene isooctane to give 3.7 g of a solid, m.p. 203-206 ° C (decomposes), identified by chemical ionization in 13 H mass spectrum analysis H and C NMR, δ-chloro-6- (2-chlorophenyl) -5,6-dihydro-11H-pyrido [2,3-b] l-47bentsodiatsepii trick.

Example 3 6- (4-Methylphenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine A solution of 3.6 g (0.012 mol) of {2- [(3-amino-2-pyridine) dyl) amino (phenyl) (4-methylphenyl) methanone in 100 mL of anhydrous toluene, treated with a catalytic amount of paratoluenesulfonic acid and heated to reflux overnight while separating water with a Dean-Stark collector. The reaction mixture was filtered hot. The product precipitated when the filtrate was cooled to room temperature and collected by filtration 77232. The weight of the solid obtained after evaporation of the solvent was 2.5 g, m.p. 203.5-205 ° C (decomposes).

Analysis: Calculated for C H N: C 79.98; H 5.30? N 14.73 19 15 3 found: C 79.95; H 5.27; N 14.76

Example 4 6- (4-Methoxyphenyl) -HH-pyrido [2,3-b] [1,47] benzodiazepine

A stirred mixture of 20.0 g (0.088 moles) of 2-amino-4'-methoxybenzophenone and 13.0 g (0.097 moles) of 3-amino-2-ol

chloropyridine (96%) was heated to 180 ° C

under nitrogen for 2.0 h. The reaction mixture was cooled to about 70 ° C and 100 mL of methylene chloride was added slowly. After the mixture was cooled to room temperature, an additional 50 mL of methylene chloride was added and the mixture was stirred overnight. The suspended solid was collected by filtration, air dried, dissolved in methanol and basified with 3N sodium hydroxide solution. The suspension was diluted with 500 ml of water and extracted with three 250 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. Mass spectral analyzes (EI and Cl) showed that the residue was a mixture of {2- [3-amino-2-pyridyl) amino] phenyl} (4-methoxyphenyl) methanone and the title compound. This residue was dissolved in 250 ml of toluene together with a catalytic amount of paratoluenesulfonic acid and the solution was heated to reflux overnight under nitrogen while separating the water with a Dean-Stark trap. The reaction mixture was filtered hot. The product precipitated when the filtrate was cooled to room temperature and collected by filtration. After recrystallization from benzene, the product weighed 1.8 g, m.p. o 198.5-200.5 C (decomposes).

Analysis: Calculated for C H N 0: C 75.73? H 5.02; N 13.94 19 15 3 found: C 75.65; H 4.98; N 14.03 17 77232

Example 5 6- (3-Chlorophenyl) -1H-pyrido [1,3-b] Z, 1,4-benzodiazepine A mixture of 14 g (0.0433 moles) of {2 - [(3-amino-2-pyridinyl) amino] phenyl} (3-chlorophenyl) methanone and 0.3 g of para-toluenesulfonic acid in 500 mL of toluene were heated to reflux with cooling overnight using a Dean-Stark trap to collect water. Towards the end of the reflux time, part of the toluene (about 250 ml) was distilled off and the hot solution was filtered.

o

Petroleum ether (30-60 ° C) was then added to the cloud point. The solution was cooled overnight and filtered to give 10 g (76%) of golden crystals after air drying. Part of this was recrystallized from isopropyl alcohol isopropyl ether, m.p. 160-160.5 C.

Analysis: Calculated for C H N Cl: C 70.71, H 3.96; N 13.74 18 12 3 found: C 70.47; H 3.98; N 13.62

Example 6 6- (4-Fluorophenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine A mixture of 11.5 g (0.037 mol) of {2- [3-amino-2-pyridine] dinyl) amino / phenyl} (4-fluorophenyl) methanone and 0.6 g of paratoluenesulfonic acid in toluene, was heated at reflux for 24 h using a Dean-Stark trap to collect water. After refluxing, some toluene (300 mL) was distilled off and the hot solution was filtered. Then, petroleum ether (30-60 ° C) was added to the cloud point. The solution was cooled overnight (0 ° C) and filtered to give 10.7 g of crystals. A portion of this material was recrystallized from isopropyl alcohol and dried in vacuo overnight at 65 ° C, m.p. 203-205 C.

Analysis: Calculated for C H N F: C 74.73; H 4.18; N 14.52 19 12 3 found: C 74.61; H 4.17; N 14.54 77232 18

Example 7 8-Chloro-N, Nd-methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine oxalate (1: 1) To a stirred suspension of 1.05 g ( 0.044 moles) of sodium hydride (in mineral oil) in 50 ml of anhydrous dimethylformamide, 6.1 g (0.02 moles) of 8-chloro-6-phenyl-11H-pyrido [2,3-b] [4,4] benzodiazepine were added portionwise under nitrogen. The reaction mixture was stirred at room temperature for 1.5 h during which time hydrogen evolution ceased. 3.5 g (0.022 mol) of 3-dimethylaminopropyl chloride hydrochloride were added portionwise to the mixture. After stirring overnight at room temperature, the reaction mixture was poured into 1600 ml of water and the combination was extracted with three 250 ml portions of methylene chloride. The combined methylene chloride extracts were washed twice with 250 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in benzene and chromatographed on acetone-benzene in a 300 g "florisil" column packed in benzene. The starting material, 1.6 g, was taken up in benzene solution and 3.6 g of product were obtained as the free base by acetone-benzene elution after evaporation of the solvent. 2.5 g of crude free base was then dissolved in hot isopropyl alcohol and reacted with 0.8 g (0.0064 mol) of oxalic acid dihydrate. The oxalate salt which precipitated on cooling was collected by filtration and recrystallized from ethanol to give 2.2 g. product, mp 206-208 ° C. Drying conditions before analysis were: 5 h at 97-98 ° C / 0.02 mm Hg, overnight at room temperature / 0.02 mm Hg.

