FI63234C - REFERENCE FOR THERAPEUTIC USE OF THERAPEUTIC THERAPEUTIC 6-ENYL-4H-IMIDAZO (1,5-A) (1,4) DIAZEPINE INFLATION - Google Patents

Description

I. r i .... ANNOUNCEMENT

[B] <11) UTLÄGGININCSSKRIFT 632 3 4 C (45) Fr.exent granted 10 05 10C3 Patent ceddciat V T V (SI) Kv.lk.3 / lnt.CL3 C 07 D 487/04, 495/14.

) FINLAND — FINLAND (21) ρμμημ ^ .ρκμιμ ^ ι 752517. (22) HtkumlsplM —AiMSknlnpdag 08.09.75 '' (23) Alkupilri — Giklghutsdig 08.09 75 (41) Tullut luikikuksi - Bllvfe offuMlig, _, PX »oai · j» r ^ Ut «U» Hltu. (♦ * «*** - I.I · ****»,. * - '„

Patent- och ragltterstyralten '# Arattkai uttagd och utUkrWtun publicurud 31.01.83 (32) (33) (31) Requested prefixes —Buglrd prlorltut ll.09.7it USA (US) 50U92it (71) F. Hoffmann-La Roche & Co. Aktiengesellschaft, Grenzacherstrasse 12it-l8it, Basel, Switzerland-Switzerland (CH) (72) Rodney Ian Fryer, North Caldwell, NJ, Annin Walser, West Caldwell, NJ, USA (US) (7 * 0 0y Kolster Ah (5¾) Method The present invention relates to a process for the preparation of therapeutically useful 6-phenyl-UH-imidazo [1,5-47] l -diazepine compounds. useful for the preparation of 6-phenyl-4H-imidazo [1,5-d] diazepine compounds having the general formula "V /!

OCX

v --- C = N

\ fR

2,63234 wherein R 1 is a lower alkyl group, and R 1 is hydrogen atoms or lower alkyl groups, R is a hydrogen or halogen atom, and the group a is a, b) ΧΧ [ΓΥ C> R 4 wherein R 1 is a hydrogen or halogen atom or a lower alkyl group, and X is a hydrogen or chlorine atom, and for the preparation of pharmaceutically acceptable acid addition salts of these compounds. As used herein, the term "lower alkyl" includes both straight and branched chain, (C 1 -C 7) hydrocarbon groups, preferably C 1 -C 7 hydrocarbon groups such as methyl. , ethyl, propyl, isopropyl and butyl groups.

The term "halogen" embraces all four halogens, i. chlorine, bromine, fluorine and iodine atoms.

When lower alkyl is indicated, optical isomerism exists and such optical antipodes and racemates are included within the scope of this invention.

Preferred compounds are those in which R 1 is a methyl group, R 2 is a lower alkyl group, R 1 is hydrogen, is

JX

R 4 in which R 1 is a hydrogen or halogen atom, preferably chlorine, and R is fluorine, i.e. compounds of the formula 3 63234 CH 3 T if _ / Ν - \, Η r / WL = n5 / \ · and in particular compounds of the formula on ®3γ · 'γ' **

Cl N == N

1 F

sy wherein R 2 is hydrogen or a lower alkyl group.

Another preferred class of compounds within the scope of formula I are those in which the substituents, R 1 and R 2, have the same meaning as in formula IB 'and have a lower alkyl group, preferably methyl, i.e. compounds of formula 4 63234 CH 3 \ n \ / R 2 y - x / ch3

xxx

cf Y = N

The compounds of formula IC and their pharmaceutically acceptable salts exhibit optical isomerism. These compounds can be resolved into their optical enantiomers by the same methods described in Advanced Organic Chemistry, L ·. Fieser and M. Fieser, 1961, pp. 85-88, Reinholt Publishing Co. Both the optical isomers and the racemic form of the compound IC have a pharmacological effect. For example, of the tartrate salts of the compounds of formula IC, the (+) isomer is significantly more active than the (-) isomer. If desired, the less active (-) isomer may be converted to the active racemic form, e.g. by treatment with an anhydrous base, e.g. sodium tert-butoxide in the presence of an organic solvent in which the isomer is soluble.

The term "pharmaceutically acceptable salts" includes salts of both inorganic and organic pharmaceutically acceptable acids, such as salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid and formic acid, formic acid, maleic acid, acetic acid, acetic acid, merx with acids. These salts can be prepared very easily by those skilled in the art and in consideration of the nature of the compound to be converted into a salt.

The most preferred pharmaceutically acceptable acid addition salts of the compounds of formula IB and formula IC, respectively, are: 5 63234 8-chloro-6- (2-fluorophenyl) - 1-methyl-4H-imidazo [1,5-a] benzodiazepine maleate, and 8-Chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo, 5-47,7-benzodiazepine maleate.

The process according to the invention is characterized in that a) a compound of the formula is dehydrated

AY

u wherein R, R 1, R 2, R 3, R 2, X and are as defined above, to the corresponding compound of formula I with manganese dioxide, palladium / carbon or potassium permanganate, or b) oxidizing a compound of formula R 1 vJNC R 2 γ h R VI1 'if 6 63234 wherein R, R1, R2, R2 »R1, X and have the same meaning as above, the corresponding compound of formula I is chromic acid, silver oxide, selenium dioxide, mercury (II) acetate, mercury (II) oxide , with magnesium dioxide, ferric chloride or ferric cyanide, or (c) cyclising a compound of formula

Rw n \ / r2 'γ' 2 I c X 1 Ηχ \ xxv

r = o H

4 rY *

kJ

wherein R 1, R 2, R 2 and R 2 are as defined above, and R 1 is a chlorine or bromine atom to give the corresponding compound of formula I, after which d) if desired, the racemic compound is divided into its optically active enantiomers, and / or e) if desired, A compound of formula I as a pharmaceutically acceptable acid addition salt.

The following diagram illustrates the various steps of the method according to the invention.

7 63234 otk. θ ~ £ ·.

^. * _ / ^ - (ύι P ~ Q2vt- GCX- GÖC ..

tr ^ · φ ^ -

Θί5 ^ '- crQ

<ä & ~ 'τΰ · j \ u.

F * "» X * «η,« ,, o '' <5r: & '

B

(2 IL X vi 0 'i.

* \\ ^ * γ * ι OCXv "OCX» · CT & I ^ 'W «<£ &

Or 8 63234

Compounds of formula VII may be prepared by nitrosating a compound of the formula NHCHo GCÄ "ry" ··

CT

wherein R 2 and R 2 are as defined above in formula I, and n is 0 or 1 to give a compound of formula CH 3

N-NO

GC *;

U

where · R 'R3 and n have the same meaning as above.

Nitrosation can be performed with nitric acid formed "in situ". Useful reagents include (1) alkali metal nitrites, e.g., sodium nitrite, in the presence of organic or inorganic acids, e.g., acetic acid, and aqueous or non-aqueous solvents; (2) alkyl nitrites, e.g., methyl nitrite in the presence of a neutral solvent such as an alcohol, a chlorinated hydrocarbon, or, e.g., dimethylformamide; and (3) a solution of nitrosyl chloride gas in a neutral solvent and in the presence of an acid scavenger such as pyridine. The nitrosation reaction must be carried out at about room temperature or below, i.e. in the temperature range -20 ° C to + 25 ° C.

The nitrosoalkylamine group in the 2-position of H 3, e.g. -N-NO, represents a "leaving group". Corresponding leaving groups that can be used as 2-position substituents include, e.g., an alkoxide, e.g., -OCH 3; alkylthio, e.g. -SCHy halogen, e.g. chlorine; cyano and phosphate, e.g.

-0-P0- ^

Reactions to form alkoxide and alkylthio-2-position substituents are known; see, e.g., G. A. Archer and L.H. Sternabach, Journal of Organic Chemistry, 29, 231 (1964) and U.S. Patent No. 3,681,341, issued August 1, 1972 to Fryer et al.

Compounds of formula III can be condensed with nitroalkane to give a new intermediate of formula no2

H I

^ ACsn ^ H

Jy "· where, R and Rj have the same meaning as above.

10 63234

The condensation reaction with nitroalkane, (R 2 -CH 2 -NO 2), e.g. nitromethane, nitroethane, etc., is carried out in the presence of a base strong enough to form a nitroalkane anion. Suitable bases are alkali metal or alkaline earth metal alcoholates, e.g. potassium tert-butoxide, amides, e.g. lithium amide, or hydrides, e.g. sodium hydride. The reaction is preferably carried out in an inert solvent such as dimethylformamide, dimethyl sulfoxide, or ether, e.g. tetrahydrofuran at a temperature below or above room temperature, i.e. at a temperature in the range of -50 ° C to + 150 ° C, preferably at about room temperature.

Compounds of formula IV may be catalytically hydrogenated, e.g. with Raney nickel in the presence of hydrogen, or with other reducing agents such as lithium aluminum hydride to give a compound of formula NH2

H H

Oix "u wherein, R and R 2 have the same meaning as above.

63234

Solvents useful in Raney nickel hydrogenation include alcohols, e.g., ethanol, ethers, e.g., tetrahydrofuran and diethyl ether, hydrocarbon solvents, e.g., toluene, and dimethylformamide. The reaction temperature may be higher or lower than room temperature (i.e. -50 ° C to + 150 ° C) and the reaction may be carried out with or without pressure, i.e. e.g., at or above atmospheric pressure.

When performing hydrogenation using a reducing agent such as lithium aluminum hydride, suitable solvents include ethers, e.g., tetrahydrofuran, dioxane, diethyl ether, and mixtures of ethers and hydrocarbon solvents, e.g., a mixture of tetrahydrofuran and benzene. The reaction can be carried out at a temperature in the range of -50 ° C .., + 60 ° C.

Compounds of formula V may then be acylated with an acylating agent such as an acid halide or acid anhydride, i. with a group of formula (R 2 CO) 2 O in which R is the same as in formula I, e.g. acetic anhydride and acetyl chloride to give a compound of formula

B

ΘίΤ -

CT

wherein · R / R 2 and are as defined above and Y is hydrogen or -COR 4.

12 63234

When acylating compounds of formula V to compounds of formula VI, a mixture of the predominant monoacylated product, i. wherein the N 1 H 2 group (position 2) of compound V is converted to NHCOR 4, or a dialyzed product in which both the N 1 H 2 group (position 2) and the 1-position nitrogen of compound V are acylated. The yield of the dialyzed product can be increased by treating the compounds of formula V under more efficient conditions, i.e. by using an excess of acylating agent and prolonging the reaction time.

