DE1920908A1 - Benzodiazocine derivatives - Google Patents

Description

r. Ing. Ä. van der Werft Dr. Franz iederer

PAIENRANWALTF

RAN * ΚΧ) 8/129

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Benzodiazocine derivatives

The invention relates to 6-aryl-l, 5-benzodiazocines and 6-aryl-l _J 5-t> enzodiazocin-2 (lIl) -ones substituted in the 1-position, a process for the preparation of these compounds and pharmaceutical preparations which contain them Connections included.

The invention particularly relates to compounds of the general formula

Yard / 9 Λ. 1969

909845/1764

where A is the group

CH-K

or

D is a methylene or a carbonyl group, R and R _{1 are} hydrogen, halogen, amino, nitro or trifluoromethyl; Rp hydrogen, lower alkyl, lower alkenyl, benzenesulphonyl, lower alkylphenylsulphonyl or lower alkanoyl,

R_ and Ru hydrogen or lower

, R ₁ - water

Substance, halogen or nitro and R ^ are hydrogen, lower alkyl or lower alkenyl, but in the event that D is a carbonyl group, R "is lower alkyl or lower alkenol, and acid addition salts of these compounds.

Compounds of the formula I in which D is a methylene group and A contains the radical C = N are as l, 2,5,4-tetrahydro-l, 5-benzodiazocine. links of the formula I, in which D is a methylene group and A

contains the radical CH-N ^, are listed as 1,2,3,4,5,6 " I 6"

909845/1764

hydro-l, 5- ^ enzodiazocirie called. Compounds of formula I, where D is a carbonyl group and A is the radical

C -— N contains as 3 * 4-Dinydro-1,5-kenzodiazocin-2 (1H) -oneund Compounds of the formula I in which D is a carbonyl group

means and A contains the radical CH NL ₁₀ as

J, H , 5,6-tetrahydro-1,5-benzodiazoein-2 (1H) -one.

The term "lower alkyl" as used here relates to straight-chain or branched saturated hydrocarbon radicals having 1-7, preferably 1-4 carbon atoms, such as methyl, ethyl _, propyl, isopropyl or butyl, etc. The term "halogen" relates to all four halogens, ie chlorine, bromine, fluorine and iodine, unless specifically indicated otherwise. Representative examples of the term "lower · alkanoyl" are the acetyl, propionyl and butyryl groups. As an example of a lower alkylphenylsulfonyl group, a methylphenylsulfonyl group such as the tosyl group can be mentioned. The term "lower alkenyl" as used here includes straight-chain or branched hydrocarbon radicals with 2-7 carbon atoms which contain an olefinic bond such as, for example, the allyl group.

In a further aspect, the invention relates to a process for the preparation of Benzcdiazocinverbindungen the Formula I and acid addition salts of these compounds. That

909845/1764

The method according to the invention is characterized in that. «3 one is a compound of the general formula

N-

-D.

H ₂ N

II

wherein Ru is hydrogen, lower alkyl , lower alkenyl, benzenesulphonyl or lower alkylphenylsulphonyl, B phenyl, halogen-substituted phenyl, nitrophenyl or pyridyl and R, R., R-, L and D have the meaning given in formula I, cyclized or to prepare compounds of the formula I in which D is a methylene group, a compound of the formula

VI

909845/1764

wherein. R, R., R _; ., R _; ,, R-. and 3 have the meaning given above - and Hal denotes a halogen atom, reacts with ammonia in an inert organic solvent and, if necessary, reduces the 5-6 double bond in a compound obtained, if necessary converts an amino group present as an R ^ substituent into a halogen atom, If desired, a compound in which D is a methylene group and Rp is hydrogen, treated with a lower alkanoylating agent, if desired, a compound unsubstituted in the 1- and / or 5-position with a lower alkylating or lower alkenylating agent to introduce a lower alkyl - Treated or lower alkenyl group in the 1- and / or 5-position and, if desired, a compound obtained is converted into an acid addition salt.

According to one embodiment of the process according to the invention, a compound of the formula I in which D is a methylene group and A contains the radical C = ⁵⁵ N can be obtained by heating a compound of the formula

III

909845/176 / *

where R, R, R- and R ₂ , the meaning mentioned above, B phenyl, ilalophenyl, -iitrophenyl or pyridyl and R ^ hydrogen, - lower alkyl, lower alkenyl, benzenesulphonyl or lower alkyl-phenylsulphonyl mean,
getting produced.

This cyclization reaction is carried out in the presence of a inert organic solvent such as a lower alkanol (ζ.3. Ethanol), pyridine, aniline, triethylamine, tetrahydrofuran or dimethyl sulfoxide or a hydrocarbon such as benzene or toluene. The temperature is in terms of successful completion of the cyclization reaction is not critical. However, the reaction is preferred carried out at an elevated temperature, for example at the reflux temperature of the reaction mixture.

Compounds of the formula III, in which Ry has the meaning If hydrogen is present, it can be treated, for example, by 3handling a compound of the general formula

IF

909845/1764

wherein R, R ₁ , IU, R ^. and B have the meaning given above,
obtained with a hydrolyzing gown.

For example, among the numerous hydrolyzing agents that are useful for these purposes, there may be dilute mineral acids such as dilute hydrochloric acid, preferably dissolved in a lower alkanol, e.g. methanol. So are methanolic or ethanolic hydrochloric acid is particularly suitable for carrying out the hydrolysis. Although temperature and pressure are not critical aspects in the conversion of compounds of the formula IV into the corresponding compounds of the formula III the reaction will preferably take place at elevated temperature, i.e. at temperatures between about 50 ° and about 130 °, particularly preferably at the reflux temperature of the reaction mixture in which the hydrolysis of the compound of the formula IV to give the corresponding compound of the formula III is carried out, accomplished.

Compounds of the formula III can also be obtained by reacting a compound of the formula

909845/1764

Vi or in R, R ,, Rn and B have the meaning given above •. ",. RR ^

with a compound of the formula Hai - CHp-CH-CH-NHp, in which Hai, R, and Ru have the meaning given above, are prepared in a manner known per se.

