DE2103745A1 - New 5-AryJ- (or Heteroaryl) -3-hydroxylH-1,5-benzodiazepine-2,4- (3H, 5H) -diones and processes for their preparation - Google Patents

Description

Case 1/393 We / Hg

G. H. BOEHRINGER SOHIT, Ingelheim am Rhein

New 5-aryl (l> between heteroaryl) -

3-hydroxy-1H-1,5-benzodiazepine-2,4- (3H, 5H) -diones and Process for their manufacture

The invention relates to new 5-aryl- (or heteroaryl) -3-hydroxylH-1,5-benzodiazepine-2,4- (3H, 5H) -diones the general formula

(D

209833/1188

In this formula:

Ij is a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms, which can optionally be substituted in the co -position by a hydroxyl group, which Allyl or the cyclopropylmethyl group,

R _{2 is} a phenyl radical which can optionally be substituted by a halogen atom, a trifluoromethyl or an ITitro group, or a pyridyl radical and

R ^ a fluorine, chlorine or bromine atom or the irifluoromethyl or nitro group.

The invention also relates to methods of making the new Compounds, the following having proven to be particularly advantageous:

1. Reduction of a compound of the general formula

(II)

^L 2

or its hydrates,

wherein R ₁ , R ₂ and R _{5 have} the meaning given above, with suitable reducing agents, for. B. zinc / glacial acetic acid or tin / hydrochloric acid, preferably with heating. The reduction can also be carried out catalytically or by means of sodium borohydride. ₍

2. Gentle oxidation of a compound of the general formula

209833/1186

COPY -.,

(III)

wherein R ₁ , R ₂ and R, have the meaning given above and the radicals R, which can be identical or different, represent hydrogen atoms or straight-chain or branched alkyl radicals with preferably 1-4 carbon atoms, at low temperatures in a weakly acidic medium. Potassium permanganate or chromic acid, for example, are suitable as oxidizing agents.

3. Boiling a compound of the general formula

wherein Rg and R, have the meaning given above and

R, which has the abovementioned meaning with the exception of hydrogen, with water in the presence of a suitable one under the reaction conditions inert solvent with the addition of small amounts of copper powder or a copper salt.

Such end products of the general formula I in which R- is a hydrogen atom can, if desired, subsequently be selectively alkylated in a manner known per se. In this case one expediently starts from an alkali metal salt of the relevant Compound and sets this with common alkylating agents,

209833/1186

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such as an alkyl halide or a dialkyl sulfate to *

If R- is a hydroxyalkyl radical, the hydroxyalkyl group can advantageous by implementing a "compound of the general Formula I, wherein R-. Hydrogen means with an alkylene oxide in Presence of a strong base, "for example Triton B, and optionally a suitable solvent or solvent mixture, such as an alcohol, tetrahydrofuran, dimethylformamide, possibly in a mixture with water, to be introduced / ils another possibility For this purpose, the reaction of a compound of the general formula I, in which R ^ denotes hydrogen atom, with a haloalcohol offers itself with the addition of a weak inorganic or organic base, advantageously with heating. May be the addition of an organic solvent, for example a lower or higher alcohol, is useful here.

For example, the methods discussed above may include the following Final products obtained are:

5-Hydroxy-5-phenyl-7-trifluoromethyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione ,

7-bromo-3-hydroxy-5-phenyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione, 7-chloro-3-hydroxy-5-phenyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione ,

3-IIydroxy-1-methyl-5-pllenyl-7-trifluoromethyl-1H-1,5-benzodiazepine-2,4- (3II, 5H) -dione ,

7-Bromo-3-hydroxy-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione ,

7-chloro-3'-hydroxy-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione ,

7-Fluoro-3-hydroxy-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione ,

3-Hydroxy-1-methyl-7-nitro-5-phenyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione ,

l-ethyl-7-bromo-3-hydroxy-5-phenyl-lH-1,5-benzodiazepine-2,4- (3H, 5H) -dione,

1-ethyl-3-hydroxy-5-phenyl-7-trifluoromethyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione ,

209833/1186

dia3epin-2,4- (3H, 5H) -dione,
3-Hydroxjr._i_hydroxyäthyl-5-phenyl-7 ^^ diazepin-2 ₃ 4- (5H, 5H) -dione,
l-Allyl-3-hydroxy-5-phenyl-7-trifluo: nne ^