The acylation is preferably carried out in the presence of an aqueous or non-aqueous solvent, e.g. water, methylene chloride, benzene or chloroform, and preferably in the presence of an acid scavenger such as an organic or inorganic base such as triethylamine, pyridine or alkali metal carbonate. The compounds of formula VI can then be cyclized to new compounds of the formula ΚιγΝγβ2 o: x

^^ X C = N

wherein R 1, R 2, R 1 and d C are as defined above.

The cyclization is carried out with a dehydrating agent such as phosphorus pentoxide, polyphosphoric acid or other suitable acid catalysts, i. with organic or inorganic acids, e.g. concentrated sulfuric acid. No solvent is required, although a solvent such as an aromatic hydrocarbon solvent, e.g., toluene, xylene, may be used. The reaction is carried out at a temperature in the range of about 100 to 200 ° C.

13 63234

Compounds of formula V may also be reacted with an acylating agent such as an orthoester, e.g. triethyl orthoacetate, an orthoamide, e.g. With a compound according to N-CH, I 3 CH 3, optionally in the presence of an acid catalyst, e.g. an organic or inorganic acid, e.g. p-toluenesulphonic acid, phosphoric acid, etc., and at room temperature or higher, i.e. at a temperature between 25 ° C and 150 ° C, in which case the cyclization to compound VII takes place spontaneously. Other useful acylating agents include esters, e.g., methyl acetate; amidines, e.g. acetamidine? nitriles, e.g. acetonitrile; and ester imidates, e.g. a compound of formula OC 2 H.

I 2 5

CH -C = NH

Compounds of formula VII may then be dehydrated according to process a of the invention to give a compound of formula I.

Preferred reagents for dehydration are manganese dioxide and palladium on carbon, although potassium permanganate is also useful. Useful solvents include chlorinated hydrocarbon solvents, aromatic hydrocarbons, dimethylformamide, etc. The dehydrogenation is carried out at room temperature or higher, i.e. at temperatures of about 25 to 200 ° C.

The above new process can be carried out, if desired, starting from intermediate compounds IV or V and ending with compounds of formula I without isolating the intermediates formed before the next reaction step.

14 63234

Both optical and geometric isomerism have been observed with the compounds of formulas IV, V and VI.

Reaction of a compound of formula V with acetic acid and zinc or hydrogen in the presence of a catalyst, e.g. platinum in a dilute acetic acid solution, gives a compound of formula

Nh2 u 2 n I> - p oc ^ · & where (3> R2 and R ^ have the same meaning as above.

Depending on the chosen reduction method described above, the compound of formula V can be isolated, at 1 * 2 ° C hydrogen, as a racemic mixture of one of the two possible diastereomers.

The compound of formula V can be converted to its dihydroimidazo derivative of formula

Vv? N-V · 11 VII * GX 0 <»s

NH-CH

JY

wherein dX, R, R 1, R 2 and R 2 are as defined above, so that they do not change stereochemically, using the direct reaction described above, i. reacting compounds of formula V with an acylating agent such as an orthoester, e.g. triethyl orthoacetate, and maintaining the above reaction parameters for such a reaction.

15 63234

Compounds of formula VII 'may also be prepared by reduction of compounds of formula VII using the aforementioned reducing agents, e.g. acetic acid and zinc, or a t 1 / platinum catalyst system in dilute acetic acid, depending on the chosen reducing agent which stereoisomer is formed.

If desired, the compounds of the formula VII 'can be oxidized directly to the compounds of the formula I by using, for example, manganese dioxide in toluene or benzene solution as oxidant. Reaction conditions and various useful oxidants are disclosed in U.S. Patent No. 3,322,753, issued May 30, 1967 to Fryer et al.

In another process for the preparation of novel intermediates of formula V, a compound of formula is reduced

CN

GCGc.

rY ^ where Γ z | l, R and Rj have the same meaning as above.

The reduction reaction is the reaction of compounds of formula X with a known reducing agent such as Raney nickel in the presence of hydrogen or with other reducing agents such as lithium aluminum hydride.

Suitable solvents for hydrogenation with Raney nickel include alcohols, e.g. ethanol, ethers, e.g. tetrahydrofuran, hydrocarbon solvents, e.g. toluene, and dimethylformamide. The reaction temperature may be above or below room temperature (i.e., -50 ° C to + 150 ° C), and the reaction may be carried out at normal pressure or elevated pressure.

Solvents suitable for use in hydrogenation using a reducing agent such as lithium aluminum hydride include ethers such as dioxane, diethyl ether and tetrahydrofuran. The reaction can also be carried out at a temperature ranging from below room temperature to boiling point, preferably from -50 ° C to + 60 ° C.

A variation of the above process involves hydrolysis of compounds of formula X under mildly acidic conditions to give compounds of formula 16 63234 CONH, GX

V - / \ C = N ^ H XI

0 wherein ^ Zjj ^, R and R3 have the same meaning as above.

The hydrolysis under slightly acidic conditions is conveniently carried out with a dilute inorganic acid, e.g. sulfuric acid in a mixture of water and alcohol. The reaction temperature may vary from room temperature, i. from about 25 ° C, to a temperature above room temperature, i.e. to about 60 ° C. The compounds of formula XI can then be reduced to novel intermediates of formula V.

The above compound of formula IV can also be prepared by sequential reactions by administering compounds of formula

gxgG

ry where · R and R3 have the same meaning as above.

17 63234 to react with dimorpholinophosphine chloride to form compounds of formula

° XX

yO-P - Hj oj

CzY ~ ^ xR3 vjk / Xh X111 cp

[Y

wherein R 1, Z 2 and R 2 are as defined above, which iminophosphates are then replaced by the nitroalkane anion to form new intermediates IV.

A nitroalkane is used for the substitution reaction, i.e., nitromethane, nitroethane, etc. in the presence of a base strong enough to form a nitroalkane anion. Suitable bases are alkali metal or alkaline earth metal alcoholates, hydrides, amides or hydroxides. The reaction is preferably carried out in an inert solvent such as dimethylformamide, dimethyl sulfoxide or ether at a temperature below or above room temperature, i.e. between -50 ° C and + 150 ° C.

In another process for the preparation of N-oxides of formula IV with hydrogen, a ring expansion reaction is carried out in compounds of formula (Xyl> - QT / 1 "'X ^ (0)" X ^' 0, n fTR [T *

^ „Xx V

18 63234 where R 1 (DC / R 3 and n have the same meaning as above.

Ring expansion is performed by reacting compounds of formula VII or IX with nitromethane in the presence of a base strong enough to form the nitromethane anion. Suitable bases are alkali metal and alkaline earth metal alcoholates, e.g. potassium tert-butoxide, amides, e.g. lithium amide or hydrides, e.g. sodium hydride. The reaction can be preferably carried out in an inert solvent such as an anhydrous ether, e.g. tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, etc., and at a temperature in the range of about -20 ° to + 25 ° C.

Treatment of a compound of formula I with excess sodium nitrite in the presence of a copper sulphate / sodium sulphate mixture and using dilute sulfuric acid as solvent gives a compound of formula

R1'S | ^? Nvs ^ 'R2 - \ J / R3 | CHOH XXIII 'RJ XC ~ °

CT

KK

wherein R, R 1, R 2 and R 2 are as defined above. This compound can be converted to a compound of formula I. This reaction can be performed in three steps without isolating the bromine intermediate formed by treating a compound of formula XXIII1 with phosphorus tribromide in an inert organic solvent, e.g. dichloromethane at a temperature of about -10 ° to + 25 ° C (temperature is not critical) and then treating in situ. ammonia, preferably liquid ammonia, which is allowed to warm to room temperature to give the amino intermediate of formula 19 63234

VV

xxv R 4 u wherein R, R 1 # R 2, R 1 and R 2 are as defined above and which spontaneously cyclizes to the corresponding compound of formula I.

Results of Pharmacological Experiments A. The solubility of the compounds of the invention and the well-known drug, diazepam, in water at 20 ° C was determined. The results are shown in Table I. As can be seen from the table, the compounds according to the invention have a very good solubility in water.

B. The activity of the compounds of the invention and the reference compounds on the central nervous system was determined by standard methods (see Sternbach, LH, et al., Medicinal Research Series, Vol. 2, "Drugs affecting the central nervous system", Ed. Burger, A., Marcel Dekker Inc., New York, 1968, pp. 237-240). The results are shown in Table II, where A = Antimerazole Test B = Combat Test C = Inclined Level Test D = Watched Cat Test E = Toxicity Test

As can be seen from Table II, the compounds according to the invention are more active than the well-known drug, diazepine, and the very close imidazobenzodiazepine derivative known from French Patent 2,183,716.

20 63234

ft! I

CO I

CO I

** I

U I

o I

O I

cm I in I o

G - «I O

φ H * - * 3 * CM LO I o O) 6 m o o o ooio 4-) S. * v k. k, s ^ I «,

Φ &> o t- O O OOIO

> ^ A I

CO I

3 I

3 I

CO I

• H I

0 I

X I

3 I

• H I

P) I

• H I G I • H I

I -H I

CU I

I I I I H I φ I

33 I O H -H H -H CO I

^ r-H CO I G IG> i G I · 4-> I

I Ό -P I -H -H -H -H> 1 -H -H ft! I

• H -H 3 0 iH · Η H -H G · Η Η · Η I

H G Ό Ρ> ι Λ> ιΛ 0) α> ι Ό I

> ι · Η Ή Ό> ι Ο! > ι φ Ή φ> ι | \ Ι

> 1 · Η β> ι -Ρ C0 -Ρ C0 Ή CD -p I

Ρ Οι -H X! φ -Ρ φ -Ρ Ρ -Ρ φ 'I

Φ Φ I · Η β 3 β 3 03 β It- I

β C0 35 Ό I -H I · Η 3 -Η I '—I I

I -Ρ 'Τ I * “Τ3 τ- Ό Η Ό τ - (^ |

V 3 I · Η 10 10 Η Ο I Ή 'I

1 · Η · Η G - CO -. CO I CO - Il

? ί 3 iH -H · Η -P -H -P (N -p -H m I

H O> i -H -H G HG - G H 'I

> i «> iCU> ιΦ> i Φ ΙΦ> 1

> i -P G Φ> 1 Λ> τ XI ΙΟΛ> i I

GG Φ CO G G Γ “> I Γ>. G O I

φ Φ H -Ρ φ φ H1 '-H' »l φ G I

H _Q 13 M-l 'IH' Η 'ΉΦΙ

Η 'πν ΙΟ Η * H ν'— -H l i—> t it— -Η · Η I

Ρ · <3 "I Ό H Si P VI> i VJ p -P I

n O '-ho or> or> -ρ r> or> i

3 IT-, H co 3 3 '0 3 * Φ 3 ‘O 3’ I

o H * sl> 1 -P HI HI β I H I I

X * h r>> 1 G H m x m -nm m i

X 13 '-Ρ Φ I I O' I- 'I

3 Ml Φ Λ N Γ (N li- I IT— CN it- I

H ~ m -H g N, - ^ hVI h- XI wVjl 3 Φ Ι'Ό IV 10 10 '0 101 3 -P io η T-' into vow t-οι io co ι hg * C0 I S4 HI it— I +> -HI 4J -HI + j -HI + JI fi • H * H 0 0 * H Nj -H 3 -P -H3-P -H3-P -H3I 3 Ό P CO HP -Η Μ Ό -Ρ Ρ Ό -Ρ Ρ Ό -Ρ Ρ Ό I a £ i Ο -Ρ Μ 0 3 * Ό0 · Η30 · Η30 · Η30 · ΗΙ φ

