DE2039396A1 - New dibenzazepine derivatives and their preparation - Google Patents

Description

SO.3590 / 3741

EHONE-POÜLENO S.A., Paris / France

New dibenzazepine derivatives and their preparation

The present invention "relates to new 10,1t-dihydrodibenzo _< / F, f7a2iepine derivatives of the general formula

(I)

as well as their acid addition salts and quaternary ammonium derivatives, their manufacture and pharmaceutical compositions, which they contain in the form of the bases and / or the salts and / or the quaternary ammonium derivatives

In the general formula I, R ¹ , which can be the same or different from one another , are each a hydrogen atom or an alkyl, hydroxyalkyl, hydroxyalkoxyalkyl or phenylalkyl radical,

109808 / 213-0

where the phenyl ring is optionally replaced by one or more halogen atoms and / or one or more alkyl, alkoxy, Amino or trifluoromethyl radicals can be substituted; R- represents a hydrogen atom or an alkyl radical and one of the symbols X represents a chlorine atom and the other symbols X each represent a hydrogen atom.

It should be noted that in the above and in the following, without any indication to the contrary, the alkyl radicals and the alkyl parts of the other radicals contain 1 to 5 carbon atoms and the symbols X have the meaning given above.

According to the invention, the new products of the general formula I can be prepared by one of the following processes will:

1. The products of general formula I, for which R and R * each represent a hydrogen atom, can by

Reduction, a product of the general formula

in the R-. has the meaning given above, according to the Methods that enable an oxime to become an amine without affecting it to reduce the rest of the molecule. Sodium amalgam is preferred.

One can also use sodium in a primary aliphatic

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hol with 2 to 6 carbon atoms, such as Butanol, use or a catalytic ^ hydrogenation using, for example, Raney nickel as a catalyst while working in neutral or alkaline Make medium.

2. The products of general formula I for which

->»■■" ■■ "■> ^R 3 '■ ·' ■ - '■' ■■■■

\ represents a group -N ^ in which R * CHo "Rp

Rg is a hydrogen atom or an alkyl, hydroxyalkyl, Is hydroxyalkoxyalkyl, phenyl or phenylalkyl radical, wherein the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms and the phenyl ring optionally by one or more halogen atoms and / or one or more alkyl radicals, alkoxy radicals with 1 to 5 carbon atoms, amino radicals or trifluoromethyl radicals may be substituted, and R ^ represents a hydrogen atom or an alkyl or phenylalkyl radical, which optionally by one or more halogen atoms and / or one or more alkyl, alkoxy or trifluoromethyl radicals may be substituted, the alkyl radicals and the alkyl parts of the other radicals have 1 to 5 carbon atoms can contain, by reducing a product of the general formula

109 80 8/2130

INSPECTED

by using any method that enables ein.Carbonamidgruppe to the methyleneamino group without influence to reduce the rest of the molecule.

It is particularly beneficial as a reducing agent Lithium aluminum hydride or sodium aluminum hydride use and in an inert organic solvent such as diethyl ether or tetrahydrofuran to work.

The reaction can also be carried out using diborane as a reducing agent.

3. The products of general formula I for which

^ R R

-K represents a group -F ^ T in which ^ R ^{1 CH} 2 ^R 2

R and Rg have the meanings given above, can by simultaneous action of a compound of the general formula

R ₂ - CHO (IV)

in which Rg has the meaning given above, and of Hydrogen on a product of the general formula

(V)

R-NH ^X

in which R and R _{1 have} the meanings given above, working in the presence of a hydrogenation catalyst

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tors under conditions that do not cause dehalogenation, getting produced.

By applying this process to products of the general formula V for which R represents a hydrogen atom, depending on the amounts of aldehyde used, the general formula IY and hydrogen products of the general formula I, for which ■ ^ h: ■■■ . "'',:.. ■■," ■ - ■. ' . '■ ■ ^; ■■■■ · .- ■.

-N _n ^ either a group -KH-CH ₀ -R ₀ or a group

: R »- ,. ^{d v} - ν

-R ₂ -) ₂ represents. ■

In any case, it is advantageous to use a lower saturated primary aliphatic alcohol such as Ethanol to work and Raney-lTickel or Adams-Platinum as a hydrogenation catalyst to use,

If R- is a hydrogen atom, it may optionally be advantageous to use the aldehyde of the general formula IV and hydrogen with a compound of the general formula

X Ac X

R-NH X

in which R has the meaning given above and Ac an ayl residue that can be easily removed by acid hydrolysis represents, implement and then the rest of Ac through Remove hydrolysis.

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4 «The products of general formula I for which -EL ^ * represents a group -N ^ in which R is the above

has the meaning given and R. is an alkyl, hydroxyalkyl, hydroxyalkoxyalkyl or phenylalkyl radical which can optionally be substituted by one or more halogen atoms and / or one or more alkyl, alkoxy, amino or trifluoromethyl radicals, where the alkyl radicals and the alkyl parts of the other radicals have 1 to 5 carbon atoms, can be obtained by reacting a W compound of the general formula

R ₄ -Z (VII)

in which R has the meaning given above and Z a reactive ester residue, such as a halogen atom or a sulfuric acid or sulfonic acid ester residue (e.g. a methanesulfonyloxy »or p-toluenesulfonyloxy radical) means to be made with a compound of the general formula V »

It should be noted that by using this procedure to products of the general formula V for which R represents a hydrogen atom, depending on the amounts used on product of the general formula VII products of the general formula 'I obtained for which

-N ^ f a group -IH-R ₁ . or a group -N (R,) ,, ^ R ^{1 4} * *

represents.

It is advantageous, in an inert organic solvent, such as dimethylformamide, and in the presence of sodium bicarbonate, preferably at the boiling point of the solvent, see below »

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■■ '■■. · - ⁷ - ■

5 · The compounds of general formula I for which -UL ^ represents a group -MR _A in the

■; -R ¹ . ^

R. has the meaning given above, can by Cleavage from a derivative of the general formula

(VIII)

in the R | and R. have the meanings given above and Y represents a cyano, alkoxy carbonyl, alkanoyl, alkanesulfonyl or arylsulfonyl radical. The substitution of the substituent Y by a hydrogen atom can be carried out according to the customary methods which are specific for each meaning of Y. * J__ ~

6 · The compounds of general formula I, for which -N ^ represents a group -K ^ * in which

Rr- a hydrogen atom or an alkyl radical with 1 to

i?
5 carbon atoms can be obtained by reducing urethanes of the general formula

(IX)

1098087 2130

in which Rg denotes an alkyl radical with 1 "to 5 carbon atoms", can be prepared with lithium aluminum hydride while working in an inert organic solvent such as an ether, for example diethyl ether or tetrahydrofuran, under conditions such that the rest of the molecule is not attacked.

The products of the general formula II can be prepared from ketones of the general formula

(X)

in which R. has the meaning given above, by application by any method known per se for the preparation of oximes.

The ketones of general formula X can be obtained by carrying out the following sequence of reactions, using the usual methods used in organic chemistry:

-CO-NH

, 6

0-C = N

COOCH

3 Br

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egg

-C

Br

! X

COOCH ₃ Br

—Χ

χ.

X CN

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- ίο -

The 2-bromo-3-chloro ~ N ~ used as the starting product "Benzoylaniline can be obtained from 2-bromo-3-amino-nitrobenzene , the preparation of which is described by H. Depoorter and J · Nys, Chem. Abstr.,, 54, 22 579 c (1960) " became·

The 2-bromo-4-chloro-N-benzoylaniline used as the starting product can be obtained by the processes described by FD Chattaway and JM Wadmore, J. Chem. Soc ₀ , 85 ,, 180 (1904) ".

^ The 2 ~ bromine ~ 5-chloro ~ H ~ used as the starting product Benzoylaniline can be prepared according to the N.T. Cam-Van and staff «,, Tetrahedron, 2 £, 2198 (1964) described method can be obtained.

The 2-bromo-6-chloro-N-benzoylaniline used as the starting product can be obtained from 2-bromo-6-chloro-nitrobenzene, the preparation of which is described by Körner and Conradi, Beilstein, £, 2h9 " .

The 2-bromo-N-benzoylaniline used as the starting product can be prepared according to the method described by JB Burnett and B ₄ ,]? * Hrutfiord, J. Am, Chem. Soc. _f preservation method described 83, 1694 (1961) W are ten ·

The methyl 3-chlorosalicylate can be prepared according to the method of J, M. Shackelford, J. Org · formerly, £ 6, 49iyC ¹ % 1) described method can be produced »

The methyl 4-ehlorsalieylat can from the corresponding Acid can be prepared, the preparation of which was described by W. Aumüller et al., Ber., 85, 773 (1952).

The methyl 5-chlorosalicflate can be prepared from the corresponding SKure, the preparation of which was described by R. Neu, Ber., 2S * 1511 (1939).

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The methyl 6-chlorosalicylate can be obtained from the corresponding Acid produced v / earth, the production of which is carried out by W.A. Bonner and J.M. Craig, J. Am. Chem. Soc, 7 ^, 3480 (1950).

The ketones of the general formula X can also by performing the sequence of the following actions using conventional methods used in organic chemistry:

If the cyclization leads to two isomeric ketones, so can get the products according to physico-chemical. Methods such as fractional crystallization or chromatography can be separated.

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The 2-methoxycarbonyl-4 used as the starting substance ^! "ctilordiphenylamine can be obtained from the corresponding acid, the preparation of which is described by M, M. Jamison and
EE. Turner, J ₀ Chem. Soc., 1.9.3 . 7 t 1957, ".

The used as Ausgangsprodulct 2-methoxycarbonyl-3 ^f chlorodiphenylamine can be obtained from the corresponding acid, the preparation of F, Ullmann and
E. Tedesco, Ann., 3 ^ 5 »337 (1907) ·

The 2-methoxycarbonyl-2'-chlorodiphenylamine used as the starting material can be obtained from the corresponding acid, the preparation of which is described by SP Massie and
PK Kadaba, J. Org. Chem., 2j_, 347 (1956)
became*

The 2-methoxycarbonyl-j5-chlorodiphenylamine used as the starting material can be obtained from the corresponding acid, which in turn according to Chem. Abstr., JH, 24 820 f (1960) can be produced.

