NO762525L - - Google Patents

Description

Procedure for the production of new benzodiazepines.

The present invention relates to a method for the production of 3-fluorobenzodiazepines which are useful as ataraxics, muscle relaxants and sedatives.

US patent 3,198,789 specifies 3-chloroderivatives of benzodiazepines as starting materials in the production of benzodiazepines with an amino group in the 3_position. It is stated that the chlorine in the 3-position is very reactive, as the compounds react at room temperature or lower, and also that a person skilled in the art would realize that the analogous 3-bromo and 3-iodo compounds could be used instead of the 3-chloro compound. -

In US patent 3,296,249 it is stated that a series of reactions which includes the production of 3-'-halo-5-monocyclic aryl-1,3-dihydro-2H-1,4~benzodiazepine-2-one from the unsubstituted N-oxyd. These are intermediate products for the production of the 3-hydroxy compounds. The term halogen is not defined. It is also indicated

that the 3-hydroxy compounds can be converted to their corresponding 3-chloro derivatives by treatment with an inorganic acid halide such as thionyl chloride or phosphorus pentachloride. Thionyl fluoride has not been shown to be successful as a fluorinating agent with alcohols.

[Weichert, K. and Hoffmeister, R., J. Prakt. Chem., 10, 290-302

(1960)]..

US patent 3-296,251 states 3-halo-benzodiazepines as intermediates in the preparation of 3-mercapto-benzodiazepines, and states that a halogen in the 3-position is very active as it reacts at room temperature with mercapto compounds.

US patent 3-371,083 relates to benzodiazepines which are substituted in the 3-position with chlorine, bromine or iodine, which are useful as starting materials.

US patent 3-371,084 relates to 3-halogen-1,4-benzodiazepine-2-ones which are useful as starting materials where the halogen is preferably bromine, chlorine or iodine. Fluorine is not specified.

US patent 3-450,695 relates to 3-halobenzodiazepines as intermediates prepared by treating the 3-hydroxy compound with a halogenating agent, such as an inorganic acid halide.

In J. Med. Chem., £, 815 (1965) describes the preparation and some of the reactions of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one.

In J. Org. Chem., 27, 1691 (1962), mentions 3,7-dichloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one prepared by reacting the 3-hydroxy compound with thionyl chloride . This 3_chloro-. derivative, however, is described as extremely reactive, as

only heating in alcohol caused cleavage..

US patent 3,321,467 mentions 3-halo-1,4-benzodiazepine-2-one-4-oxides prepared by treating 2-halo-quinazoline-3-oxides with a suitable inorganic base. The halogen is defined as chlorine, bromine or fluorine, preferably chlorine. The fluorine derivative is not particularly described or exemplified.

No known publication mentions the 3-fluoro-benzodiazepines

which is produced according to the present invention. Several publications concern 3-halogen derivatives, mentioning chlorine, bromine and iodine, and especially exemplifying chlorine. The general opinion according to the state of the art is that 3-halobenzodiazepines are too reactive and unstable to be practically useful as pharmaceutical agents.

However, there are fundamental differences between chlorine,

bromine and iodine, the halogens mentioned in the state of the art, and

■fluorine. It is known in organic chemistry that fluorine is something special and peculiar compared to chlorine, bromine and iodine, and is so different that fluorocarbon chemistry has achieved an entirely separate status. The differences between these elements are many. For example, fluorine has no low-lying d-orbitals for "back-bonding" like chlorine, bromine and iodine, which leads to less polarizable bonds. .Chlorine, bromine and iodine can be in positive valence states (C1°4'Br°3 09 I2°5^ while fluorine cannot be.

The well-known "haloform" reaction occurs with bromine, chlorine

and iodine, but not with fluorine.

Metal fluorides differ from metal chlorides, bromides and iodides, for example the solubility of silver fluoride in water is 1 million times greater than the solubility of silver chloride,

-bromide and -iodide.

Many authorities have noted and acknowledged the differences

between fluorine and halogens. For example:

Sheppard and Sharts, in "Organic Chemistry", W. A. Benjamin (1969) devotes the first two chapters to the differences between fluorine and the halogens.

Cottohog Wilkinson, in "Advanced Inorganic Chemistry", Interscience (I962) discusses fluorine compounds in Chapter 14, and chlorine, bromine and iodine compounds in Chapter 22.

Roberts and Caserio in "Basic Principles of Organic Chemistry", W. A. Benjamin (1964) covers in Chapter 17 chlorine^-,

bromine and iodo compounds under the headings "Alkyl Halides", "Alkenyl Halides", "Cycloalkyl Halides" and "Polyhalogen Compounds". The fluorine compounds are covered under "Fluorinated Alkanes".

Consequently, under modern chemical practice, fluorine has attained a separate status, and it is therefore incorrect to conclude that when the halogens chlorine, bromine or iodine are mentioned, fluorine is necessarily implied.

In marked contrast to the 3-chloro-benzodiazepines according to the state of the art such as Bell and Childress. were too unstable to even give satisfactory analytical results, the 3-fluoro-bezodiazepines prepared according to the present invention are surprisingly stable against hydrolysis by both aqueous acids and

bases, which makes them particularly suitable as pharmaceuticals.

A number of benzodiazepines are well known to be useful ataraxics, muscle relaxants and sedatives. Metabolic studies with several of these compounds, including diazepam [Schwartz, M. A. et al., J. Pharmacol. Exp. Ther. , 1.^2, 423

(1965)], flurazepam [Schwartz, M.. A. and Postma, E., J. Pharm.

Sei., 59, 1800 (1970)] and nitrazepam [Rieder, J. and Wendt, G., "Benzodiazepines", Garattini, S., Mussini, E. and Randall, L. 0., eds., 799, Raven Press, New York (1973)], have shown that they are metabolized in humans and other animals by oxidative attack at the 3-position. Substitution with fluorine in this 3-position seems to retard this metabolic pathway, which leads to stronger activity for the 3-fluorine derivatives produced according to the invention.

The present invention therefore relates to a method for producing compounds with the formula:

where

X is Cl, Br, NO 2 or CF 2 ;

Y is H, Cl, Br or F; Z is H, hydrocarbyl with 1 - /+ ca carbon atoms, -CH0CF„, -CONHR, -CH CH NR or -CH CH NR A, where R is alkyl with 1-4 carbon-^ ZiL,

atoms, and A is a pharmaceutically acceptable acid;

B is 0; or

B and Z together are =N-N=C(R')- where R* is H or alkyl with 1-4 carbon atoms.