X 030 01 Ή 0β3 0 β 3 0 β 3 ΟβΙ CO

ΗΌΗ H m Ρ Η · Ηφ H -H φ H · Η φ H -H I -Ρ X -r4 Ό X'.0X \ r- ^ X ^ r- ^ X ^ r- ^ X \ l 3

I β> ί I IT- H I 32 3 1333 I 32 3 1321 -H

00 -H Xl 3 Nl Λ (O Tf g 00 g OO H "g 00 H · I Q

21 63234 3 O 'p M P „m m o ooo O' 3 t" r- ~ o ooo g r- r- o ooo t— r · Γ “Γ" o c w m 3 Q 3 P) in

O '3 Pi P

\ -p m O '3 m in in g 3 - - M o O I O IN «“ Q O m 3 Q 3 W 3 in O' 3

Pi -P

\ p O '3 e 3 U Pi _ o in m m m m o me t "<- r ~~ cnooo Q 3 <N <- W 3 in

O 'id Pi P -P

O '3 g 3 in pq ^ o o m m - m

o fN r- IN fN

m 3 »- Q 3 W 3 id O '3 Pi -P \ P O' 3 g (0 ν 'r- m y ·. ·. *

rtj o m <n <n 1— m I

m c Q 3 W 3 in 22 63234 tr -S I Ä £ *> id ^ d 13 O '3 O Ilo | si.

E A! O I / O I | -M

O ro I 3 o C r- Λ I · ΓΟ m 3 I ^

M Ω 3 I

I tn I

O 'rt i

M P

\ P | O '3 * - in li

E rt m in in *> - I

X - - * o m i

O (N o (N I

Q m c I

Ω 3

M 3 I

(0 I

0> rt I

a: -P I

\ P |

O '3 I

E rt m i i X I m o in m t

O o * - * r I

in C l

Ω d I

M d I

tn i i O 'rt i

X P I

\ P m m I

o> d - «n o i i E rt (N {N O T- | X i- m i

CQ O I

m c l Ω d l ω d i (0 | O 'rt i

X P I

\ P M ΙΟ σι | O 'd T- io co r ~ m l E rt · “» * »« »* i X I O ^ O CO ID | <o 1

m c i I

Ω d K. I

W d rt1 -h I

tn lp i l m p Oi »rt i i Ci i p- rt i rS co a> i 10 ^ T- rf’ Il -Hl - -H tn -H OPI 'P P I P | 3 p P c i tn p - H »* 1 i c · - N, i

3 o rt -H ID P rt -H '' -J> 1 '(N I -rl -H rt * I

X O Ό -H I rt P P K. P> 1 \ T- -H - o -h p I I

P ppcupoi> i «rO p ^ pp i tn 0u Soin i rt ΜΕΦΡΡΩ> οΐΡ <ι> ρνιΡιορα >> ι *. i • n iPtn ^ BiCinmBrtirtirtcnCii- i

njiP ^ ppo- ^ iiirtPOPaj ^ Pi w S rt P I C P tr— o r- ld <D P P rt P O C I

M I 'S · P <u s P P VJ I I' P> 1 B -H p w p I

p 101¾ B * j * p p O m λ p— rt> i p Ό P P p i IPÖPICUOcni P 'sl β P I 0 O rt CU I O pptn Ό - o dPP pop il s oi OOtui x n ^ PiPtnprtC ^ tnCB'vPPPtni x os ^ Cttppppp

3 O P 0) '> i rt I P P C rt -H Ό ~ 0) I P rt I

P P (1) P t “> 1 P (NEO. ΦΌΛ IPP (NIPI

d AiErNiGO '-' PtuppiuropK, - ajoi rt ii ^ rpa) Oii (QPSni> i ^ «i ^ hs.i

E-ι OOP - p P M O SC P P P P r->, ·. VO | V I

i i i «- o p p i ro o i rt« c r i p 'i

P - V | o M C P I P O K p P (1) '• sl P P it- I

<upp rv, po ai μρόρττό pp r->, ρ so "Ό ip> iPtt # ^ 3p ohoa: iooo« ji o> 1 rs i tn> ί> 1 i iPiSo> iiniotnoMi opp'i p P> 1 in oopp > 'p> iP cm ρ p pom pqji l Ό a> C - - «I v Ai PCPCA! 3 ~ At E cm ipi tu i <- im ir- i Qj a) ipoip it-, ii * · i

Sh r-P'vl '—— MooEP OCP ao P ^ J oo t— \ ro ^ I

23 tn (O 6 3 2 3 4 λ: -ρ \ 44

tn 3 O

g (O O I

Ai O

O τ-

Η m C

Q 3 J 3

C/O

tr »3 a; -p \ 4-1

Cn 3 E (0 m m

Ai * · «· o o m Q m e Q 3 W 3 co tr» cö

Ai 4-> \ +4 tn 3 E 3 tn o

Ai m o o m

U m C

Q 3 W 3 (0 tn co

Ai 44 \ 4-1 tn 3 g rt

Ai O O o m in C r- 04 Q 3 W 3 co tn co

Ai 4J

"" s 44 tn 3

E (CJ OI

e Ai ID r- ~ o * <- in β τα 3 W 3 co 0

3 CO -H

3 44 C

Ai rt -H

44 Ό -H

rt "H Oi • n E <1)

—T -H CO

1 44 h tö rt

H tT -H

I Ό O .. -H o

Ai "rH CO

Ai%> 1 44

3 $> i C

rH Ä C Φ -

3 Tn 0) .43 <D

rt * 3 Ή K r en £ i ^ r- 5 -H VO '0) §. § »vr. m 44 3 · Η XI 00 CO, 3 Oi M On. r- • H 0) O rt1 Ό CO O I 04 £ 5 44 r-1 04> H rt Ai - Oi £ O »^ £ 24 6 3 2 3 4

The following examples illustrate the invention; all temperatures are in degrees Celsius.

Example 1 8-Chloro-1-ethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a]. / 47benzodiazepine

A solution of 200 g (0.695 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 2 l of tetrahydrofuran and 250 ml of benzene , was saturated with methylamine in an ice bath under cooling. A solution of 190 g (1 mole) of titanium tetrachloride in 250 ml of benzene was added through a dropping funnel over 15 minutes. After the addition, the mixture was stirred and refluxed for 3 hours. Water (600 ml) was slowly added to the cooled reaction mixture. The inorganic material was filtered off and washed well with tetrahydrofuran. The aqueous layer was separated and the organic phase was dried over sodium sulfate and evaporated to dryness. 7-Chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine obtained as a crystalline residue was collected, m.p. 204-206 ° C. An analytical sample was recrystallized from methylene chloride-ethanol, m.p. 204-206 ° C.

8.63 g (0.125 mol) of sodium nitrite were added in three portions over 15 minutes to a solution of 30.15 g (0.1 mol) of 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4 -benzodiazepine in 150 ml of glacial acetic acid. After stirring for 1 hour at room temperature, the reaction mixture was diluted with water and extracted with methylene chloride. The extracts were washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated to dryness, finally azeotropically with toluene to give 29 g of crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazine as a yellow oil.

This material was dissolved in 100 ml of dimethylformamide, and the solution was added to a mixture of 200 ml of dimethylformamide, 50 ml of nitromethane, and 11.1 g (0.1 mol) of potassium tert-butoxide, which was stirred under nitrogen for 15 minutes.

After stirring for 1 hour at room temperature, the reaction mixture was acidified by the addition of glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate and evaporated to dryness.

Crystallization of the residue from ether gave 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine, m.p. 170-172 ° C. An analytical sample was recrystallized from methylene chloride / ethanol, m.p. 174-176 ° C.

A solution of 16.5 g (0.05 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine in 500 ml of tetrahydrofuran and 250 mL of raethanol was hydrogenated, using 5 teaspoons of Raney nickel, for 2 1/2 hours at atmospheric pressure. Separation of the catalyst and evaporation to dryness left crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine.

To a solution of 12 g of the above substance in 300 ml of methylene chloride was added propionic anhydride (20 ml). 300 ml of 10% aqueous sodium carbonate solution was poured on top of the solution, and the biphasic mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed with sodium carbonate solution and dried over sodium sulfate. Evaporation to dryness gave crude 7-chloro-2,3-dihydro-5- (2-fluorophenyl) -2-propionylaminomethyl-1H-1,4-benzodiazepine.

This material was heated in 50 g of polyphosphoric acid at 150-170 ° C for 10 minutes. The reaction mixture was cooled, dissolved in water and basified with concentrated ammonia and ice. The base was extracted with methylene chloride and the extracts were dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on 300 g of silica gel and 20% methanol in methylene chloride. The pure fractions were combined, evaporated to dryness and the residue crystallized from ether to give 8-chloro-3a, 4-dihydro-1-ethyl-6- (2-fluorophenyl) -3H-imidazo [1,5-a] / 1, 47benzodiazepine, m.p. 131-133 ° C.

A mixture of 3.4 g of 8-chloro-3a, 4-dihydro-1-ethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine, 400 ml of toluene and 30 g of activated manganese dioxide, boiled by separating water using a Dean-Stark trap for 2 hours. The manganese dioxide was filtered off through Celite and the filtrate was evaporated to dryness. The residue was crystallized from ether to give 8-chloro-1-ethyl-6- (2-fluorophenyl) -4H-imidazo [3,4-] benzodiazepine, m.p.

140-143 ° C. For analysis, part of it was recrystallized from ether, m.p. 143-145 ° C.

