DE2242918A1 - NEW 4-AMINO-S-TRIAZOLO SQUARE BRACKET ON 4.3 ANGLE BRACKET TO SQUARE BRACKET ON 1.4 SQUARE BRACKET TO BENZODIAZEPINE - Google Patents

Description

ttCHTSANWXlTE -

DR. JUR. DlPL-CHEM. WALTER BE »

ALFRED! Γ -: - PFEMEX OQ Α ,, π "

DR. JUR. ΰΙ '"..- α',: Μ. HJ. WOLFF * ^y · ^AU 9 ·

DR. JuR. HAMS C :: R. AX

FRANKFURT AM MAIH-HOCHST

Our No. 18 o71

The Upgohn Company Kalamazoo, Mich .., Y. St.A.

New 4-amino-s-triazolo / ~ 4,3 ~ a7 / "~ 1,47tenzodiazepine,

The present invention "relates to new 4-amino-6-phenyl-4H- and 6H-s-triazolo / ~ 4,3-a7 / "" i, ^ "benzodiazepine, a method for their production and intermediate products occurring in this process.

'Me new compounds and the process of their preparation can be illustrated as folnt:

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IHa

nib

■ J 09817/12 4 P

In the above formulas, 'R denotes hydrogen, an alkyl radical with 1 "to 3 carbon atoms, a cycloalkyl radical with 3 Ms carbon atoms, a phenyl or benzyl radical, a 5- or 6-membered heterocyclic radical with 1 to 4 heteroatoms in the form of nitrogen, oxygen and sulfur, fluorine, chlorine, bromine, an alkylthio radical with an alkyl group as defined above, an alkoxy radical with 1 Ms 5 carbon atoms, a cyano, pyrrolidino, piperidino, irifluoromethyl or a dialkylamino st, the alkyl group of which corresponds to the above definition, while R _?, R ,,, R and R ₁ hydrogen atoms, alkyl radicals as defined above, fluorine, chlorine, bromine, nitro, cyano, imino, trifluoromethyl and alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl or alkanoylamino groups having, the proportion of carbon atoms of 1 to 3 carbon, or ^ν: Uialky represent amino groups whose alkyl moiety is as defined above; R ¹ denotes an alkyl radical as defined above!.

The invention also relates to the N-acyl derivatives HIc IHd of the compounds of the formulas IHa and IHb, furthermore their pharmacologically acceptable salts.

The inventive method is characterized in that an ester of the formula I in a solvent with a strong base and then with 0- (2,4-dinitrophenyl) hydroxylamine treated to form the amino ester II. This is hydrolyzed with a base, whereupon it is acidified for the purpose of forming the free carboxylic acid, which decarboxylates spontaneously to form a compound of the formula IHa or IHb, depending on the base used (HIa with barium hydroxide, followed by sulfuric acid, IHb with sodium hydroxide, followed by hydrochloric acid).

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The acylation of the amines IHa and IHb with a hydrocarbon carboxylic acid anhydride results in the corresponding amides using conventional processes.

As examples of lower alkyl groups with 1 to 3 carbon atoms the methyl, ethyl, propyl and isopropyl radicals are named.

Cycloalkyl radicals with 3 to β carbon atoms include des Cyclopropyl, cyclobutyl, oyclopentyl, cyclohexyl, cycloheptyl and cyclooctylreet.

The carbon chain of the "alkoxy, alkylthio, alkylsulfinyl, Alkylsulfonyl and dialkyl amino groups include 1 to 3 Carbons, it is defined as a lower alkyl group with 1 to 3 carbon atoms.

An alkoxy radical can thus be a methoxy, ethoxy, propoxy or isopropoxy, an alkylthio radical, a methylthio- ^ ithylthio-, Propylthio or isopropylthio and a dialkylamino radical Dimethylamine ^ diethylamino, dipropylamino or diisopropylamino radical be.

The alkanoylamino radicals with 1 to 3 carbon atoms include the formamido, acetamido and propionamidoreate.

The heterocyclic aromatic ring systems include the thienyl, pyrrolyl, isopyrrolyl, oxazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,3 _t 4- and 1,2, 4-triazinyl-, 1,2,3,4- and 1,2,3,5-oxatriazolyl-, 1,2,3,4- and 1,2,3,5-thiatriazolyl-, 2H-, 1H- and 5H-tetrazolyl-, 1,2,3-, 1,2,4- and 1,2,5-thiadiazolyl-, isoxazolyl-, isothiazolyl-, imidazqyl-, 1,4,3,5-Üxathiadiazinyl-, 1,4,2 ₁ 5-dioxadiazinyl-, 1,4,2,5-dithiadiazinyl-, as-, s- and vZ-tetrazinyl-, 1,4,3-

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Oxathiazinyl, 1,4,2-dioxazinyl, 1,4,2-dithiaezinyl, 4H-1,2,4-oxadiazinyl, 2H-1,2,3-thiadiazinyl-, 2H-1,2- and 4H-1,4-oxazinyl and 211-1,2 and 4H-1,4-thiazinyl radicals.

The aromatic ring substituent, ie R., can be given by radicals according to the following table. be reproduced :

Puryl thienyl pyrrolyl

Isopyrrolyl pyrazolyl 1,2,3-triazolyl N

N ^ 'O ^ L N

1,2,4-triazolyl oxazolyl thiazolyl

Isothiazolyl 1,2,3-0xadiazolyl 1,2,4-0xadiazolyl M 0

Π + U

1,2,5-oxadiazolyl 1,3,4-oxadiazolyl pyridyl

Pyridazinyl pyrimidinyl pyrazinyl

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22A2918

N _n N

1,3,5-triazinyl 1,2,4-triazinyl 1,2,3-triazinyl

3 2

N Y

4 3

N N

• ^ 5St>

1,2,3,4-oxatriazolyl 1,2,3,5-oxa-3 triazolyl

ΐ Ν = 3

NH

N 1 2

1,2,3,4-thiatriazolyl

4 3 N—

Hn! J

^ h 9

1 1 I ^

, 2,3,5-thiatriazolyl 2H-tetrazolyl 1H-tetrazolyl

4 3 4 3 4 3 N _ — N in N-T ₁ L ^ N 5 S ^ 2 1 1 1 5H-tetrazolyl 1,2,3-thiadiazolyl 1,2,4-thiadiazolyl 4 I 5 4 I 3 If ⁴ I.
NN pn
I ^ / N 1 5 0 2
1 1 , 2,5-thiadiazolyl Isoxazolyl Isothiazolyl
4th 4 I 3
I-TN 5 ^ S _S 3 U U I. 6 ^ 0 ^ 2

Imidazolyl

1,4,3,5-0xathiadiazinyl 1,4,2,5-1'ioxadi-

azinyl

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4 5 S 5

- »- ι if

1,4,2,5-bithiadias-Te-fcrazinyl ¹

azmyj. s-tetrazinyl

if

¹ 1 1 ² '

-Tetrazinyl 1,4,3-OxateMazinyl 1,4,2-Dioxazinyl

S ι * 1 ^fc

4H-1,2,4-oxadiazi- ₂ H-1,2,3-thiadi.

1,4,2-dithiazinyl ^nyl azinyl

1 ₁ ^

2H-1,2-oxazinyl 4H-1,4-oxazinyl 2H-1,2-thiazinyl

S '

4H-1,4-thiazinyl

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Me according to the invention provided acid addition salts of Compounds of the formula IHa and IHb are the hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, cyclohexanesulfamates, Methanesulfonate and the like. By reacting a compound of the formula HIa or IHb with an equivalent Amount of the appropriate pharmacologically acceptable Acid can be obtained.

The sedative effect of ^ Amino-e-chloro-i-methyl-ö-phenyl-4H-s-triazolo / ~ 4,3-a7Z * "i »4,7l> enzodiazepine is made by the following Tests on mice demonstrated:

Chimney test : (Med. Exp. 4_, 145 (196t)): The effective intraperitoneal dose for 50% of the mice (ED ₅ ) is 6.3 mg / kg. The test determines the ability of mice to climb up and off a vertical glass cylinder within 30 seconds. The mice fail to do this at the effective dose.

Dish test: Mice in Petri dishes (diameter 1o cm, height 5 cm, partially embedded in wood chips) to climb very rapidly from the shells if they are untreated. If the mice remain in the bowl for more than 3 minutes, there is an indication of tranquilization. The ED, - corresponds to the dosla of the test compound at which 50 # of the mice remain in the dish. The ED (intraperitoneal administration) for the above compound is 4.5 mg / kg.

Pedestal test : the untreated mouse leaves the pedestal in less than an hour and climbs back onto the floor of the atandard cage. Tranquilized mice remain on the pedestal for more than 1 minute. The EDc ₀ when administered intraperitoneally is 4 _t 5 mg / kg.

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Nicotine antagonism test : groups of 6 mice each are given the Teet compound (4 ~ amino-8-chloro-1-methyl-6 ~ phenyl = 4H-striazolo / ~ 4,3-a7 / ~ "i, 47benzodiazepine) 30 minutes later, the animals, including untreated control animals, received an injection of 2 mg / kg nicotine salicylate. The control animals show over stimulation, ie, (1) continuous twitching, followed (2) tonic extensor convulsions and (3) death At a dose of 0.36 mg / kg of the test compound, 50% of the mice are protected against (2) and at 0.63 mg / kg against (3) (ED ₅₀ ).

Antagonism as strychnine (as sulfate): The effective dose ED ₁ - "is for 4-amino-8-chloro-1-methyl-6-phenyl-4H-striazolo ^ ~ 4,3-a7 ^ ~ 1,4_7benzodiazepine at Oral administration 32 mg / kg. In the test, the test compound is administered orally to groups of 6 mice each, 30 minutes later intraperitoneal administration of 3 mg / kg strychnine sulfate takes place. The activity of the compound as a muscle relaxer and anticonvulsant can be recognized by those who survived after 4 hours . A dose of 3 mg / kg strychnine sulfate is normally fatal to all control animals «,

The intermediates of formula II are also effective tranquilizers and iJedativa, but less effective, as shown in Table I below:

Table I.

ED ₅₀ (mg / kg)

K Sch P Ni

4-Amino-8-chloro-methyl-6-phenyl-4H ^ s-triazolo- / ~~ 4,3-a // 1,4_7benzodiazepine-
ethyl carboxylate 71 32 25 4.5

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- 1ο -

K = chimney test

Sch = cup test

P = pedestal test

Ni = nicotine test (3)

As pharmaceutical preparations are for the new substances those intended for oral, parenteral and rectal use, e.g. tablets, powder packets, sachets, coated tablets, capsules, solutions, suspensions, sterile injectables Molds, suppositories and the like. Suitable diluents such as carbohydrates can be used as carriers or fillers (Lactose), proteins, lipids, calcium phosphate, corn starch, stearic acid, methyl cellulose and the like can be used. For the production of solutions or suspensions, oils, e.g. coconut oil, sesame oil, saffron oil, cottonseed oil, Peanut oil and the like. Can be used. Sweeteners, colorings and flavors can also be added.