Compounds preferred for their activity are those where independently: B = 0;

X = Cl ;

Z = H ;

Z = alkyl. with 1-3 ca carbon atoms;

X = Cl and Z = H;

X = Cl and Z = alkyl with 1-3 carbon atoms.

More preferred are those compounds where:

X = Cl or Br;

Y = H, Cl or F;

Z = H, -CH3 or -CH2CH and

B = O.

Most preferred are those compounds where:

X = Cl or Br;

Y = 11 or F ;

Z = CH 2 ; and

B = 0.

Particularly preferred are the following compounds: 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-one;

3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-(2'-fluorophenyl)-2H-1,4-benzodiazepine-2-one;

3-Fluoro-1,3-dihydro-1-methyl-7-bromo-5-phenyl-2H-1,4-benzo -

diazepin-2-one;

3-fluoro-1,3-dihydro-7-bromo-5-phenyl-2H-1,4-benzodiazepine-2-one.

The term hydrocarbyl of 1-4 carbon atoms includes alkyl groups such as methyl, ethyl, isopropyl and isobutyl; cycloalkyl containing groups such as cyclopropyl and cyclopropylmethyl; and alkenyl groups such as allyl and 2-butenyl.

Pharmaceutically acceptable acids (A) include such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, maleic acid and fumaric acid.

The compounds of formula I can be prepared by the following general method: A 3-hydroxybenzodiazepine is brought into contact with a dialkylaminosulfur trifluoride at approx. -80° to 10°C under essentially anhydrous conditions:

1 2 B, X, Y and Z are as indicated above. R and R are individually a primary alkyl group of 1-4 carbon atoms or together form

-(CH2)4- or _-(CH2)5-.°

It is preferred to work in the temperature range from -80° to -10°C when Z is hydrogen, and from -80° to +10°C when Z is different from hydrogen.

The dialkylaminosulfur trifluorides decompose very easily on contact with water, so that water should be excluded from the reaction as much as possible.

"Substantially anhydrous conditions" is therefore intended to mean that the amount of water present is so small that it will not cause significant cleavage of the dialkylaminosulphur trifluoride, and consequently not intervene disturbingly in the reaction.

The reaction can be carried out by dissolving or suspending the hydroxyl compound in an inert solvent and then adding the fluorinating agent. An inert solvent is one that

do not take part in the reaction and include diethylene glycol dimethyl ether (diglyme), pentane, trichlorofluoromethane and the like-,

and preferred are chlorinated solvents which are liquid at the reaction temperature such as methylene chloride and chloroform. The product can be isolated from the reaction mixture and purified by conventional means, e.g. the reaction mixture can be poured into water, the organic layer separated and washed with water and then evaporated to dryness. The crude 3-fluorobenzodiazepines obtained can then be further purified by recrystallization from suitable solvents.

The 3-hydroxy-benzodiazepines used in this reaction are either known compounds or they can be prepared by methods described in the literature. For example: Bell and Childress, J. Org. Chem., 2_2, 1691 (1962); Bell et al., Tetrahedron Lett., p. 2889 (1965); Bell et al., J. Org. Chem. 33, 216 (1965); Miyadera et al., J. Med. Chem.,. Uj., 520 (.1971);

Ning et al., J. Org. Chem., 3£, 4206 (1973); Sankyo Company, German Patents 1,812,252 (1969); 1,952,201 (1970); 1,954,065

(1970); Schlager, Tetrahedron Lett., p. 4519 (1970);

Stempel et al., J. Org. Chem., 32, 4267 (1967); Stempel et al., J. Org. Chem., 30, 4267 (1965).

The dialkylaminosulfur trifluorides can be prepared by reacting a dialkylaminotrimethylsilane with sulfur tetrafluoride at low temperature in an inert solvent. Diethylaminosulfur trifluoride, dimethylaminosulfur trifluoride and pyrrolidinosulfur trifluoride can be prepared by this method. When this reaction is carried out in trichlorofluoromethane at -70°C, high yields of a product of high purity are obtained because it. the only significant by-product is fluorotrimethylsilane, an easily separable low-boiling

end material. These three trifluorides are stable products as . can be distilled and stored in plastic bottles at room temperature.

The production and use of these fluorinating agents

is described by Middleton, W. J., J. Org. Chem., ^0, 574 (1975)

and US Patent 3,914,265.

Diethylaminosulphur trifluoride

(C2H5)2N-Si(CH3)3 + SF4> (C2H5)2NSF3 .+ FSi(CH3)3

A dry 1-liter four-necked round-bottom flask is fitted with a thermometer (-100° to 50°C), a fixed carbon dioxide-cooled reflux condenser (protected from the atmosphere by a drying tube), a gas inlet above the liquid surface, and a magnetic stirrer. The apparatus is flushed with dry nitrogen, and 300 ml of trichlorofluoromethane is introduced into the flask. While the nitrogen atmosphere is maintained, the trichlorofluoromethane is cooled to -70°C by means of a solid carbon dioxide-acetone bath and 119 g (1.1 mol) of sulfur tetrafluoride is added from a cylinder through the gas inlet line. The gas inlet tube is then replaced with a 250 ml pressure equalized drop straight containing a solution of 145 Q (1 mol) N,N-diethylaminotrimethylsilane in 90 ml trichlorofluoromethane. This solution is added dropwise with stirring to the sulfur rafluoride solution at a rate sufficiently slow to keep the temperature of the reaction mixture below -6o°C (about 40 minutes). The cooling bath is removed, and the reaction mixture is allowed to warm spontaneously to room temperature. The cooler is replaced with a single distillation head,

and the solvent (bp 24°C) and fluorotrimethylsilane by-product (bp 17°C) are distilled off to a well-cooled stock by heating the reaction mixture carefully to 45°C with the aid of a heating mantle. The yellow to dark brown residual liquid is transferred and distilled under reduced pressure through a spinning belt column whereby 129-145 g (80-90%) of diethylaminosulphur trifluoride is obtained

as a pale yellow liquid with a boiling point of 46-47°C (10 mm).

An alternative method of preparing benzodiazepineones where Z is different from hydrogen is to contact a 3-fluorobenzodiazepineone with sodium hydride at ca. 0-30°C in an inert solvent such as tetrahydrofuran, 1,2-dimethoxymethylene or diethyl ether, to form the sodium salt, which appeared in the same solvent as an isolation, is brought into contact with an alkylating agent to form a 1- alkyl-3-fluorobenzodiaze-, pinone. The alkylating agent can have the formula Q2?~ where 7?~ has the same value as stated above for Z, with the exception of hydrogen; and Q is I, Cl, Br, CFoS000-, FS0„0-, CCloS000- or Z10S000-.

