KR890000764B1 - Process for preparing of phenyl substituted pyrido(1,4)benzodiazepines and products thereof - Google Patents

Abstract

Title cpds. (I)[R=H, alkyl, alk'-NR1R2, alk'-N=CH-OC2Hs; R1, R2=H, alkyl, C(O)O-alkyl, NR1R2=heterocyclic residue; Ar=(un) substd. Ph, pyridinyl, thienyl; alk'=hydrocarbon; Z=H, halogen, alkyl, alkoxy, OH, NO2; Y=H, alkyl, alkoxy, OH; n=0-1 and their salts, useful as antidepressants, were prepd.. Thus, a mixt. of 2-aminobenzophenone and 3-amino-2-chloropyridine was heated under N2 at 190≰C to give (I)[Ar=Ph, Z, R=H, n=0, Y=H).

Description

Phenyl substituted pyrido [1,4] benzodiazepines and methods for preparing the same

The present invention relates to a novel pyrido [1, 4] benzodiazepines of the general formula (I) and acid addition salts thereof useful as a therapeutic agent for depression.

Wherein R is hydrogen, lower alkyl, -alk ¹ -NR ¹ R ² or alk ¹ -N = CH-OC ₂ H ₅ , wherein R ¹ and R ² are hydrogen, lower alkyl or -C (O ) O-lower alkyl, or R ¹ and R ² together with adjacent nitrogen atoms are 1-phthalimido, 1-pyrrolidinyl, 4-morpholino, 1-piperazino and 4-substituted piperazine-1 A heterocyclic moiety selected from the group consisting of: Ar represents 2-, 3- or 4-pyridinyl, 2- or 3-thienyl or phenyl, halo, lower alkyl, lower alkoxy, Phenyl substituted by one to three identical or different radicals selected from trifluoromethyl and nitro: alk ¹ represents a straight or branched chain hydrocarbon of 1 to 8 carbon atoms: Z is hydrogen, halogen, lower alkyl, lower Alkoxy, hydroxy or nitro: Y is hydrogen, or in 1 selected from lower alkyl, lower alkoxy and hydroxy There are two identical or different radicals: n is 0 or 1, and when n is 0, the dotted line is a double bond.

The invention also provides novel pyrido [1,4] benzodiazepines of general formula (I), pharmaceutical methods and compositions for treating depression in the human body.

Methods for preparing certain dibenzodiazepines substituted with phenyl radicals on carbon and substituted with alkyl or aminoalkyl radicals on bridging nitrogen atoms present between phenyl rings are described in Wander.A., British Patent No. 907,646. have.

See Greig, M.E., et al., J. Med. Chem. 14, No. 2, p153 (1971), describes similar dibenzodiazepines in the above-mentioned Vander reference cited as effective for anaphylactic shock.

Japanese Patent No. 73 / 43,520 (CA80: 133501n) exemplifies 6-phenyl-2, 3, 4, 4a-tetrahydro-11H-, which is exemplarily made from 2-aminobenzophenone and ornithine, and has a hardening effect. Pyrido [2, 3-b] [1, 4] benzodiazepines are described.

Formula (I) compounds are useful as antidepressants to treat depression or as intermediates for preparing other compounds of formula (I).

A novel 2-[(amino-pyridinyl) amino] phenyl] arylmethamethoxide, which is produced in the reaction mixture prior to ring closure with diazepine and is also useful as a therapeutic agent for depression, is an intermediate (or precursor) and pharmaceutically toxic acid addition salts thereof. It is represented by general formula (II):

Wherein Ar, Z and Y are as defined above.

Symbols defined in the general formula described throughout the specification and claims have the following meanings.

The term “alk ¹ ” refers to a straight or branched hydrocarbon of 1 to 8 carbon atoms, specific examples of which are methylene (—CH ₂ —), ethylene (—CH ₂ —CH ₂ ), propylene (—CH ₂ CH ₂ CH ₂ —) Ethylidene

, 이소프로필리덴 ,

1,3-부틸렌

등이 있다.1,2-propylene

Isopropylidene,

1,3-butylene

Etc.

The term "lower alkyl" is a straight chain and branched chain hydrocarbon radical having 8 or less carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl and the like. .

The term “halogen” includes chlorine, bromine, fluorine and iodine, preferably chlorine, bromine and fluorine.

The term “4-substituted-piperazin-1-yl” refers to a piper substituted at the 4-position by a lower alkyl or alkyl-carbonyl blocker, which can subsequently be removed to obtain an unsubstituted piperazine. Say Rajin.

Pharmaceutically nontoxic acid addition salts refer to salts formed by pyridobenzodiazepines of the invention with all acids that are physiologically acceptable in warm blooded animals, which salts are formed in strong or weak acids. Representative examples of strong acids include hydrochloric acid, sulfuric acid and phosphoric acid, and representative examples of weak acids include fumaric acid, maleic acid, succinic acid, oxalic acid and cyclohexamic acid.

6-aryl-11H-pyrido [2, 3-b] [1,4] benzodiazepines and their 5, 6-dihydro derivatives belonging to general formula (I) are represented by the following general formula (IW):

6-aryl-11H-pyrido [3, 4-b] [1,4] benzodiazepines and their 5, 6-dihydro derivatives belonging to formula (I) have the structure of formula (VII):

10-aryl-5H-pyrido [4, 3-b] [1,4] benzodiazepines and their 10, 11-dihydro derivatives belonging to formula (I) have the structure of formula (Iy):

10-aryl-5H-pyrido [3, 2-b] [1,4] benzodiazepines and their 10, 11-dihydro derivatives belonging to formula (I) have the structure of formula (Iz):

In the above formulas (IW) to (Iz), the symbols R, Ar, Z and Y are as defined above.

In order to test the antidepressant action of the compounds of the present invention, Englehardt, EL, et al., J. MEd. Chem. 11 (2): 325 (1968)] using the method described above: 20 mg / kg of test compound was administered to five mature mouse females (ICR-DUB species) with tetrabenazine (as methanesulfonate salt). Intraperitoneal administration 30 minutes before administration of sewage induction (32 mg / kg, intraperitoneal). After 30 minutes, each animal is examined for the presence of complete ptosis. See Litchfield et al., J. Pharmacol. Exp. Thearp. 96: 99-113 (1949), the ED ₅₀ (average effective dosage) of each test compound that inhibits tetrabenazine-induced depression in mice can be obtained.

The general formula (I) compound of the present invention and the pharmaceutically toxic acid addition salt thereof which exhibit antidepressant action in the above-described method are represented by the following general formula (Ip):

Wherein R is hydrogen, lower alkyl or -alk ¹ -NR ¹ R ² , wherein R ¹ and R ² are hydrogen or lower alkyl, or R ¹ and R ² together with adjacent nitrogen atoms are 1-pyrrolidinyl , 4-morpholinyl, 1-piperazinyl and 4-lower alkyl-piperazin-1-yl can form a heterocyclic moiety; Ar is 2-, 3- or 4-pyridinyl, 2 Or 3-thienyl or phenyl or phenyl substituted by one to three identical or different radicals selected from halo, lower alkyl, lower alkoxy, trifluoromethyl and nitro; alk ¹ is a straight or branched hydrocarbon having 1 to 8 carbon atoms; Z is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or nitro; Y is hydrogen or one to two identical or different radicals selected from lower alkyl, lower alkoxy and hydroxy; n is 0 or 1, and when n is 0, the dotted line is a double bond.

Compounds of the general formula (Ip) wherein R is -alk ¹ -NR ¹ R ² and R ¹ and R ² are lower alkyl or hydrogen have a low incidence of side effects of antihistamine, anticholinergic and cardiotoxicity in animals. Appeared.

Preferred pyridobenzodiazepines useful for treating depression include:

Formula (I) compounds containing phthalimido, chloro, carbamoyl or imidate components in the R site are intermediates rather than therapeutic agents for depression.

It is therefore an object of the present invention to provide novel 6-aryl-11H-pyrido [1,4] benzodiazepines having antidepressant action.

Another object is to provide a method of treating depression and a pharmaceutical composition thereof.

Another object is to provide novel intermediates for the preparation of aryl substituted 11H-pyrido [1,4] benzodiazepines, which are antidepressants, which also have antidepressant action.

Other objects and advantages of the present invention will be apparent to those skilled in the art, and others will be apparent from the following description and appended claims, which are the best way to carry out the invention.

Novel pyridobenzodiazepines and metanon intermediates of the general formulas (I) and (II) of the present invention and the use of these compounds as antidepressants or as intermediates for the preparation of other antidepressants.

The method for preparing the compound of the present invention is shown in Scheme 1 below. Other methods of preparing compounds of Formula (I) are shown in Schemes 2, 3 and 4.

Methanone of general formula (II) (see Scheme 1)

The metanon intermediates may be prepared by heating a mixture of halo-amino pyridine and amido benzophenone for a time shorter than the time required for ring closure with pyrido benzodiazepines, as indicated by chemical ionization mass spectrometry. The reaction conditions necessary to prepare 2-[(3-amino-2-pyridinyl) aminophenyl] methanol are at a temperature of 170 to 200 ° C. and about 1 to 1.5 hours. Methanone can be cooled, if necessary, by addition of a suitable organic solvent (e.g. methylene chloride) capable of dissolving unreacted starting material and some closed ring compound (Ia), followed by solvent and aqueous base or methanolic aqueous base. Separation, washing, drying, evaporation of the solvent layer and recrystallization from a suitable solvent can be separated as the main product in the same way as partitioning in between.

Unsubstituted pyrido benzodiazepines (R = hydrogen) of formulas (Ia) and (Ia-1) (see Scheme 1)

Purified compound (II) or crude compound (II) can be further heated in an aprotic solvent by removing the water under reflux in a conventional manner, for example using a Dean-Stark trap apparatus, from a reaction compound. ) Can be closed with the compound. However, it is not necessary to stop the heating in the intermediate stage, and in general, the original reaction compound (III + IV) must be continuously heated for a long time to be closed with the compound of general formula (Ia). In the ring closure step, when using another method, the relationship between temperature and reaction time varies somewhat depending on the reactants used and only heating for a sufficient time until the desired product is produced, as indicated by the chemical ionization mass spectrum. need. Unsubstituted pyrido benzodiazepines are purified by partitioning between methylene chloride and aqueous base solution, washed to dry the solvent layer, evaporated and chromatographed in a suitable solvent system such as acetone-benzene. The corresponding dihydrodiazepine can be prepared by reduction with sodium borocyanohydrin.

Substituted pyrido benzodiazepines of general formula (Ib) and Ib-1, (R = lower alkyl), see Table 1

Compounds of general formula (Ia or Ia-1) wherein R is hydrogen are alkylaminolated or first reacted with sodium hydride and then halo-alk ¹ Q (where alk ¹ is as defined above and Q is represented in Scheme 1). Radicals to induce alkylaminoation by reaction with an appropriate reagent. The compound suspended in an appropriate solvent (eg dimethylformamide) is added to a stirred suspension of sodium hydride in the same solvent. Halo-alk ¹ -Q reagent (alkyl amination agent or alkyl amination reagent) is added at room temperature and confirmed by thin layer chromatography and the reaction mixture is stirred until the reaction is complete. Next, it is added to water to decompose the unreacted sodium hydride and the product is extracted with a suitable solvent such as methylene chloride, the solvent layer is extracted with an acid aqueous solution, the aqueous layer is neutralized and re-extracted from methylene chloride, and then evaporated, Precipitates as acid addition salts such as hydrochloride, oxalate, maleate and the like. The acid addition salt obtained can be purified and the salt can be partitioned between a basic aqueous solution and a suitable solvent (eg methylene chloride) and the methylene chloride layer is evaporated to regenerate the free base. The corresponding dihydrodiazepines can be prepared by reduction with sodium borocyanohydrin. In contrast, compounds of formula (Ib) in which Q is halo can be converted to compounds in which Q is N- (lower alkyl) ₂ by reaction with an appropriate dialkylamine, as shown in Scheme 2.

Primary amines of general formula (Ic), wherein R ¹ and R ² are both hydrogen, as described in Scheme 1, alk ¹ -W- (1-phthalimido) derivatives are described in Org. Syn. Coll. Vol. Prepared by reacting with hydrazine hydrate using the method of III, pages 151-153). After refluxing for 2-3 hours, the aqueous solution is added and the mixture is filtered. The primary-alk ¹ -amine is separated from a suitable solvent such as isopropyl alcohol. Hydrochloride and hydrochloride hydrates are preferred salts in the separation step. The corresponding dihydrodiazepines can be obtained by reduction with sodium borocyanohydrin.