Analysis: Calculated for C25H25ClN4O4: C, 62.43; H 5.24; N 11.65 found; C 62.52; H 5.23; H 11.76

Example 8 N, N-Dimethyl-6-phenyl-11H-pyrido [2,3-b] 1,4] benzodiazepine-11-propanamine-1-fumarate (1: 1) 19,77232

To a stirred suspension of 1.68 g (0.070 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide was added portionwise under nitrogen a suspension of 8.0 g (0.029 mol) of 6-phenyl-11H-pyrido / 2,3-b7 / l / N-benzodiazepine in 20 ml of anhydrous dimethylformamide The mixture was stirred for 30 min after the addition was complete, warmed to 65 ° C for 15 min and cooled again to room temperature 5.6 g (0.035 mol) was added. 3-Dimethylaminopropyl chloride hydrochloride After stirring overnight at room temperature, thin layer chromatography indicated that the reaction was almost complete.The reaction mixture was poured into 1500 ml of water and extracted with 250 ml of methylene chloride.The methylene chloride extract was washed with three 250 ml portions. dried over magnesium sulfate and evaporated under reduced pressure, the residue was dissolved in methylene chloride and extracted with 100 ml and 150 ml portions of 3N hydrochloric acid. The 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine starting material was precipitated from aqueous acid and carefully separated by decantation from the solid. The aqueous solution was basified with 3N sodium hydroxide solution and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulphate and evaporated under reduced pressure to give 7.7 g of a residue, the free base of the title compound. A solution of 6.6 g of this residue in hot isopropyl alcohol was reacted with 2.15 g of fumaric acid and the mixture was therefore heated until dissolution was complete. After standing for 48 h, the precipitated salt was collected by filtration. After recrystallization from isopropyl alcohol isopropyl ether, 5.9 g of product were obtained, m.p. 171-173 ° C. Drying conditions before analysis were 4 h at 90 ° C / 0.1 mm Hg; overnight at room temperature / 0.1 mm Hg.

20 77232

Analysis: Calculated for C 27 H 28 H 4 O 4: C, 8.63; H 5.97; N 11.86 Found: C 68.37; H 6.05; N 11.73

Example 9 N, N-Dimethyl-6-phenyl-11H-pyrido [2,3-b] [3,4-b] benzodiazepine-11-ethanamine fumarate (1: 1)

To a stirred suspension of 1.48 g (0.062 mol) of sodium hydride (in mineral oil) in 35 ml of anhydrous dimethylformamide was added portionwise 7.0 g (0.026 mol) of 6-phenyl-11H-pyrido [2,3-b] under nitrogen. // l, 4 / benzodiazepine. After the reaction mixture was cooled to room temperature, 4.46 g (0.031 mol) of 2-dimethylaminoethyl chloride hydrochloride was added portionwise and stirring was continued overnight. The reaction mixture was poured into 1500 ml of water, and the resulting mixture was extracted with 250 ml of methylene chloride. The methylene chloride extract was washed with three 500 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure to give 8.6 g of an oil, the free base of the title compound. A portion of this oil, 6.9 g, was reacted with an equal molar amount of fumaric acid in isopropyl alcohol. Addition of isopropyl ether gave an oily solid. The mixture was evaporated under reduced pressure and the residue crystallized on standing. The crystals were triturated with acetone and recrystallized from acetone-isopropyl ether to give 4.3 g of the fumarate salt, m.p. 175 to 177.5 ° C.

Analysis: Calculated for C 26 H 26 N 4 O 4: C H 5.72; N 12.22 Found: C 67.88; H 5.72; N 12.17

Example 10 11- [3- (4-Morpholinyl) propyl] -6-phenyl-11H-pyrido [2,3-b] [1] benzodiazepine fumarate (1: 1)

To a stirred suspension of 1.10 g (0.046 moles) of sodium hydride (in mineral oil) in 25 ml of anhydrous 21,77232 dimethylformamide was added portionwise under nitrogen under 5.0 g (0.0184 moles) of 6-phenyl-11H-pyrido / 2,3-b7 / I, Q-benzodiazepine. The reaction mixture was stirred at room temperature for 15 min and warmed to 65-70 ° C for 10 min and allowed to cool to room temperature. To this mixture was added portionwise 4.1 g (0.02 moles) of 4- (3-chloropropyl) morpholine hydrochloride. The reaction mixture was stirred at room temperature for 16 h and then poured into 800 ml of water. This mixture was extracted twice with 200 ml portions of methylene chloride. The combined methylene chloride extracts were extracted with 150 mL and 75 mL portions of 3N hydrochloric acid, and the combined aqueous extracts were basified with 3N sodium hydroxide. The resulting suspension was extracted with two 150 ml portions of methylene chloride and the two extracts were combined, dried over magnesium sulphate and evaporated under reduced pressure. The residue, the free base of the title compound, was reacted with an equal molar amount of fumaric acid in warm isopropyl alcohol and the mixture was treated with isopropyl ether. The fumarate salt was collected by filtration and recrystallized from ethanol-ethyl acetate to give 5.6 g of product, m.p. 154-157 ° C. Drying conditions before analysis were: 4 h at 97-98 ° C / 0.1 mm Hg; overnight at room temperature / 0.1 mm Hg.