In a further embodiment for the production of connections of the formula I, in which D is a methylene group and A

contains the radical C = N, a compound of the general my formula

Ή — Hal

VI

where R, R ₁ , R ^, R ^, R ^, Hai and B. have the meaning given above,

treated with ammonia in the presence of an inert organic solvent. As inert organic solvents can a lower alkanol such as ethanol will. The reaction is preferred in the presence of an "alkali metal halide" such as a ^ alkali metal iodide (preferably

909845/1764:

-9- 19209Q8

Potassium iodide or sodium iodide). Temperature and pressure are not critical aspects of this process step. The reaction is preferably carried out at elevated temperature, for example at temperatures of about 75 ° to about '150 °, and under pressure, for example at a pressure of about 6 to about 80 atm., Accomplished. In treatment of a compound of formula VI with ammonia the corresponding compound of the formula III is obtained. The compound of the formula III does not have to be isolated from the reaction mixture, but can be converted directly into the corresponding compound of the formula I by heating.

In a further aspect of the process, compounds of the formula I in which D is a carbonyl group can be obtained be made by making a compound of the'Formula

VII

where R ₈ R ₁ and B have the meaning given above fo © sifcz. @ n and R- denotes lower alkyl or lower alkenyl,

IQ § 141 / i IS 4

with a compound containing a carbobenzoxy radical of formula

Q H

X C

II O

I It

N C-

OCH

VIII

wherein FU and R ₂ have the meaning given above and X is chlorine, fluorine or bromine,

converts, whereby a compound of the general formula

C OCH,

IX

wherein R, R ,, Rp, R .., Rj, and B have the meaning given above,
receives ^ which then in a manner known per se

S88S45 / ^: 1784

speaking compound of the general formula

PIPE

I ² II

where R, R ,, Rp * R ,, R ₁ , and B have the meaning given above »
can be hydrolyzed. -

The compound of the general formula X obtained in this way can be cyclized by heating, preferably in a temperature range from approximately 50 ° to approximately the reflux temperature of the reaction mixture, and the corresponding compound of the formula I is obtained, in which A contains the radical C ^{=== 1N} and D means a Carbony! Group.

Compounds of the formula X do not have to be isolated from the reaction medium in which they were prepared, but can directly into the corresponding compounds of the formula I, in which D is a carbonyl group and A is the radical ; ss = iN contains, transferred by heating the reaction mixture will.

90S84S / 1764

. - 12 -

192Ö908

To remove the acyl radical, a compound of the formula IX ₁ can be treated with any conventional hydrolysis system, for example with a mixture of hydrobromic-acetic acid, in order to hydrolyze the carbobenzoxy radical, whereby the corresponding compound of the formula X is obtained. As noted above, the compound of the general formula X obtained in this way can then be converted into the corresponding compound of the formula I either without prior or after prior isolation by heating the reaction mixture to the temperature mentioned above. It is therefore not necessary to isolate a compound of the formula X before the ring closure, but the ring closure to a compound of the formula I, in which D is a carbony group and A contains the radical C ^ = N, can take place in situ in the reaction mixture, which contains the compound of the formula X, can be carried out by simply heating. If the compound of the formula X is isolated from the reaction mixture, the latter is heated in the presence of an inert organic solvent such as, for example, toluene or benzene, whereby the ring closure is brought about.

'The formation of a compound of the formula IX by reaction a compound of formula VIII with a compound of formula VII happens preferably at a temperature between about 10 and about 75 °, more preferably at room temperature in the presence of an inert organic solvent such as an ether such as ethyl ether, methylene chloride,

90984S / 1764

Chloroform or a hydrocarbon such as benzene.

Compounds of the formula I in which the group Λ is an intrinsic bond between positions 5 and 6 can be found in converting the corresponding compounds of the formula I in which A contains the radical CH - NH by reduction. Let it be For example, the compounds containing an imino bond react with hydrogen in the presence of a suitable hydrogenation catalyst, for example Raney nickel or a noble metal catalyst such as Reduce palladium, and a compound of the formula I is obtained in which A contains the radical CH - NH. This reduction can also be carried out with lithium aluminum hydride.

The choice of reactants and reaction conditions should be made in accordance with the result sought will. For example, if a compound of formula I wherein

A contains the radical C = N """*" and R, means halogen, is hydrogenated in the presence of a noble metal catalyst such as palladium or platinum, can simultaneously. Dehalogenation and reduction of the imino bond in group A occur and a compound of the formula I is obtained in which R _{1 is} hydrogen

and A contains the group CH Ns _n T ₁ . Continue if

¹
in a compound of the formula I, R, and / or R ^. represents a nitro group), a conversion of the nitro group into an amino group goes hand in hand with the reduction »The amino group

909S4S / 1764 ■ - '.

can be converted to halogen by, for example the compound with nitrous acid and then with a Hydrohalic acid, for example hydrochloric acid ^ in the presence of a copper halide, for example copper (I) chloride treated. A compound of the formula I is obtained in which R, or R, - is halogen, for example chlorine. Will

a selective hydrogenation of the imino bond to a CH N \ u -

Binding sought in compounds of formula I, which one Contain nitro group, so as reducing agent dirnethylaminoborane or diborane is used in the usual manner. The reduction is achieved by using diborane or dirnethylaminoborane the imino group is achieved without a nitro group present in a compound of the formula I being affected.

_{Furthermore, compounds of the formula I in which R 1} or R 1 denotes nitro can be prepared from the corresponding compounds of the formula I in which R or R 1. Hydrogen means to produce by treating the latter compound with nitric acid in the presence of a mineral acid such as sulfuric acid.