5 - (o-ZFliaorphenyl 3-3-iryäroasy-l-aae tiyl-T-ti-ifltioaaoeasyl-lH-l ₉ 5-

■ benzodiazepine — 2,4— (3H, 5H) -dione-,

5- (o-Bromplieiiyl) -7-ciilor-3-lijäro2y-l-inetliyl-lH-l, 5-lbenzodiazepiii- 2 _f 4- (3ir, 5H) -dione,

5- (o-Glilophenyl) -3-li.ydroxy-.l-iDethyl-7-feriflTiorniethyl-lH-l, 5-T3-benzodiazepine-2,4- (3H, 5H) -dione ,

7-chloro-3-hydroxy-1-methyl-5- (o-i; ri £ lT3onnetliylphen.yl) -lH-1,5-benzodiazepine-2,4- (3H » 5H) -dione,

5- (m-Fluoroplienyl) -3-hydroxy-1-n] ethyl-7-trifluoromethyl-1H-1,5-tdenzoaiazepine-2 , 4- (3H, 5H) -dione,

3-Hydroxy-1-methyl-5- (m-nitrophenyl) -7-trif luonneth.yl-1H-1 ₁ 5- ■ benzodiazepine-2,4- (3H, 5H) -dione,

5- (p-chlorophenyl) -3-hydroxy-l-methyl-7-trifluoromethyl-lH-l, 5-benzodiazepine-2 _r 4- (3H, 5H) -dione,

7-Clilor-3-hydroxy-1-methyl-5 ~ (a-pyridyl) -lH-1,5-'benzodiazepine-2,4- (3H, 5H) -dione ,

7-Bromo-3-kydroxy-1-methyl-5- (a ~ pyridyl) -IH-1,5-t> enzodiazepine-2,4- (3II, 5H) -diome .

The starting materials required for processes 1-3 are new and can be obtained as follows:

Compounds of the general formula II can be divided, for example, according to the information in the DBP (German patent application Gases 1/394) by oxidation of compounds of the general formula III.

Compounds of the formula EI are described in the DBP (German Patent application P 20 53 681.6, Caae 1/375); they let themselves obtained by implementing an appropriately substituted 1H-1,5-Benzodiazepine-2,4 - (3H, 5H) -dione with a phosphorus pentahalide and a dialkylformamide. The one in this reaction Compounds of the formula III formed have no substituents in the 1 position; should therefore R-, in one End product of the formula I has a meaning other than hydrogen possess, the compounds of the formula III must be correspondingly alkylated either before or after the oxidation.

2Q9833 / T1 & 6

Me "in procedure 3 required connections of the general Formula IV are formed "when a correspondingly substituted one is implemented lH-l, 5-benzodiazepine-2,4- (3H, 5H) -dione with tosylazide using sodium hydride according to DBP (German patent application ... Case 1/392).

The compounds according to the invention are valuable drugs with tranquillizing and anticonvulsant effects as well as intermediates for the production of such drugs. It has been found that the rate of excretion of the new compounds is significantly greater than that of known commercially available tranquillizers, which can prevent any chronic side effects. Particular emphasis is given to those compounds in which R, the methyl or ethyl group, R _{2 is} a phenyl radical or a pyridyl radical optionally substituted in the o-position by a fluorine atom and R 1 is a bromine atom or the trifluoromethyl group.

AIa dose for the application of the new compounds of the general Formula I are 0.5 to 50 mg, preferably 1 to 25 mg, as a single dose and 5-150 mg suggested daily dose.

The compounds obtainable according to the invention can optionally be used alone or in combination with other active ingredients according to the invention also in combination with other pharmacologically active ones Active ingredients such as antispasmodics or psychotropic drugs are used. Suitable application forms are, for example Tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Corresponding tablets can, for example by mixing the active ingredient (s) with known auxiliaries, for example inert diluents such as calcium carbonate, Calcium phosphate or lactose, disintegrants such as corn starch or alginic acid such as starch or gelatin, lubricants such as Magnesium stearate or talc, and / or agents for obtaining the Depot effect, such as carboxypolymethylene, carboxymethyl cellulose,

209833/1186

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 the tablets with usually coated tablets agents used, for example collidon or shellac, gum arabic, talc, titanium dioxide or sugar will. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers exist. Likewise, the coated tablet shell can also consist of several layers in order to achieve a depot effect, with the excipients mentioned above for the tablets can be used.