For mammals and birds, feed premixes with starch, oatmeal, dried fish meat, fish meal, Wheat flour and the like. Can be produced.

The compounds of the formulas IHa and IHb are used as tranquilizers in doses of 0.2 to 50 mg / kg orally or as injectables Preparations twisted to relieve tension and anxiety in mammals or birds, such as these occur during the transport of the animals.

For the intermediate products of the formula II, the doses are higher, namely 5 to 200 mg / kg.

To achieve faster growth, better feed utilization and improved weight gain, as well as increased

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Ice cream and milk production in poultry and cattle can Feedstuffs can be prepared which contain 1 Ms 100 g of a compound IHa or IHb per 907 kg of the putter.

Me preparation of the starting materials of the invention Process (Pormel i) is illu- in the following preparations. striert.

When carrying out the process according to the invention, an ester I is treated in solution with a strong base » Dimethylformamide, diethy! Formamide, Dimethyl sulfoxide, diethyl sulfoxide, dioxane, diglyme, tetrahydrofuran and the like. The base used is an alkali metal alkoxide or hydride, e.g. sodium or potassium methylate, ethylate, potassium or sodium hydride or the like. According to a preferred embodiment of the invention the reaction is carried out with a base at -1o to 2o ° C for a period of 5 to 30 minutes. The mixture can stand at room temperature (20 to 30 ° C.) for 1/2 to 3 hours are left and is then cooled to -10 to 15 G before the 0- (2,4-dinitrophenyl) hydroxylamine is added. It is preferred to work with an excess of hydroxylamine from 5 to 20% (molar ratio). The reaction mixture is then left to stand noohmals 1/2 to 3 hours, after the reaction has ended, the compound II is isolated and according to standard methods, for example, purified by extraction, chromatography, crystallization and the like.

The compound II is then hydrolyzed and decarboxylated at the same time. Treatment of compound II with 1/3 - »" * - . -aqueous sodium hydroxide solution in a solvent, ZvB. a lower alkanol, at room temperature and then neutralizing the mixture with dilute sulfuric acid leads to connection IHa. Treating compound II

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with a higher base concentration, e.g. with 1n to 5n sodium or potassium hydroxide, the compound of the formula IIIb is obtained after neutralization with hydrochloric acid.

The treatment of the compound II with a base is preferably carried out at room temperature for a reaction time of Performed 1/2 to 3 hours in methanol, ethanol, 1- or 2-propanol. Treatment (neutralization) of the resulting Salt solution with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or the like is required only minutes. Conventional measures are used to isolate the Ilia or IHb products, for example salts such as barium sulfate are filtered off or removed by extraction, further processing is carried out by chromatography, Recrystallization and the like.

The treatment of a connection IHa or IHb with a Acid halide, e.g. with acetyl chloride, in pyridine or with an acid anhydride leads to the corresponding amide, the can be isolated in a conventional manner, for example by evaporating the solvents, extraction, chromatography, Crystallization and the like.

Preparation 1

2'-Benzoyl-4'-chloroacetanilide.

8113 g (1 »o37 mol) of acetyl chloride are stirred into a solution of 2oo.0 g (0.864 mol) of 2-amino-5-chlorobenzophenone and 68.4 g (0.864 mol) of pyridine in 4 liters of dry ether was added. The mixture is kept at room temperature for 2 hours and treated with 500 ml of water. The layers are separated the ether phase is over anhydrous sodium sulfate

30981? / 1? 40

dried and concentrated. Crystallization from ethyl acetate-Skellysolve B des'Rückstands-hexanes 114-115 ° C are obtained 124 ₉ og Benayl 2'-4'-chloroacetanilide from IY further two other fractions of this compound were obtained ι 67.8 g, mp 113 , 5-114.5 ° G and 33, ο g from Έ. 113-114 ° C

Preparation 2

6-chloro-4-phenyl-2 (iH) ~ quinoline.

It was according to the method of A ₀ E. Drukker and 0.1.

Judd, J., Heterocyclic Chem-, 3, 359 (1966) (reaction of 2'-benzoyl-5 ¹ -chloroacetanilide with sodium hydroxide) worked, yield Π ^σ />. Two other preparations are from SG Bell, TS Bulkowski, G. Gochman and SJ Childress, J. Org.

Chem. 27, 562 (1962) and G.A. Reynolds and CR. Houses,

J. Amer., Ghem. £> oc. 72, 1852 (195o) has been described.

Preparation 3

2,6-dichloro-4-phenylquinoline.

It was made according to the method of Ä.E. Drukker and CI. Judd, J. Heterocyclic Chem. 3, 359 (1966), yield $ 62.

Preparation 4

o-chloro-Z-hydrazino ^ -phenylquinoline.

A mixture of 2.7 g (0.01 mol) 2,6-l) chloro-4-phenylquinoline

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and 6.8 g of hydrazine hydrate were refluxed for 1 hour with stirring in a nitrogen atmosphere and concentrated in vacuo. The residue was suspended in v / poor water, the pesticide was filtered off, dried and recrystallized from ethyl acetate Skellysolve B, 1.81 g (67 ^) 6-chloro-2-hydrazino-4-phenylquinoline with a melting point of 156. 5 to 157 ⁰ C
Anal. Ber. for C _iK H. _o ClN _x :

C: 66.79; H: 4.49; Eq: 13.15; N: 15.58. Found: C: 67.15; ii: 4.65; 01: 13.19; N: 15.32.

Preparation 5

7-chloro-1-methyl-5-phenyl-s-triazolo / 4,3-α7 -quinoline.

A mixture of 1.4 g (0.052 mol) of 6-chloro-2-hydrazino-4-phenylquinoline, 0.925 g (0.057 mol) of triethyl orthoacetate and 100 ml of xylene was stirred in a nitrogen atmosphere for 2 hours 40 minutes Refluxed. During this reaction time, the ethanol formed in the reaction was distilled off through a short column packed with glass coils. The mixture was then concentrated to dryness in vacuo and the residue was crystallized from methanol-ethyl acetate, 1.02 g of 7-chloro-1-methyl-5-phenyl-striazolo / ~ "4,3-α7quinoline from F. 253.5 to 255 ° C and o, 26 g, mp 253.5 to 255 ⁰ C, (83.9 $ yield). The analytical sample was crystallized from methylene chloride / methanol, melting point 252.5 to 253.5 ° C .
Anal. Ber. for C ₁₇ H ₁₂ ClN ₅ :

G: 69.5o; II: 4.12; Cl: 12.07; N: 14.31. Found: G: 69.39; H: 4.02; Cl: 12.1o; N: 14.49.

Preparation 6

5-> chloro-2- (3-methyl-4H-1,2,4-triazol-4-yl) -benzophenone (Oxidation of 7T-chloro-1-methyl-5-phenyl-s-triazolo / 4,3-α7-quinoline).

A suspension of 2.94 g (o, o1 mol) of 7-chloro-1-methyl-5-phenyl-s-triazolo _i / ~ 4,3-a7chinolin in 11o ml of acetone was gektih.lt with stirring in an ice bath and slowly treated with a solution "obtained by adding 2 g of sodium periodate with stirring to a suspension of 2oo mg of ruthenium dioxide in 35 ml of water. The mixture turned dark on the addition. In the course of the next 15 minutes, more sodium periodate became The ice bath was then removed and the mixture was stirred for 45 minutes, additional sodium pergodate (4g) was added and the mixture was stirred at room temperature for 18h and filtered, the solid was washed with acetone and the combined filtrate was concentrated in vacuo. The residue was suspended in water and extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and concentrated. The residue was chromatographed on 100 g of silica gel with 100% methanol: 90% ethyl acetate aphiert, whereby fractions of 50 ml each were collected. The product was eluted in fractions 1o to 2o, upon crystallization from itthylacetat obtain o, 4O5 g of 5-chloro-2- (3-methyl-4H-1 _t 2,4-triazol-4-yl) -benzophenone from F . 168 to 169.5 ⁰ C and o, 291 g, mp 167.5 to 169 ° C (23.4 $ yield) The analytical sample melted at 168 C. Anal. Ber. for C ₁₆ H ₁₂₅

C: 64.54? H: 4.06; Cl: 11.91; W: 14.11. Found: Ci 64.56; H: 4.35; Cl: 11.97; 11.93; N: 14.29.

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Preparation 7

Oxidation of 7-chloro-1-methyl-5-phenyl-s-triazolo / "" 4 _f 3-a7 ~ quinoline.

A suspension of 2.94 g (0.01 mol) of 7-chloro-1-methyl-5-phenyl · s-triazolo ^ "~ 4,3-α7quinoline and 2oo ml of acetone was cooled in an ice bath and over the course of 15 A solution prepared from 200 mg of ruthenium dioxide, 4 g of sodium periodate and 35 ml of water was added dropwise in minutes. A slightly exothermic reaction was observed, the mixture turned dark ml of water was added over 10 minutes, the mixture was stirred for 2 hours, then the remaining sodium periodate solution (41 ml) was added over the next 3 hours, followed by concentration in vacuo to remove the acetone, and the resulting aqueous mixture became extracted with methylene chloride, the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated.The residue was chromatographed on 150 g of silica gel with 2% methanol / 98% chloroform, fractions of 60 ml each being taken up were received. Recovered starting material was eluted by the 11 fractions BIB 14, when crystallized from methanol / Wethylenchlorid is so continuously from o, o69 g of a substance of melting point 251.5 to 253.5 ⁰ C. A mixture of two products was then in the fractions 15- 39 eluted. When this mixture was crystallized from ethyl acetate, 618 mg (2o, 8? S) of 5-chloro-2- (3-methyl-4H-1,2,4-triazol-4-yl) -benzophenone with a melting point of 165.5 were obtained -168 ⁰ C. the residue of the mother liquors gave on crystallization from methanol o, 126 g of a substance of melting point 1o8-112 ° C and o, 588 g of melting point 1dl, 5 to 1o5,5 ° C (decomposition), ie, in 19 , 9 $ yield the methanol solvate of 4- (2-benzoyl-4-chlorophenyl) -5-

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methyl-4H-1,2,4-triazol-3-carboxaldeh.yda The Analysenpro "be melted at loo-Ιοί, 5 ⁰ C

Anal. Ber. for G ₁₇ H ₁₂₅₂

G: 62.68; H: 3.71; Cl: 10.89; H: 12.9 o.

Found: C: 59.37; H; 4.89; Cl: 9.75; N: 11.3ο.

MeOH: 9.347 °; H ₉ O: o, 4o $. Corr. For MeOH and H ₉ Os

C: 61.9o; H: 4.06; Cl: 1o, 8o; N: 12.52.