4-fluorotriazolobenzodiazepines, such as 4-fluoro-8-chloro-1-methyl-6-phenyl-4H-s-triazolo-[4.3-a]-[1,4]-benzodiazepine•eg, can be prepared as follows : by treating a solution of

8-Chloro-4-hydroxy-1-methyl-4H-s-triazolo-[4•3-a][1,4]-benzodiazepine in methylene chloride with diethylaminosulfur trifluoride at

-70°C and warm the reaction mixture to -20°C and then pour it into cold water. 4-fluoro-8-chloro-1-methyl-6-phenyl-4H-s-triazolo-[4•3-a][1,4]-benzodiazepine can be isolated from the organic layer by evaporation of the solvent. The particular 4-hydroxy compound shown here can be prepared as described in US patent 3,907,820.

The following examples further illustrate the preparation of the process compounds. Parts are given by weight where not otherwise specifically stated.

Example 1

3- fluoro- 1, 3- dihydro- 7- chloro- 5- phenyl- 2H,- 1, 4- benzodiazepine- 2- one

A well-stirred suspension of 10 g (0.03 mol) of 3-hydroxy-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-one and 500 ml of methylene chloride was cooled to - 70°C. 25 ml (0.2 mol) •diethylaminosulfur trifluoride was then added dropwise while excluding moisture and air. After the addition was finished, the dry ice-acetone bath was removed, the contents of the flask were allowed to heat up for approx. 25 minutes at -10°C, and the reaction was then immediately stopped by pouring the reaction mixture into a beaker containing 400-500 ml of ice water. (If the reaction mixture is allowed to warm to 25°C, none of the desired product is obtained). Vigorous stirring of the ice-water mixture was continued for 7-10 minutes. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure, whereby a bright orange powder was obtained. The product was dissolved in hot benzene, treated with de-colouring charcoal and filtered hot.. By adding heptane to benzene solutions followed by cooling in ice, 3~fluoro-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-one crystallized as a white powder in an amount of 8.199(82%); m.p. 190-192°C (dec.); <19>F hmr (DMSO-dg) g-161.5 ppm (d, d, J = 56, 4 Hz, 1H)

-'"H nmr (DMSO-dg) £ 7.2-7.8 (m , 8H) , i 5.72 (d, J = 56 Hz, 1H) ,

& 11.0 ppm (N-H). Anal. Calc., for C^H^CII^OF: C 62.40; H 3.49; N 9.70

Found: C 62.77; H 3.97; N 9.29

62.72 4.01 9.31

Example 2

3-Fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-one

A. A solution of 12.1 g (0.04 mol) of 3-hydroxy-1,3-dihydro-1-methyl-7-chloro-5-x"enyl-2H-1,4-benzodiazepine-2-one in 25 ml of anhydrous methylene chloride was added dropwise over 15 min to a stirred solution of 12.6 ml (0.1 mol) of diethylaminosulfur trifluoride in 300 ml of anhydrous methylene chloride cooled to -70° C. The reaction mixture was allowed to to be heated slowly over 45 minutes to 5° C. and then poured into 500 ml of ice and water. The lower organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure whereby gave 10.99 g (90% yield) of crude product as a pale yellow solid residue.Recrystallization from heptane gave 8.48 g (70% yield) of 3-fluoro-1,3-dihydro-1-methyl-J-chloro -5-phenyl-2H-1,4-benzodiazepine-2-one as colorless crystals: mp 138-140°C; 19F nmr (CC^D) -'5-161.7 ppm (d, J = 57Hz);

1Hnmr (CC^D) . g 3.43 ppm. (s , 3H) , 5.54 ppm (d, J = 57 Hz, 1H) , 7.5 ppm (m, 8H). "..

Anal. Calculate. for C 2 H 2 Cl 2 O : C 63.47; H 4.00; F 6.28; N 11.71

Found: C 63.53; H 4.21; F 6.21; N 11.50

B. The same compound can be prepared by the alternative method as follows:

To a well-stirred solution of 3.0 g (0.01 mol) of 3-fluoro-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-one, 75 ml of dry THF and 25.56 g (0.18 mol, 11.2 mL) of methyl iodide was added to a suspension of 0.48 g (0.02 mol) of sodium hydride in 20 mL of THF. There was an instant evolution of hydrogen. The contents of the flask were stirred under a nitrogen atmosphere for exactly two hours. The product mixture was left for approx. 100 ml of water and methylene chloride were added to extract the product. The organic layer was separated and washed twice with approx. 50 ml portions of fresh water and then allowed to dry over magnesium sulphate. Evaporation of the solvent under reduced pressure gave 1.38 g of a yellow crystalline material. Recrystallization from hot heptane gave 0.97g of an off-white powder identified as 3-fluoro-1-(N-methyl)-7-chloro-5-phenyl-1,4~benzodiazepine-2-one: ^H nmr (DMSO-dg) : S 7.2-7.72 ppm (m, 8H), £5.8Ppm'(d, 1H, 56 Hz), £3.37 (m, 3H, N-methyl);<19>F nmr- (DMSO-dg) &-160.14 ppm (d, J =56 Hz).

Example 3

luoro-1, 3-dihydro-7-chloro-5-( 2-fluorophenyl)-2H-1,4-benzodiazepine-2-one ■ '

A well-stirred suspension of 3.0 g (0.01 mol) of 3-hydroxy-1,3-dihydro-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one in 150 ml of methylene chloride was cooled to -70°C, and 7.5 ml (0.06 mol) of diethylaminosulfur trifluoride was added dropwise over 10 minutes. The reaction mixture was then allowed to warm slowly over 26 minutes to -10°C and then poured into 200 ml of ice water. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure, whereby 2.9-5 g (98%) of crude product was obtained. Recrystallization from benzene-heptane gave 2.00 g (67%) of 3-fluoro-1,3-dihydro-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one as off-white crystals : m.p. 206-207°C (dec.): 1H nmr (DMS0-dg) 6 5.95 ppm (d, J = 56 Hz, 1H), 7.47 ppm (m, 7H), 11.25 ppm (s, 1H); 19F nmr (DMS0-d6) 5-162.0 ppm (d, J = 56 Hz, 1F) and 8 -113.0 ppm

(m, 1F) .