Formula (Ⅰe) of the alk ¹ -W- monoalkyl amine (R1 = methyl, R ² = hydrogen), a top -alk ¹ -NK ₂ derivative (Ⅰc) or (Ⅰc-1) As is shown in the reaction scheme 1 It can be prepared by reacting with reflux triethylorthoformate for a time sufficient to produce methaneimide acid ester (I-d) and then with sodium borohydride. The unreacted sodium borohydride can be decomposed with water and the product can be extracted with an appropriate solvent such as ethyl acetate, column chromatographed and purified by fractionation with basic solvent. Hydrochloride is preferred in the separation step. This method is described in more detail in Examples 27 and 28. The corresponding dihydrobenzodiazepines can be prepared by reduction with sodium-borocyanohydrin.

alk ¹ -W-monomethylamine can also be prepared by reacting a primary amine with ethylchloroformate as in Example 29 and then reducing it with lithium aluminum hydride as in Scheme 3.

-저급알킬에 의한 방법이다. 모든 일반식 (Ⅰa), (Ⅰa-1), (Ⅰb), (Ⅰb-1), (Ⅰb-2), (Ⅰb-3), (Ⅰb-4), (Ⅰc), (Ⅰc-1), (Ⅰc-2), (Ⅰd), (Ⅰe) 및 (Ⅰe-1) 은 일반식(Ⅰ) 에 포함된다.Other more general methods of introducing -alk ¹ -W-mono lower alkyl amine radicals are radicals, -alk ^1-

-By lower alkyl. All general formulas (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ic), (Ic-1) , (Ic-2), (Id), (Ie) and (Ie-1) are included in general formula (I).

The general formula (I) compound wherein -NR ¹ R ² residue is unsubstituted 1-piperazinyl is a pipette in which -NR ¹ R ² is substituted with alkylcarbonyl (eg t-butoxycarbonyl) at position 4 It can be prepared by hydrolysis of the laginine general formula (I) compound.

Scheme 1

-저급알킬 또는 할로임.Q is -N- (lower alkyl) _2, 1-pyrrolidinyl, 1-piperidinyl, 4-substituted-piperazin-1-yl, 4-morpholino, 1-phthalimido also, -

Lower alkyl or haloim.

Scheme 2

Scheme 3

Scheme 4

The preparation of novel [(amino-pyridinyl) aminophenylaryl] methanones used as intermediates in the preparation of phenyl substituted-pyrido [1,4] benzodiazepines is described in more detail in the following intermediates 1-16. The structure of the intermediate is shown in Table 1.

Structure of Metanon Intermediates

Intermediate 1

[2- [3-amino-2-pyridinyl) -amino] phenyl] phenylmethanone

A stirred mixture of 39.4 g (0.02 mole) 2-amino-benzophenone and 28.3 g (0.22 mole) 3-amino-2-chloro-pyridine is heated to 180 ° C. for 1.5 h under a nitrogen atmosphere. The mixture is cooled slightly and 200 ml of methylene chloride are added slowly. After stirring for 3 hours and left at room temperature overnight, 40.1 g of solid was separated by filtration and recrystallized twice with methanol isopropyl ether to obtain 4.3 g with hydrochloride having a melting point of 187 to 190 ° C. The solid is dissolved in a water-methanol mixture, basified with 3N sodium hydroxide and extracted with methylene chloride. The methylene chloride extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from isopropyl ether (charcoal) to give 2.1 g of product having a melting point of 91 to 93 占 폚. Analyze after drying at room temperature / 0.02 mmHg overnight.

Elemental analysis: C ₁₈ H ₁₅ N ₃ O

Calculated Value: C; 74.72, H; 5.23, N; 14.52

Found: C; 74.94, H; 5.23, N; 14.69

Intermediate 2

[2-[(3-amino-2-pyridinyl) -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 is heated to 180 ° C. for 2.5 hours under a nitrogen atmosphere. The mixture is cooled at room temperature to solidify and triturated with a spatula. The solid is suspended in 100 ml of methylene chloride and collected by filtration. The filter cake is dissolved in a mixture of water-methanol, made basic with 3N sodium hydroxide solution and extracted twice with methylene chloride. The methylene chloride extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The crystallized residue is triturated with isopropyl ether and filtered to collect solids (16.7 g). 3 g of sample was recrystallized from isopropyl ether to obtain 1.6 g of product (melting point: 153 to 155 ° C).

Elemental Analysis: C ₁₈ H ₁₄ ClN ₃ O

Calculated Value: C; 66.77, H; 4.36, N; 12.98

Found: C; 67.06, H; 4.36, N; 13.17

Intermediate 3

[2-[(3-amino-2- (pyridinyl) amino) phenyl] (4-methylphenyl) -methanone

A stirred mixture of 20.0 g (0.095 mole) 2-amino-4'-methylbenzophenone and 13.95 g (0.104 mole) 3-amino-2-chloropyridine (96%) was stirred at 180 ° C. under a nitrogen atmosphere for 2.0 h. Heat. The mixture is cooled to give a glassy solid, triturated, triturated with methylene chloride and stirred overnight. The solid is collected by filtration and dissolved in warm methanol. The solution is basified with 3N sodium hydroxide and diluted with 500 ml of water and extracted three times with 250 ml of methylene chloride. The methylene chloride extract is dried over magnesium sulfate and evaporated under reduced pressure. The crystallized residue upon standing was recrystallized twice with benzene-isooctane to give 4.2 g of product (melting point: 126-127.5 ° C.).

Elemental Analysis: C ₁₉ H ₁₇ N ₃ O

Calculated Value: C; 75.23, H; 5.26, N; 13.85

Found: C; 75.81, H; 5.69, N; 13.96

Intermediate 4

[2-[(3-amino-2-pyridinyl) amino] -5-chlorophenyl] -2 (2-chlorophenyl) methanone

A stirred mixture of 20.0 g (0.156 mole) of 3-amino-2-chloropyridine and 37.3 g (0.14 mole) of 2-amino-2 ', 5-dichlorobenzophenone is heated at 190 ° C. for 5.5 hours under a nitrogen atmosphere. . Thin layer chromatography on silica gel (5% methanol-benzene) showed no reaction. The mixture is stirred overnight at 190 ° C. and somewhat cooled to add 100 ml of methylene chloride carefully. The suspension is stirred for 2 hours and once a black solid is formed it is filtered off. The solid is suspended in 500 ml of methylene chloride and 300 ml of water is added sodium hydroxide. The mixture is filtered by allowing an emulsion to form and the layers to separate. The methylene chloride layer is extracted twice with 250 ml of water each time, washed, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in benzene and filtered through a 300 g Florisil column to remove material with low Rf values. All fractions are combined and evaporated under reduced pressure. Thin layer chromatography shows that there are two main components with spots with low Rf values. The residue is dissolved in benzene and chromatographed on a 600 g Florisil column packed in benzene. High Rf material is eluted with 1% acetone-benzene. After evaporation, the residue is triturated with benzene and recrystallized with benzene-isooctane to give 2.7 g of product. Melting Point: 162 to 164 ° C

Elemental analysis: C ₁₈ H ₁₃ Cl ₂ N ₃ O

Calculated Value: C; 60.35, H; 3.66, N; 11.73

Found: C; 60.67, H; 3.67, N; 11.77

Intermediates 5a to 5u

Equivalent molar amount of the following benzophenones, ie 2-amino-4'-ethylbenzophenone, 2-amino-4'-isopropylbenzophenone, instead of 2-amino-4'-methylbenzophenone according to the preparation method of intermediate 3 , 2-amino-4'-bromobenzophenone, 2-amino-3'-fluorobenzophenone, 2-amino-4'-ethoxybenzophenone, 2-amino-4'-nitrobenzophenone, 2- Amino-4'-trifluoromethylbenzophenone, 2-amino-3'-methylbenzophenone, 2-amino-3'-ethylbenzophenone, 2-amino-3'-methoxybenzophenone, 2-amino- 3'-ethoxybenzophenone, 2-amino-2'-nitrobenzophenone, 2-amino-3'-trifluoromethylbenzophenone, 2-amino-2'-methylbenzophenone, 2-amino-2 ' -Ethylbenzophenone, 2-amino-2'-methoxybenzophenone, 2-amino-2 ', 4'-dichlorobenzophenone, 2-amino-3', 4 ', 5'-trimethoxybenzophenone, Next step using 2-amino-2'-fluorobenzophenone, 2-amino-2'-chlorobenzophenone and 2-amino-4'-bromobenzophenone Obtain the compound.

a) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(4-ethylphenyl) methanone.

b) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(4-isopropylphenyl) methanone.

c) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(4-bromophenyl) methanone.

d) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(3-fluorophenyl) methanone.

e) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(4-ethoxyphenyl) methanone.

f) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(4-nitrophenyl) methanone.

g) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(4-trifluoromethylphenyl) metanon.

h) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(3-methylphenyl) methanone.

i) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(3-ethylphenyl) methanone.

j) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(3-methoxyphenyl) methanone.

k) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(3-ethoxyphenyl) methanone.

l) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2-nitrophenyl) methanone.

m) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(3-trifluoromethylphenyl) methanone.

n) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2-methylphenyl) methanone.

o) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2-ethylphenyl) methanone.

p) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2-methoxyphenyl) methanone.

q) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2,4-dichlorophenyl) methanone.

r) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(3,4,5-trimethoxyphenyl) methanone.

s) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2-fluorophenyl) methanone.

t) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2-chlorophenyl) methanone.

u) [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2-bromophenyl) methanone.

Intermediates 6a to 6o

According to the preparation method of the intermediate 2, instead of 2-amino-4-chlorobenzophenone, an equimolar amount of the following benzophenone, namely 2-amino-5-chlorobenzophenone, 2-amino-6-chlorobenzophenone, 2-amino 4-fluorobenzophenone, 2-amino-4-bromobenzophenone, 2-amino-4-trifluorobenzophenone, 2-amino-4-methylbenzophenone, 2-amino-5-methylbenzophenone , 2-amino-6-methylbenzophenone, 2-amino-4-ethylbenzophenone, 2-amino-4-methoxybenzophenone, 2-amino-4-ethoxybenzophenone, 2-amino-4-nitro Using benzophenone, 2-amino-5-nitrobenzophenone, 2-amino-3-methylbenzophenone and 2-amino-3-chlorobenzophenone, the following compounds are obtained:

a) [2-[(3-amino-2-pyridinyl) amino] -5-chlorophenyl] phenylmethanone.

b) [2-[(3-amino-2-pyridinyl) amino] -6-chlorophenyl] phenylmethanone.

c) [2-[(3-amino-2-pyridinyl) amino] -4-fluorophenyl] phenylmethanone.

d) [2-[(3-amino-2-pyridinyl) amino] -4-bromophenyl] phenylmethanone.

e) [2-[(3-amino-2-pyridinyl) amino] -4-trifluoromethyl] phenyl] phenylmethanone.

f) [2-[(3-amino-2-pyridinyl) amino] -4-methylphenyl] phenylmethanone.

g) [2-[(3-amino-2-pyridinyl) amino] -5-methylphenyl] phenylmethanone.

h) [2-[(3-amino-2-pyridinyl) amino] -6-methylphenyl] phenylmethanone.

i) [2-[(3-amino-2-pyridinyl) amino] -4-ethylphenyl] phenylmethanone.

j) [2-[(3-amino-2-pyridinyl) amino] -4-methoxyphenyl] phenylmethanone.

k) [2-[(3-amino-2-pyridinyl) amino] -4-ethoxyphenyl] phenylmethanone.

l) [2-[(3-amino-2-pyridinyl) amino] -4-nitrophenyl] phenylmethanone.

m) [2-[(3-amino-2-pyridinyl) amino] -5-nitrophenyl] phenylmethanone.

n) [2-[(3-amino-2-pyridinyl) amino] -3-methylphenyl] phenylmethanone.

o) [2-[(3-amino-2-pyridinyl) amino] -3-chlorophenyl] phenylmethanone.

Intermediates 7a to 7c

Instead of 3-amino-2-chloropyridine, equimolar amounts of 4-amino-3-chloropyridine, 3-amino-4-chloropyridine and 2-amino-3-chloropyridine are used, according to the preparation method of Intermediate 1. To yield the following compounds, respectively:

a) [2-[(4-amino-3-pyridinyl) amino] phenyl] phenylmethanone.

b) [2-[(3-amino-4-pyridinyl) amino] phenyl] phenylmethanone and.

c) [2-[(2-amino-3-pyridinyl) amino] phenyl] phenylmethanone.