In all of the compounds described above, the substituents R, R _{1, R 2 and R 2 can have} a meaning other than hydrogen if the starting material or the benzodiazocine end product is treated accordingly. For example, the starting material or any d®r intermediates can directly halogenated in a known manner "or nitrating be =:

909845/1764

■ - 15 -

Compounds of the formula I in which D is a methylene group and R _{2 is} hydrogen can be converted into the corresponding compounds in which R _{2 is} lower alkyl by alkylation. The alkylation can be effectively carried out by treating the compound of formula I in which R is hydrogen with sodium hydride or with an alkali metal alkoxide such as sodium methylate in the presence of an inert organic solvent such as toluene, whereby the corresponding sodium derivative of the compound is prepared and subsequent reaction of the so obtained sodium derivative with a dialkyl sulfate or an alkyl halide in an inert organic solvent - for example a hydrocarbon or dimethylformamide - accomplish. Suitable dialkyl sulfates include methyl sulfate. Suitable alkyl halides include methyl iodide. If a compound of the formula I, in which D denotes a methylene group and R 1 denotes a lower alkenyl group, is sought, the same technique as described above for the alkylation is used, with the exception that a lower alkenyl halide is used instead of a lower alkyl halide how an allyl halide can be used. If an excess of alkylating or alkenylating agent is used in the alkylation or alkenylation, for example a lower alkyl or lower alkenyl halide, treatment of a sodium derivative of a compound of the formula I in which D is a methylene group and A is the radical CH-N ^ is obtained _ contains * i-rorin R, meaning hydrogen, one

I % ^ö

1,5-disubstituted compound «A 1,5-disubstituted compound

S09845 / 1764

Binding can also be achieved by treating a compound of the formula I in which R_ is different from hydrogen and A is the

Group CH NH contains, with an excess of "down

Alkyl halide or lower alkenyl halide obtained.

Compounds of the formula I in which D denotes a methylene group and which contain a benzenesulfonyl group or a lower alkylphenylsulfonyl group in the 1-position can be prepared from the corresponding compounds of the formula V in which Hn denotes a benzenesulfonyl or lower alkylphenylsulfonyl group. Furthermore, a compound of the formula I, in which D is a methylene group and Rp is lower alkanoyl, can be obtained from the corresponding compounds of the formula I in which R _{2 is} hydrogen, by treating the last-mentioned compound with a lower alkanoylating agent such as acetic anhydride or acetyl chloride in the usual way Treated wisely. In a similar manner, compounds of the formula I in which D is a methylene group and Rp is hydrogen, by treatment with a benzenesulfonyl halide or an alkylphenylsulfonyl halide, for example tosyl chloride, can be converted into a corresponding compound of the formula I in which R _{2 is} benzenesulfonyl or lower alkylsulfonyl .

Alternatively, if a compound of the formula I contains a sulfonyl group in the 1-position, this can be removed by treatment be removed with, for example, ^ .Lithiumaluminiumhydrid.

909845/1764

A connection can also be made with lithium aluminum hydride

means N _x ^

of the formula I, in which D is a carbonyl group / and A is C == - N Contains radical, in a corresponding compound of the formula I,

means "^ v" * ■ "* ■ in which D contains a methylene group / and A contains a CH — NII radical, without converting at the same time as dehalogenation.

As mentioned above, the invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula I. The compounds of formula I form pharmaceutically acceptable acid addition salts with one or several moles (depending on the number of basic nitrogen atoms present in the molecule) of inorganic or organic acids such as hydrochloric acid, hydrogen bromide acid, sulfuric acid, phosphoric acid, nitric acid, citric acid, tartaric acid, salicylic acid, toluenesulfonic acid, ascorbic acid, Maleic acid, succinic acid, formic acid and acetic acid.

In a preferred embodiment of the invention, R 1 and Ru in formula I are each present as hydrogen atoms. In a further preferred embodiment, R, R_ and R _{1 are} each hydrogen, Rp is hydrogen or lower alkyl, R, chlorine, bromine, hydrogen or nitro. In a particularly preferred embodiment, R ₁ denotes chlorine, bromine or nitro, R 1 and Rp. Each denote hydrogen (when D denotes a methylene group, R ₂ denotes hydrogen or lower alkyl and when D denotes a carbonyl group, Rp denotes lower alkyl) and

909845/1764

- ιβ -

A · contains the radical C = ¹ H, where B is preferably phenyl. In a further preferred embodiment, A contains a 2'-halo, preferably the 2'-pluorpheiiyl radical, a 2'-nitrophenyl radical or the 2-pyridyl radical.

Compounds of formula I and their acid addition salts are valuable as anticonvulsants. '■

Compounds of the formula I and the corresponding acid addition salts can be used in common pharmaceutical preparations. E.g. you can in on the individual Dosages tailored to requirements in liquid or solid suitable for enteral or parenteral administration Forms of preparation such as tablets, capsules, coated tablets, suppositories, Suspensions, solutions, emulsions, etc. are used, which are the usual carrier materials suitable for pharmaceutical purposes or excipients such as lactose, corn starch, talc, calcium stearate, polyalkylene glycols, ethanol, vegetable Contains oils, cocoa butter and the like. Possibly the preparation forms can be sterilized and contain further pharmaceutical auxiliaries such as buffers for adjustment a suitable pH, emulsifier, preservative, Means for changing the osmotic pressure usvr »You can also contain other therapeutically valuable substances.

The following examples illustrate the result. All

Temperatures are given in degrees Celsius

009845/1784. ■ -

example 1

A solution of 5.0 g (16.2 mtfol) 9-chloro-1,2,5,5-tetrahydro-7-phenylpyrlmldoll, 2-a] ll, 4] benzodlazepine in 25 ml 3 η hydrochloric acid and 25 ml of ethanol xilvä heated to reflux for 18 hours. The reaction mixture is poured onto excess ice and ammonium hydroxide and the resulting mixture is extracted with methylene chloride. The organic extract is washed with water and dried, and the solvent is stripped off in vacuo. A yellow, rubbery residue remains. Crystallization of this gummy residue from methylene chloride / cyclohexane / petroleum ether gives yellow prisms with a melting point of 78-85 °. The free base is converted into 2 (3-aminopropylamino) -5-chlorobenzophenone hydrochloride. After recrystallization from isopropanol / ether, the hydrochloride is obtained in the form of yellow needles which melt at 170 °.

A solution of 2.7 g (1 mmol) of 2 (3-aminopropy.lamino) -5-chlorobenzophenone in 100 ml of pyridine is refluxed for 17 hours. The solvent is removed under reduced pressure and the residue is taken up in methylene chloride and water, the organic layer is washed with water, getPSSiCnet and evaporated. A gummy residue remains. The gummy residue becomes with aluminum oxide Benzene chromatographed. 8-chloro-6-phenyl-l, 2,3> 4-tetrahydro-l, 5-bensodlaHocin is obtained with a melting point of 146-150 °.

909845 / 17RA

'- 20 -

After Umkrintallisatio'n from cyclohexane / hexane, the product melts ■ at 150-151 °.