Example 2 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,47] benzodiazepine

Acetic anhydride (7 ml) was added to a solution of 6.16 g of crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine in 200 ml of methylene chloride. 200 ml of saturated aqueous sodium hydrogencarbonate solution was poured onto the solution, and the mixture was stirred for 20 minutes. The organic layer was separated, washed with sodium hydrogen carbonate, dried over sodium sulfate and evaporated to dryness to leave resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine . This material was heated with 40 g of polyphosphoric acid at 150 ° C for 10 minutes. The cooled reaction mixture was dissolved in water, basified with ammonia and ice, and extracted with methylene chloride. The extracts were dried and evaporated to dryness and the residue was chromatographed on 120 g of silica gel and 20% methanol in methylene chloride. The pure fractions were combined and evaporated to dryness to give resinous 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] 3,4,4-benzodiazepine. A mixture of this material in 500 ml of toluene and 30 g of manganese dioxide was heated at reflux for 1 1/2 hours. Manganese dioxide was separated by filtration through Celite. The filtrate was evaporated to dryness and the residue was crystallized from ether to give 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,47] benzodiazepine, m.p. 152-154 C. The analytical sample was recrystallized from a mixture of methylene chloride and hexane.

Example 3 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-] 73,4-benzodiazepine maleate A warm solution of 6.5 g (0.02 moles) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,47] benzodiazepine in 30 ml of ethanol was combined with a warm solution of 2.6 g (0.022 mol) of maleic acid in 20 ml of ethanol. . The mixture was diluted with 150 mL of ether and heated on a water bath for 3 minutes. After cooling, the crystals were collected, washed with ether and dried in vacuo to give 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] · 2,7-benzodiazepine maleate, m.p. 148-151 ° C.

Example 4 8-Chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-b] 73,47 benzodiazepine dihydrochloride A solution of 0.32 g (1 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [T. 1,5-benzodiazepine in 5 ml of ethanol was treated with an excess of ethanolic hydrochloric acid solution. The salt was crystallized by the addition of 2-propanol and ether. The colorless crystals were collected, washed with ether and dried to leave 8-chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] -3,7-benzodiazepine dihydrochloride, m.p. 290-295 ° C.

27 63234

Example 5 S-Chloro-ε-β-fluorophenylp-1-methyl-1H-imidazo [4 H] benzodiazepine hydrochloride A solution of 0.325 g (1 nunol) of 8-chloro-6- (2-fluorophenyl) methyl) -1-methyl-4H-imidazol-5-yl-benzodiazepine in 3 mL of ethanol was combined with a suspension of 0.4 g (1 mmol) of the dihydrochloride of this compound in 5 mL of ethanol. After filtration, ether was added to the solution, and the mixture was heated on a water bath for 5 minutes for crystallization. The crystals were collected, washed with ether and dried to leave 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine hydrochloride, m.p. 295-297 ° C.

Example 6 8-Chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazol-1,5-g7ZX4-benzodiazepine

The procedure was as in Example 1, but starting from 152.5 g (0.5 moles) of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one saturated with methylamine; was obtained by reaction with a solution of 133 g (0.7 mol) of titanium tetrachloride in 2 l of tetrahydrofuran and 400 ml of benzene, 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-1,4 benzodiazepines, m.p. 216-219 ° C. An analytical sample was recrystallized from methylene chloride-diethanol and m.p. was 217-219 ° C.

Sodium nitrite (10 g, 0.145 mol) was added portionwise over 45 minutes to a solution of 22.4 g (0.07 mol) of 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-1,4-benzodiazepine. In 150 ml of glacial acetic acid. After the addition, stirring was continued for 20 minutes under nitrogen. The product was precipitated by the addition of ice water, collected and dissolved in toluene. The solution was washed with saturated aqueous sodium hydrogen carbonate solution, dried and evaporated to dryness in vacuo. The yellow viscous oil was predominantly the desired nitrosamidine as determined by plate chromatography. This material was dissolved in 100 ml of dimethylformamide and added to a mixture of 30 ml of nitromethane, 100 ml of dimethylformamide and 10 g of potassium tert-butoxide. The reaction mixture was heated to 85 ° C with slow stirring and a stream of nitrogen.

After 5 minutes, the reaction mixture was cooled, acidified by the addition of 10 ml of glacial acetic acid. The product was crystallized by gradually adding water, and using seed crystals (seed crystals were obtained by chromatography on silica gel using 10% ethyl acetate / methylene chloride). The separated crystals were collected, washed with water and recrystallized from methylene chloride / ethanol-28,63234 to give 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2-nitromethylene-2H-1,4-benzodiazepine, mp. 182-185 ° C.

Hydrogenation of 7 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2-nitromethylene-2H-1,4-benzodiazepine in 300 ml of tetrahydrofuran and 150 ml of methanol in the presence of Raney nickel ( 5 teaspoons) for 1 hour gave crude 2-aminoethyl-7-chloro-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine. This material was acylated in the usual manner to leave oily 2-acetaminomethyl-7-chloro-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine, which was heated in 15 g of polyphosphoric acid for 10 minutes 140 -150 ° C. Further work-up in the usual manner gave a yellow resin which was chromatographed on 250 g of silica gel using 20% methanol / methylene chloride.

The pure fractions left resinous 8-chloro-6- (2-chlorophenyl) -3a, 4-dihydro-1-methyl-4H-imidazo [1,5-a] 2Z, E-benzodiazepine. This material was oxidized with 10 g of manganese dioxide in 200 ml of toluene. After boiling the mixture for 1 1/2 hours, the manganese dioxide was separated off and the filtrate was evaporated to dryness. Crystallization of the residue from ether gave 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,47] benzodiazepine, m.p. 140-144 ° C. For analysis, it was recrystallized from methylene chloride / hexane, m.p. 142-144 ° C.

Example 7 8-Chloro-1-methyl-6-phenyl-4H-imidazo [1,5-b] 1,7-benzodiazepine

A solution of 33 g (0.1 mol) of 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine-4-oxide in 100 ml of dimethylformamide was added to the mixture, with 50 ml of nitromethane, 12.5 g (0.11 mol) of potassium tert-butoxide and 100 ml of dimethylformamide. The reaction mixture was stirred under nitrogen for 1 hour. After adding 10 ml of glacial acetic acid, the product was crystallized by gradually adding 250 ml of water. The precipitated yellow material was collected, washed with water, methanol and ether to leave 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine-4-oxide, m.p. 253-255 ° C (dec.). The analytical sample was recrystallized from methylene chloride and had the same melting point. Raney nickel (5 teaspoons) was added to a solution of 16.5 g (0.05 moles) of 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine-4- oxide in 500 ml of tetrahydrofuran and 250 ml of methanol. The mixture was hydrogenated for 5 hours at atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was dissolved in 2-propanol and the solution was strongly acidified with ethanolic hydrochloric acid. The dihydrochloride of the product crystallized on evaporation of some of the solvent. The orange crystals were collected to leave 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine dihydrochloride, m.p. 230-240 ° C.

Acetic anhydride (10 ml) was added to a solution of 10 g of the above dihydrochloride in 50 ml of water and 50 ml of methanol. Within 5 minutes, 10% aqueous sodium carbonate solution (100 ml) was added with stirring. After the addition, the mixture was stirred for an additional 10 minutes and then extracted with methylene chloride. The extracts were washed with sodium carbonate solution, dried over sodium sulfate and evaporated to dryness, finally azeotropically with toluene. 2-Acetaminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine was obtained as a yellow gum.

The above material was heated in 50 g of polyphosphoric acid at 135-140 ° C for 10 minutes. The original orange color of the reaction mixture faded to pale yellow. The cooled reaction mixture was dissolved in water, basified with concentrated ammonia and ice, and extracted with methylene chloride. The extracts were dried and evaporated to dryness. The yellow resin was dissolved in 2-propanol and treated with ethanolic hydrochloric acid to crystallize the colorless dihydrochloride of the product, m.p. 240-245 ° C.

This hydrochloride was partitioned between methylene chloride and aqueous ammonia. The organic phase was dried and evaporated to dryness. Crystallization of the residue from ether gave 8-chloro-3a, 4-dihydro-1-methyl-6-phenyl-3H-imidazo [1,47] benzodiazepine as a colorless product, m.p. was 116-118 ° C.

A mixture of 3.1 g (0.01 mol) of 8-chloro-3a, 4-dihydro-1-methyl-6-phenyl-3H-imidazo [1,5-a] 2J, 4-benzodiazepine, 20 g of activated manganese dioxide and 150 g of ml of toluene, boiled for one hour. The manganese dioxide was removed by filtration through Celite and washed well with methylene chloride. The filtrate was evaporated to dryness and the residue was crystallized from ether to give 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as colorless crystals, m.p. was 187-188 ° C.

30 6 3234

Example 8 8-Chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine

A mixture of 11.2 g (0.1 mol) of potassium tert-butoxide, 50 ml of nitroethane and 200 ml of dimethylformamide was stirred at room temperature for 15 minutes. A solution of 29 g (0.088 mol) of crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine in 100 ml of dimethylformamide was then added and stirring under nitrogen was continued for 6 hours. . The reaction mixture was neutralized by adding glacial acetic acid and diluted with water. The product was extracted with ether. The extracts were washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated to dryness. Crystallization from ether gave 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (1-nitroethylene) -2H-1,4-benzodiazepine as yellow crystals, m.p. was 136-142 ° C.

Raney nickel (5 teaspoons) was added to a solution of 17.3 g (0.05 moles) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (1-nitroethylene) -2H- 1,4-benzodiazepine in 750 ml of tetrahydrofuran. The mixture was hydrogenated at atmospheric pressure for 4 hours. The catalyst was removed by filtration through Celite and washed well with methanol. The filtrate was evaporated to dryness to leave crude 2- (1-aminomethyl) -7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine as a reddish oil.

This material was dissolved in 300 mL of methylene chloride. After 14 ml of acetic anhydride was added thereto, 300 ml of saturated aqueous sodium hydrogencarbonate solution was added, and the biphasic mixture was stirred at room temperature for 1 hour. The methylene chloride layer was separated, washed with hydrogen carbonate, dried over sodium sulfate and evaporated to dryness. The residue was heated with 40 g of polyphosphoric acid for 10 minutes at 160-170 ° C. The cold reaction mixture was diluted with water, basified with ammonia and extracted with methylene chloride. The extracts were washed with water, dried and evaporated to dryness to leave a brown residue which was chromatographed on 250 g of silica gel and 20% (v / v) methanol in methylene chloride. The plates chromatographically homogeneous fractions were combined to give a resin which was oxidized as follows.

