DE2352918A1 - DIHYDROPYRIDOBENZODIAZEPINE AND BENZODIAZOCINE, THEIR SALTS, METHODS OF MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

"Dihydropyridobenzodiazepines and -benzodiazocines, their salts, Process for their preparation and medicinal products containing these compounds "

Priority: October 24, 1972, V.St-A., No. 299 986 March 8, 1973, V.St.A., No. 339 258

The invention relates to dihydropyridobenzodiazepines and benzodiazocines of the general formula I.

(D

in which R is the same or different and is a hydrogen, fluorine, chlorine or bromine atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy radical with 1 to 4 carbon atoms, an alkyl mercapto radical with 1 to 4 carbon atoms, a benzyl, phenethyl _S phenyl, phenylraercapto or a phenyl group monosubstituted by a fluorine, chlorine, bromine or iodine atom, an alkyl radical with 1 to 4 carbon atoms ^ an alkoxy radical with 1 to 4 carbon atoms © the one trifluoroethyl group means ₉ and R in the 3-., And / or 5-division, j

when R represents an halogen atom, R ^{1 represents} a hydrogen, fluorine, chlorine, bromine or iodine atom, an alkyl radical having 1 to 9 carbon atoms, an alkoxy radical having 1 to 4 carbon atoms; an alkyl mercapto group with 1 to 4 carbon atoms, an alkylsulfonyl group with 1 to A carbon atoms, a phenyl, phenyloxy, sulfamoyl or dialkylamidosulfonyl group with 1 to 4 carbon atoms in each alkyl group, a trifluoromethyl or one by a fluorine, chlorine , Bromine or iodine atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy radical with 1 to 4 carbon atoms or a tri fluorine thy I group means monosubstituted phenyl or phenyloxy group, m has the value 1 or 2 and η has the fourth 2 or 3, and their salts.

The compounds of the general formula I can be prepared according to the invention by using a compound of the general formula IV or V
©

(IV) (V)

in which R, R ", m and η have the above meaning, all in one Solvent with a base and in the presence of copper as Ka-. condensed catalyst and, if appropriate, the compound obtained is converted into a salt with an inorganic or organic acid. The compounds of the general formula IV can be prepared by reacting a 2-artiinopyridine of the general formula given below Formula II with an o-bromophenalkylene bromide of the 'below given general formula III are prepared. These .

40931-8 / 1207

Reaction is carried out in a solvent or Lösungsmitteigemisch, 'in which the reactants can be dissolved and having a boiling point of at least about 100 ⁰ C. Typical examples of suitable solvents are aromatic hydrocarbons, ethers, aliphatic alcohols or aryl-substituted aliphatic alcohols. Toluene and xylene are examples of preferred aromatic hydrocarbons. Examples of ethers used with preference are the monomethyl ether of diethylene glycol, the dimethyl ether of diethylene glycol (diglyme), the monomethyl ether of ethylene glycol and the dimethyl ether of ethylene glycol (glyme). A specific example of a preferably used aliphatic alcohol is η-amyl alcohol, while benzyl alcohol is a specific example of a preferred aryl-substituted aliphatic alcohol. By heating the mixture of the compound of the general formula II with the compound of the general formula III in a solvent of the type described above or a solvent mixture to temperatures of about 100 to about 140 ° C. for a period of several hours, preferably from about 3 to 24 hours, the pyridinium compound of the general formula IV is obtained. This compound is made by reacting with an alcohol which is miscible with water and an alkali metal alcoholate with 1 to. 3 carbon atoms converted into the imino compound of the general formula V. The implementation takes place at Räumomperatur. over a period of about 1 to 4 hours. The compounds of general formula V can be converted into compounds of general formula I by reacting with an alkali metal alkoxide having 1 to 3 carbon atoms in a water-miscible alcohol and in the presence of copper al <3,

409818/1207

Catalyst at temperatures of about 60 to 120 ⁰ C for a period of several hours, preferably from about 2 to ■ 4 hours, transferred. The compounds of general - ', formula IV: LEVERAGING also directly into the compounds of formula I der.allgemeinen by heating to temperatures of about 60 to 12O ⁰ C for several hours, preferably from about 1 to x 4 hours and in? Present of potassium carbonate and copper in a solvent, preferably dimethylformamide, dimethylacetainide, dichlorobenzene, trichlorobenzene or diethylbenzene, are converted. Preferably, v / however, the compounds of the general formula IV ground directly into the compounds of general formula I ■ by heating to temperatures of about - 60 to 120 ⁰ C for several hours, preferably from .Approximately 1 to 4 hours, and in the presence of a Converted alkali metal hydroxides, alkali metal carbonate, a tris-alkali metal phosphate, an alkali metal metaborate or an alkali metal tetraborate in a mixture of water and a water-miscible alcohol and in the presence of copper as a catalyst. Specific examples of suitable condensing agents are LiOH, NaOH, KOH, RbOH, - CsOH, Na ₂ CO ₃ , K ₂ CO ₅ , Rb ₂ CO ₃ , Cs ₂ CO ₃ ,

. Na ₃ PO ₄ , K ₃ PO ₄ , Rb ₃ PO ₄ , Cs ₃ PO ₄ , Na ₂ B ₂ O ₄ , Na ₂ B ₄ O ₇ , K ₂ B ₂ O ₄ and

a K ₂ B ₄ Oy. Water and alcohol are mixed in / such an amount ratio that a single, homogeneous phase preservation is ten. The reactions explained above can be represented by the following reaction equations: '

^ \ n Br (CH ₉ ) ^

K-iOl ₊

\ ^^ NH ₂ Br

(II)

/ (CH ₂ )

NH Br

( ^V )

(I)

• The intermediates of general formula III, has the .η the ■ value 2, of the general formula VI with PBr ^ may be prepared by reacting an o-Brombenzylalkohols at temperatures of about 0 to 100 ⁰ C for a period of about 1 to 6 hours -getting produced. The resulting o-Brombenzylbromide of the general formula VII _r then reacted with sodium cyanide in the presence of water and a water-miscible alcohol to the corresponding o-Bromphenylacetonitrilen of the general formula VIII Treatment of these compounds with an alcohol in the presence of concentrated sulfuric acid provides the corresponding esters of general formula IX. The reaction of the ester with lithium aluminum hydride yields the corresponding o-Bromphenäthanole ₅ by reacting with IBR, at temperatures from about 0 ·· Ms 100 ⁰ C for a period of about 1 to

