DE2165311A1 - NEW 1-ARYL-3H-1,4-BENZODIAZEPINE2,5- (1H, 4H) -DIONE - Google Patents

Description

C. H. BOEITRIFGER ßOHtf, Ingelheim am Rhein

New l-aryl ~ 3H-1,4-benzodiazepine

2,5- (1H, 4H) -diones

The invention relates to new 1- / \ ryl-3H-1,4-'benzodiazepine-2,5- (1H, 4H) -diones the general formula

Il

C - UH

(D

309828/1106

In this formula "means: ■

It, a Phenylreat, which is optionally in the o-, m- or p-position by a fluorine, chlorine or bromine atom or a trifluoromethyl or nitro group or an α-pyridyl radical and Πλ is a hydrogen, fluorine, chlorine or bromine atom or one Trifluoromethyl, nitro, amino, cyano or Ilydroxycruppe.

The new connections can be established

a) by closing a compound of the general formula

(II)

- in the

R, and R _{2 have} the meaning given above, R is a hydroxy, O-tosyl or lower acyloxy group or a halogen atom, but preferably a lower alkoxy group;
b) by oxidation of a compound of the general formula

(III)

R- and Rp have the meaning given above.

The ring closure in reaction a) is carried out using conventional inert solvents, e.g. B. a lower alcohol, ethyl acetate,

309828/1106

Tetrahydrofuran, dimethylacetamide, optionally with addition a condensation agent such as sodium methylate, sodium bicarbonate or triethylamine and optionally with heating. Ilan can be either from an isolated compound of the general lOmel II proceed or alternate according to the equation

II

Π - C - CH ₂ - X
O

(IV)

amino compound II forming the ring closure without prior isolation subject.

In this equation, X generally stands for a nucleophobic group that can easily be exchanged for the HHg group, e.g. B. a chlorine, bromine or iodine atom, an O-tosyl or lower acyloxy group.

In the latter case one carries a compound of formula IV either in liquid ammonia or sets it, dissolved in one inert solvents such as tetrahydrofuran, dioxane, dimethylformamide or !! ethanol with an ammonia-yielding compound, a. B. an Ammoniumaalζ or urotropine to.

Compounds of the formula IV have not yet been described. Ilan receives £? B. for R = OCII ₃ and X = Cl according to the equation

309878/1 106

O = O

H H

CO H

W. O

309828/1 106

Here, the phenylarylamine derivative V is in an inert organic Solvents, e.g.! Benzene, toluene, xylene or dimethylformamide, dissolved and refluxed with chloroacetic anhydride. The compound II a obtained in this way is described in dissolved a dilute lower alcohol and mixed with a slight excess of diazomethane. Ilan receives a "connection Hb, which, as described above, is reacted with ammonia or an ammonia-supplying compound to form starting product II.

Process b) proceeds using suitable oxidizing agents such as gliromic acid / sulfuric acid, potassium permanganate or activated Manganese dioxide.

For oxidation with hromic acid / sulfuric acid and potassium permanganate In particular, water-miscible solvents have proven themselves, which cannot be oxidized even under the given heating conditions, e.g. B. acetone, ethyl ethyl ketone, glacial acetic acid, Dioxane, tetrahydrofuran or mixtures of these solvents.

The oxidation with activated Ilangandioxyd can also be used also perform well using ethyl acetate, diethyl ether, methylene chloride or chloroform.

The reaction temperature to be used depends on the particular starting material used and generally varies between 20 0 below the boiling point of the selected solvent »

The synthesis of the l-aryl-5,4-dihydro- (211,5H) -I, 4-benzodiazepin-5-ones used as starting material in process b) of the general Formula III can be obtained by ring joining the appropriately substituted ring-open compound of the formula

0 Il σ - 0 - lower alkyl

7 - OiI ₂ - CH ₂ - ITH ₂

^ ¹ 309828/1106

BATH ORIGINAL

(VI)

take place; it is "described in the German patent application ... Case 1/425.