Intermediate 8

[2-[(3-amino-2-pyridinyl) amino] phenyl] (3-chlorophenyl) methanone

A stirred mixture of 35 g (0.152 mol) of 2-amino-3'-chlorobenzophenone and 23.4 g (0.182 mol) of 3-amino-2-chloropyridine is heated to 180 ° C. for 2 hours. The hot melt is cooled to 110 ° C. and 100 ml of hot toluene is added dropwise with vigorous stirring. The mixture is cooled to 30 ° C. with stirring and 50 ml of methylene chloride are added. After further stirring for 30 minutes, the mixture is filtered and the filter cake is suspended in methylene chloride with stirring for 0.5 hours, and then the methylene chloride is isolated by filtration. The filter cake containing product (25.4 g) was partially dissolved in hot methanol (150 ml total) and 50% sodium hydroxide solution was added to make the mixture basic. Ice water is added and the solution is extracted with methylene chloride, the methylene chloride extract is washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in isopropyl alcohol and boiled with activated charcoal. The mixture is filtered and the volume reduced to yield 16 g (33%) of primary product crystals. A portion of the crystals is recrystallized with isopropyl alcohol to give a dark red solid. Melting Point: 119 ~ 120 ℃

Elemental Analysis:

Calculated Value: C; 66.77, H; 4.36, N; 12.98

Found: C; 66.78, H; 4.42, N; 12.94

Intermediate 9

[2-[(3-amino-2-pyridinyl) amino] phenyl] (4-fluorophenyl) methanone

A stirred mixture of 35 g (0.163 moles) of 2-amino-4'-fluorobenzophenone and 27 g (0.21 moles) of 3-amino-2-chloro-pyridine is heated at 175 to 180 ° C. for 2.5 hours. After cooling the mixture to 110 ° C., 100 ml of hot toluene are added. After cooling to 50 ° C., 50 ml of methylene chloride are added. The solvent layer is tilted and the remaining black solid skin is dissolved in hot methanol. The solution is concentrated in half and left overnight at room temperature.

The mixture is filtered and the filter cake is washed twice with suspension with methylene chloride. The resulting crude solid is 22.5 g in weight. The solid is dissolved in methanol and made basic with 50% aqueous sodium hydroxide solution. The mixture is extracted with methylene chloride, the extract is dried and concentrated. The residue is recrystallized twice with isopropyl alcohol and boiled with activated charcoal to bleach to give 14 g (28%) of a red-orange solid. Melting Point: 121.5-122.5 ℃

Elemental Analysis: C ₁₈ H ₁₄ N ₃ OF

Calculated Value: C; 70.35, H; 4.59, N; 13.67

Found: C; 70.23, H; 4.59, N; 13.64

Intermediate 10

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

According to the method of intermediate 9, (2-aminophenyl) (2-thienyl) methanone (prepared according to the method of Steinkopf & Gunther, Ann. 522, 28-34 (1936)) was prepared as 3-amino-2-chloro Reaction with pyridine affords the title compound.

Intermediate 11

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

According to the method of intermediate 9, (2-aminophenyl) (3-thienyl) methanone is reacted with 3-amino-2-chloropyridine to afford the title compound.

Intermediate 12

[2-[(3-amino-2-pyridinyl) amino] phenyl] (2-pyridinyl) methanone

(2-aminophenyl) (2-pyridinyl) methanone (prepared according to the method of Schofield, K., J. Chem. Soc. 1949, 2408-12) with 3-amino-2-chloropyridine Obtain the compound.

Intermediate 13

[2-[(3-amino-2-pyridinyl) amino] phenyl] (3-pyridinyl) methanone

See, Abramovitch R.A. & Tertzakian, G., Tetrahedron Letters, 1936, 1511-15 and Abramovitch, R. A. et al., Can. J. Chem. 43 (4), 725-31 (1965)], reacted with (2-aminophenyl) (3-pyridinyl) methanone with 3-amino-2-chloropyridine to give the title compound. do.

Intermediate 14

[2-[(3-amino-2-pyridinyl) amino] phenyl] (4-pyridinyl) methanone

[Nann. A.J. and Schofield K.J. Chem. Soc. 1952, 580-9, (2-aminophenyl) (4-pyridinyl) methanone, prepared according to the method described in the above, is reacted with 3-amino-2-chloropyridine to give the title compound.

Intermediate 15a to 15g

According to the preparation of Intermediate 1, equimolar amounts of 3-amino-2-chloro-4-methylpyridine, 3-amino-2-chloro-5-methylpyridine, 3-amino instead of 3-amino-2-chloropyridine -2-chloro-6-methylpyridine, 3-amino-2-chloro-5,6-dimethylpyridine, 3-amino-2-chloro-6-methoxypyridine, 3-amino-4-chloro-2-methyl Pyridine and 3-amino-2-chloro-5-methoxypyridine are used to yield the following compounds:

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] phenylmethanone.

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.

Intermediates 16a to 16f

According to the preparation of Intermediate 1, an equimolar amount of 2-amino-3-chloro-5-methylpyridine, 2-amino-3-chloro-4,6-dimethylpyridine, 2, instead of 3-amino-2-chloropyridine, 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 is used to obtain the following compounds:

a) [2-[(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, and

f) [2-[(4-amino-2-methyl-3-pyridinyl) amino] phenyl] phenylmethanone.

TABLE 1

The process for the preparation of the novel phenyl-substituted pyrido- [1,4] benzodiazepine compounds of the present invention is described in more detail in the following examples. The structures of the compounds prepared in the examples are listed in Table 2. However, the scope of the invention is not limited to these examples.

Example 1

6-phenyl-11H-pyrido- [2, 3-b] [1, 4] benzodiazepine

A mixture of 19.7 g (0.1 mole) 2-amino benzophenone and 15.0 g (0.12 mole) 3-amino-2-chloropyridine is heated at 190 ° C. for 1.75 h under a nitrogen atmosphere. The mixture is cooled to room temperature and partitioned between 3N aqueous sodium hydroxide solution and methylene chloride. The methylene chloride extracts are combined, washed with water, dried over magnesium sulfate and evaporated under reduced pressure. 32.7 g of the residue are dissolved in benzene and chromatographed on a Florisil column packed in benzene eluting with benzene and 1-2% acetone-benzene mixture. After evaporation, 7.3 g of product are obtained while the solid is crystallized from benzene. Melting point: 106 to 108 ° C.

Elemental Analysis: C ₁₈ H ₁₃ N ₃

Calculated Value: C; 79.68, H; 4.83, N; 15.49

Found: C; 79.70, H; 4.81, N; 15.42

Example 2

8-chloro-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine

A mixture of 15.0 g (0.0647 moles) of 2-amino-5-chloro benzophenone and 9.1 g (0.068 moles) of 3-amino-2-chloropyridine is heated at 200 ° C. under nitrogen atmosphere for 0.75 hours (in an oil bath). in). The mixture is cooled and methylene chloride is added. The mixture is stirred for 1 hour and then left overnight. 8.7 g of brown solid precipitate is isolated by filtration and the filtrate is evaporated under reduced pressure. The residue is combined with a brown solid and partitioned between aqueous sodium hydroxide solution and methylene chloride, and the crude product is isolated as in Example 1 except that ethanol is used as the crystallization solvent. Recrystallization from ethanol and drying overnight at 82 ° C./0.1 mm Hg gave 3.0 g of product. Melting Point: 156.5 ~ 158.5 ℃

Elemental Analysis: C ₁₈ H ₁₂ ClN ₃

Calculated Value: C; 70.71, H; 3.96, N; 13.74

Found: C; 70.24, H; 4.01, N; 13.76

Example 3

9-chloro-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine

A suspension of 6.6 g (0.02 mol) of [2-[(3-amino-2-pyridyl) amino] -4-chlorophenyl]-(phenyl) methanone (intermediate 2) in 200 ml of toluene was placed under nitrogen atmosphere. Heat to reflux overnight.

The reaction mixture is filtered on hot and the filtrate is again heated at reflux. The precipitate formed by cooling at room temperature was isolated by filtration, recrystallized from benzene and dried overnight at room temperature / 0.1 mmHg for 4 hours at 97-98 ° C./0.1 mmHg to give 3.7 g of product. (Melting point: 250.5 to 252 ° C). Due to the high carbon elemental analysis, the product is redried at 139 ° C. for 8 hours (xylene in dry pistol). Although the carbon analysis is still high, the quantum nuclear magnetic resonance spectrum and the mass spectrum are consistent with the proposed structure.

Elemental Analysis: C ₁₆ H ₁₂ ClN ₃

Calculated Value: C; 70.71, H; 3.96, N; 13.74

Found: C; 71.46, H; 4.06, N; 13.46

Example 4

8-chloro-6- (2-chlorophenyl) -5,6-dihydro-11H-pyrido [2, 3-b] [1, 4] benzodiazepine

In the preparation of intermediate 4, the Florisil column was further eluted with benzene containing 10-15% acetone and benzene containing 5-25% methanol to give a fraction containing 4 g and 5.7 g of the title product of this example, respectively. Two are obtained, the second fraction containing a lot of impurities. 6.4 g of fractions were recrystallized from benzene-isooctane to give 3.7 g of solid (melting point: 203 to 206 ° C. (decomposition)), which was identified by chemical ionization mass spectrum analysis, ¹ H and ¹³ C NMR to identify 8-chloro- Confirm 6- (2-chlorophenyl) -5,6-dihydro-11H-pyrido [2, 3-b] [1, 4] benzodiazepine.

Example 5

6- (4-chlorophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine

A mixture of 23.2 g (0.10 mole) 2-amino-4'-chlorobenzophenone and 14.7 g (0.11 mole) 3-amino-2-chloro-pyridine (96%) was heated to 180 ° C. for 1.5 h under a nitrogen atmosphere. Heat. The mixture is cooled to room temperature and methylene chloride is added. After stirring for 30 minutes, the solids are separated by filtration and ground with 190-degree hot ethanol. The residual insolubles were collected by filtration and recrystallized from benzene-isooctane to give 2.7 g of product (melting point: 203 to 204.5 ° C.). Analyze after drying overnight at 97-98 ° C./0.1 mmHg.

Elemental Analysis: C ₁₈ H ₁₂ ClN ₃

Calculated Value: C; 70.71, H; 3.96, N; 13.74

Found: C; 70.76, H; 3.92, N; 13.95

Example 6

6- (4-methylphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine

A solution of 3.6 g (0.012 mol) of [2-[(3-amino-2-pyridyl) amino] phenyl] (4-methylphenyl) methanone in 100 ml of toluene anhydrous was treated with a catalytic amount of para toluene sulfonic acid Reflux overnight with Dean-Stark Trap separating the water. The reaction mixture is filtered upon heat. The product precipitates as the filtrate is cooled to room temperature, which is collected by filtration. After evaporation of the solvent 2.5 g of a solid (melting point 203.5 to 205 ° (decomposition)) are obtained.

Elemental Analysis: C ₁₉ H ₁₅ N ₃

Calculated Value: C; 79.98, H; 5.30, N; 14.73

Found: C; 79.95, H; 5.27, N; 14.76

Example 7

6- (4-methoxyphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine

A stirred mixture of 20 g (0.088 moles) of 2-amino-4'-methoxybenzophenone and 13.0 g (0.097 moles) of 3-amino-2-chloropyridine (96%) was heated to 180 ° C. for 2 hours under a nitrogen atmosphere. Heat.

The reaction mixture is cooled to about 70 ° C. and 100 ml of methylene chloride are slowly added. After cooling the mixture to room temperature, further 50 ml of methylene chloride are added and the mixture is stirred overnight. The suspended replacement is collected by filtration, dried in air, dissolved in methanol and made basic with 3N sodium hydroxide. The suspension is diluted with 500 ml of water and the methylene chloride extracts are combined, dried over magnesium sulphate, and extracted three times with 250 ml of methylene chloride each time and evaporated under reduced pressure. Mass spectrum (EI and CI) analysis showed the residue to be a mixture of [2-[(3-amino-2-pyridyl) aminophenyl] [4-methoxyphenyl] methanone with the title compound. The residue-mixture is dissolved in 250 ml of toluene with a catalytic amount of paratoluene sulfonic acid and refluxed overnight under nitrogen atmosphere while separating water using Dean Starktrap. The reaction mixture is filtered upon heat. The precipitated product is collected by filtration as the filtrate is cooled to room temperature. Recrystallization with benzene yields 1.8 g of product (melting point: 198.5 to 200.5 ° C., decomposition).