The 2-methoxycarbonyl-4-chlorodiphenylamine used as the starting substance can be obtained from the corresponding acid, the preparation of which is described by M. Gomberg and
DL Tabern, J. Am. Chem. Soc, 48, 1352 (1926).

The 2-methoxycarbonyl-5-chlorodiphenylamine used as the starting product can be prepared according to that of I. Molnar and
Th. Wagner-Jauregg, HeIv. Chim. Acta, 48, 1784 (1965).

The 2-methoxycarbonyl-6-chlorodiphenylamine used as the starting substance can be derived from the corresponding acid

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will keep the production of -E-. D.- Mech, Ghem » ., 52, 2020 c (1958) «,

The Ke tone of the general formula X can also by Carrying out the sequence of the following reactions using the methods customary in organic chemistry can be obtained:

HH-CO-CJI _1, 6 5

? 6 « ₅ *

C-O

H ₃ CXK) C

-X

• X

x CO-C ₆ H ₅ χ

J CH ₃ H ₃ COOc T χ χ

■ j CH ₃ H ₃ COOC

(χ)

10980 87 2 130

The 2-methylbenzanilide used as the starting material can be obtained from o-toluidine

Used as a starting substance 2-methyl-3-chlorobenzanilide can after. by P. Cohn ,monthsh. Chem ,, 22_, 484 (1901) can be obtained.

The 2-methyl-4-chlorobenzanilide used as the starting product can be obtained from 2-methyl-4-chloroaniline by the usual methods, the preparation of which was described by E. Lillmann and G, Klotz, Ann., 23J _- , 317 (1884) .

The 2-methyl-5-chlorobenzanilide used as the starting product can be obtained from 2-methyl-5-chloroaniline, the production of which was described by H. Goldschmidt and M. Honig, Ber., JM2 ,, 2440 (1886).

The intermediate 2-methyl-6-chloro-2'-carboxydiphenylamine can be prepared by the method described by 0. Hromatka, MONTHSH, Chem., 97, 1125 (1966) will.

The products of the general formula III, for which R ₁ , Rp and Rz have the meanings given above, can be selected from compounds eier general formula

T E-HH X

Ί 0 9 8 0 8/2 1 3 0

in which R- and R, have the meanings given above, through use of any acylation method known per se getting produced. ....

It is particularly advantageous to use acid chlorides or anhydr,! - en to use and in an inert solvent · such as for example benzene or toluene, under reflux of the solvent and in the absence or presence of a base, such as for example a tertiary amine such as pyridine. work.

If represents in the general formula III, the radical R 'of a Wasserst fat om, it is particularly advantageous to carry out the acylation with Ä'thylformiat and to work in an autoclave at temperatures between 50 and 150 ⁰ C.

The products of the general .. Formula IX, for which R, - and Rg have the meanings given above, can by Use of any method known per se for the preparation of urethanes from compounds of the general Formula.

(XII)

X R_-NH X 5

in which R ^ has the meaning given above »produced becoming

The products of general formula V and XI for which R and R ^ have one of the meanings given above with the exception of the hydrogen atom, can by - on each other ---

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following application of one or more of the processes described herein to products of the general formula

χ (XIII)

in which R _{1 has} the meaning given above, "produced"

The products of the general formula VIII can according to
one of the following methods:

a) By reacting cyanogen bromide, an alkyl formate or an aliphatic or aromatic sulfochloride with a product of the general formula

R ₄ H-CH ₃

in the IL and R. have the meanings given above,

b) By alkylating a product of the general formula

1 09808/21 30

X H-N-YX

in which R ₁ and Y have the meanings given above, with a reactive ester of the general formula VII in the presence of an alkaline condensing agent,.

The products of the general formula XV can be obtained from a product of the general formula XIII, for which R ^ the Has the meaning given above, through the action of bromineyan, an alkyl chloroformate, an acid halide or an aliphatic or aromatic sulfochloride can be obtained.

The new products of the general formula I can, if appropriate, by physical methods (such as, for example Distillation, crystallization or chromatography) or by chemical methods (such as formation of Salts, crystallization of the same and subsequent decomposition in an alkaline medium). at The nature of the anion of the salt plays a role in these operations does not matter, the only condition is that the salt should be well defined and easily crystallizable,

The new products prepared according to the invention can be converted into addition salts with acids or into quaternary ammonium derivatives.

The addition salts can be prepared by reacting the new compounds with acids in suitable solvents.

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will be presented. The organic solvents used are, for example, alcohols, ethers, ketones or chlorinated solvents. The salt formed precipitates, if appropriate after concentration of its solution _f , and is separated off by filtration or decanting.

The quaternary ammonium derivatives can by reaction of the new compounds with esters, optionally in an organic solvent, at ordinary temperature or more rapidly with gentle heating.

The novel products according to the invention and their addition · Salts and quaternary ammonium derivatives have interesting pharmacodynamic properties on «You are on that Central nervous system as antidepressants, analgesics, anticonvulsants and tranquilizers very effective. They have to be administered in physiological experiments on animals oral route at doses between 2 and 50 mg / kg body weight has given good results «

For medical use, the new compounds are used either in the form of the bases or in the form of the pharmaceutical usable, i. non-toxic addition salts or quaternary ammonium derivatives in the use doses,

Examples of pharmaceutically usable addition salts are the salts of mineral acids (such as, for example the hydrochlorides, sulfates, nitrates, phosphates) or of organic acids (such as the acetates, propionates, Succinates, benzoates, fumarates, maleates, tartrates, Theophylline acetates, salicylates, "phenolphthalinates, methylene-bis-ß-oxynaphthoate) or of substitution derivatives of these acids.

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As examples of pharmaceutically acceptable quaternaries Ammonium derivatives can be the derivatives of inorganic or organic esters, such as the chlorine,; Bromine or iodine methylates, ethylates, allylates or benzylates, the methyl or ethyl sulfates, the benzenesulfonates or substitution derivatives of these compounds

The following examples serve for further explanation of the invention «The nomenclature used in these examples of the products is based on the following illustrations!

where X is a chlorine atom.

example 1

A solution of 6.9 g of J-chloro-S-methyl-H-hydroximino-10,11-dihydro-dibenzo / b ", f7azepine in 152 cnr ethanol and 7» 6 cnr distilled water is mixed with 234 g 3 # Sodium amalgam is ^{treated for 7 hours at 70 °} C. The reaction medium is buffered in the course of the reaction by adding pure acetic acid to pH 8 to 9. 100 cm of distilled water are added to the reaction mixture and the mercury regenerated in the course of the reaction is separated off The ethanol is evaporated under reduced pressure. The aqueous suspension obtained is purified by adding 100 cnr distilled water and 30 cm 5N Na-

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3 tronlauge diluted and three times with a total of 300 cm Ether extracted «The ether loosens are extracted twice with

5
a total of 100 cm of an aqueous 1n-methanesulfonic acid

solution and then extracted with 30 cm of distilled water. The combined acidic aqueous solutions are made alkaline by adding 5N sodium hydroxide solution. That

3 separating oil is three times with a total of 300 cm Ether extracted. The combined ethereal solutions become

washed three times with a total of 90 cm of distilled water, with 0.1 g of biochar "treated, dried over potassium carbonate and concentrated" The oily residue

3
(6.0 g) is dissolved in 12 cm of anhydrous ethanol. the

The solution obtained is added to a boiling solution of 2.7 g of fumaric acid in 32 cm of anhydrous ethanol. After 4 hours of cooling at 20 ⁰ C the crystals formed are filtered off with suction, with ice-cold 7 enr Ätha-

3 ··

nol and then washed twice with a total of 15 cm of ether

■ and dried under reduced pressure (20 mm Hg) «Man receives 6.0 g of 3-chloro-5-methyl-11-amino-10,11-dihydrodibenzo / b ", f7azepine-» fumarate from P = 247 ° C «

The 3-chloro-5-diethyl-11-

flf / azepin can open be made in the following way ι

Production of 2-bromine- ~ 5- = ehlor-N-'bens5Qylanilin (P = 134 ⁰ C) according to NT Cam-Van and Mitart., Tetrahedron »20, 2198 (1964)

Preparation of 230 g of 2-bromo-5-chloro-I-phenylchlormethylenylanilin by reacting γοη 146 g Hiosphorpentachlorid with 217.5 g of 2-bromo-5-ehlor-N-benzoylaniline at 95 ⁰ C,

Herst el """ag τοη 219 g 2- / T2» Me th © xy carbonyl phenoxy) -phenylmethyleiiylaiain ^ -4-chlorobromobenzene (E = 105 ⁰ C) by converting -128 g "sodium derivative clay methyl salicylate in

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methanolic solution with 230 g of 2-BrQm-5-chloro-N-phenylchloromethylenylaniline in an ethereal solution at about 20 C.

Preparation of 198 g of 2-bromo-5-chloro-2'-methoxycarbonyl-N-benzoyldiphenylamine (F = 170 ⁰ G) by Chapman ¹ see rearrangement of 219 g of 2- ^ f2-methoxycarbonylphenoxy) -phenylmethylenylamino74-chlorobromobenzOl at 230 to 240 ⁰ OV

Preparation of 146.6 g of 2-Brbm-5-chloro-2 ^l -carboxydiphenylamin (F = 226 ⁰ C), by reaction of 147 g of potassium hydroxide with 198 g 2-bromo-5-chloro-2 · -methoxycarbonyl-N-benzoyldiphenylamin in dimethyl sulfoxide with a content of 8 $> water at 90 to 95 ⁰ O,

Preparation of 147.2 g of 2-bromo-5-chloro-2'-methoxycarbonyldiphenylamine (F = 108 ^° C.) by reacting an excess of methanol with 146.6 g of 2-bromo-5-chloro-2'-carboxydiphenylamine in dichloroethane under reflux in the presence of pure methanesulfonic acid .