β hours the corresponding o-Brpmphenäthylbromide the general. ι deliver my formula XI »The conversions explained above are through the following. Reaction equations reproduced;

401111/120 /

CH ₂ OH

■>

(VI)

^iH 2 ^COOR / ROH

(IX)

I LiAlH 4-

CH ₂ OH

(χ)

CH ₂ Br

(VII)

I NaCN ψ

Br

(viii)

₂ CH ₂ Br

The intermediates of the general formula III, in which η has the value 3, can be prepared by reacting a compound of the general formula XI with sodium cyanide in the presence of ¥ water and a water-miscible alcohol to form the corresponding o-bromophenylpropionitrile of the general formula XII. These compounds are reacted with an alcohol in the presence of concentrated sulfuric acid to give the corresponding esters of the general formula XIII '. By reducing these compounds with lithium aluminum hydride, the corresponding o-bromophenylpropanols are obtained, which by reacting with PBr-z at temperatures of about 0 to. 10O ⁰ C yield the corresponding o-bromophenylpropyl bromides of the general formula XV over a period of about 1 to 6 hours.

Dj, e above-explained reactions are carried out by the following Reaction equations reproduced?

^% '"' ■ '4QI81S / 12Ö7

CH ₀ CH ₀ Br NaCN

CH ₂ CH ₂ CN

(XI)

(XII)

CH ₀ CH ₀ OH LiAlH

CH ₂ CH ₂ COOR

(XIV)

PBr.

(XIII)

CH ₂ CH ₂ CH ₃ Br

R ¹

(XV)

If the radical R ^{1 is} an alkyl mercapto radical, the compounds of the general formula Xl or XV can be prepared by nitrating an o-bromobenzyl alcohol of the general formula XVI at temperatures of about ⁰ ° C. with a mixture of nitric acid and sulfuric acid. The mixture of isomers of nitrated 2-bromobenzyl alcohols obtained is known per se

. Way separated. Each isomer of the general formula XVII is then converted to the corresponding amine of the general formula XVIII reduced with zinc and hydrochloric acid. The implementation of the amino

. bonds of the general formula XVIII with nitrous acid and then supplies with sodium methyl mercaptide, the corresponding

■ corresponding methyl mercapto - ^ - bromobenzyl alcohols of the general

^: Formula XIX. These reactions proceed according to the following reaction

40 98: 18/1207

ti on equations:

CH ₂ OH

(xvi)

(χνΐΐ)

CH ₂ OH

(XVIII)

1) ₂

2) AlkyISNa

The implementation of the compounds of general formula XIX with PBr ^ in the manner outlined above provides the connections of the general formula XI or XV, in which R 'represents an alkyl mercapto radical.

If the radical R ^{1 is} a trifluoromethyl group, the intermediate of the general formula VII can be prepared by reacting a trifluoromethylphenylmagnesium bromide of the general formula XX with methyl iodide to form the corresponding trifluoromethyltoluene of the general formula XXI. Implementation of this connection with. Bromine at temperatures of about 20 ⁰ C in the presence of iron powder provides a bromo-substituted-trifluoromethyltoluene of the general formula XXII. The reaction of this compound with bromine in the presence of light and a Pero3tidkatalysator provides the corresponding. Bromotrifluoromethylbenzylbroraid of the general formula XXIII. These conversions proceed according to the following reaction equations:

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Iron file

Br ₂ AV

Il

CH ₂ Br

(XXIII)

The starting compounds of the general formula II, in which R denotes a phenyl group optionally substituted by a halogen atom, an alkyl radical, an alkoxy radical or a trifluoromethyl group, can be obtained by heating a 3- (N-acetamido-N-nitroso) pyridine of the general formula XXIV with a benzene optionally substituted by a halogen atom, an alkyl radical, an alkoxy radical or a trifluoromethyl group according to the method described in J .. Chem. Soc. (London), 1940, pp. -372 and J. Chem. Soc. Is be produced The product of general formula XXV is a 3-substituted pyridine in which the N-acetamido-N-nitroso group by an optionally substituted phenyl group is replaced, the ^(London), p ~ Method "described in 1954 4516th. derived from the compound with which the 3- (N-acetamido-N-nitroso) pyridine was heated.The product of the general formula XXV is then treated with sodium amide according to J. Russ. Phys. Chem. Soc, Vol. 46 (1914), p. 1216 (Chem. Zentralblatt II, 1915, p. 1064)

implemented to the arainopyridines of the general formula XXXII and XXXIII /

23529TiB

NO O

I H -CCH.

t ^

R = halogen,

Alkyl, alkoxy,
CF or H

(xxv)

XXXII

. The compounds of the general formula II in which R is a fluorine atom or in which one of the radicals R is a fluorine atom and the other radical is an alkoxy radical can be prepared by reacting a 3-aminopyridine of the general formula XXVI or
of a 3-alkoxy-5-aminopyridine with amyl nitride and fluoroboric acid according to the method described in J. Am. Chem. Soc, 69 (1947), pp. ' 2443 produced v / earth. The received
3-fluoropyridine of the general formula XZVII. is on this with
Sodium amide to that described by Chichibabin et al., J. Russ. Phys. Chem. Soc, Vol. 46 (1914), p. 1216 to form a mixture of 2-amino-3-fluoropyridine and 2-amino-5-fluoropyridine, which is separated in a manner known per se. The process proceeds according to the following reaction scheme:

Z = H or alkoxy

H ₂ NN

Compounds ^{: of} the general formula III, in which R ¹ denotes a phenyl group optionally substituted by a halogen atom, an alkyl or alkoxy group or a trifluoromethyl group, can be prepared by reacting an amino-substituted o-bromobenzoic acid of the general formula XXVIII with acetic anhydride and then with nitrous acid will. The resulting N-ethamido-N-nitroso-o-bromobenzoic acid of the general formula XXIX is then treated with benzene or an R-substituted benzene in which R is a halogen atom, an alkyl or

'Alkoxy radical or a trifluoromethyl group means on that before implemented in the manner described above. The aryl-substituted o-bromobenzoic acid is then with LiAlH ^ or AlH, in itself

. known way to the aryl-substituted o-bromobenzylallcoliol general formula XXXI reduced. The reaction proceeds according to the following reaction scheme:

iCOOH

COQH

1)

2) ENT

(XXIX)

R = halogen, alkyl, H, alkoxy or CF,.