Elemental Analysis: C ₁₉ H ₁₅ N ₃ O

Calculated Value: C; 75.73, H; 5.02, N; 13.93

Found: C; 75.65, H; 4.98, N; 14.03

Example 8

8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine oxalate [1: 1]

6.1 g (0.02 mol) of 8-chloro-6-phenyl-11H-pyrido [2,3-b] in a stirred suspension of 1.05 g (0.044 mol) of sodium hydroxide (in mineral oil) in 500 mL of anhydrous dimethylformamide. ] [1,4] benzodiazepine is added in small portions under a nitrogen atmosphere. The reaction mixture is stirred for 1.5 hours at room temperature while hydrogen evolution stops in the movement. The mixture was added in portions of 3.5 g (0.022 mol) of 3-dimethylaminopropyl-chloride hydrochloric acid in small portions. After stirring overnight at room temperature, the reaction mixture is poured into 1600 ml of water and the mixture is extracted three times with 250 ml of methylene chloride each time, combined 250 ml of methylene chloride extract each time. The combined methylene chloride extracts are washed twice with 250 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in benzene and chromatographed with acetone-benzene on a 300 g Florisil column packed in benzene. 1.6 g of starting material was recovered in the benzene eluent and the solvent was evaporated in the acetone-benzene eluate to yield 3.6 g of product as the free base. Some of the crude free base (2.5 g) is dissolved in hot isopropyl alcohol and reacted with 0.8 g (0.0064 moles) of oxalic acid dihydrate. The oxalate precipitated upon cooling was collected by filtration and recrystallized with ethanol to yield 2.2 g of product (melting point: 206-208 ° C.). Dry overnight at room temperature / 0.02 mmHg at 97-98 ° C./0.02 mmHg before analysis.

Elemental analysis: C ₂₂ H ₂₅ ClN ₄ O ₄

Calculated Value: C; 62.43, H; 5.24, N; 11.65

Found: C; 62.52, H; 5.23, N; 11.76

Example 9

N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine fumarate [1: 1] 1.68 g in 25 ml of anhydrous dimethylformamide ( 0.070 mole) of a 20 mL solution containing 8.0 g (0.029 mole) of 6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine in a stirred suspension of sodium hydride (in mineral oil) under a nitrogen atmosphere. Anhydrous dimethyl formamide suspension is added in portions. After the addition is complete, the mixture is stirred for 30 minutes, warmed to 65 ° C. for 15 minutes and cooled back to room temperature. To this mixture is added 5.6 g (0.035 mol) of 3-dimethylaminopropylchloride hydrochloride. After stirring overnight at room temperature and confirmed by thin layer chromatography, the reaction was almost complete. The reaction mixture is poured into 1500 ml of water and extracted with 250 ml of methylene chloride. The combined methylene chloride extracts are washed three times with 250 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in methylene chloride and extracted with 100 ml and 150 ml 3N hydrochloric acid, respectively. The unreacted 6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine starting material precipitates out of the aqueous acid solution, so the liquid is carefully decanted from the solid. The aqueous solution is basified with 3N sodium hydroxide and extracted three times with 100 ml of methylene chloride. The methylene chloride extracts are combined and dried over magnesium sulfate and evaporated under reduced pressure to give 7.7 g of the residue as the base of the title compound. The hot isotropy alcohol solution containing 6.6 g residue is reacted with 2.15 g fumaric acid and the mixture is heated until complete dissolution. After standing for 48 hours, the precipitated salt is collected by filtration. Recrystallization with isopropyl alcohol-isopropyl ether gives 5.9 g of product having a melting point of 171-173 ° C. Dry for 4 hours at 90 ° C./0.1 mmHg and overnight at room temperature / 0.1 mmHg before analysis.

Elemental Analysis: C ₁₇ H ₂₈ N ₄ O ₄

Calculated Value: C; 68.63, H; 5.97, N; 11.86

Found: C; 68.37, H; 6.05, N; 11.73

Example 10

N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-ethanamine fumarate [1: 1]

7.0 g (0.026 mole) of 6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine was added to a stirred suspension of 1.48 g (0.062 mole) of sodium hydroxide (in mineral oil) under nitrogen atmosphere. Add in small portions under After cooling the reaction mixture to room temperature, 4.46 g (0.031 mol) of 2-dimethylaminoethylchloride hydrochloride is added in small portions and stirring is continued overnight. The reaction mixture is poured into 1500 ml of water and the resulting mixture is extracted with 250 ml of methylene chloride. The combined methylene chloride extracts were washed three times with 500 ml of water, dried over magnesium sulfate and evaporated under reduced pressure to give 8.6 g of the free base of the title compound as an oil. A portion of the oil (6.9 g) is reacted with an equimolar amount of fumaric acid in isopropyl alcohol. Adding isopropyl ether gives an oily solid. The mixture is evaporated and left under reduced pressure to crystallize the residue. The crystals were ground with acetone and recrystallized with acetone-isopropylether to give 4.3 g of fumarate.

Melting Point: 175 to 177.5 ° C

Elemental Analysis: C ₂₆ H ₂₆ ClN ₄ O ₄

Calculated Value: C; 68.11, H; 5.72, N; 12.22

Found: C; 67.88, H; 5.72, N; 12.17

Example 11

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

To a stirred suspension of 25 ml of anhydrous dimethylformamide containing 1.10 g (0.046 moles) of sodium hydride (in mineral oil), 5.0 g (0.0184 moles) of 6-phenyl-11H-pyrido [2, 3-b under nitrogen atmosphere] ] Add [1, 4] benzodiazepines in small portions. The reaction mixture is stirred at room temperature for 15 minutes, warmed to 65-70 ° C. for 10 minutes and then cooled to room temperature. To this mixture is added 4.1 g (0.002 mol) of 4- (3-chloropropyl) morpholine hydrochloride in small portions. The reaction mixture is stirred at rt for 16 h and then poured into 800 ml of water. The mixture is extracted twice with 200 ml of methylene chloride each time. The methylene chloride extracts are combined and extracted with 150 ml and 75 ml 3N hydrochloric acid, respectively, and the aqueous extracts are combined and basified with 3N sodium hydroxide. The resulting suspension is extracted twice with 150 ml of methylene chloride and these two extracts are combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue (free base of the title compound) is reacted with an equimolar amount of fumaric acid in warm isopropyl alcohol and the mixture is treated with isopropyl ether. The fulates are collected by filtration and recrystallized with ethanol-ethyl acetate to give 5.6 g (melting point 154-157 ° C.) of the product. Dry for 5 hours at 97-98 ° C./0.1 mmHg and overnight at room temperature / 0.1 mmHg before analysis.

Elemental Analysis: C ₂₉ H ₃₀ ClN ₄ O ₅

Calculated: C; 67.69, H; 5.88, N; 10.88

Found: C; 67.52, H; 5.84, N; 10.90

Example 12

N, N-diethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine oxalate [1: 1]

5.0 g (0.0184 moles) of 6-phenyl-11H-pyrido [2, 3-b] [14] in a stirred suspension of 25 ml anhydrous dimethylformamide containing 1.10 g (0.0461 moles) of sodium hydride. Add benzodiazepine in portions. The reaction mixture is stirred at room temperature for 30 minutes, warmed to 65-70 ° C. and then slowly cooled to room temperature. To this mixture is added 3.77 g (0.020 mole) of 3-diethylaminopropyl chloride hydrochloride, the reaction mixture is stirred at room temperature for 16 hours, the mixture is poured into 750 ml of water and extracted three times with 150 ml of methylene chloride each time. . The methylene chloride extracts are combined and extracted with 150 ml and 75 ml 3N hydrochloric acid, respectively. The combined aqueous extracts were basified with 3N sodium hydroxide and extracted three times with 10 0 ml each of methylene chloride. The methylene chloride extracts are combined and dried over magnesium sulfate and evaporated under reduced pressure to give 7.5 g of the free base of the title compound. Some 5.6 g of the product is reacted with a thermal isopropyl alcohol solution containing an equimolar amount of oxalic acid dihydrate and the precipitated oxalate is collected by filtration to give 5.5 g of the product having a melting point of 196 to 199 ° C. Dry at 1 ° C./0.1 mm Hg for 1 hour.

Elemental Analysis: C ₂₇ H ₃₀ N ₄ O ₄

Calculated Value: C; 68.43, H; 6.37, N; 11.81

Found: C; 68.31, H; 6.43, N; 11.86

Example 13

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 25 ml anhydrous dimethylformamide containing 0.98 g (0.041 moles) of sodium hydroxide (in mineral oil) 5.0 g (0.016 moles) of 9-chloro-6-phenyl-11H-pyrido [2 , 3-b] [1,4] benzodiazepine is added over 45 min. The reaction mixture is stirred at room temperature for 1 hour, warmed to 70 ° C. and then slowly cooled to room temperature. To the mixture is added 2.84 g (0.018 mol) of 3-dimethylaminopropylchloride hydrochloride over 30 minutes and the reaction mixture is stirred at room temperature for 17 hours. The reaction mixture is poured into 750 ml of water and extracted once with 150 ml of methylene chloride and twice with 100 ml. The methylene chloride extracts were combined and washed twice with 100 ml of water each time and extracted with 100 ml and 75 ml of 3N hydrochloric acid, respectively. The acidic extracts were combined and the precipitate formed was filtered and separated. The filtrate was basified with 3N sodium hydroxide and extracted three times with 100 ml of methylene chloride. The methylene chloride extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in methylene chloride and filtered through 50-60 g of Florisil in a sintered glass funnel. The florisilbed is washed successively with 1%, 2%, 3% and 5% methanol-methylenechloride mixture and the filtrates are combined and evaporated under reduced pressure to give the free base of the title compound. The free base is reacted with hot isopropanol containing an equimolar amount of fumaric acid to yield 3.3 g of fumarate (melting point 199-202 ° C.).

Elemental Analysis: C ₂₇ H ₂₇ N ₄ O ₄ Cl

Calculated Value: C; 68.96, H; 5.37, N; 11.05

Found: C; 63.63, H; 5.36, N; 11.00

Example 14

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

To a stirred suspension of 25 ml of anhydrous dimethylformamide containing 1.0 g (0.0461 mol) of sodium hydride (in mineral oil) 5.0 g (0.018 mol) of 6-phenyl-11H-pyrido [2, 3-b under nitrogen atmosphere] ] Add [1, 4] benzodiazepines in small portions. The reaction mixture is stirred for 30 minutes, warmed to 70 ° C. and then cooled back to room temperature. To this mixture is added 4.14 g (0.0203 mol) of N- (3-chloropropyl) piperidine hydrochloride in portions and the reaction mixture is stirred for 16 hours at room temperature. The mixture is poured into 750 ml of water and stirred for 15 minutes to extract with 150 ml of methylene chloride. The aqueous layer is extracted two more times with 100 ml of methylene chloride each time and the combined methylene chloride extracts are extracted with 150 ml and 75 ml of 3N hydrochloric acid, respectively. The acid extracts are combined and basified with 3N sodium hydroxide and extracted three times with 100 ml of methylene chloride. The methylene chloride extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in a small amount of methylene chloride and filtered through a sintered glass funnel through a bed of 100 g of Florsil. The Florisil bed is washed successively with methylene chloride, 1%, 2%, 3% and 5% methanol-methylenechloride mixtures and the filtrates are combined and evaporated under reduced pressure. The residue is reacted with 1.3 g of fumaric acid in thermal isopropyl alcohol and isopropyl ether is added. Amorphous precipitates are formed. The total mixture is evaporated to dryness and the residue is dissolved in 200 ml of ethanol. The solution is warmed to reflux and filtered to add isopropyl ether to the filtrate. Filtration of the resulting crystals overnight yielded 4.1 g of fumarate (melting point 153-156 ° C.). Dry at 97-98 ° C./0.1 mm Hg for 4 hours before analysis.

Elemental Analysis: C ₃ H ₃₂ N ₄ O ₄

Calculated Value: C; 70.29, H; 6.29, N; 10.93

Found: C; 70.38, H; 6.32, N; 10.92

Example 15

6- (4-chlorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine fumarate [1: 1]

To a stirred suspension of 25 mL of anhydrous dimethylformamide containing 1.57 g (0.065 mol) of sodium hydroxide (in mineral oil) 8.0 g under a nitrogen atmosphere.

(0.026 mole) 6- (4-chlorophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine is added. The reaction mixture is stirred at room temperature for 1 hour, warmed to 80 ° C. for 15 minutes and then cooled to room temperature. To the mixture is added 4.55 g (0.029 mol) of 3-dimethylaminopropyl-chloride hydrochloride in portions and the mixture is stirred at rt overnight. The mixture is poured into 750 ml of water and stirred with 150 ml of methylene chloride for 30 minutes. The aqueous layer is further extracted three times with 100 ml of methylene chloride. The methylene chloride extracts are combined and dried over magnesium sulfate and evaporated under reduced pressure to give the free base of the title compound. The free base is reacted with an equimolar amount of fumaric acid in thermal isopropanol. Cooling precipitates 3.6 g of fumarate. Melting point: 200.5 to 202.5 ° C. The product is further dried in air before analysis.