Preparation of 136 g of 2-bromo-5-chloro-2'-methoxycarbonyl-N-methyldiphenylamine (F - 59 ⁰ O) by reacting 147 »2 g of 2-bromo-5-chloro-2 ^l -methoxycarbonyldiphenylamine with 20.8 g sodium hydride and then 153 g methyl iodide in fetra hydrofuran under reflux

Preparation of 95 g of 2-cyano-5-chloro-2 ^f -methoxycarbonyl-N-methyldiphenylamine (b.p. _{Q 2} = 187 to 200. ⁰ Q) by reacting 136 g of copper (I) cyanide with 136 g of 2- Bromo-5-chloro-S'-methoxycarbonyl-N-methyldiphenylamine in 1-methylpyrrolidone- (2) under reflux

Production of Ö3 »1 β 2i-Qyano-5-ohlor-2 · - N-oethyldiphenylamine by reacting 7.8 g of Lithiura-

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borohydride with 95 g of 2-cyano-5-chloro-2'-methoxycarbonyl-N-methyldiphenylamine in tetrahydrofuran under reflux.

Production of 87.2 g of 2-cyano-5-chloro-2 ^! -chloromethyl-N-. methyldiphenylamine by reacting 58 g of thionyl chloride with 83.1 g of 2 ~ cyano-5-chloro-2'-hydroxymethyl-N-methyldiphenylamine in chloroform.

Preparation of 16.8 g of 2-cyano-5-chloro-2'-cyanomethyl-N-methyldiphenylamine (P = ⁰ 80 C) by the action of 9.9 g Kaliumcyänid to 29.5 g of 2-cyano ~ 5-chloro- 2 ^l -chloromethyl-N-methyldiphenylamine in aqueous ethanol under reflux.

Preparation of 21.8 g of 3-chloro-5-methyl-10-cyano-11-aminodibenzo ^, f_7azepine (P = 162 ⁰ G) by reacting 49 cm of a 1.88 N sodium propoxide solution with 25.8 g of 2-cyano ^{-5-chloro-2-N-I} -cyanomethyl methyldiphenylamine in propanol un ter reflux ·

Production of 6.1 g of 3-chloro-5-methyl-10,11-dihydroaibenzo / T), f7azepinon- (i1 ) (P = 162 ⁰ C) by the action of orthophosphoric acid on 24.7 g of 3-chloro-5- methyl-10-cyano-11-ainino-dil) enzo ^ b ", f7azepine in acetic acid under reflux

Production of 8.2 g of 3-chloro-5-methyl-11-hydroximino-10,11-dihydro-dibenzo ^ b ", f7azepine (P = 202 ⁰ C) by reaction of 4» 7 g of hydroxylamine hydrochloride and 9, 2 g of sodium acetate trihydrate with 8.7 g of 3-chloro-5-methyl-10,11-dihydro-dibenzo ^, | 7azepinone- (ii) in aqueous ethanol under reflux

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ORIGINAL INSPECTED

Example 2

To a suspension of 1.45 g of lithium aluminum hydride in 70 cm of anhydrous ether is used in small portions 7.3 g of 3-chloro-5-methyl-1 1 -formamido-10,11-dihydro-dibenzo- / H, f7azepine zu «, You rinse with 20 cm of anhydrous ether and refluxed for 2 hours. The cooled suspension is replaced within 1 hour by successive

3 3

Addition of 1.7 cm distilled water, 1.25 cm 5N sodium hydroxide solution and 5j65 cm distilled water hydrolys i e rt. The formed low chiag is sucked off and then 3 ··

with 50 cm of ether and then three times with a total of Washed 150 cm of methylene chloride. The filtrate is concentrated and the residue dissolved in 2 O cm of ether The ether-J-agu ^ Lg ^ mrJ: with 50 cm of an ice-cold aqueous 1N methanesulfonic acid solution, 30 cm of an aqueous 0.1N methanesulfonic acid solution and extracted twice with a total of 50 a distilled water. The combined acidic aqueous solutions become alkaline by adding TOn sodium hydroxide solution · The separated oil is made three times with a total of

250 cm ^ of diethyl ether extracted. The united ethereal

■. ■ ■ "■■. ■■■■ ·. 3 ■■ '. ■. Sings are washed three times with a total of 150 cm of distilled water, treated with 0.1 g of biochar, dried over anhydrous sodium sulfate and concentrated _f 6 g) is purified by transferring it to the pumparate in ethanol (8.25 g? P = 184 ⁰ O). The base released from the pumparate (5.7 g) is dissolved in 20 cm of anhydrous ethanol the erhaltenenäthanoIisehen solution are added 5.0 cm ⁵ a solution of hydrogen chloride in ether (with a content of 4.7 mol of hydrogen chloride per liter) ^ to. Kach ä hours, cooling at 2 ⁰ C the crystals formed are filtered off with suction, washed twice with a total of 10 cm ice-cold anhydrous ethanol and washed twice with a total of 40 cm anhydrous ether tmö water

109808 / X13G

dried under pressure (20 mm Hg). This gives 5.9 g of 3-chloro-5-methyl-1i-methylamino-10,11-dihydro-dibenzo ^ b ", f7azepin hydrochloride of J = 215 ⁰ C.

The 3-chloro-5-methyl-11-ΐ used as the starting substance ormamido-10, 1 1-dihydro-dibenzo / b, f_7azepine can be prepared in the following way:

Preparation of 7.3 g of 3-chloro-5-methyl-11-formamidο ~ 10.11 ~ dihydro-dibenzo ^, f7azepine (F = 146 ⁰ C) by reacting pormyl acetic anhydride with 7.0 g of 3-chloro-5- methyl-11-amino-10,11-dihydro-dibenzo / b, f7azepin (manufacturer W made as in example 1) at about 20 ⁰ C ₀

The formyl acetic anhydride is prepared by heating a mixtures of two hours 27.6 g of acetic anhydride and 12.5 g of 98 $ formic acid at 55 to 60 ⁰ C.

Example 3

A solution of 2.85 g of 4-chloro-5-methyl-11-hydroximino-10,11-dihydro-aibenzo / b ", f_7azepine in 62 cm of ethanol and 3.1 cm of distilled water is mixed with 64 g of 3 $ - Sodium amalgam at 70 ^° C. for 5 hours. The reaction mixture is brought to pH 8 to 9 in the course of the reaction by adding a total of 5.5 cm of pure acetic acid After cooling, the reaction mixture will be buffered

3 3

250 cm of distilled water and 40 cm of an aqueous one 2N methanesulfonic acid solution added. The regenerated mercury is separated. The cloudy acidic aqueous solution is washed three times with a total of 90 cm of ether and then alkali by adding 15 cm of 10N sodium hydroxide solution

emacht · The separated oil is extracted three times with a total of 150 cm of ether. The united etheric

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Solutions are washed with 50 cm of distilled water, treated with 0.1 g of plum charcoal, dried over anhydrous magnesium sulfate and concentrated. 2.5 g of 4-chloro-5-methyl-11 -amino-10,11-dihydro-dibenzo-3 are obtained , fj ^{; r} azepine from F - 106 "to 108 ⁰ C, the product can be purified by recrystallization from isopropyl ether (i ¹ - 108 ⁰ C).

The 4-chloro-5-methyl-11-hydroximino-10,11 used as the starting substance -dihydro ^ dibenzo ^ b ", f7azepine can refer to the following Way to be made:

Production of 2-Garboxy-2'-ehlordiphenylamine (]? = 192 to 193 ⁰ C) according to S. P, Massie and PK, Kadaba, J> Org. Chem., £ t, 347 (1956) ·

Preparation of 296 g of 2-methoxycarbonyl-2 ^l -chlordiphenylamin (J ¹ = 78 ⁰ C) by the action of an excess of methanol to 342 g 2-0arboxy-2 · -chlordiphenylamin under Eückfluss in the presence of pure sulfuric acid ·

Preparation of 206 g of 2-chloro-2 ^l -methoxycarbonyl-N-methyldiphenylamine by the action of 27 »2 g of sodium hydride and then 215 g of methyl iodide on 197t of 5 g of 2-methoxycarbonyl-2 ^l -chlorodiphenylamine« in 1, 2-dimethoxyethane at about 5O ⁰ O *

Preparation of 89t 5 ß 2-chloro ^ 2 ^f -hydroxymethyl-li-ine1fhyldiphenylamine (P "■■ = 58 to 59 ⁰ O) by the action of 28.4 g lithium aluminum hydride on 103 g 2-chloro-2'-methoxycarbonyi-Jf ^ isethyldiphenylainiii in Xther at about 2 ⁰ O.

Preparation of 96 g of 2-chloro-2'-chloromethyl-N-methyl- 'dlphenylamine by mixing 45 g of thionyl chloride with 89 »5 g of 2-» 0hXor-2 * -hydroxyae1; hyl-N-öiethyldiphenylaiain in = chloroform in one Temperature between 0 and 20 ⁰ C in the presence of 67.9 β Hexamethylphosphorsäuretriamia. ;

■. . ■ (■ '-. I -ι

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ORIGINAL INSPECTED

Preparation of 68.0 g of 2-chloro-2'-cyanomethyl-N-methyldiphenylamine by reaction of 27% 5 g Natriuracyanid with 96 g of 2-chloro-2'-chloromethyl-N-methyldiphenylamine in dimethyl sulfoxide at about 100 ⁰ O.

Production of 55, Og 2-chloro-2'-carboxymethyl-N-methyldiphenylamine (P = 121 to 122 ⁰ C) by the action of 87.5 g potassium hydroxide on 68.0 g 2-chloro ~ 2'-cyanomethyl-N- methyldiphenylamine in aqueous ethanol under reflux *

Production of 2.8 g of 4-chloro-5-methyl-10,11-dihydrodibenzo / fF, f7azepinon- (11) (P = 80 ⁰ C) by the action of polyphosphoric acid on 55, Og 2-chloro-2-carboxymethyl N-methyldiphenylamine at about 140 ^° C.