If the sglvate is heated in a desiccator at 15 mmHg at 7o C for 72 hours, pure 4- (2-benzoyl-4-chlorophenyl) -5-methyl-4H-1,2,4-triazole -3-carboxaldehyde is obtained _e

Preparation 8

Oxidation of 7-chloro-1-methyl-5-phenyl-s-triazolo / 4,3-α7-quinoline.

A vigorous stream of ozone is poured into a stirred, ice-cold solution of 31.1 g (0.16 mol) of 7-chloro-1-methyl-5-phenyl-s-triazolo2f ° 4,3-alpha-quinoline in 750 ml of methanol and 500 ml of methylene chloride Bubbled in oxygen for 12 hours. The resulting mixture is filtered and the filtrate is added to an ice cold reading of 47.5 g of sodium iodide and 63 ml of acetic acid in 2oo ml of v / water. The solution is decolorized by adding sodium thio sulfate and concentrated in vacuo . The residue is mixed with water and extracted with ethylene chloride, the extract is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is chromatographed on 1.5 kg of silica gel, fractions of 175 ml being collected. Fractions 1 to 128 are eluted with v / o methanol / 99% chloroform and fractions 129-168 with 59% methanol / 95% chloroform. The first connection is in the

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- Ίο -

Fractions 49-6ο eluted, it is crystallized from methanol / ethyl acetate, giving 0.76 g of 7-chloro-1-methyl-5-phenyl-s-triazolo / "4,3-α7quinolin-4 (5H) -one from P. 229.5 to 231 ⁰ C (decomposition) and o, 535 g, mp 228 ⁰ C (decomposition). The analytical sample melted at 232-233 ° C. Anal. Calcd. for C ₁₇ H ₁₂₃

C: 65.92; H: 3.91; Cl: 11.44; N: 13.57. Found: C, 65.46; H: 3.72; Cl: 11.48; N: 13.59.

Recovered starting material was eluted in fractions 66-78; crystallization from methylene chloride / methanol gave 0.737 g of this substance with a melting point of 251-253.5 ° C. A mixture of the two remaining products was eluted in fractions 73-168. Crystallization of this mixture from ethyl acetate gave 5-chloro-2- (3-niethyl-4H-1,2,4-triazol-4-yl) benzophenone, namely 10.8 g with a melting point of 166.5-167 , 5 ⁰ C, o.987 g of mp 166-167 ° C and 2.52 g of mp 164-165.5 ° C (45.37 * yield). Crystallization of the mother liquor from methanol gave 5.62 g of a temperature of 14o-141.5 ° C., 1.23 g of a temperature of 1oo, 5-1o2.5 ° C. (decomposition) and 1, o4 g of a temperature of 1o5- 137.5 ° C., ie 20.8% yield of 4- (2-benzoyl-4-chlorophenyl) -5-methyl-4H-1,2,4-triazole-3-carboxaldehyde.

Preparation 9

5-chloro-2- / ~ 3- (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-yl7-benzophenone.

A mixture of 2.98 g (0.01 mol) of 5-chloro-2- (3-methyl-4-H-1,2,4-triazole -4-yl) -benzophenone, 3 g paraformaldehyde and 100 ml xylene were under nitrogen in a at 125 ° C held bath heated for 7 hours. The mixture was then im

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Concentrated in vacuo, the residue was chromatographed on 150 g of silica gel with 3% methanol / 97% chloroform, fractions of 50 ml being collected. The product was eluted in fractions 2o 'to 44th These fractions were concentrated and the residue was crystallized from ethanol / ethyl acetate, there was obtained 1.64 g, mp 138-142 ⁰ C, 0.316 g, mp 138.5 -141 ° ® and 0.431 g of mp 139-141 ° C, thus 72.8% yield of 5-chloro-2 - / "3- (hydroxymethyl) -5-methyl-4H-1,2,4 -triazol ~ 4 ~ yl7benzophenone. The analysis sample melted at 138-139 ° C

Anal. Ber. for C ₁₇ H ₁₅₂

C: 62.3o; H: 4.3oj Cl: 10.81; N: 12.82; Found: C, 62.23; Hi 4.22; Cl: 10.82; W: 11.73.

Preparation 1o

5-chloro-2- _< / ~ 3- (13romomethyl) -5-methyl-4H-1 _s 2,4-triazol-4-yl7 * benzophenone.

A solution of 328 mg (0.01 mol) of 5-chloro »2 - /" 3- (hydroxymethyl) -5-methyl-4H-1 ^^ - triazol ^ -yiyhenzophenon in 5 ml dry, hydrocarbon-stabilized chloroform-was Chilled in an ice bath and with 0.1 ml of phosphorus tribromide treated. The colorless solution was in an ice bath. For 55 minutes, held at room temperature (22 to 24 ° C) for 5 hours. The resulting yellow solution was then poured into a. Mixture of ice and dilute sodium carbonate solution poured, the mixture was extracted with chloroform. The extract was washed with sodium chloride solution over anhydrous Magnesium sulfate dried and concentrated. The residue was crystallized from methylene chloride / ethyl acetate, this gave the 5-chloro-2- / ~ 3- (bromomethyl) -5-methyl-

309812M240

4H-1,2,4-triazol-4-yl7benzophenone in the form of a fraction of 0.285 g of F. 2oo-24o ° 0 (decomposition) and a fraction of 0.030 g with a temperature of 200-240 ° C (decomposition). The analysis sample melted at 200-240 ° C.

Anal. Ber. for C ₁₇ H ₁₅₅

• C: 52.26; H: 3.35; Br: 2o.46; CIi 9.08; N: 1o, 76. Found: C: 52.13; 52.45; H: 3.77; 3.66; Br. 2o, 44; Cl: 9.2o; N: 1o, 43.

Preparation 11

5-Ohlor-2 - / "3- (diormethyl) -5-methyl-4H-1 _f 2,4-triazol-4-yl7-benzophenone.

A solution of 328 mg (o _t oo1 mole) of 5-chloro-2- / ~ 3- (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-yl7benzophenon in 2 ml of thionyl chloride was added over heated 40 minutes to a bath temperature of 78 ° C and 1 hour 25 minutes at 78-83 ⁰ C. The solution was then cooled and poured into ice water. The mixture was neutralized with sodium bicarbonate and extracted with chloroform, the extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. (chloromethyl) -5-methyl-4H-1,2,4-triazol-4-yl, 7benzophenon in a fraction of o, 24o g, mp 144.5 to 147 ⁰ C, and o, 45 g, mp 144 , 5 to 146.5 ⁰ C. The analytical sample melted at 139-14o C. Anal. Ber. for C ₁₇ H ₁₅ Cl ₂ N ₅ O:

C: 58.96; H: 3.78; Cl: 20.48; N: 12.14. Found: C, 59.22; Hi 3.80; Cl: 2o.66; Ni 11.91.

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Preparation 12

5-chloro-2 - / "3- (dodmethyl) -5-metlayl-4H-1,2,4-triazol-4-yl7-benzophenone.

346 mg (o, oo1 mol) of 5-chloro-2- / ~ 3- (chloromethyl-5-methyl-4H-1, 2,4-triazol-4-yl7frenzophenone were stirred into a solution of 300 mg (o, Oo2 mol) of sodium iodide in acetone was added and the resulting mixture was stirred at room temperature for 6 hours 54 minutes and then poured into ice water. It was then extracted with chloroform, the extract was washed with brine, dried and concentrated. The residue gave on crystallization from methylene chloride / Ethyl acetate ο, 227 g of 5-chloro-2 - / "" 3- (3odmethyl) -5-methyl-4H-1,2,4-triazol-4-yl7 ^ enzophenon vom]?. 185.5-192 g (Decomposition), The analysis sample melted at 185-2oo ° C (decomposition). Anal. Calc _{. For G 17} H _{13 GlIH 5} O:

C: 46.65; H: 2.99; Cl: 8.1o; I: 29.00; R: 9.60; Found: C: 46.78; H: 2.88; Cl: 8.59; I: 26.98; H: 9.23.

Preparation 13

8-chloro-1-methyl-6-phenyl-4H-s-triazolo / "4,3-a7 / ~ 1 t azepine.

A suspension of 391 mg (0.01 mol) of 5-chloro-2 - / "" 3- (bromomethyl) -5-methyl-4H-1 ^^ - triazol ^ -ylTbenzophenon in 15 ml Tetrahydrofuran was cooled with stirring in an ice bath and with 12.5 ml of a saturated ammonia solution in Treated methanol. The resulting solution was allowed to warm to room temperature and stand for 24 hours, then was im Reduced vacuum. The residue was suspended in water,

30ÖÖ12 / 12A0

treated with a little sodium bicarbonate and extracted with methylene chloride. The extract was washed with saline, dried over anhydrous potassium carbonate and concentrated. The residue was crystallized from methylene chloride / ethyl acetate, this gave 0.220 g of crude product from P. 227-228.5 ° C. When this material was recrystallized from ethyl acetate 8-chloro-1-methyl-6-phenyl-4H-s-triazolo / ~ 4,3-a7-, 4-7benzodiazepine was obtained in the form of o, 142 g of F. 228-229.5 ° G,

o, o53 g of the mp 228.5-229.5 ° G and o, o21 g of the mp 228-229.5 ° C

The conversion of 5-chloro-2- / ~ "3- (chloromethyl) -5-methyl-4H-1,2,4-triazol-4-yl, 7-tenzophenone with ammonia in methanol also gives e-chloro-i-methyl-o-phenyl ^ H-s-triazolo- / ~ 4 »3-§7 /" "ΐ , 4_7benzodiazepine, but the reaction is slower and takes more than 2 days.

In an analogous manner, from 782 mg (0.02 mol) of 5-chloro-2- / ~ 3- (bromomethyl) -5-methyl-4ii-1 _t 2,4-triazol-4-yl7benzophenone in methylene chloride with cooling in a dry ice-methanol bath with anhydrous ammonia 515 mg B-chloro-i-methyl-ophenyl-4H-s-triazolo / 4,3-a7 ~ / ~ 1, 4_7benzodiazepin mp 226-227 ⁰ C.

Preparation 14

8-Chloro-1-methyl-6-phenyl-4H-s-triazolo / "4,3-a7 /" i, £ 713enzodiazepine-4-carboxylic acid ethyl ether.

A mixture of 61.8 g (0.2o mol) of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo / ~ 4,3-a7 / ~ 1,4_7benzodiazepine and 1 1 of diethyl carbonate is added successively with sodium hydride (8.43 g a 57% suspension in mineral oil) and 2 ml of ethanol

acts. It is then refluxed for 11/2 hours under nitrogen, cooled and concentrated in vacuo. The residue is treated with 1 l of biswater which _{contains 0.2 mol of hydrochloric acid 4} , then it is extracted with methylene chloride. The extract is dried over anhydrous potassium carbonate and concentrated, the remaining pesticide is boiled with ethyl acetate and filtered off. Then, from methylene "chloride / ethanol recrystallized 'thereby obtained 35.7 g' 8-chloro-1-methyl-6-phenyl-4H-s-triazolo ~ / '~ 4' 3-a7 / ~" i $ 47ke : ßzodiazepine-4-carboxylic acid aryl ester with a melting point of 224-225 ° C. (decomposition), the analysis sample melted at 223-224 ° C. (decomposition).