Juices of the active ingredients or combinations of active ingredients according to the invention You can also use a sweetener such as saccharin, cyclamate, glycerin or sugar and a taste-enhancing agent Means, e.g. B. flavorings such as vanillin or orange extract contain. You can also use suspension aids or dik-. . agents such as sodium carboxymethyl cellulose, wetting agents, for example Contains condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoates.

Injection solutions are used in the usual way, for. B. with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali salts of ethylenediaminetetraacetic acid and filled into injection bottles or ampoules.

The capsules containing one or more active ingredients or active ingredient combinations can be produced, for example, by mixing the active ingredients with inert carriers such as lactose or sorbitol and encapsulating them in gelatin capsules.

Suitable suppositories can be made, for example, by mixing. with appropriate carriers, such as neutral fats or Manufacture of polyethylene glycol or its derivatives.

209833/1186

--he-

The following examples serve to illustrate the invention without restricting its scope;

example 1

2,4- (5H, 5H) -dione (according to method 3)

0.05 mole - 18 g of S-1,5-benzodiazepine-2,4-dione are dissolved in 100 ml of acetonitrile and heated after adding 10 ml of water and 1 g of copper powder

Between 50 ° and 6O ⁰ C is a

significant evolution of nitrogen, which * 15 Minutes "is complete after approx. The reaction mixture is suction filtered through kieselguhr and evaporated M and the FiItrat. The residue is recrystallized from acetonitrile or dioxane.
Yield of Bndproduktι 14 g = 80 $ d. Th. From m.p. 245-248 ⁰ O.

Example 2

-lH-l, 5-benzodiazepIn-2 _t 4-

(3H.5H) -dione (according to method 5)

0.25 mol s = 55 g 3-diazo-7-chloro-l-methyl-5-pyridyl-l, 5-benzodiazepine-2,4-dione in 15 minutes with stirring at 50 ° to 60 ⁰ C in a solution of 250 ml of acetonitrile and 25 ml of a 5% copper sulphate solution was added, a vigorous evolution of nitrogen being observed. On cooling, most of the oil crystallizes out. The remainder is obtained by evaporating the mother liquor. The crude product is recrystallized from methanol.
Yield: 5.9 g = 75 fi * d * Th, mp 204-206 ⁰ C..

example 3

yl ^ -trifluoromethyl-lH-1.5-benzodia, zepin-2,4-

(3H.5H) -dione (after l $ yt ears 2)

0.04 mol * 15 g of 2-ß-ButylaiBinomethylidden «7-trifluoiii>#thyl-5-phenyl * -3LH-1,5-benzodIftg0pIn-2,4- (3H _r 5H) -dione are in 2.5 2 .

209833/1111

JO

Dissolved pure acetone and added 200 ml of 6% sulfuric acid. Within 20 minutes 18 g of potassium permanganate are 'carbonate, dissolved in 400 ml water was added dropwise, stirred for one hour at a temperature of-25 to -50 ⁰ C, filtered off over kieselguhr, most of the acetone was evaporated and the reaction product in methylene chloride recorded. After drying with magnesium sulfate and evaporation, it is recrystallized from tetrahydrofuran. 9.6 g = 72 $ d are obtained. Th. Colorless crystals from Pp. 260-264 ⁰ G.

Example 4

7-Bromo-3-hyaroxy-5-phenyl-1H-1,5-benzodiazepine-2,4- (3H.5H) -dione (according to procedure 1)

10 g (= 0.027 mol) of 7-bromo-3,3-dihydro: xy-5-phenyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione are dissolved in 150 ml of glacial acetic acid, with 12 g of zinc powder are added and the mixture is heated to the boil for 30 minutes while stirring. Then it is suctioned off hot over kieselguhr and washed with glacial acetic acid. About 600 ml of ice water are added, the mixture is allowed to crystallize for one hour, suction filtered and washed with water. After drying, 9.1 g of crude product remain, which is ufflated from alcohol.
Yield: 9.0 g = $ 94> d. Th. From m.p. 264-266 ⁰ C.