Production of 2.85 g of 4-chloro-5-methyl-11-hydroximino-10,11-dihydro-dibenzo ^ E, | 7azepine (P = 182 to 183 ° 0) by reacting 1.51 g of hydroxylamine hydrochloride and 2.96 g of sodium acetate trihydrate with 2.8 g of 4-chloro-5-methyl-10,11-dihydro-dibenzo ^ E, f7azepinon- (i1) in aqueous ethanol under reflux

Example 4

To a suspension of 0.64 g of lithium aluminum hydride in 90% anhydrous ether is added 3.2 g of 4 ~ 0hior-5-methyl-11-formamido-10,11-dihydrodibena ^ f tazepine in small portions. It is rinsed with 20 cm of anhydrous Ether and refluxed for 3 hours. The cooled suspension is hydrolyzed within one hour by successive addition of 0.75 cm of distilled water, 0.65 cm of 5N hydroxide solution and 2.5 cm of distilled water. The precipitate formed is filtered off with suction and ^{washed four times with a total of 120 cm 5} ether.

101108/1130 "

ORJQiNALfNSPEOTED

• · - 27 -

3 trated ether solution is extracted three times with a total of 120 cm of an ice-cold aqueous in-methanesulfonic acid solution. The combined acidic aqueous solutions are made alkaline by adding 50 cnr 5N sodium hydroxide solution. The separated oil is extracted three times with a total of 150 cm of ether. The combined ether solutions are washed with 50 ml of distilled water, treated with 0.1 g of biochar, dried over anhydrous magnesium sulfate and concentrated. »The residue (2.84 g; F = 110 to 111 ^° C) is dissolved in 12 cm of boiling isopropyl ether. after two hours, cooling at 2 ⁰ G, the crystals formed are filtered off with suction, washed with ice cold isopropyl ether and 4 cm uiiter reduced pressure (20 mm Hg). 2.4 g of 4 * -chloro-5-methyl-11-methylamino-

from F = 115 to 116 ⁰ C.

The 4-chloro-5-methyl-11-formamido-10,11 ~ dihydro-dibenzo / E, f7azepine used as the starting substance can be produced in the following ways:

This gives 3.3 g of 4-chloro-5-methyl-11-formamido-10,11-dihydro-dibenzo / EjfJazepin (F = 180-182 ⁰ C) by reacting with formylacetic 3 _t 25 g of 4-chloro-5 -methyl-11-amino-10,11-dihydro-dibenzo ^ bVjTazepine (prepared as in Example 3) at about 20 ° C _#

Example ^

A solution of 2519 g of i-Clilor-5-methyl-IO-hydroximino-IQ-ii-aihydro ^ iben ^ p ^ FtlTazepine in 600 ca ³ ethanol and 3ά cm ⁵ distilled water is mixed with 59Og 3 * sodium amalgam

109808/2130

Treated “at 70 ^° C. for seven hours”. During the reaction, the reaction medium is buffered to pH 8 to 9 by adding pure acetic acid. The reaction mixture

250 cm of distilled water is added, and that regenerated mercury is separated. The ethanol is evaporated under reduced pressure. The obtained aqueous

3 suspension is distilled by adding 500 cm

V / water and 50 cm of 5N caustic soda diluted. The separating Oil becomes ether twice with a total of 400 cm

extracted. The ether solutions are grounded with 200 cm of an ice cold aqueous 2N methanesulfonic acid solution, then with

3
100 cm of an aqueous 0.1N-Hethanesulfonic acid solution and

extracted twice with a total of 200 cm of distilled water. The combined acidic aqueous solutions are made alkaline by adding 5N sodium hydroxide solution. That The oil that separates out is extracted twice with a total of 300 cm of ether. The combined ethereal solutions become

washed three times with a total of 180 cm of distilled water, treated with 0.1 g of biochar, dried over anhydrous sodium sulfate and concentrated. The residue (21.2 g; P = 70 ^° C.) is dissolved in 25 cm boiling isopropyl ether. After cooling for 18 hours at 2 ^° C., the crystals formed are filtered off with suction, three times with a total of

18 cm ice-cold isopropyl ether and washed under reduced Print (20 mm Hg) dried. 15 g of "1-chloro-5-methyl-10-amino-10,11-dihydro-dibenzo ^ b", f7azepine are obtained

from P = 73 ⁰ C.

The i-chloro-5-methyl-IO-hydroximino-10,11-dihydro-dibenzo / b ", fJ7azepine used as the starting substance can be made in the following ways:

Production of 2-methyl-3-chlorobenzanilide (P = 170 to 171 ^On ) according to P, Conn ,months. Chem., 22, 484 (1901).

109808/2130

- 29 -. ■■. · ■; ν

Preparation of 256 g ^ -chloro-ö-phenylchlormethylenylaminotoluol by reacting 202 g of phosphorus pentachloride with 238 g of 2-methyl-3-chlorl) enzanilid at about 95. ⁰ CV

Preparation of 378 g of 2-Ghlor-6- ^ | "2 - inethoxycarbonylphenoxy) -phenylmethylenylajninoJ7-t oluol (P = 68 ⁰ C), by reaction von174 g Fatriumderivat of methyl salicylate in methanolic solution with 256 g of 2-chloro-6- phenylchlormethylenylaminotoluol in solution in tetrahydrofuran at about 20 ⁰ C.

Preparation of 268 g of 2-methyl-3-chloro-2'-methoxycarbonyl-ΪΓ-benzoyldiphenylamine (F = 125 ⁰ C) by Chapman ¹ see rearrangement of 370 g ■ 2-chloro-6-ε i ("2-methoxycarbonylphenoxy) -phenylmethylenylamino7-toluene at 205 to 210 ⁰ C.

Production of 189 g of N- (2-chloro-3-chlorophenyl) -anthranilic acid (P = 210 ⁰ C) by the action of 240 g of potassium hydroxide on 274.4 g of 2-methyl-3-chloro-2 ^l -methoxycarbonyl- N-benzoyldiphenylamin in dimethyl sulfoxide with a content of 8 io water at 90 to 95 ⁰ C.

Production of 190 g of methyl lI- (2-methylr-3-chlorophenyl) anthranilate (P = 70 ⁰ C) by reacting 110 g of thionyl chloride and then an excess of methanol with 184 g of ΓΓ- (S-methyl ^ - chlorophenyl) anthranilic acid in the presence of 330 g of hexamethylphosphoric triamide in chloroform at a lemperatur between 0 and 20 ⁰ C.

Production of 165 g of 2-methyl-3-chloro-2 ^l -methoxycarbonyl-N-methyldiphenylamine (P = 91 ⁰ C) by the action of 24 g of sodium hydride and then 252 g of methyl iodide on 195 g of methyl-I- (2-methyl- 3-chlorophenyl) -anthranilat in 1,2 ethane at about 60 ⁰ C.

10 9808/213 0

Production of 85 g of i-chlorine ^ -niethyl-IO ,! 1-dihydrodibenzo / b ", | 7azepinon- (10) ( ^F = ^Ί2 9 ⁰ O) by the action of 206 g of lithium diethylamide in solution in a mixture of benzene and hexamethylphosphoric acid triamide on 129 g of 2-methyl-3-chloro ~ 2 ' -methoxycarbonyl-N-methyldiphenylamine in solution in ether at about -20 ⁰ C.

Production of 25.9 g of 1-chloro-5-methyl-10-hydroximino-.10,11-dihydro-dibenzo-F, f7azepine (P = 193 ⁰ C) by reacting 13.9 g of hydroxylamine hydrochloride and 27, 2 g of sodium acetate trihydrate with 25.7 g of 1-chloro-5-methyl-10,11-dihydro-dibenzo (Fjf / azepinon-CiO) in aqueous ethanol tint the reflux.

Example 6

To a suspension of 2.54 g of lithium aluminum hydride in

3
300 cm of anhydrous ether are added in small portions to 13.1 g of i-chloro ^ -methyl-IO-formamido-IOjH-dihydrodibenzo ^ / EjfTazepin. It is rinsed with 20 cm of anhydrous ether and refluxed for 4 hours. The cooled suspension is increased within 45 minutes by

3
subsequent addition of 3.0 cm of distilled water,

3 3

2.18 cm 5N sodium hydroxide solution and 10.0 cm distilled Y / water hydrolyzed. The precipitate formed is filtered off with suction and washed three times with a total of 150 cm of methylene chloride.

3 The piltrate is concentrated and the residue is in 200 cm

Ether dissolved. The ether solution obtained is a 50 cm aqueous 0, in-mebharumlphonic acid solution and then twice

3
extracted with a total of 40 cm of distilled water. The combined acidic aqueous solutions are made alkaline by adding 5N sodium hydroxide solution. The oil which separates out is extracted twice with a total of 200 cm of ether. The combined ethereal solutions ground three times with a total of

3
60 cm of distilled water, washed with 0.1 g of vegetable

109808/2130

Treated charcoal, dried over potassium carbonate and concentrated. The residue (11.0 g) is boiled in 25 cm anhydrous Ethanol dissolved »Add to the resulting solution

■■■ '■■ - - 3

to a boiling solution of 4.45 g of fumaric acid in 65 cm of anhydrous ethanol. After cooling for three hours at 2 ^° C., the crystals formed are filtered off with suction, twice

washed with a total of 16 cm of ice-cold anhydrous ethanol and then with 15 cm of anhydrous ether and dried under reduced pressure (20 mm Hg) 13.7 g of 1-chloro-5-methyl-i0-methylamino-10,11-dihydro- dibenzo- ^, f / azepine fumarate from P = 218 ⁰ C.

The i-chloro-5-methyl-IO-formamiäo --- 10,11-dihydro-dibenzo / b ", f7azepine used as the starting substance can be made in the following ways!

13.1 g of i-chloro-5-methyl-10-formamido-10,11-dihyäro-dibenzo / b ", f7azepine are obtained (i \ = 174 ° C) by conversion of formyl acetic anhydride with 13.0 g of i-chloro-5-methyl-10-amino-10.11 -dihydro-dibenzo ^ b ", fJ7azepine (manufactured here as in example 5) at about 20 ° C

Example 7

A solution of 37.0 g ^ -Ohlor-S-methyl-IO-hydroximino-10 _t 11-dihydro-dibenzo ^ b ", f7azepine in 935 cm ^ ethanol and 46.8 cm distilled water is 825 g 3 $ sodium sodium amalgam at 70 ⁰ C for 5 hours. the reaction mixture is ³ pure acetic acid to pH buffered in the course of the reaction by addition of 60 cm 8 to 9.