A mixture of the above substance, 20 g of activated manganese dioxide and 300 ml of toluene was heated at reflux for 3 hours and using a Dean-Stark trap to remove water. Mann 63234 gane dioxide was filtered off through Celite and washed well with methylene chloride. The filtrate was evaporated to dryness and the residue was chromatographed under pressure on 150 g of silica gel H using a mixture of 3% ethanol and methylene chloride. The first major component eluted was 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] 1,4-benzodiazepine.

It was converted to crystalline dihydrochloride by treatment with ethereal ethanolic hydrochloric acid; mp. 247-250 ° C (dec.).

The more polar portion could be crystallized from methylene chloride / ether / hexane to give 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] E / 4 / benzodiazepine, m.p. was 178-180 ° C.

Example 9 (+) - 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] D-> 4-benzodiazepine-1-tartrate A mixture of 17 g (0.05 moles) of racemic 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] N, N-benzodiazepine liberated from its dihydrochloride salt by treatment with aqueous methylene chloride and ammonia, 18 8.8 g (0.05 mol) of 0,0'-dibenzoyl-d-tartaric acid hydrate and 170 ml of ethanol were boiled until complete dissolution. For crystallization, the solution was allowed to stand overnight. The separated crystals were combined, washed with ethanol and ether to give 0,0'-dibenzoyl-d-tartaric acid, m.p. was 140-142 ° C.

Recrystallization from ethanol / ether gave the product, m.p. 141-142 ° C and ε-δ -43.39 (c = 1% in methanol).

A solution of 1.6 g (0.0106 mol) of 1-tartaric acid in 11 ml of ethanol was added to a solution of 3.5 g of a levorotatory base liberated from the above-mentioned 0,0'-dibenzoyl-d- tartrate in 11 ml of ethanol. The resulting crystals were combined and washed with ethanol and ether to give (+) - 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,47] benzodiazepine. l-tartrate, m.p. 178-180 ° C. Recrystallization from ethanol gave the product, m.p. 183-185 ° C and + 25.69 ° (c = 1.012% in methanol). The rotation of the amorphous base released from this salt was “36.74 ° (c = 0.039% in methylene chloride).

Example 10 (N, N-Chloro-1H-dimethyl-N-fluorophenyl) -4H-imidazo [1,5-a] [2] benzodiazepine-d-tartrate The mother liquor remaining after separation of the solution described in the previous example. The crystalline salt formed with 0,0'-dibenzoyl-d-tartaric acid 32 632 34, evaporated to dryness and basified again by treatment with a mixture of aqueous ammonia and methylene chloride. The methylene chloride solution was dried over sodium sulfate and evaporated to dryness to give a partially resolved base.

A solution of 9.7 g (0.029 mol) of this substance in 15 ml of ethanol was treated with a solution of 4.4 g of d-tartaric acid in 14 ml of ethanol. After several hours, the separated crystals were combined to give (-) - 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] D-, 47-benzodiazepine-d-tartrate. , sp. 176-178 ° C. Recrystallization from ethanol gave the pure product, m.p. was 182-184 ° C and -24.96 ° C (0.9616% in methanol). The amorphous base liberated from this salt had a rotation of + E (-J] -) +37.6 (c = 1.0% in methylene chloride).

Example 11 8-Chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,14] benzodiazepine maleate 41.3 g of 8-chloro-1,4-dimethyl-6 - (2-Fluorophenyl) -4H-imidazo-δ-, 5-α, β, 4,7-benzodiazepine dihydrochloride was partitioned between methylene chloride and aqueous ammonia. The methylene chloride solution was washed with water, dried over sodium sulfate and evaporated to dryness to leave the free base. This material was dissolved in 50 any 2-propanol and the solution was treated with a solution of 12 g of maleic acid in 40 ml of 2-propanol. The solution was gradually diluted with 300 mL of ether. The precipitated crystals were collected and dried to give 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [X, 4] benzodiazepine maleate, m.p. 130-132 ° C, after recrystallization from a mixture of ethanol and ether.

Example 12 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazol-5,7-7,7-benzodiazepine maleate A mixture of 17.4 g (0.05 mol) of 7-chloro-1,3 -dihydro-5- (2-fluorophenyl) -2- (1-nitromethylene) -2H-1,4-benzodiazepine-4-oxide, 500 ml of tetrahydrofuran, 200 ml of methanol and 5 teaspoons of Raney nickel, hydrogenated at atmospheric pressure for 5 hours . The catalyst was removed by filtration and the filtrate was finally evaporated to dryness azoetropically with xylene to leave crude 2-aminomethyl-7-chloro-5- (2-fluorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine.

33,632 34 This material was dissolved in 200 ml of ethanol / 14 ml of triethyl orthoacetate and 2.8 g of p-toluenesulfonic acid were added to the solution, and the solution was heated under reflux for 2 hours. The solvent was evaporated in vacuo and the residue partitioned between methylene chloride and 10% aqueous sodium carbonate solution. The organic layer was dried and evaporated to dryness to give oily 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -1-methyl-3H-imidazo [1,5-d] 3,4-benzodiazepine. This crude product was dissolved in 500 ml of xylene. After adding 50 g of activated manganese dioxide to the solution, the mixture was stirred and heated by refluxing for 1 1/2 hours and separating the water with a Dean-Stark trap. The inorganic material was removed by filtration and the filtrate was evaporated to dryness to leave 10 g of a brown oil.

To this residue was added a warm solution of 4.65 g (0.04 mol) of maleic acid in 50 ml of ethanol. After dissolution, the product was crystallized by the addition of ether. It was collected and washed with ether to leave 8-chloro-6- (2-fluorophenyl-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate, mp 112-115 °). C. When this product was heated at 90-100 ° C under vacuum, it converted to a higher melting form, mp 148-151 ° C.

Example 13 1-Methyl-6-phenyl-4H-imidazol-1,5-a7 / T, 47-benzodiazepine

A solution of 23.6 g (0.10 moles) of 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one per liter of tetrahydrofuran (containing about 20 moles of monoethylamine) was cooled in an ice bath. . To this mixture was added 14 ml (om.p. = 1.73 0.124 mol) of titanium tetrachloride dissolved in 200 ml of benzene.

This mixture was stirred at room temperature for two days. The titanium complex was decomposed in 20 ml of water. The precipitated inorganic salts were removed by filtration. The solvent was evaporated to dryness in vacuo and the residue partitioned between methylene chloride and water. Colorless, amorphous solid, m.p. 227-229 ° C, removed by filtration. After drying over sodium sulfate, drying over sodium sulfate, evaporation to dryness, and crystallization from ethyl acetate, an additional sample was obtained as a colorless solid, m.p. was 226-228 ° C.

An analytical sample was prepared by recrystallization of the sample from dimethylformamide to give colorless prisms, m.p. 227-229 ° C.

To a cooled (10 ° C) stirred solution of 10.0 g (0.04 mol) of 2-methylamino-5-phenyl-3H-1,4-benzodiazepine in 100 ml of pyridine was added 100 ml of saturated nitrosyl chloride. acetic anhydride solution. The solution was stirred for 3.5 hours during which time it was allowed to warm to room temperature. The solution was poured into 300 ml of ice water, and the aqueous solution was extracted five times with 150 ml portions of methylene chloride. The combined organic extracts were washed with water and brine, dried (CaSO 4), and the solvent removed in vacuo to give a dark, semi-solid. Chromatography on 500 g of silica gel (chloroform elution) gave 2- (N-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine, m.p. 192-199 ° C (dec.). This substance was used in the following step:

The nitromethane conjugate base was prepared by treating 500 ml of nitromethane in 200 ml of dimethylformamide with 5.7 g (0.05 mol) of potassium tert-butoxide. The resulting stirred yellow suspension was treated with 10.9 g of crude 2- (N-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine in 100 mL of demethylformamide. The dark mixture thus obtained was stirred for 2 hours at 25 ° C and for one hour at 85 ° C and then cooled to 25 ° C and poured into a liter of water. The aqueous solution was oxygenated, extracted with four 250 mL portions of methylene chloride, and the combined organic extracts were then washed with water and brine, dried (CaSO 4), and concentrated in vacuo to give a dark oil which was purified by chromatography on 1 kg of silica gel (elution). CHCl 3) to give crude 1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine, m.p. 131-142 ° C.

Analytical sample, m.p. 141-142 ° C, prepared by recrystallization from ethanol.

A mixture of 8.4 g (0.03 mol) of 1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine, 75 ml of tetrahydrofuran, 75 ml of methanol and 2 teaspoons of Raney nickel, hydrogenated at atmospheric pressure for 6 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness to leave crude 2-aminomethyl-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine.

This material was dissolved in 50 ml of methylene chloride and treated with a mixture of 6 ml of acetic anhydride and 35 6 3 2 3 4 200 ml of saturated aqueous sodium hydrogencarbonate solution with stirring for 15 minutes. The methylene chloride layer was separated, washed with hydrogen carbonate solution, dried and evaporated to dryness. The residue was treated with 25 g of polyphosphoric acid at 130-150 ° C for 15 minutes. The cooled reaction mixture was treated with a mixture of water and ether. The aqueous phase was basified with ammonia and extracted with methylene chloride. The extracts were dried and evaporated to dryness. Chromatography of the residue on 70 g of silica gel with 20% (v / v) ethanol in methylene chloride gave 3a, 4-dihydro-1-methyl-6-phenyl-3H-imidazole-1,5-αβ. .47benzodiazepine as a pale yellow resin.

This material was heated to reflux in 50 mL of toluene with 7 g of active manganese dioxide for 1 1/2 hours. The inorganic material was filtered off and the filtrate was evaporated to dryness. The residue was purified by chromatography on 30 g of silica gel using 10% ethanol in methylene chloride. The pure fractions were combined and evaporated to dryness. Crystallization of the residue from ether gave 1-methyl-6-phenyl-4H-imidazo [1,5-d] ZZ / 47benzodiazepine.

Example 14 8-Chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a], 4-benzodiazepine dihydrochloride To a stirred solution of 6 g (0, 02 moles) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-methyl-2H-1,4-benzodiazepin-2-one in 100 ml of dry tetrahydrofuran, 1.05 g (0 , 25 moles) of 57% sodium hydride mineral oil dispersion. The mixture was kept under argon and heated to reflux for 1 hour. After cooling to room temperature, the mixture was treated with 7.4 g (0.03 moles) of dimorpholinophosphinic acid chloride and stirring under argon was continued at room temperature for 2 hours.