Elemental Analysis: C ₂₇ H ₂₇ ClN ₄ O ₄

Calculated Value: C; 63.98, H; 5.37, N; 11.05

Found: C; 64.18, H; 5.33, N; 11.07

Example 16

8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] -benzodiazepine-11-ethanamine oxalate [1: 1]

6.1 g (0.02 mol) of 8-chloro-6-phenyl-11H-pyrido [2, 3- in a stirred suspension of 5 mL of anhydrous dimethylformamide containing 1.05 g (0.044 mol) of sodium hydride (in mineral oil). b] [1, 4] benzodiazepine is added dropwise. The reaction mixture is stirred for 1.5 hours at room temperature while hydrogen evolution stops in the movement. Cool the reaction mixture to 5 ° C and add 3.2 g (0.022 mol) of 2-dimethylaminoethylchloride hydrochloride in small portions to the mixture. Then continue stirring at room temperature for about 60 hours. The reaction mixture is poured into 1600 ml of water and the mixture is extracted three times with methylene chloride 500 ml each time. The combined extracts were washed twice with 500 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure. Thin layer chromatography (using 20% methanol / benzene, silica gel) indicates the presence of free base and starting material of the title compound. The residue is dissolved in benzene and chromatographed on 200 g of Florisil column filled in benzene. 1.3 g of 8-chloro-6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepines as starting materials were eluted with benzene and the free base of the title compound was eluted with a mixture of acetone in benzene. Let's do it. Reaction of the free base with an equimolar amount of oxalic acid dihydrate in reflux isopropyl alcohol and recrystallization of the product with isopropyl alcohol yields 1.6 g of product. Melting point 228.5-232 ° C., 6 hours at 82 ° C./0.1 mmHg before analysis, room temperature Dry overnight.

Elemental Analysis: C ₂₄ H ₂₃ ClN ₄ O ₄

Calculated Value: C; 61.74, H; 4.96, N; 12.00

Found: C; 61.62, H; 4.95, N; 11.98

Example 17

8-chloro-11-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine

To a stirred suspension of 15 ml of anhydrous dimethylformamide containing 0.25 g (0.01 mol) of sodium hydroxide (in mineral oil) 3.05 g (0.01 mol) of 8-chloro-6-phenyl-11H-pyrido [2, 3- b] Add [1, 4] benzodiazepines in small portions. The reaction mixture is warmed at about 60 ° C. for 1 hour. A solution of 10 ml of anhydrous dimethylformamide containing 1.42 g (0.01 mol) of methyl iodide is added dropwise over 0.5 hour, and the reaction mixture is stirred at room temperature overnight, then poured into 400 ml of water and stirred for 2 hours. Recrystallization of the precipitated solid twice with isopropyl alcohol yields 2.0 g of product (melting point 153-156 ° C.). Dry at 82 ° C./0.1 mm Hg for 1 hour before analysis.

Elemental Analysis: C ₁₉ H ₁₄ ClN ₃

Calculated Value: C; 71.36, H; 4.41, N; 13.14

Found: C; 71.64, H; 4.43, N; 13.32

Example 18

N, N-dimethyl-6- (4methylphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine fumarate [1: 1]

To a stirred suspension of 25 ml of anhydrous dimethylformamide containing 0.51 g (0.022 mol) of sodium hydride, 4.2 g (0.0147 mol) of 6- (4-methylphenyl = 11H-pyrido [2, 3-b] under nitrogen atmosphere. [1,4] benzodiazepine is added dropwise over 45 minutes The reaction mixture is stirred at room temperature for 1 hour, warmed to 75-80 ° C. for 11 hours, then cooled to room temperature and 0.0184 mole of 3-dimethylaminopropyl alcohol chloride 10 ml of anhydrous dimethylformamide solution was added dropwise, the reaction mixture was stirred overnight at room temperature, poured into 1000 ml of water and extracted three times with 150 ml of methylene chloride each time. Extract twice with 3N hydrochloric acid, precipitates formed in acidic solution are filtered off and discarded The filtrate is made basic with 3N sodium hydroxide and extracted three times with 100 ml of methylene chloride. The chloride extracts are combined and dried over magnesium sulfate and evaporated under reduced pressure to give the free base of the title compound as an oil Residual oil is dissolved in hot isopropyl alcohol and reacted with an equimolar amount of fumaric acid The solution is cooled to room temperature to fumarate When crystallized, recrystallization from isopropyl alcohol and isopropyl ether twice gave 1.7 g of a product having a melting point of 189 to 1189 ° C (decomposition).

Elemental analysis: C ₂₈ H ₃₀ N ₄ O ₄

Calculated Value: C; 69.12, H; 6.22, N; 11.52

Found: C; 68.86, H; 6.32, N; 11.36

Example 19

6- (4-methoxyphenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine fumarate [1: 1]

To a stirred suspension of 25 ml of anhydrous dimethylformamide containing 0.45 g (0.0187 mol) of sodium hydride under 4.5 g (0.015 mol) of 6- (4-methoxyphenyl) -11H-pyrido [2,3] under nitrogen atmosphere. -b] [1,4] benzodiazepine is added over 30 minutes. The mixture is stirred for 30 minutes at room temperature, warmed to 90 ° C. for 80 to 1 hour, then cooled to room temperature and a solution of 5 ml of anhydrous dimethylformamide containing 0.019 mol of 3-dimethylaminopropylchloride is added dropwise. The reaction mixture is stirred overnight at room temperature and then poured into 800 ml of water. The suspension is extracted twice with 150 ml of methylene chloride each time. The combined extracts were washed with 500 ml of water and extracted twice with 100 ml of 3N hydrochloric acid. The acid extracts are combined and the solid precipitated therefrom is filtered off. The filtrate is basified with 3N sodium hydroxide and extracted three times with 100 ml of methylene chloride each time. The methylene chloride extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. Since the residual oil is partially crystallized, it is polished with methylene chloride and filtered to leave 0.32 g of the residue. The filtrate was evaporated under reduced pressure and the residual oil was triturated with hot benzene to filter, leaving 0.8 g of the residue. The benzene filtrate is evaporated under reduced pressure and the residual oil is reacted with 1.02 g of fumaric acid in hot isopropyl alcohol. Cooling separates the oil from the solution. Incline the supernatant and seed the oil. After partial crystallization, the mixture is filtered to yield 2.5 g of solid (melting point: 157 to 160 ° C). Recrystallization with isopropyl alcohol-isopropyl ether gives an oil-solid mixture again. The mixture was reheated with additional isopropyl alcohol to dissolve and collected by filtration to yield 2.0 g of product (melting point 159-161 ° C.).

Elemental analysis: C ₂₈ H ₃₀ N ₄ O ₅

Calculated Value: C; 66.92, H; 6.02, N; 11.15

Found: C; 66.90, H; 6.08, N; 11.08

Example 20

6- (3-chlorophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine

A mixture of 500 ml containing 14 g (0.0433 mol) of [2 [(3-amino-2-pyrididyl) amino] phenyl] (3-chlorophenyl) -methanone and 0.3 g of paratoluene sulfonic acid in 500 ml of toluene Heat overnight under reflux, using a water trap to collect water. At the end of reflux, part of the toluene (about 250 ml) is distilled off and the hot solution is filtered. Petroleum ether (30-60 ° C.) is added to the cloud point. The solution was stored in the refrigerator overnight, filtered and dried in air to afford 10 g of golden crystals (yield 76%). Some of these are recrystallized from isopropyl alcohol-isopropyl ether.

Melting Point: 160 ~ 160.5 ℃

Elemental Analysis: C ₁₈ H ₁₂ N ₃ Cl

Calculated Value: C; 70.71, H; 3.96, N; 13.74

Found: C; 70.47, H; 3.98, N; 13.62

Example 21

6- (3-chlorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine fumarate [1: 1]

To a solution of 250 ml of anhydrous dimethylformamide containing 3.4 g (0.07 mole) of sodium hydride (in mineral oil) 8.5 g (0.028 mole) of 6- (3-chlorophenyl) -11H-pyrido [2 , 3-b] [1,4] benzodiazepine in small portions and added. The mixture is stirred for 30 minutes at room temperature. The temperature is raised to 80 ° C. for 3 hours and then cooled at room temperature. To the reaction mixture is added dropwise a solution of 4.9 g (0.031 mol) of 3-dimethylaminopropyl chloride hydrochloride in 30 ml of dimethylformamide over 20 minutes. The reaction mixture is stirred overnight at room temperature under a nitrogen atmosphere. Thin layer chromatography shows the presence of starting material. 1.4 g (0.03 mol) of sodium hydride are further added, and after 15 minutes, 4.7 g (0.03 mol) of 3-dimethylaminopropyl chloride hydrochloride is added and stirred for 4.5 hours. Water (20 ml) is added dropwise and the reaction mixture is filtered and concentrated on a rotary evaporator. The residue is partitioned between diethyl ether and dilute sodium hydroxide. The ether layer is washed three times with water and extracted with dilute hydrochloric acid solution. The aqueous layer is made basic with sodium hydroxide pellets and extracted with methylene chloride. The methylene chloride layer is concentrated to dryness to yield 7.5 g of product. The free base is reacted with fumaric acid and the fumarate is recrystallized from ethyl acetate-ethanol.

Melting Point: 167.5 ° C. to 168.5 ° C.

Elemental Analysis: C ₂₃ H ₂₃ N ₄ Cl

Calculated Value: C; 63.96, H; 5.47, N; 11.05

Found: C; 63.95, H; 5.39, N; 11.00

Example 22

6- (4-fluorophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine

A solution of 11.5 g (0.037 mol) of [2- [3-amino-2-pyridinyl) amino] phenyl] (4-fluorophenyl) -methanone and 0.6 g of paratoluene sulfonic acid in toluene Collect water by refluxing for 24 hours using Starktrap. After reflux, some of the toluene (about 300 ml) is distilled off and the hot solution is filtered. Petroleum ether (30-60 ° C.) is added to the cloud point. The solution was stored overnight in the refrigerator (0 ° C.) and filtered to yield 10.7 g of crystals. Some of these are recrystallized from isopropyl alcohol and dried overnight under vacuum at 65 ° C.

Melting Point: 203 to 205 ° C

Elemental Analysis: C ₁₈ H ₁₁ F

Calculated Value: C; 74.73, H; 4.18, N; 14.52

Found: C; 74.61, H; 4.17, N; 14.54

Example 23

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

8.7 g (0.03 moles) of 6- (4-fluorotophenyl) -11H-pyrido in a stirred suspension of 250 ml of anhydrous dimethylformamide containing 3.6 g (0.075 moles) of sodium hydride (in mineral oil) Add [2, 3-b] [1, 4] benzodiazebine pin separately. The mixture is stirred for 30 minutes at room temperature. The temperature is raised to 80 ° C. for 3.5 hours and then cooled to 45 ° C. again. To the reaction mixture is added dropwise a solution of 5.2 g (0.033 mol) 3-dimethyl aminopropyl chloride hydrochloride in 30 ml of dimethylformamide. After stirring overnight at room temperature, thin layer chromatography reveals the presence of starting material. Further 3.6 g (0.075 moles) of sodium hydride are added and stirred for 45 minutes, and then the reaction mixture is heated to 50 to 60 ° C. for 0.5 hour. It is colored green with the production of gas. The mixture is stirred at room temperature for 3 hours. A solution of 30 ml of dimethylformamide containing 5.2 g (0.0 33 mol) of 3-dimethylaminopropyl chloride is added dropwise. After about half and half of the drop, it turns green and temporarily stops dropping for about an hour. The reaction mixture is stirred overnight at room temperature. While cooling, 30 ml of water is added to the mixture. After gas evolution has ceased, the mixture is filtered and concentrated with a rotary centrifuge. The residue is partitioned between diethyl ether and water and the ether layer is extracted with dilute aqueous hydrochloric acid. After 1/2 hour the aqueous layer is filtered to remove solids and the filtrate is made basic with sodium hydroxide pellets and then extracted with methylene chloride. The extract is concentrated to dryness. The residue is bisected and purified by dry column chromatography on two silica gel columns (20 ″ × 1 1/2 ″) using 10% methanol, 1% ammonium hydroxide, 89% methylene chloride as eluent. The center of the column is cut out and extracted with developer. The combined extracts are concentrated under reduced pressure and the residue is dissolved in an ethyl acetate-ethanol mixture and acidified with concentrated hydrochloric acid. Hydrochloride is recrystallized from ethanol-ethyl acetate mixture. The solid obtained was filtered and dried at 99 ° C. for 48 hours to afford the title compound as monohydrochloride hemihydrate.