According to the method described above, for example, the the following end products can be obtained:

3-Chloro-1-phenyl-3H-1,4-benzodiazepine-2,5- (1H, 4H) -dione, 8-bromo-1-phenyl-3H-1,4-benzodiazepine-2,5- (1H , 4II) -dione, 8Vbromo-1- (p-bromophenyl) -3H-1,4-benzodiazepine-2,5- (1H, 4Ii) - dione, 8-.chloro-1- (o-chlorophenyl) - 3H-1,4-bensodia2; epin-2 _f 5- (1H _t 4H) -dione, 8-ciilor-i <3-f Iuophenyl) -3H-1,4-benzodiazepine-2, 5- (1H, 4H ) -dione, ψ ö-.lmino-l-phenyl-3H-l _f 4-benzodiazepine-2,5- (lH _f 4H) -dione, 8-trifluoromethyl ~ l-phenyl-3H-l, 4-benzodiazepine- 2,5- (UI, 4H) -dione, S-cyano-l-phenyl-3H-l, 4-benzodiazepine-2,5- (IH, 4H) -dione, 8-hydroxy-l-phenyl-3H- 1,4-benzodiazepine-2 _f 5- (III, 4H) -dione, 8-nitro-1-phenyl-3H-1,4-benzodiazepine-2,5- (IH, 4H) -dione. The end products of the general formula I obtained as described above are new. They have strong psychosedative and anticonvulsant properties with very little toxicity and are said to be used as tranquilizers.

The proposed dose for the application of the new compounds of the general formula I is 1 - 50 ^, preferably 5 - 25 rag as jilnzel t dose and 10 - 150 mg as daily dose.

The compounds erfindungagemäß available can be used alone or in combination with other active substances, optionally in combination with other pharmacologically active substances such as antispasmodics or psychotropic _t methodology is used. Suitable application forms are, for example, tablets, TCapsules or dispersible powders. Corresponding tablets can be made, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents such as gallium carbonate, calcium carbonate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or

309828/1106

Talc, and / or means for achieving a depot effect, such as Carboxypolymethylene, carboxyinethyl cellulose, cellulose acetate phthalate or polyvinyl acetate.

The tablets can also consist of several layers.

Correspondingly, coated tablets can be produced by coating cores produced analogously to tablets with agents typically used in tablet coatings, for example Kollidon or Shellac, gum arabic, talc, titanium dioxide or sugar will. In order to achieve a depot effect or to reduce the risk of incompatibilities, the core can also consist of several Layers exist. The coated tablet can also do the same to create a depot effect a consist of several layers, v / whether the auxiliaries mentioned above for the tablets can be used.

Containing the one or more active ingredients or active ingredient combinations Capsules can be produced, for example, by combining the active ingredients with inert carriers such as lactose or sorbitol, mixes and encapsulates in gelatin capsules.

The following examples serve to explain the invention in more detail:

309828/110 6 BAO ORfQINAL

example 1

8-ITitro-l-phenyl-3H-l ₁ 4-benzodiazepin-2,5- (IH, 4H) -dione

a) 9 g of W-chloroacetyl-N-phenyl-4-nitro-antliranilic acid v / ground dissolved in 150 ml of acetone and mixed with 8 g of potassium iodide. After stirring for 20 hours at room temperature, the solution is evaporated in vacuo and the residue with water added, extracted with 'ethyl acetate, the organic phase dried with magnesium sulfate and the solvent evaporated in a vacuum. An oil remains which is dissolved in 20 ml of methanol. This solution is made with 200 ml of liquid Ammonia is added, the mixture is left to stand for 1 hour and the batch is then poured onto ice. ! laugh at the neutralization with Glacial acetic acid is then extracted several times with vinegar 3. The solution is mixed with activated charcoal and dried and sucked off. liach the evaporation of the solvent in the The residue is recrystallized from acetonitrile in vacuo »,

Yield of 3-nitro-l-phenyl-3H-1,4-bensodiazepine-2,5- (IH, 4H) -dione 4.9 g ( $ 64> d.Th) with a melting point of 222-23 ° C.