Anal. Calculate, for C^HgClF^O in C 58.74; H 2.96; F 12.39; N 9,14

Found: C 58.54; H 3.21; F 12.11; N 8.98

Example 4

3-Fluoro-1,3-dihydro-1-ethyl-7-chloro-5-phenyl-2H-1,4-berizodiazepin-2-one ■ ' ' '

A solution of 3.5 g (0.01 mol). 3-hydroxy-1,3-dihydro-1-ethyl-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-one in 7 ml of anhydrous methylene chloride was added dropwise to a stirred solution of 3, 53 ml (0.028 mol) of diethylaminosulfur trifluoride in 84 ml of anhydrous methylene chloride cooled to -70°C. The reaction mixture was allowed to warm slowly to 5°C and then poured into 150 ml of ice and water. The lower organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure, whereby 2.84 g (90% yield) of crude product were obtained as pale yellow crystals. Recrystallization from 200 mL of heptane gave 1.81 g (57% yield) of 3-fluoro-1,3-dihydro-1-ethyl-7-chloro-5-phenyl-2H-1,4-benzodiaz.epin- 2-on: m.p. 156-158°C; <1>H nmr (DMSO-dg) <$ 7.2-7.8 ppm (m, 8H3, $ 5.85 ppm (d, 1H, J - 57 Hz), & 3.5 -4.38 (m, 2H, methylene protons on nitrogen), £1.02 (t, 3H).

Anal.Calc., for C17<H>14N2ClF: C 64.46; H 4.46; F 6.00; N 8.84

Found: C 64.46; H 4.71; F 6.57; N 8.67

Example 5

3-Fluoro-1,3-dihydro-1~methyl-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one

A solution of 1.4 g of 3-hydroxy-1,3-dihydro-1-methyl-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one in 10 ml of methylene chloride was added dropwise to a stirred solution of 1.5 ml of diethylaminosulfur trifluoride in 50 ml of methylene chloride cooled to

-70°C. The reaction mixture was allowed to warm slowly to 5°C and then poured into 100 ml of ice water. The lower organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from heptane, whereby 1.17 g of 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one was obtained as cream-colored crystals: m.p. 91-95°C; ''"H nmr (CCl3D)

S 3.51 ppm (s, 3H), 5.66 ppm (d, J = 57 Hz, 1H) and 7.5 ppm

(m, 7H).

Anal. Calculate, for.c16H11clF2N2°2: C 59'91'H 3/46'F 11.85; N. 8.74

Found: C 60.00; H 3.57; F 11.55; N 8.69

Example 6 3-fluoro-1-(allyl)-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-one

To. a well-stirred solution of 3.0 g (0.01 mol) 3-fluoro-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-one, 75 mL dry THF

and 21.78 g (0.18 mol) of 3-bromopropene was added to a suspension of 0.48 g (0.02 mol) of sodium hydride in 20 ml of THF. There was an instant evolution of hydrogen. The contents of the flask were stirred under a nitrogen atmosphere for exactly 2 hours. The product mixture was poured into 100 ml of water and methylene chloride was added to extract the product. The organic layer was washed twice with 50 ml portions of water, and then allowed to dry over magnesium sulfate. Evaporation of the solvent under reduced pressure gave an orange colored gummy material which was recrystallized from. 450 ml of hot heptane yielded 1.42 g of 3-fluoro-1-(allyl)-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-one as a very pale orange powder: m.p. 138-140°C, H nmr (CDCl3)

«5 7, 2-7., 9 ppm (m, 8H) , £ 5 , 6 ppm (d, J = 57 , 5 Hz , 1H) , 6 4.85-5.95 ppm (m, 3H, olefinic ), £ 4.58 ppm (2H, N-CH~);

19

F nmr (CDC13) §161.97 ppm.

Anal. Calculate, for C18H14N2C1F: C 65.76; H 4.29; F 5.78; N 8.52

Found-: C 66.06; H 4.55; F 5.46; N 8.29

Example 7

3- fluoro- 7- bromo- 1, 3~ dihydro- 5- pheny1- 2H- 1, 4- benzodiazepine- 2- one

A well-stirred suspension of 6.0 g (0.018 mol) of 7-bromo-. 1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepine-2-one in 250 ml of methylene chloride was cooled to -70°C, and 7.5 ml (0.06 mol) of diethylaminosulphur- trifluoride was added dropwise. The reaction mixture was allowed to warm slowly to -10°C over 30 minutes and was held at -10°C for 20 minutes, until most of the solid had dissolved. The reaction mixture was then poured into 500 ml of ice water and stirred until the yellow color disappeared. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in 300 ml of hot benzene and filtered hot. The filtrate was mixed with 400 ml of hexane and cooled. The precipitated crystals were collected on a filter, washed with hexane and dried in air to give 5.28 g (88%) of 3-fluoro-7-bromo-1,3-dihydro-5-phenyl-2H-1,4 -benzodiazepine-2-one as colorless crystals: m.p. 207-209°C

■ 19

1(split.); F nmr (acetone-d,) 8-162.6 ppm (d, J = 57 Hz);

H nmr (acetone-dg) 5.86 ppm (d, J = 57.Hz, 1H), 7.2-8 ppm

(m, 8H), 9.90 ppm (NH); ir (KBr) 5.84 u (C=0). A sample was » dried in a vacuum oven for analysis.

Anal. Calculate, for C^F^ BrFN20: C 54.07; H 3.03; N 8.41; N 5.70

Found: C 54.31; H 3.17; N 8.40; F 5.62

The 7-bromo-1,3-dihydro-3-hydoxy-5-phenyl-2H-1,4-benzodiazepine-2-one used in this preparation was prepared by the following method. A 10.0 g (0.03 mol) sample of 7-bromo-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one-4-oxide was added portionwise to 50 ml of trifluoroacetic anhydride, and the reaction mixture was stirred at room temperature for 2 hours. A suspended solid was collected on a filter, washed thoroughly with pentane and dried in vacuo over potassium hydroxide pellets to give 12.8 g (99%) of 7-bromo-1,3-dihydro-5-phenyl-3-trifluoroacetoxy-2H -1,4-benzodiazepine-2-one as a white crystalline powder;: m.p. 181-183°C; <1>H nmr (DMSO-d ) £6.28 ppm (s, 1H), 7.64 ppm

19 (m, 8H), and 11.38 ppm (NH); F nmr (DMSO-dg) 5 -74.6 ppm (s). Anal. Calculate, for C17H10<B>rF3N2O3: C 47.79; .H 2.36; N 6.56

Found: C 47.66; H 2.33; N 6.26

A suspension of 10 g (0.023 mol) of 7-bromo-1,3-dihydro-5-phenyl-3-trifluoroacetoxy-2H-1,4-benzodiazepine-2-one in a mixture with 130 ml of ethanol and 130 ml of 5%- of aqueous sodium bicarbonate was stirred at room temperature (25°C) for 20 hours. The suspended solid was then collected on a filter, washed with water and recrystallized from ethanol to give 6.5 g (85%) of 7-bromo-1,3-dihydro-3-hydroxy-5-phenyl-2H-1, 4-benzodiazepine-2-one as colorless plates: m.p. 190-192°C; <1>H nmr (DMSO-Dg) 6 4.86 ppm (1H), 6.27 ppm (1H, OH), 7.18-7.90 ppm (m, 8H).