109808/2130

After cooling, the reaction mixture is de-

■ 3.

distilled water and 1000 cm of an aqueous 2N ~ methanesulfonic acid solution offset. That regenerated mercury is disconnected. The cloudy acidic aqueous solution is washed twice with a total of 1500 cm of ether and then made alkaline by adding 10N ~ sodium hydroxide solution. That

The oil that separates out is extracted twice with a total of 800 cm of ether. Ground the combined ethereal solutions

3 '■' ■ "■■

washed twice with a total of 1200 cm of distilled water, treated with 0.2 g of biochar, dried over anhydrous magnesium sulfate and concentrated. The residue (31.5 g; F = 101 to 103 ⁰ C) is dissolved in 340 cm ⁵ boiling isopropyl ether, and the solution is filtered. After the filtrate has cooled for 16 hours at 2 ^° C., the crystals formed are filtered off with suction, twice

3
washed with a total of 34 cm of ice-cold isopropyl ether and dried under reduced pressure (20 mm Hg). This gives 22.5 g of 2-chloro-5-methyl-10 ~ amino-10,11-dihydro-dibenzo ^ E, f7azepin of F = 102-103 ⁰ C.

Used as a starting substance 2-chloro-5-methyl-10-hydroximino-10,1i-dihydro-dibenzo / fjf / azepine can be prepared in the following manner ι

P Production of 2-carboxy-4-chlorodiphenylamine (F = 208 to 210 ⁰ C) according to M. Gomberg and D..L. Tabern, J. Am. Ch. Soc. 48, 1352 (1926).

Preparation of 270 g of 2 ~ methoxycarbonyl-4-chlorodiphenylamine (Kp _Q ^ = 172 to 175 ⁰ C) Eiiiwirkung an excess of methanol to 272 g of 2-carboxy-4-chlorodiphenylamine under reflux in the presence of pure sulfuric acid O

109808/2130

-33 - ■■■ ν. ■; - ■;

Production of 217.5 g of 2-methoxycarlDonyl-4 ■ -clllor-lί-methyldiphenylarain by reacting 48 g of sodium hydride and then 342 g of methyl iodide with 250 g of methyl 5-chloro-N-phenylanthranilate in tetrahydrofuran it is refluxed.

Production of 175.7 g of 2-hydroxymethyl-4-chloro-N-methyldiphenylamine by exposure to 33 »0 g of lithium aluminum hydride on 217.5 g of 2-methoxycar ^^ onyl-4-chloro-N-IIIethyldiphenylaniin in ether under reflux

Production of 129 g of 2-chloromethyl-4-chloro-lT-methyldi ~ phenylamine by reacting 60.1 g of thionyl chloride with 120 g of 2-hydroxymethyl-4-chloro-l.T-methyldiphenylamine in chloroform at about 0 ⁰ G in the presence of 94 g of hexamethylphosphoric acid triamide.

Production of 98.5 g of 2-cyanomet ^: hyl-4-chloro-III-methyldiphenylamine by reacting 33.6 g of atrium cyanide with 129 g of 2-chloromethyl-4 "-chloro-N-methyldiphenylamine in dimethyl sulfoxide at about 100% ⁰ C..

Preparation of 79.6 g of 2-Garboxymethyl-4-chloro-E'-2nethyldiphenylamin (]? = 154-155 ⁰ C) by the action of 127 g of potassium hydroxide to 98.5 g of 2-Gyanomethyl-4-chloro-lT-methyldiphenylamine in aqueous ethanol under reflux,

-Production of 17., 3 g of 2-chloro-5-methyl-10,11-dihydrodiben3G _i / b, r / ^r azepinone- (iO) (F =, 146 ⁰ C) by mixing in polyphosphoric acid to 27, 0 g of 2-carboxymethyl-4-chloro-N-methyldiphenylamine in -about 120 ⁰ C,

Preparation of 2-9.0 g of 2-chloro-5-methyl-10-hydroximino-. 10, H »d'ihydro-dlbenzo / F, f7azepine (P = 180 to 182 ⁰ G) by reacting 15.8 g of hydroxylamine hydrochloride and 31.5 g

109808/2130

Sodium acetate trihydrate with 29.8 g of 2-chloro-5-methyl-iO, 11-dihydro-dibenzo / b, f_7azepinon- (iO) in aqueous ethanol under reflux,

example 8th

To a suspension of 3.4 g lithium aluminum hydride in

3
To 300 cm of anhydrous ether is added in small portions 8.58 g of Z-chloro-S-methyl-IO-formamido-IOjH-dihydro-dibenzo ^ / E, £ 7azepine. It is rinsed with 100 cm of anhydrous ether and refluxed for 4 hours. The cooled suspension is

3

W ■ successive addition of 3.9 cm of distilled water,

3 3

2.95 cm of 5N sodium hydroxide solution and 13.4 cm of distilled water hydrolyzed. The precipitate formed is filtered off with suction and washed four times with a total of 400 cm of ether.

The filtered ethereal solution is used twice with a total of

■ 5
160 cm of an ice-cold aqueous In-Methanesulfonic acid solution extracted. The combined acidic aqueous solutions are made alkaline by adding 40 cm of 10N sodium hydroxide solution. The oil which separates out is extracted twice with a total of 200 enr ether. The combined ether solutions are dried over potassium carbonate and concentrated

k narrows. The residue (8.17 g) v / ird in 25 cm anhydrous ^w 3

Ethanol and 25 cm of anhydrous ether dissolved

Holding solution is added to 8.15 cm of a solution of hydrogen chloride in ether (with a content of 3.6 mol hydrogen chloride per liter). After two hours of cooling at 2 ^° C., the crystals formed are filtered off with suction,

with 10 cm ice cold anhydrous ethanol and then twice

washed with a total of 40 cm of anhydrous ether and washed under vei'LiiiiderGu.j. Print (.20 mm Hg) dried. This gives 8.3 g of 2-chloro-5-N-ethyl ~ 1O-methylamino-i0,11-dihydrodiben2o _</ b, f / ^r ~ azcpin hydrGchlorid P - 232-234 C.

109808/2130 ■ .-- ■■?

3AD

• "* r -'-, -V. . * J..J,, Ji _v -,

Av , · ··. · '■' ■ 11 ·· -

I «- V 'u> * <* VV 5.

The 2-chloro-5-methyl-1.0 -.- used as the starting substance _; fpnnamid.o-.10,1 i-dihydro-dibenzo / bj ^ azepin can be produced in the following way: - '' ■■ ''". ■ · ■ ^; ■." - - ^{; :}

One receives ^{; {} lö, -Ö ^:! g ^! 2tßhior - 5 ^{<-methyl-10rrforlnamido} 1.0vi enced '' ■ dihydrö-diT3ehzo ^ f7azepih (F = 159 to 160 ⁰ C ^). by reduction of XJm- r 'Forrnylessigsäureailhydrid with "10.5 g · 2-ChIOr- 5-methyl-10-amino-10,11 -dihydro-Diben ^ o ^ b, fjazepin ^{(manufacturer,} provided as ■ - in. Example 7) at around 20 ⁰ C. - ■ -. '^;'-> -

Example 9 ''"' ^v "

A solution of 8.2 g of iJ-Ohlor-S-methyl-IO-hydroximino-10, ii-dihydro-dibenzo / pjftazepine in 185 cm ethanol and

· 9.2 cm "distilled water is treated C 7 hours 277 g 3 5 ^ sodium, sodium amalgam at 70 ^0th The Realctionsmedium is buffered in the course Eder reaction by the addition of pure acetic acid to pH 8 to 9. The reaction mixture is mixed with 70 cm of distilled water are added and the mercury regenerated in the course of the reaction is separated off. The ethanol is evaporated under reduced pressure. The aqueous suspension obtained is made up by adding 150 cm of distilled water and 15 cm of 5N fatron gas.

■ z

lye diluted and extracted three times with a total of 350 cra ^ ether. The combined ether solutions are 100 cm an ice-cold aqueous solution of ethanesulfonic acid,

3 '

then with .40: -cm. an aqueous 0.1 N methanesulfonic acid solution Trinket d: ann. three times with. a total of 120 cm ^ distilled Viasser extracted. The combined acidic aqueous solutions

3
gen are with "3OQ cm"? distilled water and diluted by adding. Made alkaline by vonilOn caustic soda.

109808/213 0

3 The separating oil is three times with a total of 400 cm Ether extracted. The combined ethereal solutions become

washed three times with a total of 210 cm of distilled water, treated with 0.2 g of biochar, dried over potassium carbonate and concentrated. The oily residue (7.0g)

is dissolved in 20 cm boiling isopropyl ether. After two hours of cooling at 2 ^° C., the crystals formed earth

suctioned off, washed twice with a total of 10 cm ice-cold isopropyl ether and dried under reduced pressure (20 mm Hg). This gives 6.6 g of 3-chloro-5-methyl-10-amino-10,11-dihydro-dibenzo / b, "f7azepin from F = ⁰ 93 G,

The 3-chloro-5-methyl-10-hydroximino-10,11-dihydro-dibenzo ^ / b, f7azepine used as a starting substance can be made in the following ways:

Preparation of 2-methoxycarbonyl-5-chlordiphenylamins (P = 58 ⁰ C) according to I. Molnar and Th. Wagner-Jauregg, Helv. Ghim. Acta, 48 ^ 1784 (1965).

Preparation of 30.4 g of 2-methoxycarbonyl-5-chloro-N-methyldiphenylamine by the action of 5.9 g of sodium hydride and then 44 g of methyl iodide on 32.4 g of 2-methoxycarbonyl-5-chlorodiphenylamine in tetrahydrofuran under reflux,

Preparation of 21.4 g of 2-hydroxymethyl-5-chloro-N-methyldiphenylamine by the action of 3.7 g of lithium aluminum hydride on 24.4 g of 2-methoxycarbonyl-5-chloro-N-methyldiphenylamine refluxed in ether.