Me required IT-chloroacetyl-IT-phenyl-4-nitro-antliranilic acid as the starting compound can be obtained in the following way:

b) 26 g of 4-nitro- (N-phenyl) -antranilic acid are in 500 ml absolute benzene with 26 g of chloroacetic anhydride for 1 hour. Heated under reflux. Then shake it several times Water out, the organic phase is dried with magnesium sulfate and filtered off with suction. ! lan evaporates in a vacuum and crystallizes the Residue from isopropyl ether / cyclohexane. Yield: 3D g (98 '/. Of theory) of pp. 172-73 ° G

309828/1 106

c) Manufacture ... of IT ~ 0hloracetylriI ^^ gaure ^ methyleater

IO g-iI-Ghlöraö0tyl-li-phönyl - 4 - »itrö - atitkE ^l atiilsätire are dissolved in 1 liter« methanol and 100 ml »barrels« into the! LoStJn ₁ ; a small excess of ethereal diazomethane solution is allowed to flow in over the course of 10 minutes, while stirring. The residue is then evaporated in vacuo from methanol.

Yield ι 10 g (97 £ d.Th ") of Pp" 126-27 ^ 0

Beie.t? .I.e.l ... 2

e-IErIf I ¹ U orae thyl »» l-> phenyl *> $ H »l« .4-Ί? οϊϊ, 2; o.aiage..T? .i.ttf 2 «g -, (111» 4H)

25 g of U-chloroacetyl-III-phenyl-4-trifltionhethyl-anthanilic acid (prepared analogously to Example 1) are dissolved in 250 ml of dimethyl acetamide and mixed with 40 g of methyl iodide and 30 g of potassium acetate and allowed to react for 50 minutes while stirring then diluted with 1 liter of water. It is extracted several times with methylene chloride, dried and evaporated in vacuo. A little acetonitrile is added to the oily residue, and crystalline by-product is filtered off. ^ l etonitrile solution is evaporated in vacuo, the residue is dissolved in 300 ml of acetone and 10 g of sodium iodide are added to the acetone solution. The mixture is stirred for 20 hours at room temperature, the solvent is evaporated in vacuo and the residue is mixed with water. It is extracted with Issigester, the organic phase is dried with magnesium sulfate and the solvent is again evaporated in vacuo. An oil remains behind for 13s, which is dissolved in 30 ml of methanol} 250 ml of liquid ammonia are added to the solution, left to stand for one hour and the mixture is then poured ^{onto 1 ^ Ls} extracted. The solution is then mixed with activated charcoal, dried and the cavity is sucked off. After the solvent has been evaporated in vacuo, the residue is

309 8 28/1106
BATH ORIGINAL

7165311

- ίο -

Isopropyl ether recrystallized.

Exploits 9.3 g (4t% of theory) of mp. 249-51 ⁰ C.

Example 3

e-chloro-1-phenyl ~ 3H-1,4-benzodiazepine-2.5- (1H.4H) -dione

2.5 g of 8-chloro-1-phenyl-3 * 4-dihydro- (2H, 5H) -1,4-benzodiazepin-5-one ^ are dissolved in 250 ml of acetone. At room temperature, 5 ml of a solution of 2.7 g of chromium VI oxide, 2 _r 3 ml of conc. Sulfuric acid, made up to 10 ml of solution with distilled water. The reaction is allowed to continue for a further hour with stirring at room temperature, suction filtered through kieselguhr and washed with acetone. It is evaporated in vacuo and the residue is crystallized from acetonitrile.

Yield: 2.4 c = 88 % of theory of m.p. 244-45 ° C

Analogously to the procedures described above, the following end products were also obtained:

example R ₁ R ₂ Mp. ⁰ C 4th ^C 6 ^H 5 Br 261-262 5 P-Br-C ₆ H ₄ Br 280-281 6th ^C 6 ^H 5 HO 170-71 7th C ₆ H ₅ CN 8th ^C 6 ^H 5 NH ₂ 285-287

309828/1106

- li - '

Examples of pharmaceutical applications

a) Dragees

1 dragee contains:

8-chloro-l-phenyl-3H-l, A-

bensodiazepine-2,5- (1H, 4H) -dione 5.0 mg

Milk sugar 28.5 mg

Corn starch ■ ■ 15.0 ng

Gelatin "1.0 mg

Magiiesiunistearate 0.5 mg

50.0 mg

Manufacturing:

The mixture of the active substance with lactose and corn starch is carried out with a 10> iigen aqueous gelatin solution Sieve with 1 mra mesh size, granulated, dried at 40 ° 0 and driven through a sieve again. The granules thus obtained is mixed with magnesium stearate and pressed. the cores obtained co v / earth coated in the usual way with a shell, which with the help of an aqueous suspension of sugar, Tetanedioxide, talc and gum arabic is applied. The finished coated tablets are polished with beeswax.