CH ₂ OH

COOH

Br

The compounds of the general formula I are valuable medicinal substances with central nervous system stimulating properties. They also act as muscle relaxants. At the appointment Following on from rats, the stimulating effect is demonstrated by increased activity and tremors in the body. The muscle relaxants Characteristics are shown by reduced tone or paralysis of the extremities and reduced grip. With both the stimulating and the muscle-relaxing effect, the effect of rasGh sets in, i.e. within about 15 minutes. a. The effect lasts at least about 2 hours. By-the rat the dose for both effects is about 6.25 to about 50 mg / kg, while in humans the daily dose is about 40 to '2000 mg divided into four doses for both effects is.

The pyridinium compounds of the general formula IV are not only intermediates for the preparation of the compounds of general formula I, but they are themselves valuable bactericides. To determine the bactericidal effect, the Connections to those described in "The Microbial World", R.γ. Stanier, M. Doudoroff and E.A. Ädelberg, Prentice-Hall, Inc. Englewood -Cliffs, N.J., 3rd Edition, p. 858 Test examined. Staphylococcus aureus (1), Streptococcus pyogenes (2), • Salmonella schottmuelleri (3), Salmonella gallinarum (4), Pseudomonas aeruginosa (5), Proteus vulgaris (6) Escherichia coli (7), Pasturella mul-tocida (8) and · * ■ .Mycobacterium tuberculosis (9) used. \

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Sterile agar plates are inoculated with the test organism ", and then a number of glass cylinders are placed on the surface of the agar plates to form a number of small cups. A known dilution of the one under investigation Compounds are added to each beaker and the entire plate is then incubated until significant bacterial growth he follows. The compounds of the invention diffuse from the beaker into the agar and create a zone of inhibition. To this In this way, the minimum inhibitory concentration that creates a recognizable inhibition zone can be determined. In the table below the results are summarized.

Micro- Minimum Inhibitory Concentration, y / ml

organism Verb, from
Example 12,
Column 3 Verb. Of
Example 10,
Column 3 Verb, from
Ex. ^ Verb. Of
Example 6 1 6.25 6.25 12.5 3.13 2 25.0 50.0 50.0 12.5 3 12.5 12.5 50.0 12.5 4th 12.5 12.5 25.0 6.25 VJl 25.0 25.0 25.0 12.5 ■ 6th 25.0 25.0 25.0 12.5 7 · 6.25 12.5 25.0 3.13 8th 12.5 25.0 12.5 6.25 9 0.78 1.57 6.25 0.39

The compounds of the invention can be administered orally, intraperitoneally, subcutaneously, intramuscularly or intravenously in the doses indicated administered.

The drugs can be administered orally, for example, together with an inert Diluents or with an assimilable edible carrier administered or they can be in a hard gelatin.- or

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Soft gelatin capsules can be enclosed or compressed into tablets. Furthermore, they can be incorporated directly into the diet ',/earth. The drugs can be administered orally mixed with excipients and in the form of tablets, capsules, elixirs, suspensions, syrups, chewing gum and the like are processed. Such drugs contain at least 0.1 percent of the drug. The content of the drug can for example from about 5 to 75 weight percent. Medicaments to be administered orally preferably contain the medicinal substance in an amount of about 10 to 2.00 mg in the dosage unit.

The above-mentioned orally administered medicinal products can contain the following components:

«A binding agent such as tragacanth, gum aracum, corn starch or gelatin, an excipient such as dicalcium phosphate, a disintegrant such as corn starch, potato starch or alginic acid, a lubricant such as magnesium stearate and a sweetener such as cane sugar, lactose or saccharin. Furthermore, flavorings, such as peppermint or cherry flavor can be used. For the production of capsules, the mixture can also contain a liquid carrier, like a fatty oil. Tablets, pills or capsules can be coated with shellac and / or sugar. A S ^ irup or elixir can contain the medicinal substance, cane sugar, a preservative, such as p-hydroxybenzoic acid methyl ester or propyl ester, a color and a flavor such as cherry flavor

or orange flavor. The examples illustrate the invention.

A09818 / 1207

A) o-bromobenzyrbromide

271 g of phosphorus tribromide are added dropwise to 187 g of o-bromobenzyl alcohol at room temperature and with stirring. After completion · addition, the mixture is stirred for 3 hours at room temperature · ', then heated for 3 hours at 90 to 10O ⁰ C and then poured in 6 kg of crushed ice. After hydrolysis, the mixture is extracted three times with 600 ml of diethyl ether each time. The ether extract is washed, dried and evaporated. The title compound is obtained with a boiling point of 130 to 132 ° C. . - - · -

- ^B ) o-bromophenylacetonitrile '.

A suspension of 220 g of sodium cyanide in 265 ml of water and 380 ml of ethanol is mixed with a solution of 911 g of δ-bromobenzyl bromide in 911 ml of ethanol while stirring. An exothermic reaction ensues. Finally, the mixture is refluxed for about 30 minutes, then heated, then cooled in an EigToad and filtered. The filter residue is washed with diethyl ether, the Piltrat evaporated and the residue suspended in 300 ml of water and extracted three times with 500 ml of diethyl ether. The ether extract is washed, dried and evaporated. The residue is distilled. Removing yield, 730 g of the title compound, bp. ^ 'I4i to 142 ⁰ C.

- C) ethyl o-bromophenylacetate . .