Preparation 15

5-chloro-2- (3-methyl-4H-1,2,4-triazol-4-yl) -benzophenone.

A solution of 0.357 g (0.021 mol) of silver nitrate in 1.8 ml of water is treated with 4.1 ml of sodium hydroxide solution. The resulting silver oxide suspension is added with stirring a warm solution of 326 mg of 4 ~ (2-benzoyl ~ 4-chlorophenyl) -5-methyl-4H-1,2,4-triazole-3 = carboxaldehyde methanol solvate in 15 ml of methanol is added, then the resulting mixture is stirred under nitrogen at room temperature for 18 hours, The solid is filtered off and washed with water and methanol. The filtrate is concentrated in a vacuum to obtain the Remove methanol, and the resulting aqueous solution is cooled in an ice bath, neutralized with hydrochloric acid and extracted with chloroform. The residue is crystallized from ethyl acetate, giving 0.162 g 5-Ohlor-2- (3-methyl-4H-1,2,4-triazol-4-yl) -benzophenone from 169.5-171 ° C

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Preparation 16

4- (2-Benzoyl-4-chlorophenyl) -5-methyl-4H-1,2,4-triazole-3-carboxaldehyde-3-oxime.

A mixture of 3 »26 g of 4- (2-benzoyl-4-chlorophenyl) -5-methyl-4H-1,2,4-triazole-3-carboxaldehyde, 0.765 g (0.011 mol) of hydroxylamine hydrochloride, o , 903 g (0.11 mol) of sodium acetate, 50 ml of ethanol and 12.5 ml of water is refluxed for 4 1/2 hours with stirring in nitrogen atmosphere (the product precipitates from the initially clear solution during the reflux time). The cooled mixture is poured into cold water, the solid is filtered off, washed with water and dried, 2.7 g of crude 4- (2-benzoyl-4-chlorophenyl) -5-methyl-4H-1,2 are obtained , 4-triazole-3-carboxaldehyde-3-oxime. .. ', ·' . "■■

ν 1 i. When crystallizing from methylene chloride / methanol, this material gives the following product fractions: 2.03 g of a mp 28o-281 ° C (decomposition), o.325 g of a mp 278.5-279.5 ⁰ C (decomposition) and o, 154 g of F. 276-277 ° C (dec.). The analytical sample melted (decomposed) at 283.5 to 284 ⁰ C. Anal. Ber. for C ₁₇ H ₁₅ ClN ^ O ₂ :

C: 59.92; H: 3.84i Cl: 10.41; N: 16.44. Found: C: 60.2o; H: 4.22 | Cl: 9.92; N: 16.78.

Preparation 17

8-chloro-5,6-dihydro-1-methyl-6-phenyl-4H-s-triazolo / ~ 4,3-a7-

309612/1

A mixture of 0.5oo g of 4- (2-benzoyl-4-chlorophenyl) -5-methyl-4H-1 ^^ - triazole ^ -carboxaldehyde - ^ - oxime, o, 2 g platinum oxide and 50 ml of acetic acid was added to a Parr hydrogenator an initial pressure of 2.25 kg / cm 8 hours 52 minutes hydrogenated. It was then filtered through Celite diatomaceous earth and the filtrate was concentrated in vacuo. A mixture of the residue and warm water was mixed with activated charcoal (Darco G6o) decolorized, cooled in an ice bath, alkaline with sodium hydroxide placed and extracted with Ghloroform. The extract was washed with brine, dried over anhydrous potassium carbonate and concentrated. A solution to the residue in ethyl acetate was acidified with ethereal hydrochloric acid. The precipitated solid was filtered off with Washed ethyl acetate and recrystallized from ethanol / ethyl acetate. This salt was converted back to the free base, by suspending it in dilute sodium bicarbonate solution and extracted it with chloroform. The extract was washed (brine) over anhydrous potassium carbonate dried and concentrated, the residue resulted in the crystal! - " size from methanol / ethyl acetate 31 mg e-chloro-S ^ -dihydro-imethyl-6-phenyl-4H-s-triazolo / "~ 4,3-a7 / ~ 1 , 4_7benzodiazepine.

Preparation 18 -

8-chloro-1-methyl-6-phenyl-4H-s-triazolo / ~ 4,3-a azepin.

A mixture of 311 mg (0.001 mol) of 8-chloro-5,6-dihydro-1-methyl-6-phenyl-4H-s-triazolo / "" 4,3-a7 / "~ 1,4_7benzodiazepine 35o mg (o, oo2 mol) diethyl azo-dicarboxylate and 1o ml dry benzene was refluxed in a nitrogen atmosphere for 2 hours 45 minutes, then 18 hours at room

300812/1240

left to stand temperature and concentrated in vacuo. The crystalline residue was washed with ether and the resulting pesticide was crystallized from ethyl acetate, thereby obtaining the e-chloro-i-methyl-o-phenyl- ^ Hs-triazölo · / ~ 4 »3-β7 /" * 1.47benzodiazepine in two fractions: o, 123 g of P. 228,5-23o ° C and o _f O53 g, mp 223-226 ⁰ C. the mixing Bchmelzpunkt the first fraction with an authentic sample showed no lowering, the first fraction was identical to the authentic sample.

Preparation 19

6-chloro-4- (2,6-difluorophenyl) -2-hydrazinoquinoline.

According to the instructions of preparation 4, 2,6-dichloro-4- (2,6-difluorophenyl) -quinoline is used reacted with hydrazine hydrate under reflux to give the title compound.

Preparation 2ο

7-chloro-1-methyl-5- (2,6-difluorophenyl) -s-triazolo / "~ 4,3-a7chino- * lin.

6-Chloro-4- (2,6-difluorophenyl) -2-hydrazinoquinoline is obtained as described in preparation 5 and triethyl orthoacetate is refluxed in xylene to give the title compound .

3Ö9Ö12 / 1240

Preparation 21

5-chloro-Z ¹ _> 6 ^l- difluoro-2- (3-methyl-4H-1,2,4-triazol-4-yl) -benzophenone.

According to the instructions for preparation 6, 7-chloro-1-methyl-5- (2,6-difluorophenyl) -s-triazolo-4,3-α-quinoline is used oxidized at low temperature with sodium periodate and ruthenium dioxide, whereby the title compound is obtained.

Preparation 22

5-chloro-2 ', 6'-dil ^ uor-2- / ~ "3- (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-yl7" benzophenone »

According to the instructions of preparation 9, 5-chloro-2 ', 6'-difluoro-2- (3-methyl-4H-1,2,4-triazol-4-yl) -benzophenone is used heated with paraformaldehyde to 125 ° 0, whereby the title compound receives.

Preparation 23

5-chloro-2 ', 6' difluoro-2 - / "" 3- (bromomethyl) -5-methyl-4H-1 _1, 2,4-triazol-4-yl7benzophenon.

According to the instructions for preparation 1 o, 5-chloro »2 ·, 6'-difluoro 2- / ~ 3- (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-yl7 ^ ^{enzo puene} reacted with phosphorus tribromide, whereby the Tite! compound is obtained.

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Preparation 24

8-chloro-1-methyl-6- (2,6-difluorophenyl) -4H-e-triazolo / "" 4,3-a7-f 4_7benzodiazepine.

According to the instructions of preparation 13, 5-chloro-6'-difluoro-2- / ~ 3- (bromomethyl) -5-methyl-4H-1,2,4-triazol-4-yl7benzophenone is used reacted with a saturated ammonia solution in methanol, whereby the title compound is obtained.

Preparation 25

6-chloro-4- (o-chlorophenyl) ^ - hydrazinoquinoline.

According to the instructions for preparation 4, 2,6-dichloro-4- (o-chlorophenyl) -quinoline is used reacted with hydrazine hydrate at reflux to obtain the title compound.

Preparation 26

7-chloro-1-methyl-5- (o-chlorophenyl) -s-triazolo / ~ 4, J-a

According to the instructions for preparation 5, 6-chloro-4- (o-chloro phenyl) -2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give the title compound.

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Preparation 27

2'j 5-DiGhlor-2- / ~ 3-methyl-4H-1,2,4-triazol-4-yl7'benzophenone.

According to the instructions for preparation 6, 7-chloro-1-methyl-5- (o-chlorophenyl) -s-triazolo / 4,3-α7quinoline is used oxidized at low temperature with sodium periodate and ruthenium dioxide, whereby the title compound is obtained.

Preparation 28

2 ', 5-dichloro-2 - / "3- (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-ylTbenz ο phenon.

According to the instructions of preparation 9, 2 ^f , 5-dichloro-2- (3-methyl-4H-1,2,4-triazolo-4 ".yl) -benzophenone is heated to 125 G with paraformaldehyde, the title compound is obtained .

Preparation 29

2 ', 5-I) chloro-2- _i / f "3- (bromomethyl) -5-methyl-4H-1 _f 2 _f 4-triazol-4-yl7-benzophenone.

According to the instructions of preparation 1o, 2 ', 5-dichloro-2- / ~ 3- (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-yl7henzophenone is used treated with phosphorus tribromide to give the title compound receives.

Preparation 3ο 8-chloro-1-methyl-6- (o-chlorophenyl) -4H-s-triazolo / "" 4,3-a7 / ~ 1 _t 47-

309812/1240

- 3ο -

benzodiazepine.

According to the procedure of Preparation 13, 2 ^1/3 ~ 5-Mchior-2 - ( 'bromomethyl) -5methyl-4H-1, 2,4-triazol-4-y reacted l7benzophenon with a saturated ammonia solution in methanol, this gives the i'it elver connection.

Preparation 31

5-nitro-6-propyl-4- (m-trifluoromethylphenyl) -2-hydrazinoquinoline.

According to the instructions of preparation 4, 2-chloro-5-nitro-opropyl-4- (m-trifluoromethylphenyl) -quinoline is used reacted with hydrazine hydrate at reflux temperature, whereby the title compound receives.

Preparation 32

6-nitro-7-propyl-1-ethyl-5- (m-trifluoromethylphenyl) -s-triazolo-, 3-α7quinoline.

According to the instructions for preparation 5, 5-nitro-6-propyl-4- (m-trifluoromethylphenyl) -2-hydrazinoquinoline are used and triethyl orthopropionate in xylene refluxed, with the Title compound receives.

Preparation 33

6-nitro-5-propyl-2- (3-ethyl-4H-1,2,4-triazol-4-yl) -3 '- (trifluoromethyl) benzophenone.