Ij) tablets

3-TrifluorL '] eti _i yl-l-phenyl ~ 5H-l, 4-

bensodiazepine - 2.5- (1H, 4H) -dione 3 mg

Kilchzucker 50 mg

Corn starch ■ 32 mg

soluble f5ty.rke 4 mg

1 mg 90 mg

309828/1106 BAD

7165311

- 12 -

Manufacture;

Active ingredient and nagnesiurastearate are mixed with an aqueous Granulated solution of the soluble starch, dried the granules and mixed intimately with lactose and corn starch. That The mixture is then compressed into tablets weighing 90 mg, each containing 3 mg of active fit off.

c) suppositories

1 suppository contains:

8-broin-l-phenyl-3H-

1,4-benzodiazepine-2,5- (1H, 4H) -dione 5.0 ag

Suppository mass 1695.0 mg

1700.0 mg

Manufacturing:

The finely powdered substance is made using an immersion homogenizer in the melted and 40 ° C cooled suppository mass stirred in. ' The mass is poured into slightly pre-cooled molds at 35 ° C.

309828/1 1 06
BAD OfIfOtNAt

Claims (1)

7165311 1 /) Heue l -. 'U? Yl-? Hl, 4-'bensQfeEiazepIn-2 _f 5- (lH _# 4Η) -5ΙοΏβ of the general formula ΙΠΙ worm IU a plienyl radical, which optionally: in ο—, m— or p — position dttroli a fluorine "-,. Clilor- or Brouiatoro- or an irifluoromethyl or nitro group substituted is or -an a-pyridyl radical and Ilp a 'hydrogen -'-, fluorine, chlorine or BrOtaatom or 2rix * luornethyl-, iritro- _f amino, Gyano- or I! Ydro :: ycruppe mean. 2.) l-phenyl-8-tri.fluoromethyl-3H-1,4-ben3odiazepine-2,5- 3. ) 3-chloro-l-phenyl-'5II-l, 4-benzodiazepine-2 _r 5- (lH, 4H) -dione, 4.) 8-] 3ron] -l-phenyl-5H-l, 4 -benzodiazepine-2, [> - (1H, 4H) -dione. ü.) 3-iritro-l-phenyl - ;; II-l, 4-benzodiazepine-2,5- (liI, 4H) -dione, . ö) 'A method for producing novel l -, - \ ryl-3H-l, 4-benzodia: ePIN-2,5- ^(lI;, 4H) -diones of the general formula. 30 9 8 2.8 / 1 106 ORIGINAL BATHROOM in which, R-j is a phenyl radical, which is optionally in σ-, m- or p * position by a fluorine, chlorine or bromate or a trifluoromethyl or uritro group is substituted or a cx-pyridyl radical and Hydrogen, I ¹ iuor, chlorine or bromine atom or a trifluoromethyl, nitro, imino, cyano or hydroxyl group, characterized in that a) a compound of the general formula C - CH ₂ - HH ₂ O wherein r-j and Rg have the meaning given above, R is a hydroxy, 0-losyl or lower acyloxy group or an ilalogen atom, preferably a lower alkoxy group means subjecting to the ring closure or that one 309828/1106 b) a compound of the general formula Il C IT wherein R ^ and R ₂ have the abovementioned meaning, are oxidized by strong oxidizing agents. 7 ·) Pharmaceutical preparations containing one or more compounds of the general formula I as active ingredient in combination with the usual auxiliaries or carriers. 8,) Pharmaceutical preparations containing substances of the general formula I in combination with others pharmaceutical 'active ingredients as well as usual auxiliary and / or carriers. 9.) Process for the production of τοη pharmaceutical preparations according to claim 7, characterized in that one one or more compounds of the general formula I with customary pharmaceutical auxiliaries and / or carriers processed into common pharmaceutical application forms, 10.) Process for the production of pharmaceutical preparations according to claim 8, characterized in that compounds of the general formula I are used in combination with other active ingredients as well as usual auxiliary and / or excipients from common pharmaceutical ingredients processed. 309828/1 106 BAD GRfGiNAL