Example 2

A solution of 17.4 g (50 nmoles) of 7-chloro-1- (3-chloropropyl) -lO-dihydro-S-phenyl-SH-l / ^ - benzodiazepin ^ -one in 100 ml of hydrochloric acid and 100 ml of ethanol is refluxed overnight. The reaction mixture is cooled, washed with ether, neutralized with ammonium hydroxide and extracted with ether. The organic phase is washed with water, dried, evaporated in vacuo. A yellow oil remains behind. Chromatography of the crude product on aluminum oxide with hexane gives 2 (j5-ChlorpropylaminG) -5-chlorobenzophenone as pure yellow oil, which crystallizes when standing. Pp. 60-62 °. Recrystallization from hexane yields yellow prisms, which at 61.5-635 ° melt.

A solution of 15.9 g (51 * 6 mmol) of 2 (3-chloropropylamino) -5-chlorobenzophenone in 100 ml of 90-100% formic acid is treated with 50 ml of a ½% solution of aqueous formaldehyde. The reaction mixture is refluxed for 17 hours. After that the color has changed to yellow. The reaction mixture is poured onto ice, made basic with sodium hydroxide and extracted with methylene chloride. The extract is chromatographed on aluminum oxide with hexane. One obtains

909845/1764

2 ^ -ChlorpropylmethylamlnoJ-S-chlorobenzophenone. After distillation the product has a Kp.:0.6 mm 191-193 °

A mixture of 5.7 g (17.7 mmol) of 2 (3-chloropropyl-methylamino) -5-chlorobenzophenone, 5.32 g (20 mmol) potassium iodide, 35 ml of ethanol and an excess of ammonia is 6 hours at 90 ° and at a pressure of 11.2 atm. shaken. The unimplemented Potassium iodide is filtered off and the solvent distilled off from the filtrate in vacuo. The residue will taken up in 1 η sodium hydroxide solution and methylene chloride. The organic layer is separated, washed with water and dried. It is evaporated in a vacuum. An orange colored oil remains. The crude product is made with hexane and ether chromatographed on aluminum oxide. O-chloro-1-methyl-6-phenyl-l, 2,3i ^ -tetrahydro-l, 5-benzodiazocine is obtained. After recrystallization from petroleum ether, the product melts at 111-113 °

Example 3

A solution of 244 g (0.6 mol) of 2- (p-toluenesulfonamido) -5-chlorobenzophenone. in S / Bitei · dry dimethylformamide is stirred with 6G5 »7 SO * O mol) l ^ -dibromopropane over NaOH at 60 *». The Reatefcionsgemisoh wi, -rö '"-gegossen suf 2 Lite ?. ice water and" stfcrahiept with * ^ fJltafe lenphlopiii;.., .The organlsöhe phase WlTiS with' 10 ώ "IJat ^ liiiilifösmwiSloBesig vmä flsssef g-gi-iasahe-s . That"

Is MafefMiSefJatsin, · ·. *

ORIGINAL INSPECTED

brown oil. The oil is added to ether and after 3-wöehiKOin When standing, 5-chloro-2iN- (p-toluenesulfonyl) ~ 3-bronipropylaminoj-benzophenone crystallizes from, which has a melting point of 92-96 ° »After recrystallization from ether, the product melts at 106-108 °.

A mixture of 52 g (0.26 mol) ^ sulfonylj-j-bromopropylaminoj-benzophenon, 90 g potassium iodide and an excess of ammonia in ethanol (300 ml) is at a pressure of 10.2 atm. Heated to 100 ° for 5 hours. That The potassium iodide is filtered off and the piltrate is evaporated. The residue is taken up in methylene chloride and dilute sodium hydroxide solution. The organic phase will washed with water, dried and evaporated. What remains is an oil consisting of numerous components, column chromatography on aluminum oxide with benzene and ether results

benzodiazocine with a melting point of 170-100 °.

"Sine solution of 0.5 g (1 * 65 mmol) of 8-chloro-6-phenyl - lj2, .3,4-

tetrahydrc-3,, 3-benzcdiaBsei » 'in 15 ssii Fyrldln and. IO ml- Äc @ t- -anhydriil is 5 hours at ZlPJiarfeiSiBperafcui? stirred * _: Bas - ■ -. ■:> ■ "- LISsnngsLiilitGl is used in the V & kaism- abss®gen unu. @S" hlsiberblelb ^: an "" orange colored © solid masses UsatoiLstsallisation; Äefeto © r / H £ ± äü - :

.- -OWGSMAL

tsvwäu- '. -

gives l-acetyl-e-chloro-b-pheriyl-l, 2,3 * 4-tetrahydro-l, 5-o diazocin as colorless prisms that melt at 154-156.5 °. That product melts at 156.5-158 ° after recrystallization Hexane.

Example 5

A mixture of 0.25 g of 8-chloro-6-phenyl-l, 2,3,4-tetrahydro-l, 5-benzodiazocine, 1 g of lithium aluminum hydride and 300 ml of anhydrous ether are refluxed for "90 hours. The reaction mixture is hydrolyzed and the ethereal solution is separated off. The ethereal solution is made with hydrogen chloride saturated. The precipitate is filtered off and the pale yellow S-chloro-ö-phenyl-l ^^ i ^^. Iö-hexahydro-l ^ - benzodiazocine hydrochloride recrystallized from methanol / ether. Colorless prisms with a melting point of 218-225 ° ♦ are obtained

Example 6

A mixture of 8.2 g (.19 * 3 mmol) of 8-chloro-6-.phenyl.-lp-toluenesulfonyl-l, 2,3,4-tetrahydro-l, 5-benzodiazocine, 5> 0 g lithium aluminum hydride and 400 ml ml anhydrous ether Heated under reflux with stirring for 96 hours. The reaction mixture is hydrolyzed and the ethereal solution is filtered. The solvent is removed in vacuo and it remains an OeI. The oil is in ether with a solution of chlorine

9098V5 / 1764

• - 24 -

Treated hydrogen in ethanol and b-chloro-ö-phenyl · lj-2,3,4 _i 5iö-hoxah, ydro-l _i 5- ^{| is obtained} '> enzodiazocin — dihydrochloride that melts at 200-210 °. . . . ■. .