3 0 98 12/1 24-0

According to the instructions for preparation 6, 6-Hitro-7-propyl-1-ethyl-5- (m-trifluoromethylphenyl) -s-triazolo / 4,3-α7quinoline is used at low temperature with sodium periodate and cuthenium dioxide oxidized to give the title compound. '

Preparation 34

6-Nitro ~ 5-propyl-2 - / "3- (hydroxyinethyl) -5-ethyl-4H-1,2,4-triazole 4-yl7-3- (trifluoromethyl) benzophenone.

According to the instructions for preparation 9, 6-nitro ~ 5-propyl-2- (3-ethyl-4H-1,2,4-triazol-4-yl) -3- (trifluoromethyl) -benzophenone is used heated with paraformaldehyde to 125 ° 0, whereby the title compound receives.

Preparation 35

6-nitro-5-propyl-2 - / "3- (bromomethyl) -5-ethyl-4H-1,2,4-triazol-4-yl7-3- (trifluoromethyl) benzophenone.

According to the instructions of preparation 1o, 6-nitro-5'-pi ^> opyl ~ 2- / ~ 3- (hydroxymethyl) -5-ethyl-4H-1,2,4-triazol-4-yl7 "3- (trifluoromethyl ) -benzophenone treated with phosphorus tribromide to obtain the title compound.

Preparation 36

7-Kitro-8-propyl-1-ethyl-6- (m-trifluoromethylphenyl) -4H-s triazolo / ~ "4,3-a7 / '~ 1,

6-Nitro-5-propyl-2- / ~ 3- (bromomethyl) -5-ethyl-4H-1,2,4-triazol-4-yl7-5- (trifluoro- methyl) benzophenone with a saturated ammonia solution reacted in methanol to give the title compound.

Other benzodiazepines can also be prepared according to the instructions of the above preparations, e.g.

8-chloro-1, 6-diphenyl-4H-s-triazolo / ~ "4,3-a7 /""i, £ 7benzodiazepine, 8-chloro-6-phenyl-4H-s-triazolo /" ~ 4,3 -a7 / ~ 1, £ 7benzodiazepine _f 8-trifluoromethyl-1-benzyl-6-phenyl-4H-s-triazolo / ~ 4,3-a7 / "i , £ / - benzodiazepine,

8-chloro-1-cyclopropyl-6- (of luophenyl) - ^ Hs-triazolo / "" 4,3-a7 · / "~ 1 _r £ 7benzodiazepine,

7- (ethylthio) -1-propyl-6- (o ~ bromophenyl) -4H-s-triazolo- / ~ 4,3-a7 / ~ 1, £ 7benzodiazepine,

1o- (trifluoromethyl) -6- / ~ p- (propionylamino) -phenyl7-4H-striazolo / ~ 4,3-a7 / ~ 1,47benzodiazepine,

9-propoxy-8-bromo-1-ethyl-6- / ~ m- (ethylsulfinyl) -phenyl7-4H-s-triazolo- / ~ 4,3-a7 / ~ 1, £ 7benzodiazepine, 9-nitro-8- ethyl-1-propyl-6 - / "o- (ethylsulfynyl) -phenyl.7-4H-G-triazolo / ~ 4,3-a7 / ~ 1, £ 7benzodiazepine, 1-methyl-7-fluoro-6- (o-fluorophenyl) -4H-s-triazolo / "4 _t 3-a7- £ ~" \ , £ 7benzodiazepine,

1-lGopropyl-6- (p-tolyl) -4H-s-triazolo _i / ~ 4 _> 3-a7 / ~ 1.47benzodiaze-

1-propyl-7,1o-dibromo-6- (p-chlorophenyl) -4H-s-triazolo / "4,3-a7- £ ~ \ _f j | 7benzodiazepine,

1-ethyl-8-amino-6- (p-nitrophenyl) -4H-s-triazolo / "4,3-a7 ^> / "i,4.7-benzodiazepine,

1-isopropyl-8-fluoro-6- (o-cyanophenyl) -4H-s-triazolo / ~ 4,3-a7- £ ~ \ , ^ benzodiazepine,

1-isopropyl-9-acetamido-7-chloro-6- (m-aminophenyl) -4H-s-triazolo- £ ~ A , 3-a7 / ~ 1,47benzodiazepine,

309012/1240

7-Dimethylamino-6- / ~ o- (methylsulfynyl) -phenyl7-4H-s-triazolo / ~ 4,3-a7 / ~ 1,47 ^ enzodiazepine,

8 ~ (Propylt] iio) -1-propyl-6- (p-ätlioxyphenyl) -4H-s-triazolo-Z ~ 4,3-a7 / ~ 1,47 ^ enzodiazepine,

9-methyl-6- (o-aminophenyl) -4H-s-triazolo / "~ 4,3-a7 / ~" '1.47 "benzodiazepine and the like

Preparation 37

8-chloro-i-methyl-6- (2,6-difluorophenyl) -4H-s-triazolo / ~ 4,3-a7-f 4 _; 713e ^: D-zodiazepiii-4-carboxylic acid ethyl ester.

According to the Torschrift of preparation 14, a mixture of 8-chloro-1-methyl-6- (2,6-difluorophenyl) -4H-s-triazolo / ~ 4,3-a7- / ~ 1,47t> enzodiazepine ,, Sodium hydride and diethyl carbonate refluxed to give the title compound.

Preparation 38

8-Chloro-1-methyl-6- (o-chlorophenyl) -4H-s-triazolo / ¹ "4,3-a7-, 47 ^ ^egg izodiazepine-4-carl) onic acid methyl ester.

According to the instructions for preparation 14, a mixture of 8-chloro-1-methyl-6- (o-chlorophenyl) -4H-s-triazolo / ~ 4,3-a72f "i , 47- ■ benzodiazepine, sodium hydride and dirnethyl cartonate under reflux cooked, obtaining the Tite! compound.

Preparation 39

3Ö9Ö12 / mO

1-Ethyl-7-nitro-8-propyl-6- (m-trifluoromethylphenyl) -4H-striazolo / "" 4,3-a7 / -1, jl / uenzodiazepin ^ -carboxylic acid propyl ester

According to the instructions for preparation 14, a mixture of 1-ethyl-7-nitro-8-propyl-6- (m-ti "ifluoromethylphenyl) -4H-striazolo / 4,3-a7 / ~ 1,4; 7benzodiazepine, sodium hydride and dipropyl carbonate refluxed to give the title compound.

Other 4-carboxylic acid esters of the general formula I can also be prepared according to the instructions for the above preparation, e.g .:

8-chloro-6-phenyl-4H-s-triazolo ^ 4,3-a7 / ~ "i, 4: 7benzodiazepine-4-carboxylic acid methyl ester,

8-chloro-1-phenyl-6- (of luophenyl) -4H-s-triazolo / '~ 4,3-a7-Z "~ 1,47t> enzodiazeρin-4-carboxylic acid ethyl ester, 7-ethylthio-1- propyl-6- (o-bromophenyl) -4H-s-triazolo / ~ 4,3-a7- £ ~] , 4 _l 7 ^ enzodiazepine-4-carboxylic acid propyl ester, 1o- (trifluoromethyl) -6- / ~ p - (propionylamino) -phenyl7-4H-s-triazolo- / ~ 4,3-a7 / ~ 1, £ 7t ⁾ enzodiazepine-4-carboxylic acid isopropyl ester, 9-propoxy-8-bromo-1-ethyl-6- / ~ m- (ethylsulfinyl) -phenyl7-4H-

9-Nitro-8-ethyl-1-propyl-6- / ~ o- (ethylsulfinyl) -phenyl7-4H-s-triazolo ^ f " 4,3-a7 / ~ 1,47 benzodiazepine-4-carboxylic acid ~ methyl ester, 1, g-Dimethyl-T-fluoro-o- (o-fluorophenyl) -4H-s-triazolo / ~ 4,3-a7-benzodiazepine-4-carboxylic acid ethyl ester, 1-isopropyl-6- (p-tolyl2-4H-s-triazolo / ~ 4,3-a7 / ~ "i, 47 ^ enzodiazepine-4-carboxylic acid ethyl ester,

1-propyl-7,1o-dibromo-6- (p-chlorophenyl) -4H-s-triazolo ^ ~ 4,3-a7-

, 4_7 ^ enzodiazepine-4-carboxylic acid ethyl ester, , 1o-l) iäthyl-8-amino-6- (p-nitrophenyl) -4H-3-triazolo / ~ 4,3-a7 -, ^ "benzodiazepine - ^ - carboxylic acid ethyl ester,

309812/1240

, 7-Diisopropyl-8-fluoro-6- (o-cyanoplienyl) -4H-s-triazolo / ~ 4,3-a7 - "" 1,4jft> enzodiazepine-4-carboxylic acid ethyl ester, 1-isopropyl-g-acetamido-7-clilor-6- (m-aminoplienyl) -4H-s-

7-Bime thylainino-e- ^ o- (methylsulfynyl) -phenyl7-4H-s-triazolo Z ~ " ^/ I-» 3-a7 / ⁱ ~ 1, ^^ enzodiazepine ^ -carboxylic acid ethyl ester, 8- (Propyltliio ) -1-propyl-6- (p-ethoxyplienyl) -4H-s-triazolo-

8-chloro-1-fl-uor-6- (o-chlorophenyl) -4H-s-triazolo / ^l ~ 4,3-a7- / ~ 1.47 "benzodiazepine-4-cart) onsäiire-et] iyl ster , 8.1 - I) iclilor-6- (o-chlorop] ienyl) -4H-s-triazolo ^ f "4,3-a7 / ~ 1» 4.7- ■ benzodiazepine-4-carbonic acid Ethyl ster, 8-Otilor-1-'bromo-6- (o-clilorphenyl) -4H ~ s-triazolo / ~ 4,3-a7 / ~ 1 * T3enzodiazepine-4-carT3onic acid ethyl ester _t 8-chloro- 1 -metlioxy-6- (o-clilorplienyl) -4H-s-triazolo / ~ "4 , 3-a7-

8-chloro-1-ethyltliio-6- (o-chlorophenyl) -4H-s-triazolo _i / ~ "4,3-a7-

8-Ätllyl-t-trifluorometl·lyl-6- (o-clllorpllenyl) -4H-s ~ triazolo- £ ~ ύτ ₁ 3-a7 / "~ 1, ^ laeiizodlazepin ^ -carboiic acid ethyl ester, 8-chloro- 1-cyano ~ 6- (o-clilorp3aenyl) -4H-s-triazolo _{j (} r "4,3-a7- £ ~ Λ , 47 ¥ benzodiazepine-4-carboxylic acid ethyl ester, 8-clilor-1 -pyrrolidino-6- (o-chlorophenyl) -4H-s-triazolo- »47t ⁾ 6nzodiazepine-4-carborylic acid ethyl ester ^

-e- (o-clilorpkenyl) -4H-s-triazolo2f "4 , 3-a7-

8-Chloro-1-diethylamino-e-Co-clalorpiaeiiyl) -4H-S- £ ~ 4,3-a7 / ~ 1,4_713enzodiazepine-4-cariDonic acid ethyl ester, 7,9-dimethyl-6- (o-aminoplienyl ) -4H-s-triazolo / "~ 4,3-a7 /""i, 4_7- ■ benzodiazepine-4-carlDonic acid isopropyl ester, 8-brora-1- (4-pyridyl) -6- (m- nitrophenyl _} _- 4H-s-triazolo / "4,3-a7- £" * \ , 47 "benzodiazepine-4-car" bonsäure-isopropyl ester, 1-benzyl-7-methyl-8-ätllylsulfinyl-6- (p-äthylsulfiIlylpllenyl) -4H-s ■ triazolo _jj f "4,5-a7 / ~ 1,47faenzodiazepine-4-carboxylic acid methyl ester and the like.

example 1

4-Amino-8-chloro-1-methyl-6-phenyl-4H-s-triazolo / "" 4,3-a7 -, ^ benzodiazepine - ^ - carboxylic acid ethyl ester.