The mixture was filtered and evaporated to dryness in vacuo to give a resinous residue. Mixing the resin with 100 ml of dry ether gave white crystals which were filtered, washed with a small amount of ether and air dried. The 7-chloro-2-di- (morpholino) phosphinyloxy-5- (2-fluorophenyl) -3-methyl-3H-1,4-benzodiazepine thus obtained m.p. was 90-95 ° C.

To a stirred solution of 2.4 g (0.04 mol) of nitromethane in 50 ml of dry dimethylformamide was added 1 g (0.024 mol) of a 57% dispersion of sodium hydride mineral oil at room temperature under argon. After stirring for 1 hour at room temperature, 5.2 g (0.01 mol) of 7-chloro-2-di (morpholino) -phosphinyloxy-5- (2-fluorophenyl) -3- ii-ethyl-3H-1,4-benzodiazepine, and stirring under argon was continued at room temperature for 24 hours. The dark mixture was poured with stirring into a mixture of ice and glacial acetic acid to give a yellow solid. Stirring was continued until the ice had melted. The solid was filtered off, washed with water and air dried in a funnel to give 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-methyl-2-nitromethylene-2H-1,4-benzodiazepine, m.p. was 215 ° C (dec.). Recrystallization of a sample of this from a 1: 1 mixture of methanol / methylene chloride gave yellow needles, m.p. 219-221 ° C (dec.).

A solution of 5.2 g (0.015 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-methyl-2-nitromethylene-2H-1,4-benzodiazepine in 450 ml of tetrahydrofuran / methanol mixture was hydrogenated for 3 hours using a Parr apparatus, Raney nickel catalyst (3 teaspoons) and an initial pressure of 1.3 kp / cra. The mixture was filtered and evaporated to dryness in vacuo to give crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -3-methyl-1H-1,4-benzodiazepine as a yellow oil.

The crude aminomethyl compound was mixed with 5 ml of triethyl orthoacetate and 0.5 g of p-toluenesulfonic acid monohydrate in 100 ml of ethanol. After heating at reflux for 2 hours, the solution was evaporated to dryness in vacuo. The residue was cooled to room temperature, treated with a mixture of ice and concentrated ammonium hydroxide, and extracted with methylene chloride. Evaporation of the dry extracts to dryness in vacuo gave crude 8-chloro-3a, 4-dihydro-1,4-dimethyl-6- (2-fluorophenyl) -3H-imidazo [1,5-a] N- [3,4-benzodiazepine as a resin.

The crude dihydroimidazobenzodiazepine was mixed with a mixture of 20 g of activated manganese dioxide and 200 ml of toluene and the mixture was heated at reflux for 2 hours. The mixture was filtered and the manganese dioxide was washed with methylene chloride. Evaporation of the combined filtrate and washings to dryness in vacuo gave a brown resin. 8-Chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo-C5-5-a [7Z] -1,4-benzodiazepine dihydrochloride was obtained as a white powder by stirring the resin with ethanolic hydrochloric acid for a few minutes. The salt melted at 247-250 ° C.

37 63234

Example 15 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,47] benzodiazepine

A mixture of 100 g (0.8 moles) of chloroacetaldehyde dimethyl acetal and 100 ml of 1.5 N hydrochloric acid was heated by redistillation for 15 minutes and then cooled and added to a solution of 130 g (0.5 moles) of ) 2-amino-2'-fluoro-5-nitrobenzophenone and 46 g (0.28 mol) of hydroxylamine sulphate and one liter of ethanol. The mixture was stirred at room temperature for 2 hours and then refluxed for 1.5 hours. The mixture was cooled and the product was recovered by filtration. Recrystallization from a mixture of chloroform and methanol gave pure 2-chloromethyl-4- (2-fluorophenyl) -6-nitro-1,2-dihydroquinazoline-3-oxide as yellow prisms, m.p. 220-224 ° C.

A solution of 142 g (0.423 moles) of 2-chloromethyl-4- (2-fluorophenyl) -6-nitro-1,2-dihydroquinazoline-3-oxide in 2.3 liters of dichloromethane was treated with 400 g of manganese dioxide, and when the solution was stirred for 18 hours, filtered. The manganese dioxide was washed with 600 ml of tetrahydrofuran and 800 ml of dichloromethane. The combined filtrates were concentrated to 400 ml, and to this was added a liter of ether. This mixture was cooled and filtered to give 2-chloromethyl-4- (2-fluorophenyl) -6-nitroquinazoline-3-oxide. A sample of this was recrystallized from a mixture of dichloromethane and methanol to give the pure product as pale yellow prisms, m.p. 127-130 ° C.

To a mixture of 500 ml of dimethyl sulfoxide and 75 ml (1.4 moles) of nitromethane was added, with stirring and under nitrogen, 15.6 g (0.678 moles) of lithium amide. After 30 minutes, the solution was cooled to 5 ° C and 104 g (0.31 mol) of 3-chloromethyl-4- (2-fluorophenyl) -6-nitroquinazoline-3-oxide was slowly added, maintaining the temperature at 8 ° C: below. After 68 hours at room temperature, the reaction mixture was poured into a mixture of 2.5 liters of ice and water and 25 ml of acetic acid, and the solution was filtered. The resinous precipitate was dissolved in a liter of dichloromethane, washed with dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ethyl acetate to give 1,3-dihydro-5- (2-fluorophenyl) -7-nitro-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide, and the filtrates were evaporated to dryness, dissolved in dichloromethane and was filtered through a sintered la crucible containing 200 g of Florisil. Florisil was eluted with dichloromethane (600 ml), ether (600 ml) and ethyl acetate (1.2 liters). The ether and ethyl acetate fractions were combined and concentrated to give more final product. A sample of this was recrystallized from a mixture of tetrahydrofuran and hexane to give the pure product as yellow prisms, m.p. 216-220 ° C.

To a suspension of 25 g (0.0698 mol) of 1,3-dihydro-5- (2-fluorophenyl) -7-nitromethylene-2H-1,4-benzodiazepine-4-oxide in 1.3 liters of anhydrous ethanol was added 10 a teaspoon of Raney nickel and the mixture was hydrogenated at atmospheric pressure and room temperature for 9 hours. The mixture was filtered through Celite and the filtrate was evaporated to dryness, a sample of the oil was crystallized from tetrahydrofuran to give 7-amino-2-aminomethyl-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine as a yellow intermediate. as prisms, melting with decomposition at 185-192 ° C.

The oil obtained in the reduction was heated without further purification by refluxing for 2 hours in a solution of 300 ml of absolute ethanol, 4.5 ml (0.0257 mol) of ethanolic hydrochloric acid solution and 50 g (0.309 mol) of triethylorthoacetate. The mixture was then evaporated to dryness and the residue was dissolved in 150 ml of dichloromethane, washed with 100 ml of dilute ammonium hydroxide, dried over sodium sulphate and evaporated to dryness.

The residual oil, crude 8-acetylamino-3a, 4-dihydro-6- (2-fluorophenyl) -1-methyl-3H-imidazoZ-T, 5-α / 1/47-benzodiazepine, was dissolved in 500 ml of: benzene and 100 g of activated manganese dioxide was added to the solution. The mixture was heated to reflux and stirred for 9 hours using a Dean-Stark trap. An additional 25 g of activated manganese dioxide was added and after boiling for 4 hours the manganese dioxide was removed by filtration and washed with 500 ml of tetrahydrofuran. The filtrates were combined and evaporated. The residual oil, 8-acetylamino-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, was dissolved in 75 ml of methanol, and an excess of ethanolic hydrochloric acid was added to the solution. After 10 minutes, 100 ml of water were added, and after a further 20 minutes during which the 8-acetyl group was hydrolyzed, a mixture of ice and dilute ammonium hydroxide was added until the solution was basic. The reaction mixture was filtered and the precipitate and filtrates were extracted separately with dichloromethane. Extracts 39,63234 were dried and evaporated to dryness. The extract from the filtrates was crystallized from isopropanol to give 8-amino-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-b] 4,7-benzodiazepine-isopropanol and the precipitate extract was chromatographed through Florisil, first with dichloromethane. and then ether and ethyl acetate with 10% (v / v) methanol to give, after evaporation to dryness and crystallization from isopropanol, more product. Recrystallization of the combined products from isopropanol gave the product as white rods, m.p. 135-145 ° C.

To a mixture of 0.1 g (0.000273 moles) of 8-amino-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5] a7, 4-benzodiazepine-isopropanol and 5 ml of water , 1 ml of concentrated hydrochloric acid was added. The reaction mixture was cooled in an ice bath and 0.15 g (0.00217 mol) of sodium nitrite was slowly added with stirring. After 1 hour, the reaction mixture was poured into a solution of 0.2 g (0.00202 moles) of cuprous chloride in 50 ml of water heated to 70 ° C. After 18 hours, the reaction mixture was basified with sodium hydroxide, extracted with dichloromethane (2 x 50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The residue was run on a plate with a thick layer of silica gel using a mixture of ethyl acetate and methanol (10/1) as eluent. The product with an Rf value of 0.7 was scraped off the plate, mixed with methanol and filtered. Evaporation of the crude product to dryness and crystallization from a mixture of ethyl acetate and ether gave (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-1-iroidazolyl) -5-chlorophenyl] methanone as white prisms, m.p. and the melting point of the mixture with the authentic sample was 159-166 ° C.

A solution of 0.5 g (0.00145 moles) of (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-1-imidazolyl) -5-chlorophenyl] -methanone in 25 ml of dichloromethane was treated with 0.15 ml (0.00155 moles) of phosphorus tribromide in an ice bath and, after standing for one hour at room temperature, poured into 50 ml of liquid ammonia. After evaporation of the ammonia, the reaction mixture was partitioned between 50 ml of dichloromethane and water-soluble portions. The organic phase was separated and dried over anhydrous sodium sulfate. The solution was concentrated and the residue was applied to two plates with a thick layer of silica gel and eluted with a mixture of ethyl acetate and 10% methanol.

40 63234

The compound with an Rf value of 0.6 was scraped off, mixed with methanol and filtered. The solution was treated with 0.1 g (0.000962 moles) of maleic acid and evaporated to dryness. The remaining salt was crystallized from a mixture of isopropanol and ether to give 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo-IX15-§7ΖΪ, 47benzodiazepine as white prisms, m.p. and the melting point of the mixture with the authentic sample was 112-115 ° C (melting point of the saccharified product). The base was obtained by dividing the salt into dichloromethane and water-soluble portions, adjusting the pH, separating the layers and evaporating the organic phase to dryness. Crystallization of the product from ether gave white prisms, m.p. and the melting point of the mixture with the authentic sample was 154-157 ° C.