Example 7

A solution of 6.5 g (23.8 mmol) of U-chloro-6-phenyl-1,2,3,4,5,6'-hexahydro-1,5-benzodiazocine in ethanol with hydrogen at a pressure of 5.4 atm. in the presence of palladium hydrogenated as a catalyst at 50 °. After the theoretical Amount of hydrogen is absorbed, the catalyst is filtered off and the filtrate is evaporated in vacuo. The crude residue is dissolved in methylene chloride and dilute ammonium hydroxide added and the organic phase dried. The solvent is removed in vacuo. What remains is 6-phenyl-1,2,3 * 4,5,6-hexahydro-1,5-benzodiazpcin. The dihydrochloride of this base is produced in the usual catfish and from methanol / ether recrystallized. Colorless prisms are obtained which are at 225-231 ° melt.

Example 8

A solution of 1.0 g (3 * 7 mmol) 8-chloro-6-phenyl-l, 2- ^^ - tetrahydro-l ^ -benzodiazocine, 50 ml of acetic acid and 100 ml Water is hydrogenated in hydrogen at atmospheric pressure and room temperature in the presence of platinum as a catalyst. A linear uptake of 2 equivalents of hydrogen will be

90984B / 1764

observed »The catalyst ¹ is filtered off and the filtrate is made alkaline with sodium hydroxide. Extraction with methylene chloride yields a crude free base from which 6-phenyl-1,2,3 * - 4,5> 6-hexahydro-1,5-benzodiazocine dihydrochloride is obtained.

Example 9

A mixture of 6.0 g (21.1 mmol) of Ü-chloro-l-methyl-6-phenyl- "l, 2.5> ^ - tetrahydro-l, 5-t> Gnzodiazocin, 250 ml of ethanol and palladium on charcoal as a catalyst is with hydrogen at a pressure of 2.9 atm. and hydrogenated at a temperature of 50 °. After taking up 2 equivalents of hydrogen the catalyst is filtered off and the solvent in Vacuum removed. A crude oil remains. The OeI will dissolved in ether. After adding hydrogen chloride to the essential Solution falls 1,2,3,4,5, o-hexahydro-1-methyl-o-phenyl-1,5-benzodiazocine dihydrochloride the end. Recrystallization of the dihydrochloride from Aethano} / Aether provides colorless prisms that melt at 198-205 °.

Example 10

A Xib'siing of- 1.0 g (3.7 iriMol) 8 * Chlop-6-ph @ nyl-l, 2,3,4-tsfcmhydro ~ l »5 * & ^ s © äiaaooin in $ 2- ml 'Jtyvtutti is 2.0 g

"p = Toluolsuifönylehloild versafest miä flau iasiiseh over · Kacht- h®t ZiMa ^ v ^ mpfStr & tuw leave» ■ Bas PyrlölB vflva ': lm "W & lmum ab- .- ._ ä © gs? Etl? 3lc§taiiä xu. Μ®$ϊϊΐ?Χ@ηΦ.1 <8ΐίΊα. unü 3 ss "Hatron Lye

ORIGINALINSPECTED

recorded. The aqueous phase is washed with water, dried and evaporated to a yellow tar in vacuo. Chromatography on alumina provides 8-Chlcr-6-phenyl-lp ~ toluenesulfonyl-l, 2,3 _J 4-tetrahydro-l, 5-benzQdiaaocin having a melting point of 110-115 ° ·

Example 11

A solution of 7.0 g (25.6 mmol) of 8-chloro-6-phenyl-1,2,3,4,5,6-hexahydro-1,5-benzodiazocine, 4.2 g of potassium hydroxide and 100 ml of ethanol is Carefully mixed with an excess of dimethyl sulfate (51 * 5 g). The resulting mixture is then stirred at room temperature for 5 days. The reaction mixture is made alkaline with sodium hydroxide solution and taken up in methylene chloride and water. The organic layer is washed with water / water, dried and evaporated. A gummy residue remains, which is chromatographed with hexane and aluminum oxide. One obtains 8-Chlorl * 2,5i4,5,6-hexahydro-l, 5-clirnethyl-6-phenyl-l _i-5 oenzodiazocin which melts at 105-110 °. Uril crystallization from petroleum ether yields colorless prisms, which melt at 115-114 °.

Example. JLg

Solution of 5.0 g (7Λ rssMoZ} -

9-09845 / 1764

in 250 ml

IMSPEGTED

. - 27 -

Ethanol is used in the presence of platinum as a catalyst Hydrogenated hydrogen. The theoretical amount of hydrogen is quickly absorbed and then the catalyst is filtered off, that The filtrate turns into a deep-melting solid mass in a vacuum evaporated, which can be recrystallized from benzene / hexane. O-chloro-1,2,5,4,5,6-hexahydro-O-phenyl-l-p-toluenesulfonyl-1,5-benzodiazocine is obtained with a melting point of 188-189 °

Example 13

A solution of 9.0 g (21 mmol) of 8-chloro-1 ^, 3,4,5,6-hexahydro-6 ~ phenyl-l-p-toluenesulfonyl-1,5-benzodiazocine in 250 ml of ethanol and 3% potassium hydroxide is carefully mixed with 50 ml of dimethyl sulfate are added and kept at room temperature for 5 days long stirred. The reaction mixture is washed with 10 η sodium hydroxide solution and taken up in methylene chloride and water. The organic layer is washed with water, dried and evaporated in vacuo. 8-chloro-l, 2,3i4,5,6-hexahydro-5-methyl-6-phenyl-l-p-toluenesulfonyl-1,5-benzodiazocine is obtained. After recrystallization from ether / petroleum ether, the product melts at 14-143 °.

A maleate salt is made by adding B-Chlorig, 3 »^ * 5» o-hexahydro-S-methyl-ö-phenyl-1-p-toluenesulfonyl-1,5-benzodiazocin treated with an ethanolic solution saturated with maleic acid. After recrystallization of the salt

909845/1764

colorless prisms are obtained from ethanol / ether. The maleate salt "melts at 168-170 °.

Example 14

A mixture of 3.0 g (7 mmol) of 8-chloro-l, 2,3 ^ i5 # 6-hexahydro-5-methyl-6-phenyl-l ~ p-toluenesulfonyl-l, 5-benzodiazocine, 1 * 5 g lithium aluminum hydride and 700 ml anhydrous ether is refluxed for 4 days with stirring. The reaction mixture is hydrolyzed, the ethereal solution by filtration freed from salts and evaporated. 8-chloro-1,2,3 »^, Si is obtained hexahydro-S-methyl-o-phenyl-1-4 benzodiazocine. After recrystallization from petroleum ether, the product melts at 125-126 °.