Example 5

S-Hydroyy-1-methyl-S-phenyl ^ -trlf luoromethyl-1H-1 «5-benzodiazepine-2.4- (3H.5H) -dione

3 »4 g of 3-hydroxy-5-ρhenyl-7-trifluorlπethyl-lH-l, 5-benzodiazepine-2,4- (3H, 5H) -dione (prepared analogously to Example 3) are suspended in 200 ml of tetrahydrofuran and diluted with 500 ag a 50 #igen fetrium hydride dispersion added. One stirs oa. 30 minutes after, mixed with 20 ml of methyl iodide, stirred for 5 hours at room temperature, evaporated and evaporated in methylene chloride. The washed and dried methylene chloride phase is evaporated and the residue is recrystallized from methanol. Yield: 2.9 g - 76 $ d. Th. M.p. 245-248 ° C.

209833 / 1H6

Analogous to this Examples ^ ITT -ser
if-
were the following 2103745
Connections made :. Mp. ⁰ C Example I.
No.: Ί -C ₂ H ₅ R ₂ H 262-264 6th -CH ₃ - ^C 6 ^H 5 Cl 256-257 7th -CH ₃ - ° 6 ^H 5 Br 269-271 8th -CH ₃ - ° 6 ^H 5 Br 255-258 9 -CH ₃ - ° 6 ^H 5 F. 250-252 10 -CH ₃ - ^C 6 ^H 5 NO ₂ 260-262 11 -CH ₃ O-CF ₃ -C ₆ H ₄ Cl 189-190 12th -CH ₃ 0-NO ₂ -C ₆ H ₄ CF ₃ 195-197 13th -CH ₃ 0-FC ₆ H ₄ CF ₃ 218-220 14th -CH = CH ₂ Br 188-190 15th -CH ₃ 0-Cl-C ₆ H ₄ CF ₃ 178-180 16 -CHg to to
\ / - ° 6 ^H 5 CF ₃ 253 17th 5 O-Br-C ₆ H ₄ Cl 201-203 XO —XIX »> -CH ₂ -OH - ^C 6 ^H 5 «* 235-236 19 -CgH H O O CF ₃ 217-219 20 -CH ₂ CF ₃ 278-280
(Decomp.)
188-189 21
22nd -C ₆ H ₅
In-FC ₆ H ₄ .. Cl
CF ₃

209833/1186

10.0 mg 37.5 mg 25.0 mg 2.0 mg 0.5

Pharmaceutical application examples

1. Drageeg

Dragee core contains:

a) 1-ethyl-7-bromo-3-hydroxy-5-phenyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione Milk sugar Corn starch G-elatine Magnesium stearate

75.0 mg

b) 3-Hydro: xy-1-meth.yl - 5-phenyl.-7-trif luoromethyl-III-1,5-benzodiazepine-2,4- (3H, 5H) -dione 10.0 mg

Lactose 37.5 mg

Corn starch 25.0 mg

Gelatin 2.0 mg

Magnesium stearate 0.5 mg

75.0 mg

c) 7-Bromo-3-hydroxy-1-methyl-5-phenyl-H-1,5-benzodiazepine-2,4- (3H, 5H) -dione 10.0 mg

Lactose 37.5 mg

Corn starch 25.0 mg

Gelatin 2.0 mg

Magnesium stearate 0.5 mg

75.0 mg

d) 5- (o-Fluorophenyl) -3-hydroxy-1-methyl-7-trifluoromethyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione

Milk sugar corn starch gelatin

, Magnesium stearate.