Anal. Calculate, for c15linB^ 202:.C 54.40; H 3.35; N 8.46

Found: C 54.61; H 3.51; N 8.47

Example 8

3-Fluoro-7-bromo-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2^one'

A slurry of 0.34 g (0.014 mol) of sodium hydride in 20 ml of tetrahydrofuran was added to a solution of 4.0 g (0.012 mol) of 7-bromo-1,3-dihydro-3-fluoro-5-phenyl-2H- 1,4-benzodiazepine-2-one and 13 ml of methyl iodide in 125 ml of tetrahydrofuran. The reaction mixture was stirred for 2.5 hours at room temperature (25°C) and then poured into 600 ml of water containing 200 ml of methylene chloride. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated to dryness, whereby 3.4 g of a yellow residue was obtained. Recrystallization from cyclohexane gave 1.50 g of 7-bromo-1,3-dihydro-3-fluoro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one as an amorphous, cream-colored solid ( no apparent melting point): H nmr (CDC1-J & 3.46 ppm (s, 3H),

19

5.60 ppm (d, J = 57 Hz, 1H), 7.2-7.9 ppm (m, 8H), F nmr (CDCl 3 ) 6 -161.7 ppm (d, J = 57 Hz).

Anal. Calculated for C16H12BrFN20: C 55.35; H 3.49; F 5.47; N 8.07

Found: C 55.62; H 3.72; F 5.30; N 7.97

Example 9

3-fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one

A stirred suspension of 4.2 g (0.012 mol). 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one in 200 ml of methylene chloride was cooled to -70°C, and 5 ml (0 .04 mol) diethylaminosulfur trifluoride was added dropwise. The reaction mixture was allowed to warm to -10°C and was held at this temperature until most of the solid had dissolved. The reaction mixture was poured into ice-water and stirred vigorously. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from benzene-hexane to give 3.12 g of 3-fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-o 19

2-on as pale yellow crystals: m.p. 195-197 C (dec.); F nmr (DMSO-d^) S -113.0 ppm (m, 1F) and -162.1 ppm (d, J = 56 Hz, 1F);

^"H nmr (DMSO-d^) 5.88 ppm (d, J = 56 Hz, 1H), 7.2-7.9 ppm (m, 7H), 11.2 ppm (NH).

Anal. Calculate, for C^H^BrF^O: C 51.30; H 2.58; F 10.81?N 7.98

Found: C 51.50; H 2.69; F 10.53; N 8.05

The 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one used in this preparation was prepared by the following procedure.

A 9.5 g (0.027 mol) portion of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one-4-oxide was added portionwise to 50 ml trifluoroacetic anhydride, and the reaction mixture was stirred for 90 minutes. The suspended solid that formed was collected on a filter, washed thoroughly with pentane and dried in vacuo over KOH. 9.72 g (80%) of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-trifluoroacetoxy-2H-1,4-benzodiazepin-2-one were obtained as a grey-white crystalline powder: m.p. 175-177°C (dec.); 19F nmr (DMSO-d6) £-74.6 ppm (s, 3F) and -112.7PP™, (m, 1F); ~*"H nmr (DMSO-d6). £ 6.34 ppm (s, 1H) , 7.1-8.1 ppm (m, 7H), 11.5 ppm (NH). Anal. Calc., for C17HgBrF ^N2O3: C 45.86, H 2.04, F 17.70, N 6.29

Found: C 44.55; H 1.91; F 18.00; N 6.31

A suspension of 9.5 g (0.021 mol) of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-trifluoroacetoxy-2H-1,4-benzodiazepine-2-one in a

mixture of 130 ml ethanol and 130 ml aqueous 5%. sodium bicarbonate was stirred at 25°C for 18 hours „ The suspended solid was collected on a filter, washed with water, dried in air and recrystallized from ethanol to give 4.549 (62%) of 7-bromo-5- (2-fluorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one as colorless crystals: m.p. 196-198°C; "^F nmr (DMS0-d6) S-113.5 Ppm (m) ; ^ nmr (DMS0-d6)- 5 4.88 ppm (s, 1H) , 6.35 ppm (s, OH), 7.0 -7.9 ppm (m, 7H).

Anal.Calc, for Cl5H10BrFN2O2: C 51.59 in H 2.89; F 5.44; N 8.02

Found: C 51.63; H 2.97; > 5.4l; N 7.89

Example 10

3-fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2-one.

A slurry of 0.17 g (0.007 mol) of sodium hydride in 10 ml of tetrahydrofuran was added to a solution of 1.8 g (0.005 mol) of 3-fluoro-7-bromo-5-(2-fluorophenyl)-1,3 -dihydro-2H-1,4-benzodiazepine-2-one and 10 ml of methyl iodide in 100 ml of tetrahydrofuran. The reaction mixture was stirred for 3 hours at 25°C and then poured into 300 ml of ice water. The aqueous mixture was extracted with methylene chloride, and the extracts were dried over magnesium sulfate and then evaporated to dryness under reduced pressure. The residue was recrystallized from heptane whereby 0.91 g (50%) of cream-colored crystals were obtained: m.p. 127-130°C (with prior softening); H nmr (CDCl 3 ) 6 3.49 ppm (s, 3H), 5.62 ppm (d, J = 57 Hz, 1H) and 6.9-7.9 ppm (m, 7H);<19>F nmr (CDC 13 ) 6-111.9 ppm (m, 1F) and

-162.4 ppm (d, J = 57 Hz, 1F).