Melting Point: 120 ~ 123 ℃

Elemental analysis: C ₄₆ H ₅₀ N ₈ F ₂ Co ₂ O

Calculated Value: C; 65.78, H; 6.00, N; 13.34

Found: C; 65.58, H; 5.77, N; 13.47

Example 24

11- [3- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) propyl] -6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine

5.0 g (0.0184 moles) of 6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine in a stirring suspension of 25 ml of anhydrous dimethylformamide containing 0.56 g (0.023 moles) of sodium hydride. Divide by small amounts. The reaction mixture is warmed to 80 ± 2 ° C. for 1 hour and cooled to room temperature. A solution of 10 ml of anhydrous dimethylformamide containing 5.55 g (0.020 mol) of N- (3-bromopropyl) phthalamide is added dropwise and stirred for 16 hours, followed by pouring the reaction mixture into 650 ml of water and stirring for 30 minutes. . The yellow solid is collected by filtration and recrystallized three times from isopropyl alcohol to give 3.7 g of product (melting point: 170-172 ° C.).

Elemental Analysis: C ₂₉ H ₂₂ N ₄ O ₂

Calculated Value: C; 75.97, H; 4.84, N; 12.22

Found: C; 76.25, H; 4.87, N; 12.34

Example 25

6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, dihydrochloride, hemihydrate

16.2 g (0.035 mole) of 6-phenyl-11 [3 (phthalimido) propyl] -11H-pyrido [2, 3-b] [1, 4] benzodiazepine and 2.29 g (0.0387 mole) of hydrazine hydrate ( 85%) is also refluxed for 2.5 hours and a mixture of 175 ml of ethyl alcohol is left for 72 hours. A solution of 10 ml of concentrated hydrochloric acid in 50 ml of water is added to the mixture and stirred overnight. The solid precipitate is collected by filtration and discarded. The filtrate is evaporated under reduced pressure. The slightly wet residue is suspended in 200 ml of water and stirred for 2 hours and filtered through celite. The filtrate is evaporated under reduced pressure, and the residue is suspended in 100 ml of 200-degree ethyl alcohol and then evaporated under reduced pressure. Repeat the latter process. The wet crude product (42.1 g) is recrystallized from isopropyl alcohol while standing for about 15 hours. The solid is collected by filtration and dried for 3 hours at 0.1 mmHg and 82 ° C. over phosphoric anhydride.

Melting Point: 210 to 220 ° C (Decomposition)

Elemental analysis: C ₄₂ H ₄₆ Cl ₄ N ₀ O

Calculated Value: C; 61.47, H; 5.65, N; 13.65

Found: C; 61.36, H; 5.72, N; 13.90

Example 26

6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine

A part of 6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine, dihydrochloride hemihydrate obtained in Example 25 was dissolved in water and basified with sodium hydroxide Extract three times with methylene chloride. The methylene chloride extracts are combined and filtered through 50-60 g of Florisil bed in a sintered glass funnel. The beds are washed successively with 1%, 2%, 3% and 5% methanol-methylenechloride mixtures and the filtrates are combined and evaporated under reduced pressure to afford the title compound as a freebase.

Example 27

N- [3- [6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepin-11-yl] propyl] methaneimide acid ethyl ester

A solution of 150 ml of triethylorthoformate containing 8.8 g (0.021 mol) of 6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine was 41/2 hours. Heat at reflux and leave overnight. The mixture is concentrated in vacuo and the residue is washed with petroleum ether (30-60 ° C.). Chemical ionization mass spectra showed that the product was a mixture containing the title compound.

Example 28

N-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, dihydrochloride

Preparation of imidate esters [Crochet, T.A. & Blanton C.D, Jr Synthesis 1974 (1) 55-56]

25 g (0.06 mol) prepared in Example 25 was mixed with 6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine dihydrochloride hemihydrate between dilute sodium hydroxide and methylene chloride. After partitioning and drying, the methyl chloride layer was concentrated to dryness, anhydrous benzene was added and concentrated again to remove benzene, converting to a free base. The resulting free base was dissolved in 300 ml (267 g, 1.8 mol) of fresh distilled triethyl ortho formate while refluxing for 9 hours. The mixture is concentrated in vacuo and the mixture is concentrated again by adding ethanol.

Conversion of Amidate to Amine

23.4 g (0.061 mole) of amidate prepared above was dissolved in 200 ml of ethanol, and sodium was stirred at 15 to 20 ° C. until the reaction was completed by thin layer chromatography, which appeared to be a substantial absence of starting material. Borohydrate is added. Slowly add 50 ml of water with stirring and continue to cool for 15 minutes after adding water. A large amount of 21 water is added to the mixture and extracted with ethyl acetate. The ethyl acetate layer is washed with water and saturated with sodium chloride until neutral tax solution is obtained. The resulting ethyl acetate layer is dried and concentrated. Diethyl ether is added and the mixture is cooled. Some insoluble material is filtered off. The ether layer is concentrated and the product is chromatographed using ethyl acetate + methanol + traces of triethylamine as eluent on an alumina column. Fractions containing substantial product (identified by TLC) were partitioned between ethyl acetate and sodium hydroxide between aqueous solutions. Ethereal hydrogen chloride is added to the ethyl acetate layer and the crystalline product is recrystallized from an acetonitrile-water mixture.

Melting Point: 139 ~ 141 ℃

Elemental Analysis: C ₂₂ H ₂₄ N ₄ Cl ₂

Calculated Value: C; 63.62, H; 5.82, N; 13.49

Found: C; 63.81, H; 6.15, N; 13.60

Example 29

N- [3- [6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepin-11-yl] propyl] carbamic acid ethyl ester

0.53 g (0.0052 mole) of tree in a solution of anhydrous methylene chloride containing 1.6 g (0.0045 mole) of 6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propane amine Ethylamine is added. 0.54 g (0.005 mole) of ethylchloroformate is added dropwise to the solution while cooling. The mixture is stirred for 2 hours at room temperature. The methylene chloride solution (indicated by the chemical ionization mass spectrum) is washed with dilute sodium hydroxide-saturated saturated aqueous solution, dried and evaporated to dryness. The residue is triturated with isopropyl ether. Yield: 1.5 g

Example 30

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

A solution of methanolic anhydride containing 3.0 g (0.0064 moles) of N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine was dissolved in methanolic hydrochloric acid. Adjust to pH 5.6 with solution. 0.7 g (0.011 mol) of NaBH ₃ CN was added to the solution at once and refluxed for 20 minutes. Ethanol is removed under vacuum and the residue is partitioned between dilute sodium hydroxide and methylene chloride. The methylene chloride layer is dried over magnesium sulfate and concentrated to give a residue, which is crystallized twice with 2-propanol and isopropyl ether. 1.6 g (57%) of a yellow solid is obtained, which loses its crystalline structure upon heating from 156 to 160 ° C. and decomposes at 180 to 195 ° C.

Elemental analysis: C ₄₆ H ₅₈ N ₈ OCl ₄

Calculated Value: C; 62.73, H; 6.64, N; 12,72

Found: C; 62.40, H; 6.90, N; 12.61

[Examples 31a to 31r]

According to the method of Example 6, the following metanon compounds are: [2-[(3-amino-2-pyridinyl) amino] phenyl]-(4-ethylphenyl) methanone, [2-[(3-amino -2-pyridinyl) amino] phenyl]-(4-isopropylphenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] phenyl]-(4-bromophenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] phenyl]-(4-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-trifluoromethylenyl) methanone, [2- [ (3-amino-2 -pyridinyl) amino] phenyl]-(3-methylphenyl) methanone, [2- [3-amino-2-pyridinyl) amino] phenyl]-(2-ethylphenyl) -methanone , [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2-methoxyphenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] phenyl] -2 , (4-dichlorophenyl) methanone and [2-[(3-amino-2-pyridinyl) amino] phenyl]-(3, 4, 5-trimethoxyphenyl) methanone were closed to the next pyridobenzodiazepine Obtain: (a) 6- (4-ethylphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (b) 6- (4-isopropylphenyl) -11H-pyri [2, 3-b] [1, 4] benzodiazepines, (c) 6- (4-bromophenyl) -11 H-pyrido [2, 3-b] [1, 4] benzodiazepines, (d) 6- (4-fluorophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepines, (e) 6- (4-ethoxyphenyl) -11H-pyrido [2, 3- b] [1, 4] benzo Diazepine, (f) 6- (4-nitrophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (g) 6- (4-trifluoromethylphenyl) -11H-pyri [2, 3-b] [1, 4] benzodiazepines, (h) 6- (3-methylphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepines, (i) 6- ( 3-ethylphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (j) 6- (3-methoxyphenyl) -11H-pyrido [2, 3-b] [1 , 4] benzodiazepine, (k) 6- (3-ethoxyphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (l) 6- (2-nitrophenyl) -11H- Pyrido [2, 3-b] [1, 4] benzodiazepines, (m) 6- (3-trifluorophenyl) -11 H-pyrido [2, 3-b] [1, 4] benzodiazepines, ( n) 6- (2-methylphenyl) -11 H-pyrido [2, 3-b] [1, 4] benzodiazepine, (o) 6- (2-ethylphenyl) -11H-pyrido [2, 3- b] [1, 4] benzodiazepines, (p) 6- (2-methoxyphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepines, (q) 6- (2, 4- Dichlorophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepines and (r) 6- (3, 4, 5-trimethoxyphenyl) -11H-pyrido [2, 3-b ] [1, 4] Jody azepine.

[Examples 32a to 32o]

According to the method of this Example 3, the following ethanone compounds, namely [2-[(3-amino-2-pyridinyl) amino] -5-chlorophenyl] (phenyl) methanone, [2-[(3- Amino-2-pyridinyl) amino] -6-chlorophenyl] (phenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] -4-bromophenyl] (phenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] -4-fluorophenyl] (phenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] 4-trifluoro Methylphenyl] (phenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] -4-methylphenyl] (phenyl) methanone, [2-[(3-amino-2-pyridinyl) amino ] -5-methylphenyl] (phenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] -6-methylphenyl] (phenyl) methanone, [2-[(3-amino-2- Pyridinyl) amino] -4-ethylphenyl] (phenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] -4-methoxyphenyl] (phenyl) methanone, [2- [ (3-amino-2-pyridinyl) amino] -4-ethoxyphenyl (phenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] -4 -Nitrophenyl] (phenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] -5-nitrophenyl] (phenyl) methanone, [2-[(3-amino-2-pyridine) Dinyl) ami] -3 -methylphenyl] (phenyl) methanone and [2-[(3-amino-2-pyridinyl) amino] -3-chlorophenyl] (phenyl) methanone are closed to give the following benzodiazepines : (a) 8-chloro-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (b) 7-chloro-6-phenyl-11H-pyrido [2, 3- b] [1,4] benzodiazepine, (c) 9-bromo-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (d) 9-fluoro-6-phenyl -11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (e) 6-phenyl-9-trifluoromethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine , (f) 9-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (g) 8-methyl-6-pe-11H-pyrido [2, 3- b] [1, 4] benzodiazepine, (h) 7-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (i) 9-ethyl-6-phenyl-11H -Pyrido [2, 3-b] [1, 4] benzodiazepines, (j) 9-meth Methoxy-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (k) 9-ethoxy-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (l) 9-nitro-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, (m) 8-nitro-6-phenyl-11H-pyrido [2 , 3-b] [1, 4] benzodiazepine, (n) 10-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine and (o) 10-chloro-6- Phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine.

[Examples 33a to 33r]

See the following 6-phenyl-substituted pyridobenzodiazepines according to the method of Example 15 using the compounds prepared in Example 31 in equimolar amounts, respectively: (a) 6- (4-ethylphenyl-N, N -Dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, (b) N, N-dimethyl-6- [4- (1-methylethyl) phenyl] -11H -Pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, (c) 6- (4-bromophenyl-N, N-dimethyl-11H-pyrido [2, 3-b ] [1, 4] benzodiazepine-11-propanamine, (d) 6- (4-fluorophenyl-N, N-dimethyl-11H-pyrido- [2, 3-b] [1, 4] benzodiazepine- 11-propanamine, (e) 6- (4-ethoxyphenyl) -N,, -dimethyl-11 H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, (f ) N, N-dimethyl-6- (4-nitrophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, (g) N, N-dimethyl-6- [4- (trifluoromethyl) phenyl] -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, (h) N, N-dimethyl-6- (3-methylphenyl ) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, (i) 6- (3-ethylphenyl-N, N-dimethyl-11H-pyrido [2, 3- b] [1,4] benzodiazepine-11-propanamine, (j) 6- (3-methoxyphenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine -11-propanamine, (k) 6- (3-ethoxyphenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, (l ) N, N-dimethyl-6- [2- (nitrophenyl)]-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, (m) N, N-dimethyl- 6- [4- (trifluoromethyl) phenyl] -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, (n) N, N-dimethyl-6- (2 -Methylphenyl) -11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine, o) 6- (2-ethylphenyl) -N, N-dimethyl-11H-pyrido [2 , 3-b] [1, 4] benzodiazepine-11-propanamine, p) 6- (2-methoxyphenyl-N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] Benzodiazepine-11-propanamine, q) 6- (2, 4-dichlorophenyl-N, N-dimethyl-11H-pyrido [2, 3-b] [ 1,4] benzodiazepine-11-propanamine and (r) N, N-dimethyl-6- (3, 4, 5-trimethoxyphenyl) -11H-pyrido [2, 3-b] [1, 4 ] Benzodiazepine-11-propanamine,

[Examples 34a to 34o]

According to the method of Example 13, the following pyrido was obtained using an equimolar amount of the compound prepared in Example 32 instead of 9-chloro-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine. Prepare benzodiazepines: a) 8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, b) 7-chloro- N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, c) 9-bromo-N, N-dimethyl-6-phenyl- 11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, d) 9-fluoro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b ] [1, 4] benzodiazepine-11-propanamine, e) N, N-dimethyl-6-phenyl-9- (trifluoromethyl) -11H-pyrido [2, 3-b] [1, 4] Benzodiazepine-11-propanamine, f) N, N, 9-trimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, g) N, N, 8-trimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, h) N, N, 7-trimethyl-6- Phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine, i) 9-ethyl-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3- b] [1,4] benzodiazepine-11-propanamine, j) 9-methoxy-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11 -Propanamine, k) 9-ethoxy-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, l) N, N- Dimethyl-9-nitro-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, m) N, N-dimethyl-8-nitro-6-phenyl-11H -Pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, n) N, N, 10-trimethyl-6 phenyl-11H-pyrido [2, 3-b] [1, 4 ] Benzodiazepine-11-propanamine and o) 10-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine.