80.0 mg

209833/1186

15.0 mg 37.5 mg 25.0 mg 2.0 mg • 0.5

Manufacturing:

The mixture of the active ingredient with lactose and corn starch is granulated with a 10? The granules obtained in this way are mixed with magnesite stearate and pressed. The cores obtained in this way are coated in the usual way with a shell which is applied with the aid of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished coated tablets are polished with the help of beeswax
Final tablet weight: approx. 125 mg

2. Suppositories

1 suppository contains:

a) 7 ~ bromo-3-'hydroxy-1-methyl-5- ( oc-pyridyl) -1Η-1,5-benzodiazepine-2,4- (3H, 5H) -dione 10 mg

Suppository mass (e.g. Witepsol W 45;

a triglyceride mixture) 1690 mg

1700 mg

Manufacturing:

The finely powdered substance is stirred into the melted suppository mass, which has been cooled ^{to 40 °} C., with the aid of an immersion homogenizer. The mass is poured into slightly pre-cooled molds ^{at 35 ° C.}

209833/1186

Claims (15)

Claims Today 5 "aryl (or ♦ heteroaryl)" 3-hydroxy-1H-1,5 "benzodiazepine-2,4- (3Et5H) -diones the general formula (D ^R 2 wherein R ^ is a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms , which can optionally be substituted in the CaJ position by a hydroxyl group, the allyl or cyclopropylraethyl group, Rg is a phenylreath, which may optionally be replaced by a halogen atom, a trifluoromethyl or a nitro group can be substituted or a pyridyl radical and R is a fluorine, chlorine or bromine atom or the trifluorinethyl or nitro group. 2. Compounds of the general formula (I a) 209833/1186 wherein R, the methyl or ethyl group, Rg one optionally in the o-position by a fluorine atom substituted phenyl radical or a pyridyl radical and R ^ is a bromine atom or the trifluoromethyl group. 3. 3-Hydroxy-1-methyl-5-phenyl-7-trifluoromethyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione. 4. 1-Ethyl-7-bromo-3-hydroxy-5-phenyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione. 5. 7-BroIπ-3-hydroxy-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione. 6. 5- (o-I'luorophenyl) -3-hydroxy-1-methyl-7-trifluoromethyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione. 7. 7-Bromo-5-hydroxy-1-methyl-5- (a-pyridyl) -lH-1,5-benzodiazepine-2,4- (3H, 5H) -dione. 8. Process for the preparation of new 5-aryl- (or heteroaryl) -3-hydroxy-1H-1,5-benzodiazepine-2,4- (3H, 5H) -diones the general formula N er CH - OH (I) 2
wherein R-, a hydrogen atom, a straight or branched one group with 1-4 carbon atoms, which can optionally be substituted in the co -position by a hydroxyl group, the Allyl or the cyclopropylmethyl group, Rp a phenyl radical, which is optionally replaced by a halogen atom, a 209833/1186 Trifluoromethyl or a methyl group can be substituted or a pyridyl radical and R, a fluorine, chlorine or bromine atom or the trifluoromethyl or means nitro group. a) a compound of the general formula C = O (II) Rn, R2 and R _{5 have} the meaning given above, reduced, or that one b) a compound of the general formula , 0 \ CH - ^ R Ν— - / " I.
R _n \> (III) in which the radicals R- ,, R ^ _ and R ^ have the meaning given above and the radicals R, which can be the same or different, are hydrogen atoms or straight-chain or branched alkyl groups with preferably 1-4 carbon atoms, are subjected to a gentle oxidation, or that c) a compound of the general formula = N = Ή 209833/1186 wherein the radicals R ₂ ^{υη <} *% ^^ have the meaning given above and R _{1 has} the meaning given above with the exception of hydrogen, boiled in the usual way. 9. The method according to claim 8 a), characterized in that the reducing agent used is zinc / glacial acetic acid or tin / hydrochloric acid will. 10. The method according to claim 8b), characterized in that as Oxidizing agent potassium permanganate or chromic acid at deep Temperatures are used « 11. The method according to claim 8 c), characterized in that the boiling in the presence of an inert solvent and less Amounts of copper powder or copper salts. 12. Pharmaceutical preparations containing compounds as active ingredients of the general formula I in combination with customary auxiliaries or carriers. 13. Pharmaceutical preparations containing substances of the general Formula I in combination with other pharmaceutical active ingredients and customary auxiliaries and / or carriers. 14. Process for the manufacture of pharmaceutical preparations according to claim 12, characterized in that compounds of the general formula I with customary pharmaceutical auxiliaries and / or excipients processed into customary pharmaceutical application forms. 15. Process for the production of pharmaceutical preparations according to claim 13, characterized in that compounds of the general formula I in combination with other active ingredients ijowie usual auxiliaries and / or carriers to usual processed pharmaceutical application forms.