Anal. Calculate, for gH^BrF^O: C 52.62; H 3.04; F 10.41» N 7.67

Found: C 5?.49; H 3.30; F 10.31; N 7.57

Example 11

3-fluoro-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one

A well-stirred suspension of 6.8 g (0.021 mol) of 8-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepine-2-one in 350 ml methylene chloride was cooled to -72°C under nitrogen. 10.5 mL (0.80 mol) of diethylaminosulfur trifluoride was added dropwise over 10 minutes at -72 to -70°C. The suspension was allowed to warm slowly to -10°C and was held at -10°C for 30 minutes, and then poured into 500 ml of ice water with vigorous stirring. The organic layer was separated, dried over magnesium sulfate and evaporated to give 7.8 Q of orange-yellow solid. The product was dissolved in benzene and allowed to crystallize, yielding 3.59 g of white, crystalline 8-chloro-5-(2-chlorophenyl)-3-fluoro-3H-1,4-benzodiazepine-5-one: m.p. . 210-211°C (dec.);

95% pure according to high-pressure liquid chromatography and UV analysis. Another yield (1.7 g) was obtained by addition of n-hexane.

1H nmr (DMSO-dg) fill,3Ppm-(m, 1H) , 6 7.5 ppm (m , 6H.) , 7.03 ppm (d, 1H), S5.92 ppm (d, J = 56 Hz , 1H),<19>F nmr (DMSO-dg)

6 -162.3 ppm (d, J =.56 Hz, to d, J = 4 Hz).

Example 12

3-fluoro-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4~benzodiazepine-2-one

Sodium hydride (0.25 g of 50% mineralol gel emulsion washed twice with tetrahydrofuran, 0.0050 mol) in 10 ml of tetrahydrofuran was added portionwise at room temperature to a well-stirred solution of 1.7 g (0.0053 mol) 3-fluoro-7~chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one and 5.6 g (0.039 mol) methyl iodide in 50 ml tetrahydrofuran under nitrogen. The solution was stirred for 2 hours at room temperature and then poured into 100 ml of water. The product was extracted with methylene chloride, the extract dried over magnesium sulfate and the solvent evaporated to give a leather colored solid. The crude product was dissolved in benzene and allowed to crystallize to give a white solid, and another yield was obtained by addition of n-hexane, giving a total of 1.1 g of 3-fluoro-8-chloro- 5-(2-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2-one: m.p. 204-205°C; """H nmr (DMSO-dg) £ 7.6 ppm (m , 6H) ,

& 7.0<p>pm (m, 1H) , £5.94 Ppm (d, 56 Hz, 1H) , £ 3.45 ppm (s, 3H);

<19>F nmr (DMSO-dg) £-161.8 ppm (d, J = 56 Hz).

Anal. Calculate, for C .H N 0 C1 F: C 56.99; H 3.29; N 8.31;

Cl 21.03; f 5.63

Found: c 57.11; h 3.54; n 8.37;

cp 20.84; f 5.69

Example 13

3-Fluoro-1,3-dihydro-7-nitro-5-pheny1-2H-1,4-benzodiazepine-2-one

A well-stirred suspension of 3.6 g (0.012 mol) of 1,3-dihydro-3-hydroxy-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one in 200 ml of methylene chloride was cooled to - 70°C, and 5 ml (0.04 mol) of diethylaminosulfur trifluoride was added dropwise. The reaction mixture was allowed to warm slowly to -10 C, at which temperature all solids dissolved. The reaction mixture was poured into 400 ml of ice water, and the organic layer was separated, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from benzene-heptane, whereby 3>0 g (83%) of 3-fluoro-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one was obtained as a color -loose crystals: m.p. 174-175°C (dec.);<1>H nmr (DMSO-dg)

Z5, 90 ppm (d, J = 57 Hz, 1H), 7.3-7.7 ppm (m, 6H), 8.07 ppm-(d, J = 2.5 Hz, 1H) and 8.45 ppm (d, d, J = 9.0, 2.5 Hz, 1H);

<19>F nmr (DMSO-dg) £ -161.4 ppm (d, J = 57Hz).

Anal. Calculate, .for C^H^FN^: C 60.20; H 3.37; F 6.35; N 14.04

Found: C 60.02; H 3.43; F 6.21; N 13 , 88

Example 14

3-Fluoro-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzo-diazepine-2-one.

A slurry of 0.20 g (0.08 mol) of sodium hydride in 10 ml of tetrahydrofuran was added to a solution of 1.749

(0.0058 mol) of 3-fluoro-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one and 10 ml of methyl iodide in 100 ml of tetrahydrofuran at 25°C. The reaction mixture was stirred for 3 hours at 25°C, and was then poured into 300 ml of ice water. The aqueous mixture was extracted with methylene chloride, and the extracts were dried over magnesium sulfate and then evaporated to dryness under reduced pressure. The residue was dissolved in hot benzene and then fractionated by adding hexane. The first dark fractions of solid matter were discarded. The remaining fractions were collected on a filter and dried in vacuo to give 1.10 g (60%) of 3-fluoro-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4 -benzodiazepine-2-one as a light, tan, amorphous solid with no apparent melting point: <X>H nmr (CDClg) £3.53 ppm (s, 3H), 5.59 ppm (d, J = 57 Hz, 1H) , 7.2-7.9 ppm (m, 6H) and 8.2-8.9 PPm (m , 2H) ;<19>F nmr (CDCl.^)

£ -161.7 ppm (d, J = 57 Hz).

Example 15

. 3-fluoro-7-chloro-1,3-dihydro-N-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-1-ca rboxamide

A stirred mixture of 3.56 g (0.12 mol) of 3-fluoro-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one, 35 ml of benzene and

1.06 g (0.019 mol) methyl isocyanate was boiled slowly under reflux for approx. 20 hours. The cooled mixture was evaporated

dryness under reduced pressure whereby 4.42 g of crude product was obtained which

a light beige powder. Recrystallization from ca. 100 ml of hot ethanol gave 1.999 of a white powder (m.p. 224-225°C) identified as 3-fluoro-7-chloro-1,3-dihydro-N-methyl-2-oxo-5-phenyl-2H -1,4-benzodiazepine-1-carboxamide: "'"H nmr (CDCl 2 ) 8 8.4-8.7 ppm.

(1H, N-H, broad quartet); .£7.25-8.0 (8H, m, aromatic); £5.72

(1H, d, J = 56.5 Hz); £ 2.93 (3H, d, J = 4.5 Hz, N-CH 3 ).