Analysis: Calculated for C 29 H 30 N 4 O 5: C, 67.69; H 5.88; N 10.88 Found: C 67.52; H 5.84; N 10.90

Example 11 N, N-Diethyl 6-phenyl-11H-pyrido [2,3-b] -1H-benzodiazepine-11-propanamine oxalate (1: 1)

To a stirred suspension of 1.10 g (0.0461 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide was added portionwise 5.0 g (0.0184 mol) of 6-phenyl-11H-pyrido / 2,3-b in a nitrogen atmosphere. // l, 4 / benzodiazepine. The reaction mixture was stirred at room temperature for 22 h, warmed to 65-70 ° C and slowly cooled to room temperature. To this mixture was added portionwise 3.77 g (0.020 mol) of 3-diethylaminopropyl chloride hydrochloride, and the reaction mixture was stirred at room temperature for 16 h. The mixture was poured into 750 ml of water and extracted with three 150 ml portions of methylene chloride. The combined methylene chloride extracts were extracted with 150 mL and 75 mL portions of 3N hydrochloric acid. The combined aqueous extracts were basified with 3N sodium hydroxide and then extracted three times with 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulphate and evaporated under reduced pressure to give 7.5 g of the title compound as the free base. 5.6 g of this compound were reacted with an equal molar amount of oxalic acid dihydrate in hot isopropyl alcohol. The oxalate salt was collected by filtration to give 5.5 g of product, m.p. 196-199 ° C. Drying conditions before analysis were: 1 h at 97-98 ° C / 0.1 mm Hg.

Analysis: Calculated for C 27 H 30 N 4 O 4: C, 68.34; H 6.37; N 11.81 Found: C 68.31; H 6.43; N 11.86

Example 12 9-Chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine fumarate (1: 1) To a stirred suspension of 0.98 g (0.041 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide, 5.0 g (0.016 mol) of 9-chloro-6-phenyl-11H-pyrido [2,3-b] N were added portionwise under nitrogen. E / benzodiazepine within 45 min. The reaction mixture was stirred at room temperature for 1 h, warmed to 70 ° C and then slowly cooled to room temperature. To this mixture was added portionwise over 30 min 2.84 g (0.018 moles) of 3-dimethylaminopropyl chloride hydrochloride and the reaction mixture was stirred at room temperature for 17 h. The mixture was poured into 750 mL of water and extracted with 150 mL of 23,77232 and two 100 mL: n with methylene chloride. The combined methylene chloride extracts were washed with two 100 ml portions of water and then extracted with 100 ml and 75 ml portions of 3N hydrochloric acid. The acidic extracts were combined and filtered to remove the precipitate formed and the filtrate was basified with 3N sodium hydroxide and extracted three times with 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in methylene chloride and filtered through a 50-60 g layer of "florisil" in a sintered glass funnel. The layer was washed successively with a mixture of 1, 2, 3 and 5% methanol and methylene chloride, the filtrates were combined and evaporated under reduced pressure to give the title compound as the free base. This free base was reacted with an equimolar amount of fumaric acid in hot isopropanol to give 3.3 g of fumarate, m.p. 199-202 ° C.

Analysis: Calculated for C 27 H 27 N 4 O 4 Cl: C, 63.96; H 5.37; N 11.05 Found: C 63.63; H 5.36; N 11.00

Example 13 6-Phenyl-11β- [3- (1-piperidinyl) propyl] -1H-pyrido [2,3-b] [1,4] benzodiazepine fumarate (1: 1)

To a stirred suspension of 1.10 g (0.0461 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide was added portionwise under nitrogen under 5.0 g (0.018 mol) of 6-phenyl-11H-pyrido72,3-b7. / l »£ / benzodiazepine. The reaction mixture was stirred for 30 min, warmed to 70 ° C and cooled to room temperature. To the mixture was added portionwise 4.14 g (0.0203 mol) of N- (3-chloropropyl) piperidine hydrochloride, and the reaction mixture was stirred at room temperature for 16 h.

The mixture was poured into 750 ml of water and extracted with 150 ml of methylene chloride with stirring for 15 min. The water 24 77232 layer was extracted with two additional 100 mL portions of methylene chloride. The combined methylene chloride extracts were extracted with 150 mL and 75 mL portions of 3N hydrochloric acid, and the combined acidic extracts were basified with 3N sodium hydroxide and then extracted with three 100 mL portions of methylene chloride. The methylene chloride extracts were combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in as little methylene chloride as possible and filtered through a 100 g pad of florisil in a sintered glass funnel. The layer was washed successively with methylene chloride, 2, 3 and 5% methanol-methylene chloride. All filtrates were combined and evaporated under reduced pressure. The residue was reacted with 1.3 g of fumaric acid in hot isopropanol, and to this was added isopropyl ether. An amorphous precipitate formed. The whole mixture was evaporated to dryness and the residue was dissolved in 200 ml of ethanol. The solution was heated to reflux, filtered and isopropyl ether was added to the filtrate. The crystals formed overnight were separated by filtration to give 4.1 g of the fumarate salt, m.p. 153-156 ° C. Drying conditions before analysis were: 4 h at 97-98 ° C / 0.1 mm Hg.

Analysis: Calculated for C 31 H 32 N 4 O 4: C 70.29; H 6.29; N 10.93 Found: C 70.38; H 6.32; N 10.92

Example 14 6- (4-Chlorophenyl) -N- (N-dimethyl-11H-pyrido / 2,3-b7 / T, 4,7-benzodlazepine-11-propanamine fumarate (1: 1) To a stirred suspension of 1 .57 g (0.065 moles) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide were added under nitrogen to 8.0 g (0.026 moles) of 6- (4-chlorophenyl) -11H-pyrido [2,3-b] / lr. The reaction mixture was stirred at room temperature for 1 h, warmed to 80 ° C over 15 min and cooled to room temperature 4.55 g (0.029 mol) of 3-dimethylaminopropyl chloride hydrochloride was added portionwise and the mixture was stirred overnight. The mixture was poured into 750 ml of water and stirred for 30 min with 150 ml of methylene chloride, the aqueous layer was extracted with three more 100 ml portions of methylene chloride, and the combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure to give the title compound as a free base. this free base was reacted with an equal molar amount of fumaric acid in hot isopropanol. After cooling, 3.6 g of fumarate salt precipitated, m.p.