Preparation of 23 g of 2-chloromethyl-5-chloro-N-methyläiphenylamine by reacting 10.3 g of thionyl chloride with 21.4 g of 5-hydroxymethylchlor-N-methyldiphenylamine in the presence of 6.85 g of pyridine in chloroform at about ⁰ G ,

V /.

109808/2130

Preparation of 16.7 g of 2-cyanomethyl-5-Ohlor-N - me-thyldiphenylämin by reaction of 6.4 g sodium cyanide 23 g ^ -Glilormethyl-S-chloro-ir-methyldiphenylamine in dimethyl sulfoxide at about 100 ⁰ C.

Production of 15.2 g of 2-car "boxymethyl-5-chloro-li-methyldiphenylamine (]? .- ■■ 138 ⁰ C) by the action of 21.4 g of potassium hydroxide on 16.7 g of 2-CyaiiGmethyl-5- Chlorine-N-methyldiphenylamine in aqueous ethanol under reflux.

Preparation of 8.8 g of 3-chloro-5-methyl-10,11 -dihydro- * dibenzo ^, fjazepinon- (10) (I ¹ = 130 ⁰ G); by the action of polyphosphoric acid on 13.6 g of ^ -carboxymethyl-S-chloro-N-methyldiphenylamine at about 110 Ms 120 ⁰ O.

Preparation of 8.5 g of 3-chloro-10-hydroximino-10, T1-dihydrodibenzo ^ / bjfT'azepine (i ¹ = 209 ⁰ C) by converting 4 _f 2 g of hydroxylamine hydrochloride and 8.2 g of sodium acetate trihydrate with 7.8 g of 3-chloro ~ 5-methyl-10,11-dihydro-dibenzo- ^ B, f7azepinon- (10) in aqueous ethanol under reflux *

Example 10

To a suspension of 0.98 g lithium aluminum hydride

3 ··

in 100 cm of aether-free ether is placed in small portions

4.9 g 3-GhlQr-5-methyl-10-formamido-10,11-dihydro-dibenzo- ^ B, fJ7azepine to. Rinse with 20 cm of anhydrous ether and refluxed for 5 hours. The cooled suspension within an hour by successive

'■ · "" ■■ 3

subsequent addition of 1.15 cm of distilled water, 0.84 cm ^

5N sodium hydroxide solution and 3.82 cm of distilled water hydrolyzed. The precipitate formed is suctioned off and two-

3 ··

times with a total of 40 cm of ether and three times with a total of

3
60 cm of methylene chloride washed »The filtrate is

109808/2130

concentrated and the residue dissolved in 150 cm of ether. The ether

• 5
solution is mixed with 50 cm of an ice-cold aqueous 1N «methanesulfonic acid solution, then with 20 cm of an aqueous 0, In-Me-

thanesulfonic acid solution and twice distilled with a total of 40 cm Washed with water. The combined acidic aqueous solutions become alkaline by adding 10N sodium hydroxide solution made. The oil which separates out is extracted three times with a total of 225 cm of ether. The United Ether solutions are washed three times with a total of 90 cm of distilled water, treated with 0.1 g of biochar, dried over potassium carbonate and concentrated. Of the ^ oily residue (4 »35 g) is dissolved in an ethyl acetate, and the solution obtained becomes a boiling one

• 5 ..

A solution of 1.77 g of maleic acid in H cur ethyl acetate was added. After cooling for 3 hours at 2 ⁰ G v / the formed

3 deten crystals sucked off twice with a total of 12 cm

ice-cold ethyl acetate and washed twice with a total of 20 cm of anhydrous ether and dried under reduced pressure (20 mm Hg). 5.15 g of 3-chloro-5-methyl-10-methylamino-10, 11-dihydro-dibenzo ^ b are obtained ", f7azepine maleate from I ¹ = 138 to HO ⁰ C.

The 3-chloro-5-methyl-10-formamido-10,11-dihydro-dibenzo / b ", f7azepine used as the starting substance can be produced in the following ways:

Preparation of 7.15 g of 3-chloro-5 ~ methyl-10-formamido-10,11-dihydro-dibenzo / ^, f7azepin (i ¹ = ⁰ 148 C) by reacting fforrnylessigsäureanhydrid with 7.7 g of 3-chloro- 5-methyl-IO-amino-10,11-dihydro-dibenzo ^ F, f7azepin (prepared as in example 9) at about 20 ⁰ C.

109808/2130

-.39-

203-396

Example 11

A solution of 10.5 g of 2-chloro-5-methyl-11-hydroximino-10,11-dihydro-dibenzo /% f7azepine in 220 cur ethanol and

"2.

11 enr distilled water with 232 g of sodium amalgam "at" 70 ⁰ C for 6 hours. The reaction mixture is

■ -. ■■■■■■ "z

in the course of the reaction by adding a total of 20 cnr pure acetic acid buffered to pH 8 to 9. The reaction

3 ■■■ '- ■ ■

150 cm of distilled water are added to the mixture, and the regenerated mercury is separated. The ethanol is evaporated under reduced pressure. The received aqueous suspension is made by adding 150 em In-Na-

'■■■' ■■ 3- 'M

diluted tronlauge and twice with a total of 300 cnr of ether extracted. The ither solutions are 100 cm with a aqueous in-methanesulfonic acid solution and then twice with a total of 60 cm of distilled water extracted. The combined acidic aqueous solutions are by adding 1Qn caustic soda made alkaline. The separating Oil is extracted twice with a total of 300 cm of diethyl ether. The combined ethereal solutions are twice with

3
Washed a total of 60 cm of distilled water until neutral, treated with 0.1 g of vegetable oil, dried over anhydrous sodium sulfate and concentrated. The residue (8.7 g; P = 100 to 105 ^° C.) is dissolved in 110 cm ^{5 of} boiling isopropyl ether. After 3 hours at Ablcühlen 2 ⁰ C the formed crystals are sucked off, washed three times with a total of 45 cm of ice-cold isopropyl ether and dried under reduced pressure (20 mm Hg). 7.0 g of 2-chloro-5-methyl-11-amino-10,11-dihydro-dibenzo- / b, f7azepine with a P = 105 ⁰ O are obtained.

The hydroximino-IOjii-äihydro-dibenzo ^ bjf / 'azepine used as the starting substance can have the following Way to be made:

1 G98 08/213 0

Production of 2-bromo-4-chloro-N-benzoylaniline (F = 124 to 126 ⁰ C) according to FD Chattawa and JM Wadmore, J. Chem. Soc, 85, 180 (1904).

Preparation of 230 g of 2 ~ bromo ~ 4-chloro-N-phenylchlormethylenylanilin (F = ⁰ 89 C) by reaction of 146 g Phosphor. pentachloride with 217.5 g of 2-bromo-4-chloro-N-benzoylaniline at 95 ⁰ C.

Production of 222 g 2- / jf2-methoxycarbonylphenoxy) -phenylmethylenylaminoZ - ^ - chlorobromobenzene (F = 97 ⁰ C) by reacting 128 g sodium derivative of methyl salicylate in methanolic solution with 230 g 2-bromo-4-chloro-lT-phenylchlorobahylenylaniline in solution in tetrahydrofuran at about 20 ^° C.

Preparation of 98 g of 2-bromo-4-chloro-2 ^l -methoxycarbonyl-N-benzoyldiphenylamin (F = 149 ⁰ C) Chapman'sehe rearrangement of 111 g of 2- ^ 2-MethoxycarbonylpheriOxy) -phenylmethylenyiamino7-5-chloro-bromobenzene at 2JO up to 235 ° C.

Preparation of 138 g of 2-bromo-4 ~ chloro-2'-oarboxydiphenylamin (F = 254 ⁰ C) by the action of 143 g potassium hydroxide in 189.6 g of 2-bromo-4-chloro-2'-methoxycarbonyl-N-benzoyldiphenylamin Dirnethylsulfoxyd in a content of 8 <fo water at 90 to 95 ⁰ C.

Preparation of 150 g of 2-bromo-4-chloro-2'-methoxycarbonyldiphenylamin (F = 98 ⁰ C) by reaction of an excess of methanol with 144 g 2-bromo-4-chloro-2'-carboxydiphenylamin in dichloroethane at reflux in the presence of of pure methanesulfonic acid,

Production of 134.3 g of 2-B * 'om-4-chloro-2 ^l -methoxycarbonyl N-methyldiphenylamine (F = 74 ⁰ C) by the action of

109808/2130

- .4T-

21.3 g sodium hydride and then 158 g methyl iodide to 150 g 2-ßrom-4-chloro-2 * -methoxy carbonyldiphenylamine in tetrahydrofuran under reflux. .

Preparation of 92.3 g of 2-cyano-4-chloro-2 '-methoxycartionyl-N-methyldiphenylamine (Kp ₀ - Ms = 158 163 C ⁰⁾ by reaction of 84 g of copper (I) cyanide in 84 g of 2-bromo -4-chloro-2 ^f -methoxycarbonyl-N-methyldiphenylamine with reflux of the N-methylpyrrolidone- (2).

Preparation of 79.3 g of 2-cyano-4-chloro-2 ^l -hydroxymethyl-N-methyldiphenylamine (P = 74 ⁰ G) by incorporating 7.2 g of magnesium borohydride into 92.3 g of 2-cyano-4-chlorine -2 «- methoxycarbonyl-H-methyldiphenylamine in tetrahydrofuran under reflux.

Production of 82 g of 2-cyano-4-chloro-2'-malomethyl-ISimethyldiphenylamine by reacting 55 »3 g of thionyl chloride with 79.3 g of 2-cyano-4-chloro-2'-hydroxymethyl-N-methyldiphenylamine in chloroform.

Preparation of 36.5 g of 2-ayano-4-chloro-2'-cyanomethyl-limethylamin (F = 1.14 ⁰ C) by reacting 27.4 g of potassium cyanide in 82 g of 2-cyano-4-chloro-2 '-ehlormethyl -li-methyldiphenylamine in aqueous ethanol with reflux.