19F nmr (CDCl 2 £-160.75 ppm (J = 57 Hz).

Anal. Calculate, for C-^I^ ^CIO^: C 59.05; H 3.79; N 12.15; F 5.49

Found: C 59.01; H 4.00; N, 11.69; F 5.28

Example 16

3-fluoro-7-chloro-1,3-dihydro-N-ethyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-1-carboxamide

A stirred mixture of 3.56 g (0.12 mol) of 3-fluoro-7~chloro-. 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one, 35 ml of benzene and 1.29. 9 (0.018 mol) of ethyl isocyanate was slowly refluxed for about 20 hours. A suspended, insoluble solid was removed from the cold mixture by filtration. The filtrate was then evaporated to dryness under reduced pressure to give 1, 92 g of a yellow vitreous material Recrystallized from about 100 mL of cyclohexane gave 0.90 g of an off-white powder (m.p. 110-112°C) identified as 3-fluoro-7-chloro-1,3- dihydro-N-ethy1-2-oxo-5-phenyl 1-2H-1,4-benzodiazepine-1-carboxamide : ''"H nmr (CDCl^) : 6 1.2 ppm (t, 3H, J 7Hz ), £3.1-3.68 (dg, 2H) , £5.67

(d, 1H, J = 57 Hz), . S 7.2-8.0 (aromatic), £ 8.7 (N-H).

19 F nmr (CDCl 3 ): 6 - 160.67 ppm (d, J = 57 Hz).

Example 17

4-fluoro-8-chloro-1-methyl-1-6-phenyl-ZfH-s-triazolo-[4. 3-a ] [l ,4]-benzodiazepine

A solution of 5.0 g (0.014 mol) of 8-chloro-4-hydroxy-1-methyl-4H-s-triazolo-[4•3-a].[1,4]-benzodiazepine methanol solvate: in 250 ml of methylene chloride was cooled to -70°C, and 10 ml of diethylaminosulfur trifluoride was added over 10 minutes. The reaction mixture was heated over 20 minutes to -20°C, kept at -20°C for 20 minutes, and then poured into 500 ml of ice water.

The aqueous mixture was neutralized with sodium bicarbonate, and the organic layer was separated, washed with water, dried over magnesium sulfate and evaporated to dryness to give 4,194-fluoro-8-chloro-1-methyl-6-phenyl-4H-s-triazolo -[4-3-a][1,4]-benzodiazepine: m.p. 232-235 o C (decomposition); IQ yF nmr (DMSO-dg)

& -167.1 ppm (d, J = 52 Hz); 1H nmr (DMSO-dg) £2.62 ppm (s, 3H), 6.71 ppm (d, J - 52 Hz, 1H), 7.3~8.1 ppm (m, 8H).

The 4-hydroxy compound used in this preparation,,

can be produced as described in US patent 3,907,820.

Table 1 shows additional compounds that can be prepared using the appropriate 3-hydroxy starting material in the general method.

Table 2 shows additional compounds that can be prepared by the alternative method using the appropriate fluorobenzodiazepine.

Table 3 shows additional 4-fluorotriazolobenzodiazepines that can be prepared using the appropriate 4-hydroxy starting material.

The ataraxic, muscle relaxant and sedative compounds produced according to the invention can be administered to produce the desired effect in any manner that brings the active agent into contact with the agent's area of action in the body of a mammal. They can be administered in any conventional manner used in pharmaceuticals, either as individual therapeutic agents or in combination with therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The administered dose will of course vary depending on known factors such as the pharmacodynamic properties of the particular agent, and its mode and route of administration, the age, health and weight of the recipient, the nature and degree of symptoms, the type of concomitant treatment, the frequency of treatment and the desired effect . Generally, a daily dose of active ingredient can be approx. 0.001 to 100 mg per kg legal weight. Typically, 0.01 to 50 is

and preferably 0.05 to 25 mg/kg per day given in divided doses 2 to 4 times a day or in prolonged release form, effective in achieving the desired results.

Dosage forms (preparations) suitable for internal administration contain from approx. 0.1 mg to approx. 500 mg active ingredient per unit. In these pharmaceutical preparations, the active ingredient will usually be present in an amount of approx. 0.5 - 95% by weight, calculated on the total weight of the preparation.

The active ingredient can be administered orally<*>in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms such as elixirs, syrups and suspensions, and it can also be administered parenterally in sterile liquid dosage forms, or rectally in the form of suppositories.

Gelatin capsules contain the active ingredient and powdered carriers such as lactose, sucrose, mannitol, starch; cellulose derivatives, magnesium stearate and stearic acid. Similar diluents can be used to prepare pressed tablets. Both tablets and capsules can be manufactured as sustained release products to achieve continuous release of the medication over a number of hours. Pressed tablets can be

r

sugar-coated or film-coated to mask any unwanted taste and protect the tablet from the atmosphere, or be enteric-coated for selective breakdown in the digestive tract.

Liquid dosage forms for oral administration may contain

dyes and flavorings to increase patient acceptance.

In general, water, a suitable oil, brine,

aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if

necessary, buffer substances. Antioxidants such as sodium bisulphite, sodium sulphite or ascorbic acid, either alone or in combination, are suitable stabilizers. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suppositories contain the active ingredient in a suitable oily or water-soluble base. The oily class includes cocoa butter and fats with similar properties, and the water-soluble class includes polyethylene glycols.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E.W. Martin, a standard reference text in this field.

Standard methods for demonstrating and comparing the ataraxic, muscle relaxant and sedative activity of the compounds prepared according to the invention for which there is a correlation with human action are the following: pinna reflex tests, antipentylenetetrazol test, rat activity suppression test (RAST), muscle relaxant test (anti-st raw ub tail test). and mouse activity suppression test (MAST).

Stick reflex test is

Fasting white female mice, 5 per -dose, intubate with the drug at 4, 12, 36, 108 and 324 mg/kg in 1% "Met hocel"-1,25%'Tween 80", with 10 ml/kg. Hearing and touch probes are tested at 0, 5, 2, 5 and

24 hours.

Auditory pinna reflex'

The mouse is placed on a horizontal bar 9 cm from one

"Galton" whistle tuned to 13 Kc. An absence of flattening

of the ears during 1 or 2 short bursts of sound constitutes loss. of auditory-pinna reflex.

Touch pin reflex

A mouse is held by the tail, and the hairs on the inside of the right ear are touched with the fine wire rod of a 0.4 mm diameter needle. The mouse's failure to twitch or move its head constitutes loss of the touch-pinna reflex.