200.5 to 202.5 ° C. The product was further air dried before analysis.

Analysis: Calculated for C 27 H 27 ClN 4 O 4: C, 63.96; H 5.37; N 11.05 Found: C 64.18; H 5.33; N 11.07

Example 15 8-Chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] 1,4] benzodiazepine-11-ethanamine oxalate (1: 1) To a stirred suspension of 1 .05 g (0.044 mol) of sodium hydride (in mineral oil) in 5 ml of anhydrous dimethylformamide were added portionwise, 6.1 g (0.02 mol) of 8-chloro-6-phenyl-11H-pyrido [2,3-b] [Tf] benzodiazepine. nia. The reaction mixture was stirred at room temperature for 1.5 h during which time hydrogen evolution ceased. The reaction mixture was cooled to 5 ° C and 3.2 g (0.022 mol) of 2-dimethylaminoethyl chloride hydrochloride was added portionwise, followed by stirring at room temperature for about 60 h. The reaction mixture was poured into 1600 ml of water and extracted three times with 500 ml portions of methylene chloride. . The combined extracts were washed with two 500 ml portions of water, dried over magnesium sulphate and evaporated under reduced pressure. Thin layer chromatography (20% methanol / benzene on silica gel) showed the presence of 26,77232 free base and starting material of the title compound. The residue was dissolved in benzene and chromatographed on a 200 g "florisil" column packed in benzene. The starting material, 1.3 g of 8-chloro-6-phenyl-11H-pyrido [2,3-b] [1,7] benzodiazepine, was eluted with benzene and the free base of the title compound was eluted with mixtures of acetone and benzene. The free base was reacted with an equal molar amount of oxalic acid dihydrate in refluxing isopropyl alcohol and the product, recrystallized from isopropyl alcohol, weighed 1.6 g, m.p. 228.5 to 232 ° C. Drying conditions before analysis were 6 h at 82 ° C / 0.1 mm Hg overnight at room temperature.

Analysis: Calculated for C 24 H 23 Cl 2 - N 4 O 4: C 61.74 * H 4.96; N 12.00 Found: C 61.62; H 4.95; N 11.98

Example 16 8-Chloro-11-methyl-6-phenyl-11H-pyrido [2,3-b] [1,47] benzodiazepine

To a stirred suspension of 0.25 g (0.01 mol) of sodium hydride (in mineral oil) in 15 ml of anhydrous dimethylformamide was added portionwise 3.05 g (0.01 mol) of 8-chloro-6-phenyl-11H- pyrido / 2,3-b7 / ^ '- ^ benzodiazepine. The mixture was heated at about 60 ° C for 1 h. A solution of 1.42 g (0.01 mol) of methyl iodide in 10 ml of anhydrous dimethylformamide was added dropwise over 0.5 hour, and the reaction mixture was stirred overnight at room temperature, after which it was stirred. was poured into 400 ml of water and stirred for 2 h. The precipitated solid was recrystallized twice from isopropyl alcohol to give 2.0 g of product, m.p. 153-156 ° C. Drying conditions before analysis were 1 h at 82 ° C / 0.1 mm Hg.

Analysis: Calculated for C 18 H 18 ClN 2 O 2: C, 71.36; H 4.41; N 13.14 Found: C 71.64; H 4.43; N 13.32 27 77232

Example 17 N, N-Dimethyl-6- (4-methylphenyl) -1H-pyrido [2,3-b] -1,4,4-benzodiazepine-11-propanamine fumarate (1: 1) In a stirred suspension of was 0.51 g (0.022 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide, 4.2 g (0.0147 mol) of 6- (4-methylphenyl) -11H-pyrido [2,3-b] l were added portionwise under nitrogen. , / / benzodiazepine within 45 min. The mixture was stirred at room temperature for 1 h, warmed to 75-80 ° C over 1 hour, cooled to room temperature, and a solution of 0.0184 mol of 3-dimethylaminopropyl chloride in 10 ml of anhydrous dimethylformamide was added dropwise. The mixture was stirred overnight at room temperature and poured into 1000 ml of water. The suspension was extracted with three 150 ml portions of methylene chloride and the combined methylene chloride extracts were extracted with two 150 ml portions of 3N hydrochloric acid. A precipitate formed in the acidic solution and was removed by filtration and discarded. The filtrate was basified with 3N NaOH and extracted three times with 100 mL portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure to give the free base of the title compound as an oil. This residue was dissolved in hot isopropyl alcohol and reacted with an equal molar amount of fumaric acid. The fumarate salt crystallized as the solution cooled to room temperature and was recrystallized twice from isopropyl alcohol-isopropyl ether to give 1.7 g of product, m.p. 187-189 ° C (decomposes).

Analysis: Calculated for C 28 H 30 N 4 O 4: C 69 * 12; H 6.22; N 11.52 Found: C 68.86; H 6.32; N 11.36

Example 18 6- (4-Methoxyphenyl) -N, N-dimethyl-11H-pyrido [1,3-b] [1,7] benzodiazepine-11-propanamine fumarate (1: 1) 28,77232