'A cooled solution of 730 g of o-bromophenylacetonitrile in 2.9 liters of anhydrous ethanol is added dropwise within about \

2 hours and with stirring with 7 ^ -0 ml of concentrated sulfur ι L - ¹

4098 1-8 / 1-207 ■

acid added. The reaction mixture is then refluxed for 9 hours, poured into ice water and extracted with 2.5 liters of diethyl ether. Der.Ätherextrakt is washed, dried and evaporated, the residue is distilled off. Yield 786 g of the title compound with a boiling point of 115 Ms 117 ° C; ng ⁶ 1.5434. / '■

D) ο-bromophenethyl alcohol 1

A suspension of 106 g of lithium aluminum hydride in 3.7 liters of anhydrous diethyl ether is added dropwise and with stirring with a solution of 780 g of ethyl o-bromophenylacetate in .3.1 liters of anhydrous diethyl ether added. After the addition has ended, the reaction mixture is stirred for about 3 hours and then refluxed for about 5 hours. The mixture is then cooled and added dropwise with 800 ml of water as well 1.5 liters of 10 percent hydrochloric acid are added. The ether solution is washed, dried and evaporated. The residue is distilled. Yield 554 g of o-bromophenethyl alcohol

.Kp. ₈ 130 to 132 ° C ;. n§ ° 1.5760.

E) o-bromophenethyl bromide '

550 g of o-bromophenethyl alcohol are added dropwise with stirring mixed with 375 g of phosphorus tribromide. After the addition is complete, the mixture is stirred for 3 hours at room temperature and then Heated on a steam bath for 3 hours. The mixture is then poured into 6 kg of crushed ice, three times with 600 ml each time and extracted twice with 200 ml of diethyl ether each time. The combined ether extracts are washed, dried and evaporated. The residue is distilled. Yield 531 g ',

4G9818 / 1-2Q7 . .

o-bromophenethyl bromide of boiling point _Q -86 Ms-83 ⁰ C; n ^ 1.5922.

F) 2-Amino-1- (o-bromophenethyl) pyridinium bromide

A solution of 212 g of o-bromophenethyl bromide. in 400 ml of anhydrous A solution of 120 g of 2-aminopyridine in 400 ml of anhydrous xylene is added to xylene. The mixture will be about Heated under reflux for 3 hours, then cooled and the xylene solution decanted from the solid which has crystallized out. The crystals are digested with 300 ml of isopropanol and filtered off and dried. Yield 138 g of the title compound. The xylene solution is refluxed again for 16 hours and then worked up in the same way. Another 43 g obtained the title compound. The product (181 g) - is made from Isopropanol recrystallized. Yield 170 g of the title compound from 195 to 197 ° C.

G) 11,12-dihydropyrldo / 2, T-b7 / i, l / benzodiazepine

A solution of 9.0 g of 2-amino-1- (o-bromophenethyl) -p3 / ridinium- * bromide in 55 ml of dimethylformamide is mixed with 10.3 g of finely powdered anhydrous potassium carbonate and 0.5 g of copper bronze, ^{heated to 100 °} C. for about 3 hours under nitrogen as a protective gas and with stirring and then filtered while still hot. The filtrate is evaporated to dryness under reduced pressure. 8.6 g of a residue are obtained, which is extracted twice with 125 ml of boiling diisopropyl ether each time. The diisopropyl ether solution is treated with activated charcoal, filtered and evaporated to about 40 ml. 7.2 g of the Ti'telverbindungen crystallize from 120 to 122 ° C on cooling. "'""

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Example 2 2-DihydropvridoZ2,1 -hjß, 3 / benzodiazepine

A) 1 - (o-bromophenethyl) --2-JmJnOpVrJdIn -

(a) NaOCH ₃ in methanol

10.8 g of the product from Example 1 (P) are added to a solution of 3.3 g of sodium methylate in 120 ml of anhydrous methanol, and the mixture is refluxed and stirred under nitrogen as a protective gas for 5 hours. The yellow solution obtained is evaporated to dryness under reduced pressure and the residue is partitioned between 250 ml of diethyl ether and 30 ml of water / water. The ethereal solution is separated off, washed, dried and evaporated. A solid residue with a melting point of 59 to 66 ^° C. remains. After recrystallization from hexane, 6.8 g of the title compound with a melting point of 64 to -66 ^° C. are obtained.

(b) KoCO g in water-containing n-propanol

A mixture of 18 g of the product from Example 1 (F), 13.8 g of potassium carbonate, 200 ml of water and 100 ml of n-propanol is refluxed for 4 hours. .After this, 75 ml are removed from the reaction mixture, cooled and washed with 120 ml of diethyl ether. diluted. The ether solution is separated off and worked up. Yield 2.1 g of the title ^{compound with a melting point of 64 to 66 °} C., which is identical to the compound obtained in (a). ,

B) 11,12-DihydropyridoZ2,1 -hjß , 3-7benzodiazepine (a) K ₀ CO y in hydrous nP ropanol

The remaining reaction mixture from Example 2 (b) is mixed with 0.3 g of copper bronze and for 3 hours under nitrogen as an inert gas heated under reflux and stirred. Danaoh v / ird the gj

A »-» 81 8/1207

cooled mixed and diluted with 350 ml of diethyl ether. The ether solution is separated off and worked up in the usual way. Yield 8.9 g of a yellow solid. The solid is dissolved in 250 ml of diethyl ether, the ether solution is decolorized with activated charcoal, filtered with diatomaceous earth as a filter aid and the filtrate is evaporated to dryness. 7.6 g of a bright yellow crystalline product with a melting point of ₄ 119 to 122 ^° C. are obtained ... After recrystallization from 150 ml of diisopropyl ether, 5.9 g of the title compound with a melting point of 120 to 122 ^° C. are obtained, di <with the. /in..Example 1 (G) obtained compound is identical.

(b) K _n CO- Z in anhydrous n-propanol

A mixture of 6.0 g of the product from Example 1 (F), 4.6 g of anhydrous potassium carbonate, 0.2 g of copper bronze and 180 ml of anhydrous n-propanol is refluxed and stirred for 9 hours. After working up, 2.7 g of the title ^{compound with a melting point of 120 to 122 °} C. are obtained, which is identical to the compound obtained in (a).