An ice-cold mixture of 7.62 g (0.02 mol) of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo / ~ 4,3-a72T "i 47 ^P- tenzodiazepine-4-carboxylic acid ethyl ester in 1oo ml dry Dimethylformaidß with stirring in a nitrogen atmosphere with sodium hydride (o, 92 g _f o, o22 mol, 57 $ suspension in mineral oil) and held for 15 minutes in an ice bath, then for 2 hours at room temperature (about 22 to 25 g) The mixture is then cooled in an ice bath and treated with 4.38 g (0.022 moles) of O- (2,4-dinitrophenyl) hydroxylamine (T. bheradsky, J. Heterocyclic Chem. 4, 413 (1967)) , Kept for 2 hours at room temperature and then concentrated in vacuo. The residue is suspended in ice water, neutralized with acetic acid and extracted with methylene chloride. The extract is dried over anhydrous sodium carbonate and concentrated, the residue is crystallized from ethyl acetate / Skellysolve B, whereby 5 , 56 g of 4-Afflino-8-chloro-1-methyl-6-phenyl-4H-s-triazolo ^ ~~ 4,3-a.

ethyl ester with a temperature of 192-194 ° C and 0.53 g of Ϊ. 191-193 ° E (77J6 yield). The analysis sample melted at 177.5-

Anal. Ber. for C ₂₀ H ₁₈ ClN ₅ O ₂ :

C: 60.68; H: 4.58; Cl: 8.96; N: 17.69; Found: C: 60.81; H: 4.52; Cl: 8.95; Ni 17.91.

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Example 2

4-Amino-8-chloro-1-methyl-6- (2,6-difluorophenyl) -4H-s-triazolo- '

According to the procedure of Example 1, 8-chloro-1-methyl-6- (2,6-difluorophenyl) -4H-s-triazolo / ~ '4,3-a7 / ~ 1,4-7-benzodiazepine-4-carboxylic acid methyl ester with potassium methylate "and then with 0- (2,4-dinitrophenyl) hydroxylamine Traded, whereby one receives the title connection »

Example 3 - ^ ^c:

4-Amino-8-chloro-1-methyl-6- (o-chlorophenyl) -4H-s-triazolo-Z ~ "4,3-a7 / ~ 1 , ^ benzodiazepine ^ -carboxylic acid methyl ester.

According to the procedure of Example 1, 8-chloro-1-methyl-6- (o-chlorophenyl) -4H-s-triazolo _J / "" 4,3-a7 / ~ "i, 47benzodiazepii is methyl 4-carboxylate with sodium hydride and then the title compound is obtained with 0- (2,4-dinitrophenyl) hydroxylamine / _{1 .wQbaijaan.}

Example 4

4-Amino-1-ethyl-7-nitro-8-propyl-6- (m-trifluoromethylphenyl) -4H-s-triazolo ^ "~ 4f 3-a7 / ~" i, 4_7l ^{3enzO (} 3-iazepine-4- ethyl carboxylate.

According to the procedure of Example 1, 1-ethyl-7-nitro-8-propyl-6- (m-trifluoromethylphenyl) -4H-s- _triazolo / ™ "4,3-a7-Z ~ 1» 4_7-benzodiazepine-4 -carboxylic acid ethyl ester with potassium ethylate

309812/12 ^ 0

and then treated with O- (2,4-Mnitrophenyl) hydroxylamine, whereby the title compound is obtained.

Example 5

4-Amino-1-isopropyl-9-acetamido-7-chloro-6- (m-aminophenyl) -4H-8-triazolo / "" 4,3-a7 / ~ 1 * ^ benzodiazepine ^ -carboxylic acid propyl ester.

According to the procedure of Example 1, SJ-Acetamido-T-chloro-isopropyl-6- (m-aminophenyl) -4H-a-triazolo ^ 4,3-a7 / ~ 1 , ^ jtenzo diazepine-4-carboxylic acid propyl ester treated with potassium propylate and then with 0- (2,4-mnitrophenyl) hydroxylamine to give the title compound.

Example 6

-S- (o-chlorophenyl) -4H-striazolo / ~ 4,3-a7 / "* 1,4,7 ^ enzodiazepine-4-carboxylic acid ethyl ester.

According to the procedure of Example 1, i-Cyclopropyl-S-chloro-6- (o-chlorophenyl) -4H-s-triazolo / "~ 4,3-a7 / ~" i , 47benzodiazepine-4-carboxylic acid ethyl ester treated with sodium hydride and then with O- (2,4-dinitrophenyl) hydroxylamine, whereby the retention.

Example 7

4-Amino-1- (4-pyridyl) -e-bromo-6- (m_nitrophenyl) -4H-s-triazolor, ^ 7 "be ^nz ° diazepine-4-carboxylic acid isopropyl ester.

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:. 2242318

According to the procedure of Example 1, 8-bromo-1- {4-pyridyl) -6 «(m-nitrophenyl) -4H-s-triazolo / ~ 4» 3-a7 / "" i, ^ zhenzodiazepine - ^ - isopropyl carboxylate with sodium isopropylate and dough treated with 0- (2,4-dinitrophenyl) hydroxylamine, whereby one the title compound receives.

Example '.8' -

4-Amino-1-benzyl-7-methyl-8-ethysulphonyl-6- (p-ethylsulphinylphenyl) -4H-s-triazolo / ~ 4,3-a7 / ~ 1 _f £ 7 ^ enzodiazepine-4-carbonQ acid methyl ester . ■

1-Benzyl-7-methyl-8-ethylsulfinyl-6- (p-ethylsulfinylphenyl) -4H-s-triazolo- £ ~ 4- »3-a7 /" ~ 1,47henzodiazepine-4- car "bonoic acid methyl ster treated with potassium hydride and then with O- (2,4-dinitrophenyl) hydroxylamine to obtain the '-L'itelverbindungen.

Example 9

4-Amino-8-chloro-1-methyl-6-phenyl-4H-s-triazolo / '"4 | 3» a7- / 1, ^ Tbenzodiazepine.

A solution of 3.96 g (0.1 mol) of 4-amino-8-chloro-1-methyl-6-phenyl-4H-ö-triazolo _J ^ ~ "4,3-a7 _i / _i ""i, Ethyl enzodiazepine carboxylate in 125 ml of ethanol is treated with 33.6 ml of a 0.327N barium hydroxide solution while stirring and kept at room temperature for 1 hour. The mixture is then concentrated in vacuo, the residue is dissolved in water and neutralized with 10 ml of 1, o37N sulfuric acid, the solid barium sulfate is filtered off and washed with water

30981 2/1240

- 4ο -

Filtrates are concentrated in vacuo, the residue is dissolved in absolute ethanol and the solution is again in

Reduced vacuum. The resulting product is crystallized from methanol / ethyl acetate, giving 2.04 g of 4-amino-8-chloro-1-methyl-6-phenyl-4H-s-triazolo / ~ 4,3-a7 / "" i

diazepine with a temperature of 2o8 ° C (decomposition). .

Anal. Ber. for C ₁₇ H ₁₄ ClIi ₅ :

C: 63.06; H: 4.36; Cl: 10.95; N: 21.63.
Found: C, 62.87; H: 4.34; Cl: 10.88; N: 21.64.

Example 1o

4-Amino-8-chloro-1-methyl-6- (2,6-difluorophenyl) -4H-o-triazolo-, 4-7benzodiazepine.

According to the procedure of Example 9, 4-amino-8-chloro-1-methyl-6- (2,6-difluorophenyl) -4H-s-triazolo_ / ~ 4,3-a_7 / "i , 4.7-benzodiazepine-4-carboxylic acid methyl ester treated with barium hydroxide, whereupon the mixture is neutralized with sulfuric acid will. This gives the title compound.

Example 11

4-Amino-8-chloro-1-methyl-6- (o-chlorophenyl) - ^ H-s-trlazolo-, 4-7benzodiazepine.

4-Amino-8-chloro-1-methyl-6- (o-chlorophenyl ) -4H-s-triazolo / ~ 4,3-a7 / ~ 1,4j7i> enzodiazepine-4-carboxylic acid methyl ester treated with barium hydroxide, whereupon the mixture is neutralized with sulfuric acid. Included one obtains the 'l' title compound.

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Example 12

4-Amino-1-ätllyl-7-n.itro-8-propyl-6- (m-tr ± fluorometl.lylpllenyl) -4H-striazolo / "" 4,3-a7 / ~ 1 , 4_7benzodiazepine.

According to the procedure of Example 9, 4-amino-1-ethyl-7-nitro-8-propyl-6- (m-trifluoromethylphenyl) -4H-s-triazolo / "" 4,3-a7- £ ~ Λ , 4_7tenzodiazepine-4-carboxylic acid ethyl ester treated with barium hydroxide, whereupon the mixture is neutralized with sulfuric acid. This gives the title compound.

Example 13

4-Amino-1-isopropy ^ -9-acetamido-7-chloro-6- (m-aminophenyl) -4H-s-triazolo ^ ~ 4,3-a7 / "~ 1 , 47 ^ enzodiazepine.

According to the procedure of Example 9, 4-amino-1-isopropyl-9-acetamido-7-chloro-6- (m-aminophenyl) -4H-s-triazolo / "4,3-a7- £ ~ Ί , ^ tenzodiazepine - ^ - carboxylic acid propyl ester treated with barium hydroxide, then the mixture is neutralized with sulfuric acid. This gives the title compound.

Example 14

4-Amino-8-chloro-1-cyclopropyl-6- (o-chlorophenyl) -4H-s-

According to the procedure of Example 9, 4-cyclopropyl-6- (o-chlorophenyl) -4H-s-triazolo / ~ 4,3-a7 / "" i »47-benzodiazepine-4-carboxylic acid methyl ester with barium hydroxide

treated, then the mixture is neutralized with sulfuric acid

309812/1 ^ 40

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sated. This gives the title compound.