Preparation of 24.8 g 2-0hlor-5-Iaethyl-10-cyano-11-amino-dibenzo / b *, f7azepin (F = 154 ⁰ C) by reacting a 47 cm-1,86n Natriumpropylatlösung with 24 * 8 g of 2-0yano-4-chloro-2'-cyanomethyl-N-methyldiphenylamine under reflux of the propanol.

Production of 19.0 g of 2-chloro-5-methyl-10,11-dihydrodibenzo £ b ", f7azepinon- (i1) (F = 106 ⁰ G) by action

10980 8/2130

of orthophosphoric acid to 36 "4 g of 2-chloro-5-methyl-10-cyano-H-amino-dibenzo / Fjf / azepine in acetic acid under reflux «

Production of 13.3 g of 2-chloro-5-methyl-11-hydroximino-10,11-dihydro-dibenzo / E ₉ f7aaepin (P = 163 ⁰ O) by reacting 7.6 g of hydroxylamine hydrochloride and 14.8 g sodium acetate trihydrate with 14.0 g 2-chloro-5-methyl- • 10,11-dihydro-dil) enzo / H, f7azepinon- (11) in aqueous. Reflux ethanol.

Example 12

To a suspension of 1.31 g of lithium aluminum hydride in 60 cm of anhydrous ether is added in small portions 6.6 g of 2-chloro-5-methyl-11 "-: !! ormamido-10,11 -dihydro-dibenzo- ^ T> , f7azepine too. It is rinsed with 15 ml of anhydrous ether and refluxed for 3 hours.

3 3

1.13 cm 5N sodium hydroxide solution and 5.15 cm distilled water / water hydrolyzed · The precipitate formed is suctioned off and with 50 cm of ether and three times with a total of 150 cm Washed methylene chloride. The filtrate is concentrated

3 ··
and the residue dissolved in 150 cm of ether · The obtained

»3
Ether solution is mixed with 50 cm of an ice-cold aqueous

In methanesulfonic acid solution and then distilled with 50 cm Water extracted. The combined acidic aqueous solutions are cold by adding 10N sodium hydroxide solution made alkaline. The oil which separates out is extracted three times with a total of 150 cm of diethyl ether. The combined ethereal solutions are washed three times with a total of 60 cnr distilled water until neutral, treated with 0.2 g of biochar, dried over anhydrous sodium sulfate and concentrated.

109808/2130

203? 396

The residue (5 | 9 gj P-88-90 ⁰ G) is dissolved in 10 cm ⁵ boiling isopropyl ether. After 3 hours of cooling at 2 ⁰ G, the crystals formed are drained, washed three times with a total of 12 ice cold he isopropyl ether and dried under reduced pressure (20 mm Hg) dried to give 5.1 g of 2 - OIiior-5-met] iyl -tl-inetliylamlnö-10.11 ---- ".;. ■ dihydro-dibenzo £ b", f7azepine from 3? = 90 ⁰ G,

The S-formamido-IOjii-dihydro-dibenzo ^ iJ ^ azepin used as the starting substance can be made in the following way s

6.7 g of 2-chloro-5-methyl-11-formamido-10, 11 dihydro-dibenzo ^ b *, f7azepine (Ρ = 188 to 190 ⁰ G) are obtained by reacting pormyl acetic anhydride with 6.5 g of 2-chlorine -5-methyl-1i-amino-10,11-dihydro-dibenzo ^ ifjazepin (prepared as in Example 11) at about 20 ⁰ G.

Example 13

A solution of 5.3 g of ^ chloro-S-methyl-iO-hydroximino-10.11 -dihydro-dibenzo ^ bjf / azepine in 1-00 cm ethanol and 5 cm of distilled water is mixed with 120 g of 3 9 ^ iiatrium

o 3

amalgam treated for 3 hours at 70 C. It is 5 cm to pure acetic acid and heated for a further 2 -hour at 70 ⁰ C.

• 3.

The ee alctions mixture is distilled with 30 cm of water added, and the regenerated mercury is separated. The ethanol is evaporated under reduced pressure. the obtained alkaline aqueous suspension is obtained by adding

3
of 150 a distilled water and diluted twice with

a total of 180 cnr of ether extracted. The ether solutions are

10980 8/2130

• twice with a total of 100 cm of an ice-cold watery one Extracted in methanesulfonic acid solution. The United

■ 5 acidic aqueous solutions are made alkaline by adding 30 cm of 10N sodium hydroxide solution. The separating Oil is extracted twice with a total of 160 cm of ether.

The combined ether solutions are distilled with 80 cm Washed water, treated with 0.1 g of "biochar", dried over potassium carbonate and concentrated The residue (4.8 g) is dissolved in 25 cm of anhydrous ethanol. The ethanol solution obtained is added 5.0 cm of a solution of hydrogen chloride in ether (with a content of 3.6 mol per liter). After an hour

"Cooling down" 1 2 ⁰ C, the crystals formed are removed

3
sucks, washed with 8 cm of ice-cold anhydrous ethanol and then twice with a total of 30 cm of anhydrous ether and dried under reduced pressure (20 mm Hg). One he holds 4.6 g of 4-chloro-5-methyl-10-amino-10,11-dihydro-dibenzo / b "| 7azepin hydrochloride from F = 275-278 ⁰ C.

The 4-chloro-5-methyl ~ 10-hydroximino-10,11-dihydro-dibenzo ^ b, f_7azepine used as the starting substance can be made in the following ways:

Production of 2-methyl-6-chloro-2'-carboxydiphenylamine (F = 210 ⁰ C) according to 0, Hromatka u, coworkers ,months. Chem., 1127 (1966).

Preparation of 10.3 g of 2-methyl-6-chloro-2'-methoxycarbonyldiphenylamin (P = 93 ⁰ C), by reaction of 11.4 g 2-Methyl-r6-chloro-2'-carboxydiphenylamin in chloroform with 6.9 g of thionyl chloride in the presence of 10.4 g of hexamethylphosphoric triamide · and then an excess of anhydrous methanol in the presence of 10.4 g of hexamethylphosphoric triamide at about 0 ⁰ C and about 20 ⁰ C.

109808/2130

Preparation of 8.15 g of 2-methyl-6-chloro-2'-methoxycarbonyl-N-methyldiphenylamine (P «66 ⁰ G) by the action of 2.4 g of sodium hydride and then 12.1 g of methyl3odide to 9.65 g 2-M-ethyl-6 "-ciilor-2 '-methoxycarbonyldiphenylamine in 1,2-dimethoxyethane at about 70 ⁰ O,

Production of 4,4g ^ -Gloro-S-methyl-IO, 11-dihydrodibenzo / b, f7azepinon- (10) (i ¹ = 140 ⁰ C) by reaction of 7.6 g lithium diethylamide, produced in a mixture of benzene and Hexamethylphosphoric acid triamide at about 20 ⁰ O, with 6.2 g of 2-methyl-6-chloro-2 ^t -methoxycarbonyl-N ~ methyl- \ diphenylamine in ethereal solution at etv / a -25 ⁰ G.

Preparation of 5.4 g of 4-chloro-5-methyl-10-hydroximino-10,11-dihydrQ-dibenzo / b, f7azepin (F = 211 ⁰ C), by reaction of 2.9 S hydroxylamine hydrochloride and 5.65 g of sodium acetate trihydrate with 5.3 g of 4-chloro-5-methyl-10,11-dihydro-dibenzo ^ / b, fj ^ azepinone- (10) in aqueous ethanol under reflux.

Example 14 ■.

To a suspension of 1.16 g of lithium aluminum hydride in A solution is slowly added to 25 cm of anhydrous ether of 3.5 g of 4-chloro-5-methyl-10-forinamido-10,11-dihydrodibenzo / b, f7azepine in 100 egg anhydrous ither too. Man refluxed for two hours. The cooled suspension is replaced within one hour by successive

■ 3 ■■■ '■■ 3

subsequent addition of 1.33 cm of distilled water, 1.00 cm

5N sodium hydroxide solution and 4.55 cm of distilled water hydrolyzed The precipitate formed is filtered off with suction and then washed three times with a total of 300 cm of ether. The Mitrat is used twice with a total of 120 cm of an ice-cold aqueous 1n methanesulfonic acid solution extracted The combined acidic aqueous solutions are extracted by adding

1098087 2130

40 cm of 1on sodium hydroxide solution made alkaline. That deviates

3 exiting oil is twice with a total of 160 cm of ether

3 extracted. The combined ethereal solutions are 80 cm washed distilled water, dried over potassium carbonate and concentrated. The residue (3.2 g) is in 15 cm of anhydrous ethanol and 15 cm of anhydrous ether

3 solved. To the solution obtained is added 3.1 cm of a Solution of hydrogen chloride in ether (containing

3.6 moles per liter). After cooling at 2 ^° C. for one hour

3, the crystals formed are filtered off with suction, washed with 10 cm of a mixture of equal proportions of ice-cold anhydrous ethanol and ice-cold anhydrous ether and then with 20 cm of anhydrous ether and then dried under reduced pressure (20 mm Hg). 2.7 g of 4- Chlor-5-methyl-10-methylamino-10,11-dihydro-dibenzo ^, f_7azepine hydrochloride from I ¹ = 240 to 242 ⁰ G.

Used as a starting substance 4-chloro-5-methyl-10-formamido-10,11-dihydro ~ dibenzo _<£ b, f / azepine ^r can be prepared in the following manner;

3.7 g of 4-chloro-5-methyl-10-formamido-10,11-dihydro-dibenzo / b ", f_7azepine (P = 124 ⁰ C) are obtained by reacting formylacetic anhydride with 4.0 g of 4-chloro 5-methyl- "10-amino-IO, H-dihydro-dibenzo ^ bjfT'azepin (prepared as in example 13) at about 20 ⁰ C.

The Pormylessigsäureanhydrid is prepared by heating for two hours a mixture of 14.3 g of acetic anhydride and 6.6 g of 98 Seiger formic acid at 55 to 60 ⁰ C.