(c) NaOCEU in anhydrous methanol

.A solution of 5.4 g of sodium methylate in 220 ml of anhydrous Methanol is mixed with 18 g of the product from Example 1 (F) as well

■ 0.3 g of copper bronze are added and the mixture is refluxed and stirred for 3 hours. After working up, 5.8 g of the title compound with a melting point of 120 to 122 ^° C. are obtained, which in each outward *

. looks identical to the compounds obtained in (a). and (b) is.

/ 1207

Γ "1

(d) NaOH in hydrous methanol

An aliquot of 50 ml of a solution prepared according to (c) is diluted with 25 ml of water and mixed with 0.07 g of copper bronze, and the equipment is refluxed for 3 1/2 hours, stirred and then worked up. Yield 1.6g of the. Title compound of melting point 120 to 122 ^° C., which is identical in every respect with the products of (a), (b) and (c).

Example 3

11,12-dihydropyridoZ2,1-b7Zi.sTbenzodiazepine hydrochloride A solution of 1.5 g of 11,12-dihydropyrido / 2,1-b7 / i, 27benzodiaze-

. 5 ml of a 3.3 η (0.0175 Hol) solution of hydrogen chloride in ether are added to pin in 10 ml of anhydrous methanol. The resulting solution is diluted with anhydrous diethyl ether until it remains cloudy at room temperature. The solution is then cooled to ^{0 ° C.} The crystals formed are filtered off, dried and recrystallized from 20 ml of isopropanol. Yield 1.2 g of the hydrochloride from P. 205.0 to 206.5 ° C.

Example 4 '. 2-bromo-4-chlorophylene ether-yl bromide

(a) 2-Bromo-4-chlorophenvlacetonitrile

218 g (0.77 mol) of 2-bromo-4-chlorobenzyl bromide (. _{N n} Kp 98-104 ⁰ C; NJP 1.6262), are dissolved in 220 ml of ethanol and 95prpzentigem over 20 minutes with stirring to a Lösung'von 45 g (0.92 mol) of sodium cyanide are added to 55 ml of Vass'er and 80 ml of 95 percent ethanol. The temperature of the mixture rises spontaneously from 25 to 46 ° C. The mixture is 15 minutes under 'j

409918/1207

ι -

. Heated to reflux, then filtered and the filter residue with

\ 300 ml of diethyl ether washed. The combined filtrates are evaporated to dryness. The residue is between 500 ml of diethyl ether and 150 ml of water distributed ·. The ether solution is separated, dried and evaporated. Yield 171 g of 2-bronchi-4-chlorophenylacetonitrile.

(b) Ethyl 2-bromo-4-chlorophenyl acetate

171 g of the product from (a) are dissolved in 760 ml of anhydrous. Ethanol dissolved and added dropwise and with stirring with 190 ml concentrated sulfuric acid. The mixture is stirred for 1 hour at room temperature and then for 3 hours under . Heated to reflux. After cooling, the mixture is poured into 2.5 kg of crushed ice and the product is extracted with ether. The ether extract is evaporated. Yield 204 g of the Title compound.

(c) 2-Bromo-4-chloro "phenylacetic acid

204 g of the ester from (b), 3500 ml of 95 percent ethanol and 64 g (1., 0 mol) of 85 percent potassium hydroxide in 640 ml of water are refluxed for 5 hours, then evaporated to dryness under reduced pressure, and the residue is added to 1 , 5 liters of water added. The .An aqueous solution is cooled, extracted with diethyl ether and the aqueous solution to "a pH of 2 ¥ ert set. The precipitated crystals are ■ ■ .abfiltriert, urrüsristallisiert dried and crystallized from a mixture of / 200 ml of benzene and 300 ml hexane. Yield .90.3 g of 2-bromo-4-chlorophenylacetic acid with a temperature of 127 to 129 ° C.

L. -J

"A 09818/1207"

(d) 2-bromine ~ 4-chlorophene methanol

A solution of 11.5 "g of lithium aluminum hydride in 300 ml of anhydrous diethyl ether is mixed with a solution of 52 g - After the addition is complete, the mixture is refluxed for 40 minutes, then cooled, treated with 20 ml of ethyl acetate and then poured into 1.5 kg of crushed ice. After adding 200 ml of 20 percent hydrochloric acid, the product is extracted with ether and the Ether solution evaporated, yield 44.3 g of the title compound as a pale yellow oil; n ²⁴ 1.5714.

(e) 2-Bromo-4-chlorophenethyl bromide

on _o
44.2 g of the product from (d) are cooled / OC and treated with 26 g of phosphorus tribromide over the course of 20 minutes. After the addition has ended, the mixture is ^{heated to 100 °} C. for 75 minutes, then cooled and poured into 1 kg of crushed ice. The product is extracted with diethyl ether and the ether extract is evaporated. The residue is distilled. Yield 55.8 g of the title compound as a viscous oil from Kp.q λ 95-102 ⁰ C; n ^ ² 1.5838.

Example 5

5-chloro-11,12-dihvdropyrido / 2,1 -b / Z'i, s7benzodiazepine (a) 2-amino-1- (2-bromo-4-chlorophenethyl) pyridinium bromide solution of 10.4 g ( 0.11 mol) of 2-aminopyridine and 20.9 g (0.07 mol) of 2-bromo-4-chlorophenethyl bromide in 150 ml of anhydrous xylene are heated under reflux for about 10 hours. Then _j '*> AO 9 818/1207

cool the mixture and decant the supernatant from the solid product. The solid is filtered off, dried and recrystallized from 150 ml of isopropanol, · yield 17.6 g of the title compound, melting at 191 ⁰ C. 189'bis ■ ·

(b) 5-chloro-11,12-dihvdropyrido / 2,1-b7 / i, 3_7benzodiazepine A. Mixture of 6 g of the product from Example 5 (a), 6 g of anhydrous potassium carbonate, 0.2 g of copper bronze and 220 ml of n-propanol is refluxed and stirred for 12 hours. After working up and recrystallization from cyclohexane, 2.3 g of the title compound are obtained in deep yellow crystals with a melting point of 165 to 167 ° C. .