[Examples 35a to 35c]

According to the method of Example 1, using equimolar amounts of 4-amino-3-chloropyridine, 3-amino-4-chloropyridine and 2-amino-3-chloropyridine instead of 3-amino-2-chloropyridine Obtain each of the following compounds: a) 6-phenyl-11H-pyrido [3,4-b] [1,4] benzodiazepine, b) 10-phenyl-5H-pyrido [3, 4-b] [1 , 4] benzodiazepine and c) 10-phenyl-5H-pyrido- [3, 4-b] [1, 4] benzodiazepine.

[Examples 36a to 36c]

According to the method of Example 3, [2-[(4-amino-3-pyridinyl) amino] phenylmethanone, [2-[(3-amino-4-pyridinyl) amino] phenylmethanone and [2 -[(2-amino-3-pyridinyl) amino] phenylmethanone is converted to give the following compound: a) 6-phenyl-11H-pyrido [3, 4-b] [1, 4] benzodiazepine, b) 10-phenyl-5H-pyrido [4, 3-b] [1, 4] benzodiazepine, and c) 10-phenyl-5H-pyrido [3,2-b] [1, 4] benzodiazepine.

[Examples 37a to 37c]

According to the method of Example 9, equimolar amounts of 6-phenyl-11H-pyrido [3, 4-b] [instead of 6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepines 1,4] benzodiazepine, 10-phenyl-5H-pyrido [4, 3-b] [1, 4] benzodiazepine, and 10-phenyl-5H-pyrido [3, 2-b] [1, 4] benzodiazepine To obtain the following compound: a) N, N-dimethyl-6-phenyl-11H-pyrido [3, 4-b] [1, 4] benzodiazepene-11-propanamine fumarate, b) N, N-dimethyl-10-phenyl-5 H-pyrido [4, 3-b] [1,4] benzodiazepine-5-propanamine fumarate, and c) N, N-dimethyl-10-phenyl-5H-pyridine Fig. [3, 2-b] [1, 4] Benzodiazepine-5-propanamine fumarate.

Example 38

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

1.4 g (0.0035 moles) of N-[(3- (6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepin-11-yl) propyl] carbamic acid ethyl ester (Example 29 0.4 g (0.0105 mole) of lithium aluminum hydride lithium under nitrogen atmosphere is added to a solution of tetrahydrofuran containing a little exothermic reaction and the mixture is cooled to prevent overheating. Stir the thin layer chromatography to observe that only a partial conversion reaction occurred: Add 0.4 g (0.0105 mol) of lithium aluminum hydride and reflux the mixture overnight The thin layer chromatography shows that the product is a large amount of the title compound. Check it.

Example 39

6- (2-thienyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine

According to Example 20, [2-[(3-amino-2-pyridinyl) amino] phenyl] (2-thienyl) methanone was heated with a paratuluene sulfonic acid catalyst in an organic solvent and produced Water is removed with a Dean-Stark trap to give the title compound.

Example 40

6- (3-thienyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine

According to Example 20, [2-[(3-amino-2-pyridinyl) aminophenyl] (3-thienyl) methanone is heated with a paratuluene sulfonic acid catalyst in an organic solvent and the resulting water Silver is removed with Dean-Starktrap to give the title compound.

Example 41

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

According to the method of Example 3, 2-[(3-amino-2-pyridinyl) amino] phenyl] (2-pyridinyl) methanone was closed to give the title compound.

Example 42

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

According to the method of Example 3, 2-[(3-amino-2-pyridinyl) amino] phenyl] (3-pyridinyl) methanone was closed to give the title compound.

Example 43

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

According to the method of Example 3, 2-[(3-amino-2-pyridinyl) amino] phenyl] (4-pyridinyl) methanone was closed to give the title compound.

Example 44

N, N-dimethyl-6- (2-thienyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-1 1-propanamine

According to the method of Example 23, 6- (2-thienyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine was reacted with sodium hydride and then with 3-dimethylaminopropyl chloride Obtain the title compound.

Example 45

N, N-dimethyl-6- (3-thienyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-propanamine

According to the method of Example 23, 6- (3-thienyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine was reacted with sodium hydride followed by 3-dimethylaminopropyl chloride Obtain the title compound.

Example 46

N, N-dimethyl-6- (2-pyridinyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine

According to the method of Example 23, 6- (2-pyridinyl) -11H-pyrido [2, 3-b] [1,4] benzodiazepine was reacted with sodium hydride and then with 3-dimethylaminopropyl chloride Obtain the title compound.

Example 47

N, N-dimethyl-6- (3-pyridinyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine

According to the method of Example 23, 6- (3-pyridinyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine is reacted with sodium hydride and then with 3-dimethylaminopropyl chloride To give the title compound.

Example 48

N, N-dimethyl-6- (4-pyridinyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine

According to the method of Example 23, 6- (4-pyridinyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine was reacted with sodium hydride followed by 3-dimethylaminopropyl chloride Obtain the title compound.

[Examples 49a to 49g]

The metanon compound of the following intermediate 15 according to the method of Example 6, ie [2-[(3-amino-4-methyl-2-pyridinyl) amino] phenyl] -phenylmethanone, [2-[(3- Amino-5-methyl-2-pyridinyl) amino] phenyl] -phenylmethanone, [2-[(3-amino-6-methyl-2-pyridinyl) amino] phenyl] -phenylmethanone, [2- [(3-amino-5, 6-dimethyl-2-pyridinyl) amino] phenyl] -phenylmethanone, [2- [(3-amino-6-methoxy-2-pyridinyl) amino] phenyl]- Phenylmethanone, [2-[(3-amino-2-methyl-4-pyridinyl) amino] phenyl] -phenylmethanone, and [2-[(3-amino-5-methoxy-2-pyridinyl ) Amino] phenyl] -phenylmethanone is converted to give the following pyrido benzodiazepines: a) 4-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, b ) 3-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, c) 2-methyl-6-phenyl-11H-pyrido [2, 3-b] [1 , 4] benzodiazepine, d) 2, 3-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, e) 2-methoxy-6- Phenyl-11H-pyrido [4, 3-b] [1, 4] benzodiazepine, f) 1-methyl-10-phenyl-5H-pyrido [2, 3-b] [1, 4] benzodiazepine, and g ) 3-methoxy-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine.

[Examples 50a to 50g]

According to the method of Example 23, the pyridobenzodiazepine prepared in Example 49 is reacted with sodium hydride and 3-dimethylaminopropyl chloride to give the following compounds: a) N, N, 4-trimethyl-6-phenyl- 11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, b) N, N, 3-trimethyl-6-phenyl-11H-pyrido [2, 3-b] [1 , 4] benzodiazepine-11-propanamine, c) N, N, 2-trimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, d) N , N, 2, 3-tetramethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine, e) 2-methoxy-N, N-dimethyl- 6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine, f) N, N, 1-trimethyl-10-phenyl-5H-pyrido [4, 3- b] [1,4] benzodiazepine-5-propanamine and g) 3-methoxy-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11 Propanamine.

[Examples 51a to 51c]

[2-[(3-amino-2-pyridinyl) amino] phenyl] (2- instead of [2-[(3-amino-2-pyridinyl) amino] phenyl] (4-fluorophenyl) methanone Fluorophenyl) methanone, [2-[(3-amino-2-pyridinyl) amino] phenyl] (2-chlorophenyl) methanone and [2-[(3-amino-2-pyridinyl) amino] Using phenyl] (2-bromophenyl) methanone, the following compound is obtained according to the method of Example 22.

a) 6- (2-fluorophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine, b) 6- (2-chlorophenyl) -11H-pyrido [2, 3- b] [1, 4] benzodiazepine and c) 6- (2-bromophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine.

[Examples 52a to 52c]

According to the method of Example 23, instead of 6- (4-fluorophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine, the following pyrido [1, 4] benzodiazepine, ie 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-b] [1, 4] benzodiazepine to afford the following compounds.

a) 6- (2-fluorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine: melting point 92-94 ° C: isopropyl alcohol Recrystallization with isopropyl ether.

b) 6- (2-chlorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine: melting point 104 to 105 ° C; Recrystallized from isopropyl ether.

c) 6- (2-bromophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine: melting point 96-98 ° C: isopropyl ether Recrystallized by.

[Examples 53a to 53b]

According to the method of Example 9, 3-dimethylamino-2-methylpropyl chloride and 4-dimethylamino butylchloride in place of 3-dimethylaminopropyl chloride were used to obtain the following compounds.

a) N, N, β-trimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine fumarate and b) N, N-dimethyl-6-phenyl -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-butanamine fumarate.

[Examples 54a to 54b]

1- (3-chloropropyl) pyrrolidine hydrochloride and 1- (3-chloropropyl) -4-methylpiperazin hydrochloride instead of (4- (3-chlorophenyl) morpholine hydrochloride according to the method of Example 11 Using 6-phenyl-11-[(3- (pyrrolidinyl) propyl] -11H-pyrido [2, 3-b] [1, 4] -benzodiazepine and 6-phenyl-11-3- (4 -Methyl-1-piperazinyl) propyl] -11H-pyrido [2, 3-b] [1, 4] benzodiazepine.

[Examples 55a to 55c]

According to the method of Example 9, 8-methyl-6-phenyl-11H-pyrido [3, 4-b] instead of 6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine [1, 4] benzodiazepine, 6- (4-chlorophenyl) -11H-pyrido [3, 4-b] [1, 4] benzodiazepine, and 3-methoxy-6-phenyl-11H-pyrido [3 , 4-b] [1, 4] benzodiazepines to give the following compounds: a) N, N-8-trimethyl-6-phenyl-11H-pyrido [3, 4-b] [1, 4] Benzodiazepine-11-propanamine, b) 6- (4-chlorophenyl) -N, N-dimethyl-11H-pyrido [3, 4-b] [1, 4] benzodiazepine-11-propanamine, and c) 3-methoxy-N, N-dimethyl-6-phenyl-11H-pyrido [3, 4-b] [1, 4] benzodiazepine-11-propanamine.

[Examples 56a to 56d]

According to the method of Example 17, 6-phenyl-11H-pyrido [2, 3-b] instead of 8-chloro-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine [1,4] benzodiazepine, 8-chloro-6- (2-nitrophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine, 8-chloro-6- (2-nitrophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine and 8-chloro-6- (2-bromophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine To obtain the following compound: a) 11-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, b) 8-chloro-1 1-methyl-6- (2-nitrophenyl) -11H-pyrido [2, 3-b] [1,4] benzodiazepine, melting point 165 to 166 ° C; Recrystallized from ethanol c) 8-chloro-6- (2-chlorophenyl) -11-methyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine, melting point 150-152 ° C; Recrystallized from isopropyl alcohol-eastpropyl ether, d) 6- (2-bromo phenyl) -8-chloro-1-methyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine, melting point 121 To 123 ° C: Recrystallized from isopropyl ether.

Example 57

N-methyl-N-[(3- (11H-pyrido [2, 3-b] [1, 4] benzodiazepin-11-yl) propyl] carbamic acid methyl ester

The title compound is prepared by reacting 6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine with (3-chloropropyl) methyl carbamic acid methylester.