To a stirred suspension of 0.45 g (0.0187 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide was added 4.5 g (0.015 mol) of 6- (4-methoxyphenyl) -11H-pyrido / 2.3 -b // 1,4 / benzodiazepine within 30 min. The mixture was stirred at room temperature for 30 min and then heated at 80-90 ° C for 1 h, cooled to room temperature and a solution of 0.019 mol of 3-dimethylaminopropyl chloride in 5 ml of anhydrous dimethylformamide was added dropwise. The reaction mixture was stirred overnight at room temperature and poured into 800 ml of water. The resulting suspension was extracted with two 150 mL portions of methylene chloride. The combined extracts were washed with 500 ml of water and then extracted with two 100 ml portions of 3N hydrochloric acid. The solid which precipitated from the combined acidic extracts was filtered off and discarded. The filtrate was basified with 3N sodium hydroxide solution and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residual oil was partially crystallized and triturated with methylene chloride and filtered to give 0.32 g of residue. The filtrate was evaporated under reduced pressure and the residual oil was triturated with hot benzene and filtered to give a residue of 0.8 g. The benzene filtrate was evaporated under reduced pressure and the residual oil was reacted with 1.02 g of fumaric acid in hot isopropyl alcohol. After cooling, an oil separated from the solution. The liquid above the precipitate was decanted and seed crystals were placed in the oil. After partial crystallization, the mixture was filtered to give 2.5 g of a solid, m.p. 157-160 ° C. Recrystallization from isopropyl alcohol-isopropyl ether again gave a mixture of oil and solid. The mixture was reheated with additional isopropyl alcohol, dissolved, filtered, seeded and cooled. The fumarate salt was precipitated and collected by filtration to give 2.0 g of product, m.p. 159-161 ° C.

29 77232

Analysis: Calculated for C H N O: C, 66.92; H 6.02; N 11.15 28 30 4 5 Found: C 66.90; H 6.08; N 11.08

Example 19 6- (3-Chlorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [1,47] benzodiazepine-11-propanamine fumarate (1; 1)

To a stirred suspension of 3.4 g (0.07 moles) of sodium hydride (in mineral oil) in 250 ml of anhydrous dimethylformamide was added portionwise 8.5 g (0.028 moles) of 6- (3-chlorophenyl) -11H under nitrogen. -pyrido / 2,3-b7 / 1,47 ′ benzodiazepine. The mixture was stirred for 30 min at room temperature. The temperature was raised to 80 ° C for 3 hours and the mixture was then allowed to cool to room temperature. A solution of 4.9 g (0.031 mol) of 3-dimethylaminopropyl chloride hydrochloride in 30 ml of dimethylformamide was added dropwise to the reaction mixture over 20 minutes. The reaction mixture was stirred at room temperature overnight under nitrogen. Thin layer chromatography indicated the presence of some starting material. An additional 1.4 g (0.03 mol) of sodium hydride was then added, followed 15 min later by 4.7 g (0.03 mol) of 3-dimethylaminopropyl chloride hydrochloride, followed by stirring for 4 1/2 hours. Water (20 ml) was then added dropwise and the reaction mixture was filtered and concentrated on a rotary evaporator. The residue was partitioned between diethyl ether and dilute sodium hydroxide solution. The ether layer was washed three times with water and extracted with dilute aqueous hydrochloric acid. The aqueous layer was basified with sodium hydroxide beads and extracted with methylene chloride. The methylene chloride layer was dried and concentrated to give 7.5 g of product as a residue. The free base was reacted with fumaric acid and the fumarate salt was recrystallized from ethyl acetate-ethanol, m.p. 167.5-168.5 C.

Analysis; calculated for C H N Cl; C 63.96; H 5.47; N 11.05 23 23 4 Found: C 63.95; H 5.39; N 11.00 30 77232

Example 20 6- (4-Fluorophenyl) -N, N-dimethyl-1H-pyrido [2,3-b] [1 * 4 H] -benzodiazepine-11-propanamine hydrochloride hemihydrate

To a stirred suspension of 3.6 g (0.075 moles) of sodium hydride (in mineral oil) in 250 ml of anhydrous dimethylformamide was added portionwise 8.7 g (0.03 moles) of 6- (3-fluorophenyl) -11H under nitrogen. -pyrido [2,3-b] [1,4] benzodiazepine. The mixture was stirred for 30 min at room temperature.

The temperature was raised to 80 ° C for 3.5 hours and the mixture was then allowed to cool to 45 ° C. A solution of 5.2 g (0.033 mol) of 3-dimethylaminopropyl chloride hydrochloride in 30 ml of dimethylformamide was added dropwise to the reaction mixture. After stirring overnight at room temperature, the presence of starting material was determined by thin layer chromatography. An additional 3.6 g (0.075 moles) of sodium hydride was then added and, after stirring for 45 minutes, the reaction mixture was heated to 50-60 ° C for 1/2 hour. A green color and gas formed. The mixture was stirred at room temperature for 3 h. A solution of 5.2 g (0.033 mol) of 3-dimethylaminopropyl chloride in 30 ml of dimethylformamide was then added dropwise. (A green color formed about halfway through the addition and the duration of the addition was about 1 h). The reaction mixture was stirred overnight at room temperature. To the mixture was added 30 ml of water while cooling. When gas evolution ceased, the mixture was filtered and concentrated on a rotary evaporator. The residue was partitioned between diethyl ether and water, and the ether layer was extracted with dilute aqueous hydrochloric acid. The aqueous layer was filtered after 1 1/2 hours to remove solids. The filtrate was basified with sodium hydroxide beads and extracted with methylene chloride. The extract was dried and concentrated. The residue was divided into two equal 31,77232 portions and purified by dry column chromatography using two 20 x 38 mm silica gel columns deactivated with developing solvent (10% methanol, 1% concentrated ammonium hydroxide, 89% methylene chloride). The center of the statue was excised and extracted with developing solution. The combined extracts were concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-ethanol and acidified with concentrated hydrochloric acid. The hydrochloride salt was recrystallized from ethanol-ethyl acetate. The solid obtained by filtration was dried at 99 ° C for 48 hours to give the title compound as a monohydrochloride hemihydrate, m.p. 120-123 ° C.