Example 15

A solution of 25 g (89 mmol) l _i 3-dihydro-7-nitro-5-phenyl-2H-l, 4-benzodiazepin-2-one and 9.7 g (0.18 mmol) of sodium methylate in 200 ml of dry Dimethylformamide is stirred for 1 hour at 50 ° and then 42.5 g (0.27 mol) of 1-bromo-3-chloropropane are added. The reaction mixture is stirred for 17 hours at room temperature and then poured onto 1.5 kg of ice. Extraction with methylene chloride gives an organic phase which is washed with water, dried and evaporated in vacuo. A rubbery mixture is obtained. Chromatography on aluminum oxide with chloroform gives 1- (3-chloropropyl) -l, 3-dihydro-r7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one. That

909845/1764

Hydrochloric! Salt is made and made from ethanol-ether recrystallized.

Example 16

A solution of 27.6 g (77.4 mmol) l- (3-chloropropyl) -l, 3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin ~ 2-one, 150 ml of ethanol and 150 ml of 3 η hydrochloric acid are refluxed overnight held. The reaction mixture is neutralized and extracted with methylene chloride. The extract is made with water washed, dried and evaporated in vacuo. 2- (3-chloropropylamino) -5-nitrobenzophenone remains. After recrystallization from ether / hexane the compound is obtained in the form of yellow prisms which melt at 84-86 °.

A mixture of 8.5 g (26.6 mmol) 2- (j5-chloropropylamino) - »5-nitrobenzophenone, 8.3 g potassium iodide, 200 ml ethanol and an excess of ammonia is 8 hours at 100 ° in a closed vessel heated. The solid products are filtered off and the piltrate is taken up in 1.5 η sodium hydroxide and methylene chloride. The organic layer is separated, washed with water and evaporated. Chromatographic separation gives 1,3,3,4-tetrahydro-8-nitrc-6-phenyl-1,5-benao-.öiazoein. Umkristall! Sation of Methylenohlorid / Iiexan supplies * i ^ö setealzen g £ uoe $ prisms at 25 * ~ 255 "

30-mS / m * ¹ OWGiNAL INSPECTED

Example 17

A solution of 1.0 g (3 * 6 mmol) 1,2,3, ^ - Tetrahydro-b- " nitro-6-phenyl-1,5-benzodiazocine and 50 ml of dry dimethylformamide are treated with 1.5 g of a 50% suspension of sodium hydride in mineral oil. The shiny red reaction mixture is stirred at 50 ° for 1 hour. The reaction mixture is then cooled to room temperature with 5 g of methyl iodide added and stirred overnight at room temperature. The mixture is fegeWMfiH ^ Effa in dilute Sodium hydroxide solution and methylene chloride added. The organic layer is washed with water, dried and evaporated in vacuo. 1,2,3 * ^ - tetrahydro-1-methyl-8-nitro-6-phenyl-1,5-benzodiazocine is obtained, that melts at 200-205 °. After recrystallization from methylene chloride-hexane it melts Product at 206-207 °. . -

Example 18 -

A stirred suspension of 22.4 g (0.1 mol) carbobenzoxy-β-alanine 300 ml of ether are mixed with an egg and aceton bath cooled to a temperature below 0 ° and then with 25 g (0.12 mol) Phosphorpentaefilorid added. The reaction mixture is stirred for 1 1/2 hours and then the ethereal solution decalated from solid substances; " The acid chloride solution obtained quickly becomes 20 g (87 mmol) of 5-chloro-2-methylamino-benzophenone, which was dissolved in 150 ra3 chloroform, added and the reaction mixture for 1 hour at room temp

.90984? / 1-764 "■■.; _0Rie i _NAL jMSP _E CTED

touched. The mixture is washed with water, 3 n. HatrlUKihydroxyd, Water, 3 η hydrochloric acid and washed again with water, dried and · evaporated in vacuo. 2- (ß-Carbobenzoxyalanyl-N-methylamido) -5-chlorobenzophenone is obtained.

The 2- (ß-carbobenzoxyalanyl-N-methylamido) -5-chlorobenzophenone prepared in this way is treated with 80 ml of a solution of hydrogen bromide (31/6) in acetic acid. The reaction mixture is stirred for 2 hours at room temperature and then mixed with ether. The deposited precipitate is separated off and washed several times with ether. A hygroscopic precipitate in a rubbery form precipitates out in 150 ml Water is dissolved. The solution is made alkaline with ammonium hydroxide and extracted with toluene. The received Toluene solution is refluxed overnight and the water that forms is collected in a water separator. The reaction mixture is evaporated in vacuo and a gummy residue is obtained, which consists of numerous components. Crystallization from cyclohexane yields light yellow prisms of 8-ChIOr- ^ »^ -dihydro-l-methyl-o-phenyl-ljS-benzodiazocin ^ - (IH) -on, which melt at 165-168 °. After recrystallization from cyclohexane, prisms are obtained which melt at 170-171 °.

Example 19

A mixture of 2.2 g (7.3 mmol) of 8-chloro-l-methyl-3,4-

dihydro-6-phenyl-l, 5-benzodiazocin-2 (lH) -one, 8.5 g lithium

909845/1764

aluminum hydride and 125 ml of dry ether are refluxed with stirring for 2 hours. The reaction mixture is hydrolyzed and the salts are filtered off. The filtrate is evaporated in vacuo. A residue remains which is crystallized from hexane. Colorless crystals of

diazocin that melt at 93-94 °. After recrystallization from hexane, the melting point is 100-101 °. An ethereal solution of 8-chloro-l, 2,3i ⁱⁱ -i5 »6-hexahydro-l-methyl-6-phenyl-1,5-benzödiazoein is saturated with hydrogen chloride and the dihydrochloride is obtained, which at 212-215 ° melts. Recrystallization from ethanol / ether gives colorless prisms that melt at 223-225 °.