Example 3-chloro-H, 12-dihydropyrido / 2,1-

chloride

A solution of 1 g of the product from Example 5 (b) in 10 ml of poor anhydrous methanol is added dropwise with 5 ml of a 3.3 solution of hydrogen chloride in diethyl ether. Then 200 ml of anhydrous diethyl ether are added. The crystalline precipitate of the hydrochloride is filtered off and recrystallized from 40 ml of isopropanol. Yield 1.0 g of Titelyerbindung mp 232-234 ⁰ C (dec.).

Example 7

A) 2-Bromo-4-methylmercaptobenzyl bromide

2-Brora-4-methylmercaptobenzyl alcohol is produced as follows. represents:
: 2-Bromo-4-nitrobenzoic acid is mixed with iron and hydrochloric acid in aq

40-3818 / 1.207

reduced according to ethanol to 2-bromo-4-aminobenzoic acid. This compound is diazo- · with sodium nitrite in aqueous sulfuric acid. and the diazonium compound formed with sodium methyl-> mercaptid implemented. The 2-broni-4-methylmercaptobenzoic acid obtained is refluxed with methanol and concentrated sulfuric acid. The methyl ester formed is from the Reaction mixture extracted with diethyl ether. The ether extract is evaporated and the residue is distilled ^ Then the Methyl ester reduced with lithium aluminum hydride. The 2-bromo-4-methylmercaptobenzyl alcohol obtained is mixed with PBr .- * according to the example 1 (A) converted to 2-bromo-4-methylmercaptobenzyl bromide.

B) 3- (2-3rom - ^ - raethylmercapt'ophenyl) -1 -propanol

A suspension of 25 g of magnesium turnings in a solution of

CS

0.5 g of iodine in 550 ml of anhydrous diethyl ether is mixed with 5 ml of a solution of 296 g of 2-bromo-4-methylmercaptobenzylbroraid in 250 ml of anhydrous diethyl ether. The reaction is started by gentle warming. The remaining solution is then added dropwise so that the mixture is refluxed. After completion of the addition, the mixture is heated for 1 hour under reflux and stirred, and then cooled to 10 ⁰ C. Nitrogen _o was passed through a container with 48 g ethylene oxide, is introduced into the Reaktlonsgemisch. The addition of the ethylene oxide takes 2 hours. The mixture is then allowed to warm to room temperature and stirred. The mixture is then stirred for 4 hours at room temperature and then poured into a mixture of 1 kg of ice and 55 g of ammonium chloride. The mixture is then extracted with diethyl ether and the ether extract is worked up.

40981 8 / 1-207

The residue is distilled. Yield 210 g the title compound bp. _{0 6125-127} ° C

C) 3- (2-Bromo-4-methylmercaptophenyl) propyl bromide 27.1 g of phosphate bromide are added dropwise to 49 g of the product from (A) while stirring. Thereafter, the mixture is heated for 3 hours at room temperature gerührt'und then 3 hours at 90 to 100 ⁰ C. The reaction mixture is then poured into 1 kg of crushed ice. The mixture is extracted with diethyl ether, the ether extract is evaporated and the residue is distilled. Yield 52.7 g of the title compound with a boiling point of ₈ 100 to 102 ^° C.

D) 2-amino-1 - / 3- (2-bromo- »4-methyl mercaptophenyl) -propvl7-

pyridinium bromide

A solution of 154 g of the compound obtained in (C) in 400 ml of anhydrous xylene is mixed with a solution of 70 g of 2-aminopyridine added in 300 ml of anhydrous xylene and about 18 hours under Heated to reflux. After cooling, the xylene solution is of the precipitated crystals are decanted, the crystals are digested with 200 ml of isopropanol and filtered off < Yield 117 g of crude product. After recrystallization from isopropanol 98 g of the title compound were obtained.

E) 12,13-dihydro-3-methvlmercapto-11H ^ pvrido ^ 2.1-b7 / J .3 / -

benzodlazocine

A solution of 8.4 g of the compound obtained in (D) in 50 ml. Dimethylformamide are finely pulverized with 10.3 g

, free potassium carbonate and 0.5 g of copper bronze are added. The Ge ι

- 96 -

mixed is e.tx ^ a 3 Stur.denjäuf 10O ⁰ C under nitrogen as protective gas. and heated with stirring. The mixture is then filtered while it is still hot. The filtrate is evaporated to dryness under reduced pressure. 9.0 g of a residue are obtained, which is extracted twice with 120 ml of boiling diisopropyl ether. The diisopropyl ether solution is treated with activated charcoal, filtered and evaporated to about 35 ml. After cooling, the crystals formed are filtered off. Yield 4.3 g the title "link.

Examples 8-22

According to Example 1 (A), but using an equivalent amount of the substituted o-bromobenzyl alcohol listed in column 1, the corresponding o-bromophenethyl bromide listed in column 2 is obtained. The reaction of this compound with 2-aminopyridine according to Example 1 (F ") gives the pyridiniura compound listed in column 3. The reaction of this compound with K ₂ CO ₂ and copper bronze according to Example 1 (G) gives the end product listed in column 4.

40981 8/1207

Example no.

10

11

CX

CH ₂ OH

Br

Br

Br

0 V-CH ₂ OH Br

Cl- \ O / - ^CH 2 ^CH 2 ^Br "Br

CH, 0 - (O VcH ₉ CH ₉ Br

³ \ / ² ^ 3r

Br

CH ₃ SO ₂ Br

.CHo — CH - ^^ x ^ sw "ρ ¹

[QT ² ■ ² YRi .Br ^H

NH ₂ . Br _cl

Br

Br ^^ OCH-

.Br

Br ⁹

Example no.

8th.

Cl

CH ₂ -CH

OCH-

10

11

CH ₃ SO ₂

cn KJ CD

CO

4098 18/1207

Example no.

12th

15th

NH

.Br

.CH ₂ -CH ₂

NH ₂ Br

Br

• Br

.Br

, -CH,

· F

SO ₂ N (CH ₂ CH ₃ ),

Example no.