Analysis: Calculated for C 46 H 50 N 8 F 2 Cl 2: C, 65.78; H 6.00; N 13.34 Found: C 65.58; H 5.77; N 13.47

Example 21 11- [3- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) propyl] -6-phenyl-11H-pyrido [2,3-b] [1,47] benzodiazepine In a stirred suspension, containing 0.56 g (0.023 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide, 5.0 g (0.0184 mol) of 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine were added portionwise. The reaction mixture was heated at 80 ° + 2 ° C for 1 h and cooled to room temperature. A solution of 5.55 g (0.020 mol) of N- (3-bromopropyl) phthalimide in 10 ml of anhydrous dimethylformamide was then added dropwise, and after stirring for 16 h, the reaction mixture was poured into 650 ml of water and stirred for 30 min. . The yellow solid was collected by filtration and recrystallized three times from isopropyl alcohol to give 3.7 g of product, m.p. 170-172 ° C.

Analysis: Calculated for C 18 H 18 N 4 O 2: C 75.97; H 4.84; N 12.22 Found: C 76.25; H 4.87; N 12.34 32 77232

Example 22 6-Phenyl-11H-pyrido [2,3-b] 1,4] benzodiazepine-11-propanamine, dihydrochloride, hemihydrate A mixture of 16.2 g (0.035 moles) of 6-phenyl-11 - [3- (phthalimido) propyl] -11H-pyrido / 2,3-b / 1,4 / benzodiazepine and 2.29 g (0.0387 mol) of hydrazine hydrate, 85% 175 ml: (190 proof) ethyl alcohol, heated at reflux for 2.5 h and allowed to stand for 72 h. A solution of 10 ml of concentrated hydrochloric acid in 50 ml of water was added to this mixture. The mixture was stirred overnight. The solid precipitate was collected by filtration and discarded. The filtrate was evaporated under reduced pressure. The slightly moist residue was suspended in 200 ml of water, the mixture was stirred for 2 h and filtered through celite. The filtrate was evaporated under reduced pressure and the residue was suspended in 100 ml of ethyl alcohol (200 proof) and evaporated under reduced pressure. The latter treatment was repeated. The crude wet residue (42.1 g) was recrystallized from isopropanol and allowed to stand for about 15 h. The solid obtained by filtration was dried at 82 ° C with phosphoric anhydride at 0.1 mm Hg for 3 h, m.p. 210-220 ° C (decomposes).

Analysis: Calculated for C 18 H 18 Cl 2 N 2 O 2: C, 61.47; H 5.65; N 13.65 Found: C 61.36; H 5.72; N 13.90

Example 23 6-Phenyl-11H-pyrido [2,3-b] [4- [4,7] benzodiazepine-11-propanamine

A portion of the 6-phenyl-11H-pyrido [2,3-b] -1H-benzodiazepine-11-propanamine dihydrochloride hemihydrate obtained in Example 22 was dissolved in water, basified with dilute sodium hydroxide and extracted three times with methylene chloride. The combined methylene chloride extracts were filtered through a 50-60 g pad in a "florisil" sintered glass funnel. The layer was washed successively with 1, 2, 3 and 5% methanol-methylene chloride, the filtrates were combined and evaporated under reduced pressure to give the title compound as the free base.

Example 24 N- {3- [6-Phenyl-11H-pyrido [2,3-b] -1,4-benzodiazepin-11-yl] propyl} methanimidic acid ethyl ester A solution of 8.8 g (0.021 mol) of 6 -phenyl-11H-pyrido [7,3-b] [N, N] benzodiazepine-11-propanecimine in 150 ml of triethyl orthoformate, heated at reflux for 4 1/2 h and allowed to stand overnight. The mixture was concentrated in vacuo and the residue was washed with petroleum ether (30-60 ° C). The mass spectrum based on chemical ionization indicated that the product was a mixture containing the title compound.

Example 25 N-Methyl-6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine-11-propanamine, dihydrochloride (III) [§§ £ £ i§§t§ £ ii} _Y§i5) ± §Tus / Method presented by Crochet, TA & Blanton, CD, Jr. Synthesis 1974 (1) 55-567 25 g (0.06 moles) of 6-phenyl-11H-pyrido [2,3-b] [4] benzodiazepine-11-propanamine obtained from Example 22 the dihydrochloride hemihydrate was converted to the free base by partitioning between dilute sodium hydroxide and methylene chloride, drying and concentrating the methylene chloride layer to dryness, adding dry benzene and concentrating again to remove benzene. The resulting free base was dissolved in 300 mL (267 g; 1.8 moles) of freshly distilled triethyl orthoformate under reflux for 9 h. The mixture was concentrated in vacuo, ethanol was added and the mixture was concentrated again.

Conversion of the amidate to the amine 23.4 g (0.061 mol) of the amidate prepared above were dissolved in 200 ml of ethanol and sodium borohydrate was added with stirring at 15-20 ° C until reaction by thin layer chromatography showed that the reaction 34 772 32 was substantially complete in the absence of starting material. . Then, 50 ml of water was slowly added with stirring, and cooling was continued for 15 min after the addition of water. The mixture was then poured into 2 L of water and extracted with ethyl acetate. The ethyl acetate layer was washed with water until the wash water was neutral and then saturated with sodium chloride. The resulting ethyl acetate layer was dried and concentrated. Diethyl ethers were added and the mixture was cooled. Some insoluble material was filtered off and discarded. The ether layer was concentrated and the product was chromatographed on an alumina column (neutral activity 1), eluting with residual ethyl acetate + methanol + triethylamine. The fractions containing essential product (TLC) were partitioned between ethyl acetate and aqueous sodium hydroxide solution. An ethereal hydrogen chloride solution was added to the ethyl acetate layer, and the crystalline product was recrystallized from acetonitrile-water. The product sp. was 139-141 ° C.