Example 15

4-Amino-1- (4-pyridyl) -8-bromo-6- (m-nitrophenyl) -4H-striazolo / "" 4,3-a7 / "~ 1,47 benzodiazepine.

According to the procedure of Example 9, 4-amino-1- (4-pyridyl) -8 ~ bromo-6- (m-nitrophenyl) -4H-s-triazolo / "" 4 _t 3-a7 / "" i ₉ £ J}) enzoäl azepine-4-carboxylic acid isopropyl ester treated with barium hydroxide, then the mixture is neutralized with sulfuric acid, the title compound is obtained.

Example 16

4-Amino-1-benzyl-7-methyl-8-ethylsulfonyl-6- (p-ethylsulfinylphenyl) -4H-s-triazolo / ~ 4 _t 5-a7 / ~ 1, ^

According to the procedure of Example 9, 4-amino-1-benzyl-7-methyl-8-ethylsulfonyl-6- (p-ethylsulfinylphenyl) -4H-striazolo / "~ 4,3-a7 / ~ 1,4_7benzodiazepine-4- carboxylic acid methyl ester treated with barium hydroxide, then the mixture is neutralized with sulfuric acid. You get the Title compound.

Example 17

4-Amino-8-chloro-1-methyl-6-phenyl-6H-s-triazolo / ~ 4,3-a7 / ~ 1 benzodiazepine.

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A suspension of o, 792 g (o, oo2 mol) of 4-amino-8-chloro-1-methyl-6-phenyl-4H-s-triazolo / ~ 4,3-a7 / "~ 1,4_7benzodiazepin-4- Ethyl carboxylate in 25 ml of ethanol is treated with 2.5 ml of 1N sodium hydroxide and kept at room temperature for 50 minutes. It is then concentrated in vacuo. The residue is dissolved in water with dilute hydrochloric acid, Ms pH 6.8 The residue is mixed with absolute ethanol and evaporated, the resulting material is extracted with chloroform. The product is mixed with absolute ethanol and concentrated, the residue is extracted again with chloroform. That from the chloroform extract The product obtained is first crystallized from methanol / ethanol and then from methanol, giving 0.282 g of 4-amino-8-chloro-1-methyl-6-phenyl-6H-s-triazolo / ~ "4,3-a7 - / ~ 1,4_7benzodiazepine from i ¹ . 278-279.5 ° C (decomposition). Anal. Ber. for C ₁₇ H ₁₄ ClK ₅ :

C: 63.06; H: 4.36; Cl: 10.95; N: 21.63 FOUND: C: 62.71; H: 4.44; 01: 1o _f 95; N: 21.30.

Example 18

4-Amino-8-chloro-1-methyl-6- (2,6-difluorophenyl) -6H-striazolo / "4,3-a7 / ~ 1,4_7benzodiazepine.

According to the procedure of Example 17, 4-amino-8-chloro-1-methyl-6- (2,6-difluorophenyl) -4H-s-triazolo / ~ 4,3-a7- £ "\ , 4_7benzodiazepine-4- methyl carboxylate treated with 1,2N aqueous sodium hydroxide solution, then the mixture is neutralized with dilute hydrochloric acid, whereby the '-i-'itelverbindungen is obtained.

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Example 19

4-Amino-8-chloro-1-methyl-6- (o-chlorophenyl) -oH-s-triazolo- / ~ 4 _f 3-a7 / "~ 1,

Following the procedure of Example 17 is 4-amino-8-chloro-. 1-methyl-6- (o-chlorophenyl) -4H-s-triazqlo / ~~ 4,3-a7 / "~ 1 _f £ / l> enzo diazepine-4-carboxylic acid methyl ester with 1,2N aqueous sodium hydroxide solution treated, then the mixture is neutralized with dilute hydrochloric acid, which gives the title compound.

Example 2o

4-Amino-1-ethyl-7-nitro-8-propyl-6- (m-trifluoromethylphenyl) -6H-striazolo / "~ 4,3-a

Following the procedure of Example 17, 4-amino-1-ethyl-7-nitro-8-propyl-6- (m-trifluoromethylphenyl) -4H-s-triazolo- ^ f "4,3-a7, / f" i, £ 7 ^ enzodiazepine-4-carboxylic acid ethyl ester with 1,2 water Treated sodium hydroxide solution, then the mixture is neutralized with dilute hydrochloric acid. It receives • one the title compound.

Example 21

4-Amino-1-isopropyl-9-acetamido-7-chloro-6- (m-aminophenyl) -6H-s-triazolo / ~ 4,3-a7 / "i _{t <}

4-Amino-1-isopropyl-9-acetamido-7-chloro-6- (m-amino phenyl) -4H-s-triazolo / "* 4,3-a7-

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The benzodiazepine-4-cartionic acid propyl ester is treated with 1,2N aqueous sodium hydroxide solution, then the mixture is neutralized with dilute hydrochloric acid. This gives you the title connection.

Example 22

'4-Amino-8-chloro-1-cyclopropyl-6- (o-chlorophenyl) -6H-striazolo / "4,3-a7 / ~ 1, 47" benzodiazepine.

According to the procedure of Example 17, 4-amino-8-chloro-1-cyclopropyl-6- (o-chlorophenyl) -4H-s-triazolo / ~ 4,3-a7 / "i _t £ 7- benzodiazepine-4- ethyl carboxylate is treated with 1.2N aqueous sodium hydroxide solution, then the mixture is neutralized with dilute hydrochloric acid, thereby obtaining the title compound.

Example 23

4-Amino-1 - (4-ijridyl) -8-brom-6- (m-nitrophenyl) -6H-s-triazolo-, 4.7 ^ enzodiazepine.

According to the procedure of Example 17, 4-Amino-1- (4-pyridyl) -8-bromo-6- (m-nitrophenyl) -4H-s-triazolo / -4,3-a7 / -1,4.7 ^ enzodiazepine -4-carboxylic acid isopropyl ester treated with 1.2N aqueous sodium hydroxide solution, then the mixture is with dilute hydrochloric acid neutralized, this gives the title compound.

Example 24

4-Amino-1-benzyl-7-methyl-8-ethylsulfonyl-6- (p-ethylsulfinylphenyl) -6H-s-triazolo / ~ 4,3-a7Z ~ "i , 4_Tkenzodiazepine.

309812/1240

According to the procedure of Example 17, 4-amino-1-benzyl-7-methyl-8-ethylsulfonyl-6- (p-ethylsulfinylphenyl) -4H-striazolo / ~ 4 _t 3-a7 / ~ 1,4_7benzodiazepine-4-carboxylic acid -methyl ester treated with 1.2N aqueous sodium hydroxide solution, then the mixture is neutralized with dilute hydrochloric acid. This gives the title compound.

Example 25

4-Acetamido-8-chloro-1-methyl-6-phenyl-4H-s-triazolo / 4,3-a7- £ " 7

A solution of 1 g of 4-amino-8-chloro-1-methyl-6-phenyl-4H-striazolo / "~ 4 _f 3-a7Z" ~ 1,4_7benzodiazepine in 5 ml of pyridine is mixed with 1 g of acetic anhydride, then becomes the mixture was stirred at 25 ° C. for 2 hours, left to stand for 18 hours and then poured into ice water. When filtration of the aqueous solution is obtained, the 4-acetamide ^ 8-chloro-1-methyl-6-phenyl-4H-s-triazolo ^ "" 4 _f 3-a7 / ~ 1,4_7fcenzodiazepin which was purified by crystallization from aqueous ethanol will.

Example 26

4-propionamido-8-chloro-1-methyl-6- (o-chlorophenyl) -6H-strlazolo / ~ 4 »3-a7 / ~ 1,4_7 ^ enzodiazepine.

A solution of 1 g of 4-amino-8-chloro-1-methyl-6- (o-chlorophenyl) -6H-s-triazolo ^ "4,3-a7 / ~ 1, ^ 7 ^ enzodiazepine in pyridine is mixed with propionic anhydride and the mixture is stirred at 10 ° C for 4 hours, then left to stand for 18 hours and poured into ice water. The product 4-propionamido-8-chloro-

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i-methyl-o-Co-chlorphenylJ-SH-s-triazolo / ^, 3-a7 / "~ 1, 47 diazepin-benzo · is filtered off and purified by crystallization from methanol.

Example 27

4-Butyramido-8-chloro-1-cyclopropy.l-6- (o-chlorophenyl) -6H-striazolo / ~ 4,3-a7 / "~ 1,47 ^ enzodiazepine.

A solution of 1 g of 4-amino-8-chloro-1-cyclopropyl-6- (ochlorophenyl) -6H-s-triazolo / ~ 4 | 3-a7 _i / "" 1,4j7benzodiazepin i ⁿ · byyridine is mixed with butyric anhydride and the mixture is stirred at 10 ° C. for 4 hours, then left to stand for 18 hours and then poured into ice water. The product 4-butyramido-8-chloro-1-cyclopropyl-6- (o-chlorophenyl) -6H-s-triazolo / ~ 4,3-a7 / "~ 1,4_7benzodiazepine is filtered off and purified by crystallization from methanol.