16.

1S

¹ 7 H ₂ NSQ ₂

Br

P ₃ C -Zqy CH ₂ CH ₂ Br

Br

Example NT.

16

17th

18th

19th

CH ₀ -CH,

.Br ^v

Br

NH ₂ Br

.Br ⁹

CH ₀ -CH

NH

CF

Cl .Br

NH ₂ Br

• Ν

To

'SO ₂ NH ₂

CH ₀ -CH
²

Example no.

20th

22nd

CH-

CH ₂ OH

Br

. (CH- I

CH,

CH ₂ J ₂

Cl

CH ₂ OH

Br

(CH ₃ CH ₀ ).

Br

CH ₂ CH ₂ Br

Br

cn ro

OJ

cm οι cn WWW CJ - OO

OJ OJ

409818/1207

Examples 23 "through 4-2

According to example 1, but using the one listed in column 1 substituted 2-aminopyridine is obtained in column 2 listed quaternary salt. Implementation of this connection. according to example 1 gives the end product listed in column 3.

, 4088 18/1207

• Η · P, U

OJ

A 0 9 8 1 8/1 2 0 7

C \ J

Example no.

26th

27

H ₂ CH ₃

N NH,

OCH ₂ CH ₃

NH.

'N

CH ₃ CH ₂

NH,

OCH ₂ CH ₃

.Br

Br

QCH ₂ CH ₃

Br

CH ₃ CH ₂

N-

CH

N '

CH-

H ₃ CH ₂ C

CH ₂ -CH

Br

CO CM

trj tu

U— "U —O

ro CN M. K
sz U ro CN S.

- •• Η P4

• ri ω m

CTv CM

409813/1207

Φ
U CQ

• η · ruu w 's;

CD 'Τ3

CJ

U CN

Ι-Λ

CN

409818/120 7

235291a

CQ

tf ¹

υ £ W

I. in H CL) • Η · £ \ Ph • Η '' Φ PQ

A098 18/1207

Example no.

ο

CH ₃ (CH ₂ ) ₄ ^N

NH,

ov s

N NH,

CH ₃ (CH ₂ ) _4θ

.Br '

Br

NH ₂ .Br

(CH,), - (O

^l 2'2

Br

Br

.CH ₂ -CH

H CQ

U CQ

CJ

ίο

• Η ' Q) PQ

409818/1207 (Λ!

"Example" 43

11,12-Dlhvdropyrido / 2,1 ~ b // i -, 5 / benzodiazepine A solution of 18 g of 2-amino-1- (o-bromophenethyl) -pyridiniu.mbromid and 14.7 g of potassium carbonate in 100 ml of n- Propanol and 200 ml of water are mixed with 0.5 g of copper bronze "and ^{heated to 90 °} C. under nitrogen as protective gas and with stirring for 2 1/2 hours. The mixture is then cooled and extracted three times with 100 ml of diethyl ether each time. The" the extract is washed, dried and evaporated. The residue is recrystallized from diisopropyl ether. Yield 10 g of the title compound with a melting point of 122 to 124 ° C.

B e i s ρ i e 1 44

A) 1,2-dihydro-2 ~ imino-1- (o-bromophenethyl) -pyr.i.din A solution of 3.3 g of sodium methylate in 120 ml of anhydrous methanol is mixed with 10.8 g according to Example 1 (G) 2-amino-1- (o-bromophenethyl) pyridinium bromide produced. The solution is stirred for 2 hours under nitrogen as a protective gas and then heated under reflux for 5 hours. The solvent is then distilled off under reduced pressure and the residue is digested with 200 ml of anhydrous diethyl ether. the

Pressure ether solution is washed, dried and under reduced / • evaporated. 6.8 g of a yellow solid remain which, after recrystallization from hexane, melts at 68 to 70.degree.

vB) 11,12-dihydropyrido / 2,1-b / i, l7benzodlazepin · '. _ _ 5.6 g.der compound obtained in (A) in 100 ml of xylene are added to 2.8 g of potassium carbonate and 0.5 g of copper bronze and heated under reflux for hour .3 ". The mixture is then fil j

4098 1-8 / 1207

and the filtrate was evaporated under reduced pressure. The residue is recrystallized from diisopropyl ether. Yield 2.3 g of the title compound with a melting point of 122 to 124 ^° C.

Examples 45 to 47

According to Example 1 (B) to (G), but using the compounds listed in column 1 in stage (B) and using the 2-aminopyridines listed in column 2 in stage (F), the pyridinium compounds listed in column 3 and from these the benzodiazocines listed in column 4 are prepared.

40981 8/1207

CNJ

ro cn W ÜJ O

U-U-13-CQ

ro it O — U — S3—

lf \

409818/1207

CM

(N

OO CN CN \\ //

U — U-K-CO-

in

409818/1207

Examples 48 to 55

According to Example 1, but using the 2-aminopyridines listed in column 1, those listed in column 2 are obtained Pyridinium compounds. The implementation of these compounds according to Example 1 gives the end products listed in column 3. ·

409818/12 07 ^J

CD U

f-l

ω ■ Η ·

Ρη> <

WS • Η

CJ

A 09 818/1207

05

Φ H CQ

(M

ΙΓ \

409818/1

u ffl

υ -Cf \ ro in W. I. φ • rl O. Vi U ' pq

in in

4 0.98.11 / 120

Examples 56 'through 67

According to 1 (B) to 1 (G), but using the one in column -1 Compounds listed and using the aminopyridines listed in column 2 receives one.die listed in column 3 Pyridinium compounds and from these those in column 4 listed benzodiazepines.

4098 18/1207

PhJh • Η '"* O

U (Q

ΙίΛ

409818/1207

ιη

W.