Analysis: Calculated for C 22 H 24 N 4 Cl 2: ^ 63.62; H 5.82; N 13.49 Found: C 63.81; H 6.15; N 13.60

Example 26 N- {3- [6-Phenyl-11H-pyrido [2,3-b] [4,7] benzodiazepin-11-yl / propyl} -carbamic acid ethyl ester To a solution of 1.6 g (0.0045 mol) of 6-phenyl -11H-pyrido [2,3-b] [1,7] benzodiazepine-11-propanamine in dry methylene chloride, 0.53 g (0.0052 mol) of triethylamine was added. To this solution was added dropwise while cooling 0.54 g (0.0050 mol) of ethyl chloroformate. The mixture was stirred at room temperature for 2 h. The methylene chloride solution of the product (detected by mass ionization based on chemical ionization) was washed with dilute sodium hydroxide-sodium chloride, saturated aqueous solution and dried and concentrated to dryness. The residue was triturated with isopropyl ether. 1.5 g of the title product were obtained.

35 77232

Example 27 5,6-Dihydro-N, N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [[4,4] benzodiazepine-11-propanamine, dihydrochloride hemihydrate]

A solution of 3.0 g (0.0064 mol) of N, N-dimethyl-6-phenyl-11H-pyrido / 2,3-b7 / 1,47 benzodiazepine-11-propanamine in absolute methanol was adjusted to pH 5. .6 in methanolic hydrogen chloride solution. To this solution was added 0.7 g (0.011 mol) of NaBH 4 CN in one portion and the reaction mixture was heated to reflux for 20 min. The ethanol was removed in vacuo and the residue partitioned between dilute sodium hydroxide and methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated to give a residue which was crystallized twice from 2-propanol and isopropyl ether. 1.6 g (57%) of a yellow solid were obtained, which lost its crystalline structure on heating from 156-160 ° C and decomposed at 180-195 ° C.

Analysis: Calculated for C 18 H 28 N 2 OCl 2: C, 62.73; H 6.64; N 12.72 Found: C 62.40; H 6.90; N 12.61

Example 28 N, N-Dimethyl-6- (2-nitrophenyl) -11H-pyrido [2,3-b] [N] benzodiazepine-11-propanamine hydrochloride

Following the procedure of Example 14, but using an equimolar amount of 6- (2-nitrophenyl) -11H-pyrido [2,3-b] / 1,47 benzodiazepine, the title compound was obtained as the free base. This base was converted to the hydrochloride salt and recrystallized from isopropyl alcohol to give a yellow solid, m.p. 239-240 ° C Formula: C23H24N5 ° 2Cl.

36 77232

Example 29 5,6-Dihydro-6-phenyl-N-methyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine

To a solution of 1.4 g (0.0035 moles) of N- {3- (6-phenyl) -11H-pyrido [2,3-b] [λ,4] benzodiazepin-11-yl] propyl} - carbamic acid ethyl ester (obtained from Example 26) in tetrahydrofuran, 0.4 g (0.0105 moles) of lithium aluminum hydride is added under a nitrogen atmosphere, whereby a slightly exothermic reaction took place. The mixture was cooled to prevent overheating. The mixture was stirred at reflux for 16 h. TLC showed only partial conversion. An additional 0.4 g (0.105 mol) of lithium aluminum hydride was then added and the mixture was heated to reflux overnight. Thin layer chromatography showed that the product was essentially the title compound.

Examples 30a-30c

Following the procedure of Example 20, but using the following pyrido / T, 4-benzodiazepines instead of 6- (4-fluorophenyl) -11H-pyrido / 2,3-b7-T, -47-benzodiazepine: 6- (2-fluorophenyl) -11H-pyrido [2,3-b] (1,4) benzodiazepine, 6- (2-chlorophenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine, 6- (2-bromophenyl) -11H-pyrido] 2,3-b7 / 2,3-b7-benzodiazepine, gives: a) 6- (2-fluorophenyl) -N, N-dimethyl-11H-pyrido [2,3-b] [-1/.4] -benzodiazepine -11-propanamine, m.p. 92-94 ° C, recrystallization solvent isopropyl alcohol isopropyl ether, 6- (2-chlorophenyl) -N, N-dimethyl-11H-pyrido [2,3 / f] benzodiazepine-11-propanamine, m.p. 104-105 ° C, recrystallization solvent isopropyl ether and c) 6- (2-bromophenyl) -N, N-dimethyl-1H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine, m.p. . 96-98 ° C, recrystallization solvent isopropyl ether.

Examples 31a-31c When using the following compounds in the process of Example 16 instead of 8-chloro-6-phenyl-11H-pyrido [2,3-b] [1,1] benzodiazepine: 37,77232 8-chloro-6- (2-nitrophenyl ) -11H-pyrido [2,3-b] [1,4] benzodiazepine, 8-chloro-6- (2-chlorophenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine and 8-chloro-6- (2-bromophenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine are obtained: a) 8-chloro-11-methyl-6- (2 -nitrophenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine, m.p. 165-166 ° C, Recrystallization solvent ethyl alcohol, b) 8-chloro-6- (2-chlorophenyl) -11-methyl-11H-pyrido [2,3-b] [1,1 '] benzodiazepine, m.p. 150-152 ° C, Recrystallization solvent isopropyl alcohol isopropyl ether and c) 6- (2-bromophenyl) -8-chloro-11-methyl-11H-pyrido [2,3-b] [trans] -benzodiazepine, m.p. 121-123 ° C, Recrystallization solvent isopropyl ether.