Antipentylenetetrazole (PTZ) test

Fasting white female mice, IQ per dose, intubated with the drug in medium as above in doses such as 0, 1, 3, 9, 27 and 81 mg/kg. 30 minutes later, the mice were intravenously administered PTZ ("Metrazol". Original product of pentylenetetrazol, sterile 10% aqueous solution for parenteral injection, Knoll Pharmaceutical Company) in an amount of 40 mg/kg (ED98 for clonic convulsions). The dosed animals that remain on a 10 cm x 10 cm platform for 20 seconds are considered protected. Quantal ED^-^s are calculated by the moving average method.

Rat act-invited startle test (RAST)

The test apparatus consists of a circular cage with a lid and with

a floor of electrifiable steel rods. DC shock current is applied to the bars so that touching any two alternating bars shocks the rat. The floor is marked up into 4 equal sectors.

Fasting white male rats, 10 per dose, intubate with the drug as described above for mice. 30 minutes after dosing, the rat is placed in the test apparatus and given 30 seconds to cross

■ 25% of the floor area after which it receives a shock. The rat was given 5 seconds to recover from the shock, and then it was counted

"line crossings" for 60 seconds. The average number of crossings per rat for each dose is determined and compared to the mean number of crossings for the medium-treated controls. ED^0%, the dose that would increase the number of crossings 50% above controls, is determined graphically.

Muscle relaxant (anti-straub-hale) test

Fasting white female mice, 5 per dose, intubate with the test drug. 25 minutes later, morphine sulfate was given subcutaneously in an amount of 53.7 mg/kg. 30 minutes after the test drug, the mice are observed for the presence of a Straub tail. Quantitative ED^Q values for blocking morphine-induced Straub tail are calculated.

Mouse Activity Suppression Test (MAST)

The mouse activity suppression test (MAST) is a model system designed to detect compounds with possible anxiolytic activity in humans. The test is. based on punishing mice for exhibiting normal exploratory locomotor behavior. The punishment, an electric shock delivered through the mouse's paws, quickly extinguishes normal behavior. Pretreatment with a mild ataraxic prevents or slows the extinguishing, while strong ataraxics, analgesics, stimulants, anti-depressants, antihistamines and purely sedative drugs are inactive.

The test method is modified from Boissier, et al.,

European J. Pharm., 4, 145-151 (1968) • White female mice, which have fasted for 16-22 hours, are distributed randomly in fiberglass storage boxes. Mice in groups of 10-20 are dosed orally and put back in their storage boxes until experiment time. Test drug suspensions or solutions are prepared by sonication in 1% "Methocel". Typical dose ranges include 0.5, 1, 2 and 4 mg/kg or 1, 3, 9, 27, 81 mg/kg. plus a medium control and selected to include a dose of wood. which an effect such as sedation, stimulation, muscle weakening or analgesia, is seen..

The experimental apparatus is an opaque, black plastic box with a clear lid and a stainless steel grid floor. The floor of the test box is marked in 4 squares of equal size.

After dosing, the mouse is carefully placed in a corner of the experimental box, and during the next minute, each time the mouse makes a complete crossing from one square part of the box to another, the floor is electrified with 0.4 ma current in

2.0 seconds.

The number of shocks received by each mouse is noted, and the average number of shocks/dose (x) is determined. When X drug at a dose is statistically greater than X control (Student•s t-test), suppression antagonism is obtained, and the drug is assumed to have anxiolytic activity.'

The strength of antipentylenetetrazole (PTZ), MAST - and RAST

the samples indicate a strong anti-anxiety agent. High potency for blockade of the mouse auditory pinna reflex with little or no effect on the touch pinna reflex is characteristic of mild ataraxics. Potency in the mouse anti-straub tail test suggests skeletal muscle relaxant activity.

The following table includes the results of these tests carried out with a representative sample of the compounds prepared according to the invention, and it also includes the results for diazepam, oxazepam and chlordiazepoxyd, three well-known benzodiazepines which are widely used commercially as ataraxics.

Claims (5)

1. Procedure, when preparing a compound with the formula: where X is Cl, Br, NC₂ or CF₂; Y is H, Cl, Br or F; Z is H, hydrocarbyl of '1-4 carbon atoms, -CF^CF^ , -CONHR, -CH2 CH2 NR2 or -CH2 CH2 NR2 .A, where R is alkyl with 1-4 carbon atoms, and. A is a pharmaceutically acceptable acid; B is 0; or B and Z together =N-N=C(R')- where R' is H or alkyl with 1-4 carbon atoms, characterized by being under essentially water-free conditions at a temperature of -80° to +10°C brings a connection with the formula: where B, X, Y and Z are as above, in contact with a compound of the formula: where R <1> and R <2> are each a primary alkyl group with 1-4 carbon atoms or together are ~ (CH2 )^ - or - (CH2) - , or that a compound of formula I where B is 0 and Z is different from hydrogen is prepared by forming a sodium salt of a compound of the formula: where X and Y are as above, and then contacting the resulting compound with a suitable alkylating agent. 2. Process according to claim 1, in the preparation of 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-one, characterized in that a starting material with formula II where B is 0, X is chlorine, Y is hydrogen, and Z is methyl, or that where as starting material a compound of formula IV is used where X is chlorine and Y is hydrogen, and that where an alkylating agent is used methylating agent. 3. Method according to claim 1 in the preparation of 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-(2'-fluorophenyl)-2H-1,4-benzo-diazepin-2-one , characterized in that the starting material is a compound of formula II where B is oxygen, X is chlorine, and Y is fluorine, or that a compound of formula IV where X is chlorine and Y is fluorine is used as starting material, and that a methylating agent is used as alkylating agent. 4- Process according to claim 1 for the production of 3-fluoro-1,3-dihydro-1-methyl-7-bromo-5-phenyl-2H-1,4-benzodiazepine-2-one, characterized in that as starting material is used a compound of formula II where B is oxygen, X is bromine, and Y is hydrogen, or that a compound of formula IV is used as the starting material where X is bromine and Y is hydrogen, and that a methylating agent is used as the alkylating agent. 5. Process according to claim 1, in the preparation of 3-fluoro-1,3-dihydro-7-bromo-5-phenyl-2H-1,4-benzodiazepine-2-one, characterized in that a compound with formula II where B is oxygen, X is bromine, Y is hydrogen, and Z is methyl, or that a compound of formula IV where X is bromine and Y is hydrogen is used as starting material.