Example 15

By reacting lithium aluminum hydride with 2-chloro-5-methyl-IO-ethoxycarbonylamino-10,11 ~ dihydro-dibenzo / b ", f7-

109808/2130

2039 ^ 96

. ■; ■■; ; - - 47 · - ■; ■ · ■■■;

azepine In anhydrous ether, hydrolysis, extraction of the base obtained in an acidic medium and conversion to the hydrochloric acid, 2-chloro-5-methyl-10 ~ methylamino-10,11-dihydro-aibenzo / S, f / 'azepine-hydrochloride from ■ E - 232 to 234 ⁰ O.

The 2-chloro-5-methyl-10-ethoxyoar used as the starting substance bonylamino-10,11 -dihydro-d ibenzo ^ / iä, fjZaze pin can be made in the following ways:

Production of 2-chloro-5 ~ methyl-10-amino-10 ,. ti-dihydro- ' dibenzo ^ bjf ^ azepin according to example 7 »

Preparation of 2.7 g of 2-chloro-5-methyl-10-ethoxycarbonylamino-10,11-dihydro-dibenzo ^ F, f7azepinTom Ϊ - 126 to 128 - ⁰ C. by reacting 1.7 g of ethyl chloroformate with 3.9 g of 2-chloro-5-methyl-10-amino-10,11-aihydro-dibenzo in anhydrous pyridine. -

The pharmaceutical compositions containing the derivatives of the general formula I and / or one of their salts or quaternary ammonium derivatives in pure form or in the presence of a diluent or coating agent Contain, represent a further object of the present invention. These compositions can on oral, rectal, parenteral or external Application to be used

As solid compositions for oral administration, tablets, pills, powders or "granules" can be used. In these compositions, that is according to the invention Effective product with one or more inert diluents, such as sucrose, or lactose Starch, mixed. These compositions can also

109 8 08/2130

substances other than the diluents, such as "for example contain a lubricant such as magnesium stearate.

The liquid compositions for oral administration can be pharmaceutically acceptable emulsions, solutions, Use suspensions, syrups and elixirs that contain inert diluents such as water or paraffin oil, contain. These compositions can also contain substances other than the diluents, such as Contain wetting agents, flavor enhancers, sweeteners or flavorings.

The compositions according to the invention for parenteral administration can be aqueous or non-aqueous sterile Solutions, suspensions or emulsions as solvents or carriers one can propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, such as ethyl oleate, use. These compositions can also contain adjuvants, in particular wetting agents, emulsifying agents and dispersants. The sterilization can be carried out in various ways, for example with The help of a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating, they can also be made in the form of sterile solid compositions dissolved in sterile water or any other injectable sterile medium at the time of use can be.

The compositions for rectal administration are suppositories which, in addition to the active substance, excipients, such as cocoa butter or suppo wax, contain

109808/2130

th can »

In human therapy, the doses depend on the desired effect and the duration of the treatment. You are in
generally between 10 and 250 mg per day "when administered orally for an adult *

The following examples explain the invention
Compositions ί

Example A.

The following tablets are prepared according to the usual technique Composition ago;

3-chloro-5-methyl-11-methylamino-

10> 1 i-dihydro-aibGnzo ^ jfJazepine-

hydrochloride -. , 11.3 mg

Strength . ■. -, .. ■;, - ■ _. , 103 mg

colloidal silica 32 rag

Magnesium stearate. ■ -. 3.7mg

Example B.

The following tablets are prepared according to the usual technique Composition ago:

4-chloro-5-methyl-11-methylamino-10f11-dihyflro-dibenzo ^ b ", f7azepine 10 mg

Strength . "■, -, -. 105 mg colloidal silica, 32 mg

Magnesium stearate, »- 3 mg

109808/2130

Example C

Tablets with the following composition are manufactured using the usual technique:

1-chloro-5-methyl-10-methylamino

10.1 i-dihydro-dibenzo ^ jf / azepin-

fumarate. 14.2 mg

Strength . ,,, 100 mg

colloidal silica. ,. , 32 mg

I · · Magnesium stearate. - 3.8 mg

Example D

Tablets with the following composition are manufactured using the usual technique:

2-chloro-5-methyl-1O-methylamino-10,11-dihydro-dibenzo ^ b ", f7azepine hydrochloride

Strength . , ^ colloidal silica Magne siumst earat

Example E.

Tablets of the following composition are prepared according to the usual technique j

3-chloro-5-methyl-10-methylaminol OjH-dihydro-dibenzo ^ / Ejf / azepine maleate 14> 2 mg

11 , 3 mg 103 mg 32 mg 3 , 7 mg

109808/2130

2033396

Strength . 100 mg

. colloidal silica 32 mg

Magnesium stearate. 3.8mg

Example ff

Tablets with the following composition are manufactured using the usual technique:

2-chloro ~ 5-methyl-11-amino-

lOjii-dihyäro-äi'benzo ^ SjfT'äzepin ₍ ..> 10 mg

Strength . . 105 mg.

colloidal silica. 32mg

Magnesium stearate *. .-,. ,, 3 mg

Example G-

Tablets of the following are prepared according to the usual technique Composition ago:

2-Chl or-5-methylr-1 G-methylamino-10,11-dihydro-dibenzo ^ b ", f / azepin-

hydroehlorid. 11.3 mg

Strength . . _: 103 mg

coloid silica 32 mg

Magnesium stearate 3.7 mg.

10 9808/2130

Claims (3)

Claim 1J 10,11-dihydro-dibenzo ^, f7azepine derivatives of the formula in which R and R ¹ , which can be the same or different from one another, each represent a V / A water atom or an alkyl, hydroxyalkyl, hydroxyalkoxyalkyl or phenylalkyl radical, the phenyl radical optionally being replaced by one or more halogen atoms and / or one or several alkyl, -, alkoxy, amino or irifluoromethyl radicals can be substituted, R ^ represents a V / hydrogen atom or an alkyl radical and one of the symbols X represents a chlorine atom and the other symbols X each represent a hydrogen atom, the alkyl radicals and the Alkyl parts of the other radicals contain 1 to 5 carbon atoms, as well as their addition salts with acids and quaternary aramonium derivatives. 2. Process for the preparation of the products according to claim 1, characterized in that j if R and R ¹ both each represent a hydrogen atom, a compound of the general formula Ϊ-0Η X ·. · 109008/2130 ORIGINAL INSPECTED reduced, , R if -H. represents a group -Ns ^ in which Rg. an alkyl, hydroxyalkyl, hydroxyaikoxyalkyl, Phenyl or phenylalkyl radical, where the alkyl radicals and the alkyl parts of the other radicals contain 1 to 4 carbon atoms and the phenyl ring optionally by one or more halogen atoms and / or one or more Alkyl radicals, alkoxy radicals with 1 to 5 carbon atoms, Amino radicals or prifluoromethyl radicals can be substituted, and I, a hydrogen atom or an alkyl or phenylalkyl group st means, which optionally diir oh one or more halogen atoms and / or one or more alkyl radicals, Alkoxy radicals or irifluoromethyl radicals may be substituted can, wherein the alkyl radicals and the alkyl parts of the other Containing radicals 1 to 5 carbon atoms, a compound the general formula R ₃ -N-CO-B ₂ reduced if -Ϊ a group -N ' I ₂ -B ₂ represents in the R and R _{2 have} the meanings given above, at the same time a compound of the general formula Rg-CHO, in which R ₂ dig has the meaning given above, and hydrogen in the absence of a hydrogenation catalyst 109808/2130 a compound of the general formula converts, where, if R is a hydrogen atom, each according to the proportions of aldehyde and hydrogen . Product is obtained for which -N. a group -NH-CH ₂ -R ₂ or a group -N (CH ₂ -Rg) ₂ , if R _{1 is} a hydrogen atom and -N is a ¹ ^ R « Group -N means, as defined above, ^ CH ₂ R ₂ at the same time a compound of the general formula R ₂ -CHO, in which R _{2 has} the meaning given above, and hydrogen in the presence of a hydrogenation catalyst with a compound of the general formula in which Ac means an easily removable acyl radical and R has the meaning given above, -reacts and an ~ The group Ac is removed by hydrolysis, whereby, if R 'denotes a hydrogen atom, depending on the quantity. share in aldehyde and hydrogen 109808/2130 - .- ■; : '■■■■■ · ■■: -55—: _; :;:; ■ ^:. '■'"'- ■ : ■ / ^R :' ■: ■ '■■■■■; ■ Product is obtained for which -IL a group -NH-CH ₂ -R ₂ or a group -B (CH ₂ -H ₂ ) -g, .R ^ R if -Kl represents a group -NC in which K ' ^R 4' ν E has the meaning given above and R ^ is an alkyl, Hydroxyalkyl, hydroxyalkoxyalkyl or phenylalkyl radical, which is optionally replaced by one or more halogen atoms and / or one or more alkyl, alkoxy, amino or trifluoromethyl radicals can be substituted, the Alkyl radicals and the alkyl portions of the other radicals 1 to 5 Having carbon atoms, a compound of the general formula '/ ^;; - ^{; R} 4 - ^Z ■■, ■ '' ■ ■ '■■■' ■ '/ in which I. has the meaning given above andZ represents a reactive ester radical, with a compound the general formula : -NH X doing, where, if R is a hydrogen atom, each according to the proportion of the compound R.-2 a product will hold for which the group - ^ C a group R ^ or a group -N (R ^) ₂ , 1-09-608 A21-30- case? represents a group -NH-R, in which R. has the meaning given above "has a compound the general formula -K-Y X in the R. has the meaning given above and Y is a cyano, alkoxycarbonyl, alkanoyl, alkanesulfonyl or arylsulfonyl radical represents, cleaves or if -N a group - CH, represents in the Rc is a hydrogen atom or an alkyl radical with 1 to 5 Carbon atoms means a compound of general formula X R. X X— -X R ₅ -N-COOR ₆ in which R, - has the meaning given above and R ^ represents an alkyl radical with 1 to 5 carbon atoms, reduced and if appropriate, the base obtained is converted into an addition salt with acids or a quaternary ammonium derivative. 109808/2130 3. Pharmaceutical compositions which can be used in therapy, characterized by a content of at least one of the products according to claim 1 as the active substance. . - 109808/2130