Example 16 8-Ethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,47] benzodiazepine

A solution of 56.4 g (0.20 mol) of 1,3-dihydro-7-ethyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 2.0 liters of tetrahydrofuran , containing 4 moles of monomethylamine, was cooled in an ice bath. To this was added 33.0 ml (0.30 mol) of titanium tetrachloride in 350 ml of benzene. The mixture was stirred at room temperature for three days.

Titanium tetrachloride was decomposed in 100 ml of water. Inorganic salts were removed by filtration. The filtrate was evaporated to dryness in vacuo. The residue was partitioned between methylene chloride and water. The methylene chloride layer was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was obtained from acetonitrile by crystallization of 7-ethyl-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine as pale yellow prisms, m.p. 172-174 ° C.

An analytical sample was prepared by recrystallization from acetonitrile to give pale yellow prisms, m.p. 172-174 ° C.

Sodium nitrite (8.6 g, 0.125 mol) was added in three portions over 1/2 hour to a solution of 29.5 g (0.1 mol) of 7-ethyl-5- (2-fluorophenyl) -2-methylamino-3H- 1,4-benzodiazepine in 100 ml of glacial acetic acid. After stirring for another 1/2 hour at room temperature, the mixture was diluted with ice water and extracted with ethylene chloride. The extracts were washed with water and aqueous bicarbonate, dried over sodium sulfate and evaporated to dryness to leave crude 7-ethyl-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine as a yellow oil.

41 63234 This material was dissolved in 100 ml of dimethylformamide, and the solution was added to a mixture of 100 ml of dimethylformamide, 35 ml of nitromethane, and 9.9 g of potassium tert-butoxide, which was stirred for 1/2 hour at room temperature. After the addition was complete, the reaction mixture was stirred for 1 hour at room temperature and for 30 minutes in a water bath. The cooled solution was acidified with glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts were washed with water, dried and evaporated to dryness. The residue was dissolved in 50 ml of ethanol, and after crystallization, the mixture was allowed to crystallize overnight in a refrigerator. The yellow crystals were collected and recrystallized from ethanol to give 1,3-dihydro-7-ethyl-5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine, m.p. 138-140 ° C. Seed crystals were obtained by chromatography of the crude product with a 40-fold amount of silica gel using a 5% (v / v) mixture of ethyl acetate and methylene chloride. An analytical sample was recrystallized from ether-tert-hexane, m.p. 138-141 ° C.

1,3-Dihydro-7-ethyl-5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine (2.6 g) was hydrogenated for 4 hours on Raney nickel (1 teaspoon) in 30 ml of ethanol. . The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in ether and the amine was extracted with 10% aqueous acetic acid. The extracts were washed with ether and basified with ammonia. The precipitated amine was extracted with methylene chloride. The extracts were dried and evaporated to dryness to leave 1.5 g of crude 2-aminomethyl-2,3-dihydro-7-ethyl-5- (2-fluorophenyl) -1H-1,4-benzodiazepine. This material was dissolved in 50 mL of xylene. To the solution was added 3 ml of triethyl orthoacetate, and then it was heated under reflux for 2 hours. The residue obtained after evaporation to dryness in vacuo was chromatographed on 50 g of silica gel using 20% methanol in methylene chloride. The homogeneous fractions were combined and evaporated to dryness to give 3a, 4-dihydro-8-ethyl-6- (2-fluorophenyl) -1-methyl-3H-imidazo [1,5-a] N, 4,7-benzodiazepine. This material was dissolved in 50 ml of toluene, and 5 g of activated manganese dioxide was added to the solution, and the mixture was heated under reflux for 1 hour. The inorganic material was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in ether and the solution was treated with ethanolic hydrochloric acid and acetone. The crystalline dihydrochloride was collected (m.p. 248-255 °) and converted back to 42 6 3 2 3 4 by treatment with a mixture of methylene chloride and aqueous ammonia. The methylene chloride layer was dried and evaporated to dryness. Crystallization of the residue from ether / hexane gave 8-ethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, m.p. 152-154 ° C.

Example 17 8-Chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,147] benzodiazepine A) To a stirred solution of 27.8 g (92 mmol) of d1-2-aminomethyl -7-Chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine in a mixture of 450 ml of methylene chloride and 300 ml of acetic acid was slowly added to 27.8 g of zinc dust. After stirring at room temperature for 4 hours, the reaction mixture was filtered through Celite. The filtrate was diluted with ice water, basified with 50% potassium hydroxide solution and extracted with methylene chloride. The organic extract was separated, dried and evaporated to dryness in vacuo. The residue was crystallized from ether to give 2-aminomethyl-7-chloro-2,3,4,5-tetrahydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine, m.p. 119-120 ° C. . Recrystallization from ether gave the pure product as slightly yellowish prisms, melting at 127-128 ° C.

The hydrochloride was prepared by treating a solution of the base in isopropanol with excess concentrated hydrochloric acid. After recrystallization of the salt from a mixture of water and isopropanol, the pure product was obtained as yellowish needles melting at 268-271 ° C.

B) A solution of 3 g (10 mmol) of ras. 2-Aminomethyl-7-chloro-2,3,4,5-tetrahydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine in a mixture of 30 ml of xylene and 10 ml of triethylorthoacetate (97 -%), boiled for 4 hours. The reaction mixture was diluted with ether and extracted with dilute ice-cold hydrochloric acid. The acidic extract was made alkaline with dilute potassium hydroxide and extracted with methylene chloride. The organic layer was separated, dried and evaporated to dryness in vacuo. The residue was crystallized from ether to give 8-chloro-6- (2-fluorophenyl) -3a, 4,5,6-tetrahydro-1-methyl-3H-imidazo [1,5-a] 1,4-benzodiazepine (Isomer A). melting at 187-189 ° C. Recrystallization from a mixture of methylene chloride and ether gave the pure product as yellowish prisms, melting at 189-190 ° C.

43 63234 C) A mixture of 2.9 g of 8-chloro-6- (2-fluorophenyl) -3a, 4,5,6-tetrahydro-1-methyl-3H-imidazo [1,5-q] [X, 47 Benzodiazepine, 90 ml of toluene and 15 g of activated manganese dioxide were stirred at reflux for 2 hours. The reaction mixture was filtered through Hyflo and the filtrate was evaporated to dryness in vacuo. The residue was crystallized from ether to give 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] 2Z / 47benzodiazepine, the melting point of which did not decrease as a mixture with an authentic sample.

Example 18 6- (2-Fluorophenyl) -1-methyl-4H-imidazo-β, 5-α7q, 4-benzodiazepine

A solution of 2.9 g (0.00927 moles) of 2,3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-1H-1,4-benzodiazepine-4-oxide in a mixture of 1 teaspoon of Raney nickel, 90 ml of tetrahydrofuran and 45 ml of methanol were hydrogenated at atmospheric pressure and room temperature for 2.3 hours. The mixture was filtered and the nickel was washed with dichloromethane. The combined filtrates were evaporated to dryness and the resulting oil was dissolved in 50 ml of dichloromethane washed with 50 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulphate and evaporated to dryness, a solution of 2.2 g (0.019 mol) of maleic acid was added to the oil. in ethanol and after addition of ether, 2-arainomethyl-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine dimaleate hemihydrate crystallized. Recrystallization from a mixture of methanol and ether gave the product as yellow rods, m.p. 147-150 ° C.

A solution of 4.0 g (0.0149 moles) of 2-aminomethyl-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine dimaleate hemihydrate base in 125 ml of anhydrous ethanol, treated with 4 g (0.0247 moles) of triethyl orthoacetate and 0.5 g (0.00263 moles) of p-toluenesulfonic acid. After boiling the reflux mixture for 2 hours, it was evaporated to dryness. The resulting oil was dissolved in 50 mL of dichloromethane, washed with 50 mL of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness to give crude 3a, 4-dihydro-6- (2-fluorophenyl) -1-methyl-3H -imidazo / 1,5-a7 β · 4_7benzodiazepine as an oil.

A) The crude product mentioned in the previous paragraph was dissolved in 100 ml of toluene, treated with 18 g of activated manganese dioxide, and the mixture was stirred and boiled for 3.5 hours using a Dean-Stark trap. The reaction mixture was filtered through Celite and the precipitate was washed with 100 mL of tetrahydrofuran and then with 100 mL of dichloromethane. The combined filtrates were evaporated to dryness and the residue was dissolved in 25 ml of dichloromethane. This solution was chromatographed through a Florisil column with dichloromethane and then eluted with ether. Elution with ethyl acetate followed by 10% (v / v) ethyl acetate in methanol gave the crude product which was recrystallized from ether and then recrystallized from ethyl acetate to give 6- (2-fluorophenyl) -1-methyl-4H-imidazo. / 1,5-g7 / 1,4-benzodiazepine as white prisms, m.p. 164-168 ° C.

B) A solution of 1.2 g (0.0041 mol) of 3a, 4-dihydro-6- (2-fluorophenyl) -1-methyl-3H-imidazo [2H, 5,747,19,4] benzodiazepine in 50 ml: mesitylene and 0.5 g of 10% palladium / charcoal catalyst were stirred at reflux for 28 hours, then the solution was filtered and evaporated to dryness. Crystallization from ethyl acetate gave 6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-d] benzodiazepine as white prisms, m.p. 162-167 ° C; and when mixed with an authentic sample, the melting point was 162-168 ° C.

Example 19 1-Methyl-6-phenyl-4H-imidazo [1,5-a] thieno-R., 3-f-diazepine

A mixture of 10 g (0.036 mol) of 1,3-dihydro-5-phenyl-2H-thieno [3,2-e] [4,7] diazepin-2-one in 50 ml of benzene and 300 ml of tetrahydrofuran was stirred. in an ice bath and saturated with methylamine gas. To this mixture was added dropwise a solution of titanium tetrachloride (9.48 g, 0.05 mol) in 50 ml of benzene. After the addition was complete, the mixture was stirred in an ice bath for 15 minutes. The ice bath was then replaced with a blanket and the mixture was refluxed for 1/2 hour. The mixture was cooled and 100 g of ice was carefully added. The mixture was filtered and the residue was washed with tetrahydrofuran. The filtrates were combined, dried and evaporated to dryness. The product was crystallized from methylene chloride to give 2-methylamino-5-phenyl-3H-thieno [1,2-e] [1,4] diazepine, m.p. 223-227 ° C. Additional product was obtained from the concentrated mother liquors, m.p. 222-225 ° C. An analytical sample was recrystallized from methylene chloride, m.p. 222-229 ° C.