« Example 20

A mixture of 2.3 g (δ mmol) δ-chloro-1-methyl-o-phenylliS ^ i ^ -tetrahydro-ljS-benzodiazocine, 3 * 0 g lithium aluminum hydride and 125 ml anhydrous ether was refluxed for 65 hours with stirring. The reaction mixture is hydrolyzed and the salts are filtered off. The filtrate is evaporated in vacuo. What remains is crude 8-chloro-li2,3,4. _# 5,6-hexahydro-1-methyl-o-phenyl-1 ^ -benzodiazoein, from which the pure product can be obtained as the hydrochloride in the usual way.

909845/1764

Example 21 _> .

A solution of 3.0 g (10 mmol) of 8-chloro-l ~ methyl-j5,4- • dihydro-6-phenyl-1,5-benzodiazocin-2 (lH) -one in 100 ml of ethanol is mixed with hydrogen Room temperature and atmospheric pressure • hydrogenated in the presence of platinum as a catalyst. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the piltrate is evaporated in vacuo. What remains is an oil which crystallizes from ether in the form of colorless prisms with a melting point of 15 ° -155 °. Recrystallization of the crude product from benzene / hexane gives prisms of 8-chloro-3 _t , 4,5 »6-tetrahydro-1-methyl-6-phenyl-1,5-benzodiazooin-2 (1H) -one, which at 156- Melting 157 °.

Example 22

A mixture of 9 * 0 g (29.2 mmol) of 5-chloro-2- (3-chloropropylamino) benzophenone, 5.0 g (30 mmol) of potassium iodide and about 5 g of ammonia in 25 ml of ethanol is at 121 ° and at a pressure of 10.2 atm, shaken in a closed vessel for 6 hours, the reaction mixture is poured onto ice and diluted © Hatroslawge and extracted with methylene chloride * D © i? The extract is dried and evaporated in vacuo. hi & feerfeXe & fefc '© in raw mixture; - ^ © mg «- (5 * Äräinopropyls« nino) - ..

! lach clTtroaiEtegjpäpliiSPl ¹ ISf ⁵ l ¥ ssia «i6S (llether-

ORIGINAL INSPECTED

via aluminum oxide) and recrystallization from ether, t3-chloro-δ-phenyl ~ 1 _, 2, J'j ^ -tetrahydro-1jS-benzodiazociii is isolated

Example 2y

An ethanol solution of 20.0 g of 2- (3-aminopropylamino) -5-nitrobenzophenone hydrochloride (60 mmol) and an excess of ammonia is at 125 ° under an excess pressure of 67 atm. Nitrogen shaken at 125 ° for 12 hours. After filtering off the salts and crystallization by adding Benzene to the piltrate becomes 1,2,3 * 4-tetrahydro-8-nitro-o-phenyl-1,5-benzodiazocine isolated.

Example 24

Capsules that contain Ebenzodiazocin-2 (lH) -one are made as follows:

contents

• 8-chloro-1-methyl-3,4-dpiydro-6-phenyl-1,5-benzodiazoein-2 (IH) -one

Lactose corn starch l'alfeun

-, "■ oesamtg@w3.chf 210 mg

per capsule mg 10 mg 165 mg 30th JüL. ■ _5.

2CiE) -OHi XiakfeC'SS & ά n ^ isstarfze w © s? Den in. A "- suitable

! WSPECTEO "■". ■

Mixer mixed. The mixture is passed through a crusher given. The finely pulverized mixture is brought back into the mixer, talc is added and pulverized again The mixture is filled into hard gelatine capsules on a capsule filling machine.

Example 25

A preparation suitable for parenteral administration, the δ-chloro-1 "ynethyl-3» ^ - clihydro-6-phenyl-1., 5-benzodiazGcin-2 (1H). on is made as follows:

Content per ml

e-Chlor-1-methyl-Ji ^ -dihydro-o-phenyl, 5-t> enzodiazocin-2 (1H) -one 5 mg

Propylene glycol 0.4 ml

Benzyl alcohol (benzaldehyde free) 0.015 ml

Ethanol 95% 0.10 ml

Sodium benzoate 4.88 mg

Benzoic acid 1,2. mg

Water for injections 1.0 ml

50ng e-

diazocin-2 (lH) -one become in0 ^ 5. ml of benzyl alcohol dissolved, then 4.0 ml of propylene glycol and 1 ml of ethanol are added. 12 mg of benzoic acid are dissolved in this solution. 48.8 mg sodium benzoate to be dissolved in 3.0 ml of water for injections

90 9 8 45/1764

* The solution is added with water for injections made up to a volume of 10 ml. The solution is filtered -in Suitable size ampoules filled, flushed with nitrogen and sealed the ampoules. The ampoules are placed at 0.7 atm for 50 minutes. autoclaved.

Example 26

™ tablets containing 8-chloro-l-methyl-3,4-dihydro-6-phenyll, 5-benzodiazocin-2 (lH) -one were made as follows:

Contents per tablet

ö-chloro-l-methyl - ^^ - dlhydro-ö-phenyll, 5-benzodiazoein-2 (lH) ~ one 25 * 00 mg

Dicalcium phosphate hydrate (unground) 175 * 00 mg Cornstarch. 24.00 mg

Magnesium stearate 1.00 mg "

Total weight 225 * 00 rng

ö-chloro-1-methyl-5 * ^ - dihydro-6-phenyl-1,5-benzodiazocin-2 (IH) -one and corn starch are mixed and passed through a crusher. This premix is then included with Dicalcium phosphate and half of the magnesium stearate mixed and passed through a grinder again. . The mixture is lumped and the lumps are again passed through a crushing machine, with the 2nd half of the

909845/1764

Magnesium stearate is added. The powder obtained is again carefully mixed and then pressed into tablets

i 6 Sf k I / Tl I L- ■ "' ORIGINAL INSPECTED.