38 7 7 2 3 2

Table 2

Ar (H)

R

Example R Ar Z n Salt 1 HCH 9-C1 0 6 5 2 H 2-C1-C H - 8-Cl 1 6 4 3 H 4-CH - CH - H 0 - 3 6 4 4 H 4-OCH - CH - H 0 364 5 H 3-Cl-C H - H 0 - 6 4 6 H 4-FC H - H 0 - 6 4 7 - (CH) -N (CH) CH - 8-C 0 oxalate 2 3 3 2 6 5 8 - (CH) -N (CH) CH - H 0 fumarate 23 32 65 9 - (CH) -N (CH) CH - H 0 fumarate 2 3 3 2 6 5 10 - (CH) -4 - CH - H 0 fumarate 2 3 6 5 morpholinyl 11 - (CH) -N (CH) CH - H 0 oxalate 2 3 2 5 2 6 5 12 - (CH) -N (CH) CH - 9-C10 fumarate 23 32 65 13 - (CH) -1-CH-H 0 fumarate 2 3 6 5 piperidinyl 14 - (CH) -N (CH) 4-C1-C H - H 0 fumarate 2 3 3 2 6 4 15 -CH -N (CH) CH - 8-C10 oxalate 2 3 2 6 5 16 -CH CH - 8-C 0 3 6 5 17 - (CH) -N (CH) 4-CH-CH - H 0 fumarate 2 3 3 2 3 6 4 18 - (CH) -N (CH) 4-OCH -CH - H 0 fumarate 2 3 3 2 3 6 4 19 - (CH) -N (CH) 3-C1-C H - H 0 fumarate 2 3 3 2 6 4

20 - (CH) -N (CH) 4 -F-C H - H 0 HCl, 1/2 HO

2 3 3 2 6 4 2 21 - (CH) -1-C H - H 0 - 2 3 6 5 phthalimidoyl 39 77232

Table 2 continues

Ar. (H) \ / n Z 1 ^ jj

R

Example R Ar Z n Salt

22 - (CH) -NH C H - H 2 O HCl, 2 HO

2 3 2 6 5 2 23 - (CH) -NH CH - H 0 - 2 3 2 6 5 24 - (CH) -N = CH- CH - H 0 - 2 3 6 5 OC H 2 5 25 - (CH ) -NHCH CH - H 02 HCl 2 3 3 6 5 26 - (CH) -NHC (O) - CH - H 0 - 2 3 6 5

OC H

2 5 27 - (CH) -N (CH) CH - H 12 HCl, 23 3265 „c TT„ 0.5 HO 2 28 - (CH) -N (CH) 2-NO -CH - H 0 HCl 23 32 264 29 - (CH) NHCH CH - H 1 - 2 3 3 6 5 30 a) - (CH) N (CH) 2-FC H - H 0 - 2 3 3 2 6 4 30 b) - (CH) N (CH) 2-C1-C H - H 0 - 2 3 3 2 6 4 30 c) - (CH) N (CH) 2-Br-C HH 0 - 2532 64 31 a) -CH 2 -NO -CH - 8-Cl 0 3 2 6 4 31 b) -CH 2 -Cl-C 1 H 3 - 8-C 0 0 31 c) -CH 2 -Br-C H - 8-Cl 0 3 6 4

Claims (9)

40 7 7 2 32 An intermediate useful in the preparation of 6-phenyl-11H-pyrido [2,3- * 4] benzodiazepines having the antidepressant activity of the formula Ar (H) (n) Vrrr - NI (fSO °) XN XN- 't R wherein 112 12 R is hydrogen, lower alkyl or -alk -NR 1 R, wherein R and R are each hydrogen, lower alkyl, or R and R together with the adjacent nitrogen atom form a heterocyclic group which is 1-piperidinyl or 4-morpholino , Ar is phenyl which may be substituted by halogen, lower alkyl, lower alkoxy or nitro, alk is lower alkylene, preferably ethylene or propylene, Z is hydrogen or halogen, n is 0 or 1, and when n is 0, a dotted line is a double bond, and in the preparation of these acid addition salts, characterized in that the intermediate is a 2 - ((3-amino-2-pyridinyl) amino) phenylaryl-methanone derivative of the formula O Ar 1 / CHN II H wherein Ar and Z are as defined above, or its acid addition salt. 4, 7? 232 Intermediate according to Claim 1, characterized in that it is N-2-amino-2-pyrrole-d-phenylmethanone. Intermediate according to Claim 1, characterized in that it is N, N-2-amino-2-pyridyl) amino-4- (4-chlorophenyl) phenyl) imetanone. Intermediate according to Claim 1, characterized in that it is Cl-β 3 -amino-2-pyridyl) amino] phenyl- (4-methylphenylmethanone). Intermediate according to Claim 1, characterized in that it is a β-β-amino-2-pyridyl-7-chloro-phenyl-7- (2-chlorophenyl) method non i. Intermediate according to Claim 1, characterized in that it is Z 2 - [(3-amino-2-pyridyl) amino] phenyl- (3-chlorophenyl) methanone. Intermediate according to Claim 1, characterized in that it is Z 2 -Zβ-amino-2-pyridyl) amino-7-phenyl- (4-fluorophenylmethanone). A mammal product according to the invention which comprises 6-phenyl-11H-pyrido [2,3-b] [4] benzodiazepines with antidepressant compounds and with the formula Ar An) \ / n ^ N NN-JR vari 112 1 R betecnar väte , alkyl alkyl or alkyl -NR R, color R 2 12 and R betecnar envar väte, alkyl alkyl, or R and R bil- The same is used with the corresponding quaternary heterocyclic group to give 1-piperidine1 or 4-morpholino , When the phenyl is phenyl which may be substituted by halogen, alkyl, alkoxy or nitro, alkyl by alkyl, alkylated ethyl or propylene, Z is hydrogen or halogen, n is 0 or 1, and is 0 or more lining and doping, with the addition of 2-amino-2-pyridinyl) amino7phenylarylmethanone derivatives having the formula C) Ar% / CHN II H color Ar and Z having an angular addition tionssalt därav.