According to the instructions in Examples 1 to 24, further 4-Amino-triazolo-benzodiazepines are produced, for example the connections

4-Ainino-8-chloro-7-ethylthio-1 - (2-pyrimidyl) - 6- (of luophenyl) 4H-s-triazolo / ~ 4,3-a7 / ~ 1, ^ benzodiazepine, 4 ~ amino-1o -isopropyl-9-dipropylamino-i- (2-thienyl) -6- (ochlorphenyl) -4H-s-triazolo / ~ 4,3-a7 / ~ 1, ^ tbenzodiazepine, 4-amino-8-fluoro-7- acetamido-1-cyclobutyl-6- (m-methylthiophenyl) -4H-s-triazolo / "4,3-a7 / ~" i, 47benzodiazepine, 4-amino-9-isopropyl-7-ethyl-1-pheny1-6 - (2,6-difluorophenyl) -4H-s-tria ^a zolo / "4,3-a7 / ~ 1, ^ / ^ enzodiazepine,

4-Amino-7-nitro-1-propyl-6- (3,5-dinitrophenyl) -4H-s-triazolo-, 4j7benzodiazepine,

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4-Amino-7,8-dicyano-1- (3-pyrazolyl) -6- (2,4-difluorophenyl) -4H-striazolo ^ ~ 4,3-a7 / ~ 1, ^ benzodiazepine, 4-amino-8 , 10-dichloro-1- (2-pyrimidyl) -6- (o-bromophenyl) -4H-striazolo / ~ 4,3-a7 / ~ 1,4j7t »enzodiazepine _f 4-amino-9-diisopropylamino-1-cyclooctyl -6- (p-methylsulfonylphenyl) -4H-s-triazolo / "~ 4,3-a7 / ~ 1,4j7benzodiazepine, 4-amino-1o-ethyl-8-ethoxy-1-cyclohexyl-6- (o-fluorophenyl ) -4H-s-triazolo / ~ 4 % 3-a7 / ~ 1, ^ benzodiazepine, 4-amino-9-nitro-8-fluoro-1-benzyl-6- (m -cyanophenyl) -4H-8-triazolo / ~ 4,3-a7 / "if JL7t> enzodiazepine, 4-amino-7-nitro-8-bromo-1-ethyl-6- (o-chlorophenyl) -oH-s-triazolo- / ~ 4 1" 5 - £ l £ "^" l7t> enzodiazepin, 4-amino-7-cyano-8-chloro-1-methyl-6- (2 _r 4-diethylphenyl) -6-striazolo _i T "4,3-AE7 /" i, 4_7benzodiazepine, 4-Αΐη1ηο-8τ 1o-dimethyl-9-fluorine-1-cyclopentyl-6- (o-chlorophenyl) -6H-s-triazolo / 4,3-a7Z ~ "i, ^ jbenzodiazepine, 4 -Amino-8-ethylsulfinyl-1- (1,2,3,4-thiatriazolo) -6-phenyl-6H-striazolo / "4 _t 3-a7 / ~ 1,4; 7 ^ enzodiazepine, 4-amino-8 -chlor-1-pyrrolidino-6- (o-chlorophenyl) -6H-ü-triazolo-

4-Amino-6- (o-cyanophenyl) -6H-s-triazolo / ~ 4,3-a7 / ~ "i, azepine,

4-Amino-1o-trifluoromethyl-1-phenyl-6- (2,6-dichlorophenyl) -6H-s-triazolo / "4,3-a7 / ~ 1 , ^^ enzodiazepine, 4-amino-9-bromo-1-propyl-6- (p-trifluoromethylphenyl) -6H-atriazolo / ~~ 4,3-a7 / "~ 1 , j-7 ^ enz ° diazepine, 4-AmInO-S-IsOPrOPyI-1-benzyl-6- (2,4-dicyanophenyl) -6H-striazolo / ~ 4,3-a7 / f 1.47 "benzodiazepine, 4-amino-8-dimethylamino-1-fluoro-6- (2,6-diraethoxyphenyl) -6H-striazolo / ~ 4,3-a7 / ~ 1,4_7" benzodiazepine, 4-Amino-9-acetamido-1-methoxy-6- (m-nitrophenyl) -6H-e-triazolo- / ~ 4,3-a7 / T "i , 4_7benzodiazepine, and the like.

309812/1240

If the compounds of the ^x formulas Ilia or IIIb are treated with a pharmacologically acceptable acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid, loluenesulfonic acid, methanesulfonic acid, tartaric acid, citric acid, lactic acid, malic acid, maleic acid, oyclohexanesulfamic acid or the like the pharmacologically acceptable acid addition salts of these compounds, which can be used analogously to the free bases IHa and IHb. The salt formation takes place in a conventional manner by reacting the compounds of the formulas Ilia or IHb with an equivalent amount of the respective acid in a suitable medium, for example in water, a lower alkanol, ether or acetone and the salt by filtering off or evaporating off the solvent, preferably in vacuo, isolated.

981271240

Claims (9)

Claims wherein R _{1 is} hydrogen, an alkyl radical with 1 to 3 carbon atoms, cycloalkyl radical with 3 to 8 carbon atoms, phenyl radical, ben ^ yl radical, a 5- or 6-membered heterocyclic ring with 1 to 4 heteroatoms in the form of nitrogen, acid / or / furthermore
substance and sulfur, fluorine, chlorine, bromine, an alkylthiorect with an alkyl moiety as defined above, an alkoxy moiety with 1 to 3 carbon atoms, a cyano group, a pyrrolidino or piperidino moiety, a trifluoromethyl group or a dialkylamino group, the alkyl moieties of which are the above 309812/1240 Definition correspond, and Rp, ^R 3 »^ a ¹ ^ a ^Γν κ hydrogen, alkyl radicals according to the above definition, fluorine, chlorine, bromine atoms, nitro, cyano, amino, trifluoromethyl or alkoxy, alkylthio, alkylsulfonyl -, alkylsulfinyl, alkanoylamino groups, the carbon chain of which has 1 to 3 carbon atoms, or dialkylamino groups with alkyl moieties as defined above, and their 4-amino-N-acetyl, -N-propionyl and -N-butyryl derivatives and their pharmacologically acceptable Acid addition salts. 2. A compound according to claim 1 of the formula IHa IHa in which B ... hydrogen, an alkyl radical with 1 to 3 carbon atoms, Cycloalkyl radical with 3 to 8 carbon atoms, Phenyl radical, benzyl radical, a 5- or 6-membered heterocyclic Ring with 1 to 4 heteroatoms in the form of stick- and/
atoff, oxygen or sulfur; Fluorine, chlorine, bromine, an alkylthio radical whose alkyl group corresponds to the above definition, an alkoxy radical with 1 to 3 carbon atoms, 309812/1240 a cyano group, a pyrrolidino or piperidino radical, a trifluoromethyl group or a dialkylamino radical, whose alkyl groups correspond to the above definition, and Rp, R », R ^ and R, - hydrogen, β alkyl radicals according to the above Definition, fluorine, chlorine, bromine atoms, nitro, cyano, amino, trifluoromethyl or alkoxy, alkylthio, alkylsulfonyl, Alkylsulfinyl or alkanoylamino radicals, the carbon content of which has 1 to 3 carbon atoms, or Dialky! Amino groups with aikyireates as defined above, represent. 3. 4-Amino-8-chloro-1-methyl-6-phenyl-4H-s-triazolo / ~ 4,3-a7 ·· £ "λ , 4.7benzodiazepine. 4. A compound according to claim 1 of the formula IHb ^R 4 in the R. hydrogen, an alkyl radical with 1 to 3 carbon atoms, Cycloalkyl radical with 3 "to 8 carbon atoms, 309817/1240 Phenyl radical, benzyl radical, a 5- or 6-membered heterocyclic Ring with 1 to 4 heteroatoms in the form of nitrogen, oxygen or sulfur; Fluorine, chlorine, bromine, one Alkylthio radical, the alkyl group of which corresponds to the above definition, an alkoxy radical with 1 to 3 carbon atoms, a cyano group, a pyrrolidino or piperidino radical, a trifluoromethyl group or a dialkylamino radical, whose alkyl groups correspond to the above definition, and Rp, R ,, R and R, - hydrogen, alkyl radicals according to the above Definition, fluorine, chlorine, bromine atoms, nitro, cyano, amino, trifluoromethyl or alkoxy, alkylthio, alkylsulfonyl, Alkylsulfinyl or alkanoylamino radicals, their carbon portion has 1 to 3 carbon atoms, or Represent dialkylamino groups with alkyl radicals as defined above. 5. 4-Amino-8-chloro-1-methyl-6-phenyl-6H-s-triazolo_ / ~ "4,3-a7- 6. Method of making a compound of the ^ 'ormel IHa IHa 309812/1240 wherein Rv is hydrogen, an alkyl radical having 1 to 3 carbon atoms, a cycloalkyl radical having 5 to 8 carbon atoms, a phenyl radical, a benzyl radical, a 5- or 6-membered heterocyclic ring having 1 to 4 heteroatoms in the form of nitrogen, oxygen and sulfur; Fluorine, chlorine, bromine, an alkylthio group with an alkyl moiety as defined above, an alkoxy group with 1 to 3 carbon atoms, a cyano group, a pyrrolidino or piperidino group, a trifluoromethyl group or a dialkylamino group, the alkyl moieties of which correspond to the above definition, and R ₂ , R ,, Ri and R ₁ - hydrogen, alkyl radicals as defined above, fluorine, chlorine, bromine atoms, nitro, cyano, amino, trifluoromethyl or alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, alkanoylamino groups, their carbon chain Has 1 to 3 carbon atoms, or dialkylamino groups with alkyl moieties as defined above, characterized in that a compound of the formula I 309812M240 ~ ⁵⁵ - wherein Around have the above meaning and R ^{1 represents} an alkyl reet having 1 to 3 carbon atoms, treated with a strong base at a temperature between -to and sl · 20 ° C. and the resulting product treated with O- (2,4-dinitrophenyl) hydroxylamine to form the amino acid ester II COOR ' II wherein R ¹ , Rp, R have the above meaning, the ester II hydrolyzed with barium hydroxide and with sulfuric acid neutralized by forming the compound purple, 7 »Method according to claim 6, characterized in that the strong base before treatment with 0- (2,4-dinitrophenyl) hydroxylamine is used, an alkali metal hydride or alkali metal alkoxide with an alkoxy radical having 1 to 5 carbon atoms is. 309812/1240 8. Process for the preparation of a compound of the formula HIb IUb wherein R _{1 is} hydrogen, an alkyl radical having 1 to 3 carbon atoms, a cycloalkyl radical having 3 to 8 carbon atoms, a phenyl radical, a benzyl radical, a 5- or 6-membered heterocyclic ring having 1 to 4 heteroatoms in the form of nitrogen, oxygen and sulfur; Fluorine, chlorine, bromine, an alkylthio group with an alkyl moiety as defined above, an alkoxy group with 1 to 3 carbon atoms, a cyano group, a pyrrolidino or piperidino group, a trifluoromethyl group or a dialkylamino group, the alkyl moieties of which correspond to the definition above, and R ₂ , R *, R ₄ and R _{5 are} hydrogen, alkyl radicals as defined above, fluorine, chlorine, bromine atoms, nitro, cyano, amino, trifluoromethyl or alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, alkanoylamino groups, whose 309817/1240 Carbon chain has 1 "to 3 carbon atoms, -or Dialkylamino groups with alkyl components as defined above, represent, characterized in that a compound of ^ ormel I GOOR ' in which R ₁ , R ₂ , R, and R. and R, - have the above meaning and R ^{1 is} an alkyl radical having 1 to 3 carbon atoms, treated with a strong base at a temperature of -1ο to 2o ° G, the resulting product treated with 0- (2,4-dinitrophenyl) hydroxylamine to form the amino ester II 309812/1240 Ν- II in which R ¹ , R ₁ , R ₂ , R 1, R and R _{5 have} the above meaning, the ester II is hydrolyzed with sodium hydroxide and then neutralized with hydrochloric acid to form the compound IIIb. 9. The method according to claim 8, characterized in that the prior to treatment with 0- (2,4-dinitrophenyl) hydroxylamine Strong base used, an alkali metal hydride or alkali metal alkoxide with alkoxy groups of 1 to 3 carbon atoms. For: The Upjohn Company Kalamazoo, Mich., V.St.A. Dr. H. J. Wolff (Lawyer) 309812/1240