Claims (1)

Patent claims 1. Process for the preparation of benzodiazocine compounds the general formula CH-R, where A is the group CH-N or D is a methylene or a carbonyl group, R and R, Hydrogen, halogen -ils3iao ₅ Mlfcro -or TrI fluorine thy Ij hydrogen, nieoep ίύΧψ1 _Ρ Medea? Alkenyl _5, benzene "" - Vt ^ ^ t ^ njlg down klk pli ^ ^ njl ulfon ^ l οά it down ■ ■ - il _v waae _l;... Fess ^ ^ ii'sfcöff or aiedei "alkyl *.
Btotff- lfcl © g © 2s Gä <rc W% ti? O wan R _r hydrogen ":." lower alkyl or lower alkenyl, but in the event that D is a carbonyl group, R _{0 is} lower alkyl or lower alkenyl, and acid addition salts of these compounds, characterized in that that you can get a compound of the general formula R R T- I = O. -D. CH-R ₇ II where Rr is hydrogen, lower alkyl, lower alkenyl, benzenesulphonyl or lower alkylphenylsulphonyl, B is phenyl, halogen-substituted phenyl, nitrophenyl or pyridyl, and R, R ,, R ,, R ^ and D are as defined in formula I. ,
cyclized or to prepare compounds of the formula I in which D is a methylene group, a compound of the formula VI 909845/1764 in which R, R ,, R- ,, R ₁ ,, Rn and B have the meaning given above and Hal is a halogen atom, with ammonia in an inert organic solvent and, if desired, in a compound obtained 5,6 double bond reduced, if necessary one as R -sub- atituent amino group converted into an Ilalogenatom, if desired, a compound in which D is a methylene group and R "is hydrogen, P treated with a lower alkanoylating agent, if desired a compound unsubstituted in the 1- and / or 5-position with a lower alkylation? - or lower alkenylating agent to introduce a lower alkyl or lower alkenyl substituent treated in the 1- and / or 5-position and, if desired, a compound obtained into an acid addition salt convicted. 2. The method according to claim 1, characterized in that that you can get a compound of the general formula N- CHo wherein R, R ₁ , R, R ^, Rg and B are as defined in claim 1-909845/1764 have a given meaning
cyclized or a compound of the formula fa N CH ₀ R - \ - I C = O Hal wherein R, R ₁ * R- ,, R ^, Ro, B and Hal have the meaning given in claim 1, reacted with ammonia. 3. The method according to claim 2, characterized in that that a starting material, in which R, R., and R ^ hydrogen, R ₁ chlorine, bromine or nitro, R _Q hydrogen or lower alkyl 1 ο and B is phenyl or 2'-halophenyl is used. H. Process according to Claim 1, characterized in that a compound of the general formula 909845/1764 wherein R, R., R, R. and 13 have the meaning given in claim 1 and R ^ 'is lower alkyl or lower alkenyl,
cyclized. 5. The method according to claim k, characterized in that a starting material in which R, R-, and Rj, V / water st off, R _{1 is} chlorine, bromine or nitro., R /. lower alkyl and B phenyl or * 2'-halophenyl is used. 909845/1764 6. A method for the production of preparations with anticonvulsant properties, characterized in that a Benzodiazocine derivative according to formula I in claim 1 to one medical preparations such as tablets, coated tablets, capsules, suppositories by means of the usual solid or liquid Excipients as used in pharmacy is compounded. 7. drug preparation with anticonvulsant properties, characterized in that they contain a benzodiazocine derivative according to formula I in claim 1 together with a suitable one. Contains carrier material. 909848/1764 8. Benzodiazocine compounds of the general formula CH-R- /. CH-R ₄ where A is the group ■ CH or D is a methylene or a carbonyl group, · R and PL are hydrogen, halogen, amino, nitro or trifluoromethyl; Rp is hydrogen, lower alkyl, lower alkenyl, benzenesulphonyl, lower alkylphenylsulphonyl or lower alkanoyl, R, and R. hydrogen or lower alkyl, R ₁ - hydrogen, halogen or nitro, Rg is hydrogen, lower alkyl or lower alkenyl, but for the If O is a carbonyl group, R _{2 is} lower alkyl or lower alkenyl before, 90984.5 / 1764 and acid addition salts of these compounds. 9. A compound according to claim θ the general formula R 1- II> HR ₅ . wherein R, R ,, R, R ₂ , and A have the meaning given in claim 8 and R _{2 is} hydrogen , lower alkyl, lower alkenyl, benzenesulfonyl, lower alkylphenylsulfonyl or lower alkanoyl, and acid addition salts of these compounds » 10. A compound according to claim 9, wherein R, R- and R _{2 are} hydrogen, R _{1 is} chlorine, bromine or nitro, Rg is hydrogen or lower alkyl and A is the radical C = N, where B is phenyl or 2'-halophenyl , mean and acid addition salts of these compounds. 11 .. A compound according to claim 8 of the formula 9 0 9.845 / 1764 1 θ20008 wherein R, R ,, R, R ^, and A have the meaning given in claim 8 and Rp is lower alkyl or lower alkenyl,
and acid addition salts of this compound, 12. A compound according to claim 11, wherein R, L and Rh are hydrogen, R, chlorine, bromine or nitro, Rp is lower Alkyl and A the radical ^ C == Nr, where B is phenyl or 2'-Halo represents genphenyl, mean and acid addition salts of these compounds. 13. 8-halogen-l, 2,3 * ^<! l - fcefcrahydro-o-phenyl- ^1,5-fc> enzodiazooine. 14. A l-acetyl-O-halogen-liS ^ i ^ -tetrahydro-o-phenyl-1 f 5-benzodiazocine. 15 * a likewise diassocin. 909845/3364. 17. A 1,2,3,4,5,6-hexahydro-1-lower alkyl-6-phenyl-1 j5-benzodiazocine. 1Ö. An 8-halo-1,2,3,4-tetrahydro-1-lower alkyl-6-phenyl-1,5-benzodiazocine. 19. An 8-halo-1,2,3,4-tetrahydro-6-phenyl-1-ptoluenesulfonyl-1,5-benzodiazocine. 20. A e - ^^ alkyl-6-phenyl-1,5-benzodiazocine. 21. 1,2,3, ^ - Tetrahydro-S-nitro-e-phenyl-1,5-benzodiazocine. 22. A 1,2,3,4-tetrahydro-1-lower alkyl-8-nitro-6-pheny1-1,5-benzodiazocine. 25. An 8-halo-1-lower alkyl-3,4-dihydro-6-phenyl, 5-benzodiazocin-2 (1H) -one. 24 e-chloro-l-methyl-J ^ -dihydro-o-phenyl-l ^ -benzodiazo cin-2 (1H) -on. 25. An ö-halogen - ^^ Sjö-tetrahydro-1-methyl-ö-phenyl, 5-t> enzodiazocin-2 (1H) -one. · 26th e - ^^ benzodiazocin-2 (IH) -one. 8 45/1764