Example 58

9-hydroxy-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine

The title compound is prepared by reacting 11 [3- (dimethylamino) propyl] -9-methoxy-6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine with hydrogen iodide and glacial acetic acid. .

Example 59

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

The title compound is prepared by reacting 3-methoxy-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine with hydrogen iodide and glacial acetic acid. .

TABLE 2

Formulation and Administration

For therapeutic purposes, an effective amount of the compound of formula (I _p ) or (II), as described above, is prepared in a conventional formulation and administered to the human body, for example liquids, emulsions, suspensions, pills, tablets and capsules. Prepared by oral administration and prepared as a sterile solution and administered parenterally.

Solid carriers that can be administered orally include lactose, magnesium stearate, white clay, sucrose, talc, stearic acid, gelatin, agar, pectin or gum arabic.

Liquid carriers that can be administered orally include vegetable oils and water.

Intramuscularly administrable carriers or excipients are sterile parenterally administrable liquids (eg water) or parenterally administrable oils (eg arachidone oil in ampoules).

Small doses of the active ingredient of the present invention may be used when used for light therapy or when administered to patients with relatively low weight, but the unit dose may be 5 mg or more, preferably 10,25,50 or 100 mg or more. The administration is preferably divided into three to four times a day, depending on the urgency of the condition, the compound used and the desired result. A unit dose of 25 to 200 mg is suitable and within a wider range the amount used is about 10 to 500 mg per unit dose. The daily dose is generally about 0.3 to about 20 mg / kg, preferably 0.5 to 10 mg / kg. The active ingredient of the present invention can be mixed with other pharmacologically active compounds as described above. The active ingredient must be contained in an effective amount, ie, in the dosage form employed, with the appropriate effective amount. Clearly, several unit dosage forms can be administered at about the same time. Accurate doses and daily doses can be determined according to the physician's or vet's basic guidelines.

The following formulations are representative of the pharmacologically active ingredients of the invention.

Formulation

1.Capsule

Preparations containing 10 mg and 50 mg of active ingredient per capsule are prepared. If higher amounts of the active ingredient are used, the amount of lactose can be reduced.

Other capsules preferably contain a large amount of the active ingredient as follows.

In each case, the active ingredient is mixed evenly with lactose, starch and magnesium stearate and the mixture is neutralized in the capsule.

2. Tablet

Representative formulations of tablets containing 5.0 mg of active ingredient per tablet are as follows. The formulations can be used for other active ingredients by controlling the increase in dicalcium phosphate.

Mg per tablet

1.Active ingredient 10.0

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

Total amount 202.0

Mix 1,2,4 and 5 uniformly. 3 is prepared as 10% paste in water. The mixture is granulated with starch paste and the wetted material is passed through 8 mesh sieves. Dry the wet granules and pass through 12 mesh sieves. The dried granules are mixed with calcium stearate and pressed.

3. Injection (2% sterile solution)

per cc

Active ingredient 20 mg

0.5 mg preservative (eg chlorobutanol)

w / v%

Appropriate amount of distilled water for injection

The solution is prepared, filtered and clarified, filled into vials, sealed and autoclaved.

Those skilled in the art are familiar with the various modifications and can apply them to the compounds, compositions and methods of the present invention without departing from the scope and object of the invention. It is, therefore, to be understood that the invention is limited only by the scope of the appended claims.

Claims (73)

The mixture of halo-aminopyridine of formula (IV) and (aminophenyl) arylmethanone of formula (III) is heated at 170 ° C. to 200 ° C. for a time shorter than that required for ring closure with pyridobenzodiazepines. Characterized in the above formula, to prepare [2-[(aminopyridinyl) amino] phenyl] arylmethanone of the following general formula (II).

Wherein Ar is the same or different from 1 to 3 radicals selected from 2,3 or 4-pyridinyl, 2- or 3-thienyl, phenyl, or halo, lower alkyl, lower alkoxy, trifluoromethyl and nitro Is phenyl substituted with: Z is hydrogen, halogen, lower alkyl. Lower alkoxy, hydroxy or nitro: Y is hydrogen or the same or different one or two radicals selected from lower alkyl, lower alkoxy and hydroxy. A mixture of the following halo-amine pyridine of formula (IV) with (aminophenyl) arylmethanone of formula (III) or a reaction product thereof is a compound of formula (II), which is necessary for removing water from the reaction: A method for preparing lipido [1,4] benzodiazepene of the general formula (I-A), characterized in that it is closed by heating for a period of time and under conditions.

Wherein Ar is the same or different from 1 to 3 radicals selected from 2, 3 or 4-pyridinyl, 2 or 3-thienyl, phenyl, or halo, lower alkyl, lower alkoxy, trifluoromethyl and nitro Substituted phenyl: Z is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or nitro: Y is hydrogen or the same or different one or two radicals selected from lower alkyl, lower alkoxy and hydroxy: n is 0 or 1, and when n is 0, the dotted line means a double bond. The method of claim 2 wherein the temperature is 170 ° to 200 ° C. The method of claim 2 wherein the water is removed under reflux in an aprotic solvent. Reacting a compound of formula (I-A) with a halo-alk ¹ Q reagent, where alk ¹ and Q are as defined below, to prepare a compound of formula (Ib) Way.

Wherein Ar is the same or different from 1 to 3 radicals selected from 2, 3 or 4-pyridinyl, 2 or 3-thienyl, phenyl, or halo, lower alkyl, lower alkoxy, trifluoromethyl and nitro Substituted phenyl, Q is -N- (loweralkyl) ₂ 1-pyrrolidinyl, 1-piperidinyl, 4-substituted-piperazin-1-yl, 4-morpholino, 1-phthalimido ,-

Lower alkyl or halo, alk ¹ is a straight or branched chain hydrocarbon of 1 to 8 carbon atoms, Z is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or nitro, Y is hydrogen, lower alkyl, lower alkoxy and 1 to 2 radicals, which may be the same or different, selected from hydroxy, n is 0 or 1, and when n is 0, the dotted line represents a double bond. Compounds of general formula (I) and acid addition salts thereof.

Wherein R is hydrogen, lower alkyl, -alk ¹ -NR ¹ R ² or

Wherein R ¹ and R ² are hydrogen, lower alkyl or —C (O) O-lower alkyl, or R ¹ and R ² together with the adjacent nitrogen atom are 1-phthalimido, 1-pyrrolidinyl, 4 -May form a heterocyclic moiety selected from the group consisting of morpholino, 1-piperazinyl, and 4-substituted piperazin-1-yl: Ar is 2-, 3- or 4-pyridinyl, 2 Or phenyl, which represents 3-thienyl or phenyl, or is substituted by the same or different 1 to 3 radicals selected from halo, lower alkyl, lower alkoxy, trifluoromethyl and nitro: alk ¹ is 1 to 8 carbon atoms Wherein Z is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or nitro: Y is hydrogen or the same or different one or two radicals selected from lower alkyl, lower alkoxy and hydroxy n is 0 or 1, and n is 0 The dotted line in the case is a double bond. 7. The compound of claim 6, which is 6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine. The compound of claim 6, which is 8-chloro-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine. 7. The compound of claim 6, which is 9-chloro-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine. 7. The compound of claim 6, which is 6- (4-chlorophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine. The compound of claim 6, which is 6- (4-methylphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine. 7. The compound of claim 6, which is 6- (4-methoxyphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine. The compound of claim 6, which is 8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. The compound according to claim 6, which is 8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine oxalate [1: 1] compound. The compound of claim 6, which is N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. A compound according to claim 6, which is N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine fumarate [1: 1]. The compound of claim 6, which is N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-ethanamine. A compound according to claim 6, which is N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-ethanamine fumarate [1: 1]. The compound of claim 6, which is 11- [3- (4-morpholinyl) propyl] -6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine. The compound according to claim 6, which is 11- [3- (4-morpholinyl) propyl] -6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine fumarate [1: 1] compound. The compound of claim 6, which is N, N-diethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. A compound according to claim 6, which is N, N-diethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine oxalate [1: 1]. The compound of claim 6, which is 9-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. The compound according to claim 6, which is 9-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine fumarate [1: 1]. compound. The compound of claim 6, which is 6-phenyl-11- [3- (1-piperidinyl) propyl] -11H-pyrido [2, 3-b] [1, 4] benzodiazepine. The compound according to claim 6, which is 6-phenyl-11- [3- (1-piperidinyl) propyl] -11H-pyrido [2, 3-b] [1, 4] benzodiazepine fumarate [1: 1] compound. The compound of claim 6, which is 6- (4-chlorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. The compound according to claim 6, wherein 6- (4-chlorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine fumarate [1: 1] Phosphorus compounds. The compound of claim 6, which is 8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-ethanamine. The compound according to claim 6, which is 8-chloro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-ethanamine oxalate [1: 1] compound. The compound of claim 6, which is 8-chloro-11-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine. The compound of claim 6, which is N, N-dimethyl-6- (4-methylphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. The compound according to claim 6, which is N, N-dimethyl-6- (4-methylphenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine fumarate [1: 1] compound. A compound according to claim 6, which is 6- (4-methoxyphenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. The compound according to claim 6, wherein 6- (4-methoxyphenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine fumarate [1: 1 ]. The compound of claim 6, which is 6- (3-chlorophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine. A compound according to claim 6, which is 6- (3-chlorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. The compound of claim 6, which is 6- (4-fluorophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine. 7. Compounds according to claim 6, which are 6- (4-fluorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. The compound of claim 6, wherein 11- [3- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) propyl] 6-phenyl-11H-pyrido [2, 3- b] A compound which is [1, 4] benzodiazepine. 7. The compound of claim 6, which is 6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. 7. The compound of claim 6, which is 6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine dihydrochloride hemihydrate. The compound according to claim 6, which is N- [3- [6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepin-11-yl] propyl] methaneimide acid ethyl ester. The compound of claim 6, which is N-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. The compound of claim 6, which is N-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine dihydrochloride. The compound according to claim 6, which is N- [3- [6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepin-11-yl] propyl] carbamic acid ethyl ester. The compound according to claim 6, which is 5, 6-dihydro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. The compound according to claim 6, which is 5,6-dihydro-N, N-dimethyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine dihydrochloride hemihydrate. compound. The compound of claim 6, which is 8-chloro-6- (2-chloro-phenyl-5,6-dihydro-11H-pyrido [2, 3-b] [1, 4] benzodiazepine. The compound according to claim 6, which is 5, 6-dihydro-N-methyl-6-phenyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. A compound according to claim 6, which is 6- (2-fluorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine-11-propanamine. A compound according to claim 6, which is 6- (2-chlorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine. 7. Compounds according to claim 6, which are 6- (2-bromophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine. The compound of claim 6, which is 8-chloro-11-methyl-6- (2-nitrophenyl) -11H-pyrido [2, 3-b] [1, 4] benzodiazepine. The compound of claim 6, which is 8-chloro-6- (2-chlorophenyl) -11-methyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine. The compound of claim 6, which is 6- (2-bromophenyl) -8-chloro-11-methyl-11H-pyrido [2, 3-b] [1, 4] benzodiazepine. The compound according to claim 6, wherein 6- (3-chlorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine fumarate [1: 1] Phosphorus compounds. The compound of claim 6 which is 6- (4-fluorophenyl) -N, N-dimethyl-11H-pyrido [2, 3-b] [1,4] benzodiazepine-11-propanamine hydrochloride hemihydrate. Compounds of formula (II) and pharmaceutically toxic acid addition salts thereof.

Wherein Ar is 2,3 or 4-pyridinyl, 2 or 3-thienyl or phenyl or is substituted with the same or different one to three radicals selected from halo, lower alkyl, lower alkoxy, trifluoromethyl and nitro Is phenyl, Z is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or nitro and Y is hydrogen or 1 to 2 radicals which may be the same or different selected from lower alkyl, lower alkoxy, hydroxy. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] phenyl] phenylmethanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] -4-chlorophenyl] phenylmethanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] phenyl] (4-methylphenyl) methanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] -5-chlorophenyl] (2-chlorophenyl) methanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] -3-chlorophenyl] phenylmethanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] -4-fluorophenyl] phenylmethanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] phenyl] (3-chlorophenyl) methanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] phenyl] (4-fluorophenyl) methanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] phenyl]-(3-trifluoromethylphenyl) methanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] phenyl]-(3-fluorophenyl) methanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2-fluorophenyl) methanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2-chlorophenyl) methanone. 60. The compound of claim 59, which is [2-[(3-amino-2-pyridinyl) amino] phenyl]-(2-bromophenyl) methanone. The process according to claim 2, wherein the compound of general formula (Ia) is subsequently reduced with sodium cyanoborohydrin to obtain a compound of general formula (Ia-1).

Wherein Ar, Z and Y are as defined in claim 2.