H Φ • Η

LT \

4.09 8187 120 7

(N pq ir! U U U CN
S.
H m ro OJ MD UD ■ -

4 0 9 8 18/1207

υ m βΓ U U I. m H ω • Η · VO LQ ',?; • Η ω PT

409818/12

Example 68

Manufacture of a drug in capsule form Components _ '. mg / capsule

11,12-dihydropyrido / 2,1-ρ7 / ϊ, 3 / benzodiazepine 400 Thickness .80

Magnesium stearate. '"5

The drug, starch and magnesium stearate ground together mixed. "The mixture is filled into hard gelatine capsules of suitable size up to a filling weight of 485 mg / capsule.

Example 69

Manufacture of a drug in tablet form Ingredients mg / tablet

12,13-dihydro-3-methylmercapto-11H-pyrido
/2,1-b//i,37toenzodiazocin 300

Lactose '' 200

Corn starch (to mix) 50

Corn starch (for paste production) 50

Magnesium stearate '6

The drug, lactose and corn starch (to mix) are mixed together. The corn starch for paste production is dissolved in water in an amount of 10 g / 80 ml of water suspended and heated with stirring until a paste forms

det. This paste is used to granulate the powder mixture. The moist granules were passed through a sieve of 2.33 mm mesh size and dried at 50 ⁰ C. Then ^L 4Ö9818 / 1207

the moist granulate is passed through a sieve with a mesh size of 1.0 mm. The mixture is made with magnesium stearate added as a lubricant and compressed into tablets in a tablet machine. Each tablet contains 300 mg of the drug. . . ■

Example 70

Manufacture of a drug in the form of a syrup Ingredients . - crowd

11,12-dihydropyrido / 2,1 -b // i, 3_7benzodiazepine sorbitol solution (70 percent NF)
Sodium benzoate

■ sucaryl

■ saccharin

red dye (F.D. & C. No. 2) cherry aroma distilled water ad

The sorbitol solution is added to 40 ml of distilled water, and the drug is suspended in this solution. Then the sucaryl, saccharin, sodium benzoate, the cherry aronia and the red dye dissolved in the solution. The volume is made up to 100 ml with distilled water.

. In this medicine, instead of the aforementioned ingredients other ingredients can also be used. For example, a suspending agent such as bentohite magma, tragacanth,

- Carboxymethyl cellulose or methyl cellulose is used.

Phosphates, citrates or tartrates can be used as buffer substances _j

409818/1207

500 mg 40 ml 150 mg 90 mg 10 mg 10 mg- 50 mg 100 ml.

be used. Preservatives can also be added, such as hydroxybenzoic acid esters or sorbic acid, and other flavorings and colors. '-

AQ9818 / 1207 ^J.

Claims (1)

Claims 1. Common dihydropyridobenzodiazepines and benzodiazocines Formula I. (D in which R is the same or different and is a hydrogen, fluorine, chlorine or bronze atom, an alkyl radical having 1 to 4 carbon atoms, an alkoxy radical having 1 to 4 carbon atoms, an alkyl mercapto radical having 1 to 4 carbon atoms, a benzy ^ .-, phenethyl, ^ henyl, phenylmercapto- or a phenyl group monosubstituted by a fluorine, chlorine, bromine or iodine atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy radical with 1 to 4 carbon atoms or a trifluoromethyl group, and R is in the 3 and / or 5 position, presumably R represents a calogen atom, R ^{1 represents} a hydrogen, fluorine, chlorine, bromine or iodine atom, an alkyl radical with 1 to 9 carbon atoms, an alkoxy radical with 1 to 4 carbon atoms, an alkyl mercapto radical with 1 to 4 carbon atoms, an alkylsulfonyl radical with 1 up to 4 carbon atoms, a phenyl, phenyloxy, sulfaemoyl or dialkylaniidosulfonyl group with 1 to 4 carbon atoms in each alkyl radical, a trifluoromethyl or a fluorine, chlorine, bron or iodine atom, an alkyl radical with 1 to 4 carbon atoms , an Alkoxyrect with 1 to A carbon atoms or a Trifluorziothylgruppc monosubstitutedc}? henyl or Phoiiyloxygruppe bedcutotj η don I.'ert 1 or 2 and η den '/ crt 2 or 5, un <l their Salrre. 40 9818/1207 BAD ÖRK31NÄL 2 = 11,12-Dihydropyride_j2 ", 1-b / II, 3! Benzodiazepines 3. 12 , IB-Dihydro-S-Kiethylir.ercapto-IIH-pyrido (2, 1-bJ II _P 3i benzodiazozino * ■ · "409818 / 1-20? ■ 4. Process for the preparation of the compounds of the general Formula I according to Claim 1, characterized in that a compound of the general formula IV or V (IV) in the R, R ^! , m and η have the meaning given in claim 1, condensed in a solvent with a base and in the presence of copper as a catalyst and optionally the compound obtained by reacting with an inorganic or organic acid converted into a salt. 5. The method nach.Anspruch 4, characterized in that one a pyridinium compound of the general formula IV · ■ (R) JCi (CH ₉ ) 2'n · ..Br (IV) in a mixture of water and a water-miscible alcohol as solvent in the presence of copper as catalyst and at least 2 Mbläquivalenten of alkali metal hydroxides, alkali metal carbonate, alkali 'limetallmetaborats or alkali metal tetraborate-alkali metal phosphate trie on Temperature ^ of ~ twa 60 to .120 ⁰ C heated. L. 4QS818 / T207 - GL- 6. The method according to claim 4, characterized in that one a compound of the general formula V (R) St. (CH ₂ J _n NH (V) in a water-miscible alcohol and at least 1 mol equivalent of an alkali metal hydroxide, alkali metal carbonate, tris-alkali metal phosphate, alkali metal metaborate or Brings alkali metal tetraborate in the presence of copper as a catalyst to implement. 7. The method according to claim 4, characterized in that a Pyridiniumverb.verbindungen of the general formula IV .Br H ₂ Br ' (IV) with at least 2 hol equivalents of potassium carbonate and copper as Catalyst in dimethylformamide, prostitute thy! Acetamide, dichlorobenzene, Bringing trichlorobenzene or diethylbenzene to the implementation. 8. Medicaments consisting of a compound according to claim 1 and customary carriers and / or diluents and / or auxiliaries. / ■ Λ 4 0 9.8 1 8/1 20 7 BAD ORKStNAL