The nitrosyl chloride was introduced into a solution of 7.8 g (0.03 mol) of 2-methylamino-5-phenyl-3H-thieno [1,2-e] / 1,47diazepine in 100 ml of methylene chloride and 40 ml of pyridine, which was cooled. an ice water bath. The reaction was monitored by plate chromatography and upon disappearance of the starting material, the addition of nitrosyl chloride was stopped and the reaction mixture was partitioned between methylene chloride and water. The methylene chloride solution was dried and evaporated to dryness. Crystallization of the residue from methylene chloride / hexane gave 2- (N-nitrosomethylamino) -5-phenyl-3H-thieno / 3,2-e7Z3,4-diazepine as yellow crystals, m.p. 156-159 ° C. An analytical sample was recrystallized from ether / hexane, m.p. 158-160 ° C.

2- (N-Nitrosomethylamino) -5-phenyl-3H-thieno [3,2-e] [4,7] diazepine (5.7 g, 0.02 mol) was added to a mixture of 15 ml of nitromethane, 4 , 5 g of potassium tert-butoxide and 60 ml of dimethylformaride stirred for 10 minutes at room temperature. After the addition, the reaction mixture was stirred under nitrogen and heated on a water bath for 10 minutes. After acidification with 4 ml of glacial acetic acid, the mixture was partitioned between methylene chloride / toluene and saturated sodium bicarbonate solution. The organic layer was washed with water, dried and evaporated to dryness. Crystallization of the residue from methanol using seed crystals gave 1,2-dihydro-2-nitromethylene-5-phenyl-3H-thieno [3,2-e] -7,4-diazepine as yellow crystals, m.p. 160-163 ° C. The seed crystals were obtained by chromatographic purification on 30 times silica gel using 10% (v / v) ethyl acetate-methylene chloride as eluent. An analytical sample was recrystallized from methanol, m.p. 163-164 ° C.

A solution of 1.42 g (5 mmol) of 1,2-dihydro-2-nitromethylene-5-phenyl-3H-thienoZ3,2-e7T1 / 4-7diazepine in 200 ml of ethanol was hydrogenated using Raney nickel. (2 teaspoons) for one hour at atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was treated with a solution of 1.2 g of maleic acid in 10 ml of 2-propanol. The salt was crystallized by the addition of ether to give 2-aminomethyl-2,3-dihydro-5-phenyl-1H-thieno [3,2-e] [1,4] diazepine dimaleate as yellow crystals, m.p. 170-173 ° C. An analytical sample was recrystallized from methanol / 2-propanol, m.p. 187-189 ° C.

2-Amino-2,3-dihydro-5-phenyl-1H-thieno [3,2-e], 4-diazepine dimaleate (1 g, 2 mmol) was partitioned between methylene chloride and aqueous ammonia. The methylene chloride layer was dried and evaporated to dryness. The residue was heated to reflux for 1 hour with 1 ml of triethyl orthoacetate in 20 ml of xylene. The solvent was evaporated in vacuo and the residue was crystallized from 2-propanol / ether to give 1-methyl-3a, 4-dihydro-6-phenyl-3H-imidazo [1,5-a] thieno [2,3-f] diazepine, m.p. . 150-152 ° C. This material was heated to reflux in 30 mL of toluene with 2 g of activated manganese dioxide for 2 hours. The manganese dioxide was filtered off and washed well with methylene chloride. The filtrate was evaporated to dryness and the residue was chromatographed on 7 g of silica gel eluting with 3% (v / v) ethanol in methylene chloride. The fractions containing pure product were combined and evaporated to dryness. Crystallization from methylene chloride / ether and recrystallization from ethyl acetate / hexane gave 1-methyl-6-phenyl-4H-imidazo [1,5-a] thieno [2,3-f] diazepine, m.p. 223-225 ° C.

Example 20 8-Chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] thieno [3,2-f] 2Z'-diazepine

A mixture of 7.7 g (0.278 mol) of 7-chloro-1,3-dihydro-5-phenyl-2H-thieno [2,3-e] ZJ, 47-diazepin-2-one, 50 ml of benzene and 250 ml of tetrahydrofuran, stirred in an ice bath and saturated with methylamine gas. To this mixture was added from a dropping funnel a solution of titanium tetrachloride (7.38 g, 0.0389 moles) in 50 mL of benzene. After the addition was complete, the mixture was stirred in an ice bath for 15 minutes. The ice bath was then replaced with a heating mantle and the reaction mixture was boiled for 20 minutes. The mixture was cooled and 100 g of ice was carefully added. The mixture was then filtered and the residue was washed with tetrahydrofuran. The filtrates were combined, dried and evaporated to dryness. The residue was crystallized from methylene chloride / ether to give 7-chloro-5-phenyl-2-methylamino-3H-thieno [2,3-e] -1,4,7-diazepine, m.p. 246-249 ° C. An analytical sample was recrystallized from methylene chloride, m.p. 247-250 ° C.

The nitrosyl chloride was introduced into a solution of 5.8 g (0.02 moles) of 7-chloro-5-phenyl-2-methylamino-3H-thieno [R, 3-e] E, k] -diazepine in 100 ml of methylene chloride. and 50 ml of pyridine until the reaction was complete as determined by plate chromatography. The mixture was partitioned between water and toluene. The organic phase was dried and evaporated to dryness. Crystallization of the residue from ether / hexane gave 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-thieno [2,3-e] -1,4,7-diazepine as yellow crystals, m.p. 108-110 ° C. For analysis, it was recrystallized from ether / hexane, m.p. 111-113 ° C.

47,63234 7-Chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-thieno [2,3-e] -β, 47β-azepine (3.2 g, 0.01 mol) was added to a mixture of 10 ml of nitromethane, 35 ml of dimethylformamide and 2.26 g (0.02 mol) of potassium tert-butoxide, which had been stirred under nitrogen for 10 minutes at room temperature. After heating the reaction mixture on a water bath for 10 minutes, it was acidified by adding 2 ml of glacial acetic acid and partitioned between water and toluene. The toluene layer was washed with water, dried and evaporated to dryness. The residue was crystallized from ethyl acetate / hexane to give crude 7-chloro-2,3 * dihydro-2-nitromethylene-5-phenyl-1H-thieno [2,3-e] 3,47-diazepine. It was purified by chromatography on 40 g of silica gel, eluting with a 10% (v / v) mixture of ethyl acetate and methylene chloride. The pure product was obtained as yellow crystals, m.p. was 154-156 ° C.

A) A solution of 320 mg (1 mmol) of 7-chloro-2,3 - <- dihydro-2-nitromethylene-5-phenyl-1H-thieno [2,3-q] β, 47diazepine in 20 ml of ethanol hydrogenated using Raney nickel for 5 hours at atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was chromatographed on 7 g of silica gel eluting with methylene chloride, methanol and triethylamine 13: 6: 1. The fractions containing pure product were combined, evaporated to dryness and the residue treated with a 2-propanol solution of maleic acid. Crystallization of the dimaleate salt from 2-propanol / ether and recrystallization from ethyl acetate / ethanol gave 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-thieno [2,3-e] -1, 47diazepine dimaleate as yellow crystals, m.p. 176-177 ° C.

B) A solution of 320 mg (1 mmol) of 7-chloro-2,3-dihydro-2-nitromethylene-5-phenyl-1H-thieno [2 # 3-e] β, 47diazepine in 3 ml of tetrahydrofuran was added to the suspension. containing 0.8 g of lithium aluminum hydride in 20 ml of tetrahydrofuran. After refluxing for 5 minutes, the reaction mixture was cooled and hydrolyzed by adding 5 ml of water. The inorganic material was filtered off and the filtrate was evaporated to dryness. The residue was chromatographed as described above and the pure product was converted to the maleate to give 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-thieno [2/3-ey] [T, 47] diazepine maleate, m.p. . 176-178 ° C.

48 63234 2-Aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-thieno [2,3-e] [4,7] diazepine maleate (0.52 g, 1 mol) was partitioned between methylene chloride and aqueous ammonia. soluble parts. The methylene chloride solution was dried and evaporated to dryness. The residue was heated to reflux for 1 hour with 0.5 ml of triethyl orthoacetate in 10 ml of xylene. The crude product obtained after evaporation to dryness in vacuo was dissolved in 25 ml of toluene, and 2.5 g of activated manganese dioxide was added to the solution, and the solution was heated under reflux for 1 1/2 hours. The manganese dioxide was then filtered off and the filtrate was evaporated to dryness. The residue was chromatographed on 6 g of silica gel eluting with 4% (v / v) ethanol in methylene chloride. Fractions containing pure compound were combined and evaporated to dryness. Crystallization of the residue from ether / hexane gave 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] thieno [3,2-f] [3,4-diazepine, m.p. 168-170 ° C.

Claims (3)

1. A process for the preparation of therapeutically useful 6-phenyl-4H-imidazo [1,5-a7], 47-diazepine compounds of the general formula [alpha], [ix] is a lower alkyl group, R 2 and R R is a hydrogen or halogen atom, and the grouping a is al JÖC b> x [lX 'or c) * 4 where R 2 is a hydrogen or halogen atom or a lower alkyl group, and X is a hydrogen or chlorine atom, and of pharmaceutically acceptable acid addition salts of these compounds, characterized in that a) a compound of the general formula R, tn7 <h 2 R 3, R 2, X and 0C denote the same as dehydrated to the corresponding compound of formula I, with the aid of magnesium dioxide, palladium / carbon or potassium permanganate, or b) a compound of formula R 1, R 2 where X, R R, R₂, R,, X and (Z acid, silver oxide, selenium dioxide, mercury (II) acetate, mercury (II) oxide, manganese dioxide, iron (III) chloride or jam (III) cyanide, or c) a compound of the general formula -L s' * XXV R '' C: -O rV where R, R 2, R 2 and R 2 are the same as above, and R 4 is a chlorine or bromine atom, cyclized to the corresponding compound of formula I, whereupon d) if desired, a racemic compound is dissolved in its optically active enantiomers, and / or e) if desired, a compound of formula I is converted to a pharmaceutically acceptable acid addition salt. 2. A process according to claim 1 for the preparation of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a], benzodiazepine or its maleate, characterized in that the starting material is used as a starting material. a compound of formula VII or VII1, where Z is the group of C, R 4 R is a fluorine atom, R 2 is a methyl group, R 2 and R 3 are hydrogen atoms and R 2 is a chlorine atom, or a compound of formula XXV, wherein R is a fluorine atom , R 2 is a methyl group, R 2 and R 2 are hydrogen atoms and R 2 is a chlorine atom. 3. A process according to claim 1 for the preparation of 8-chloro-6- (2-fluorophenyl) -1,4-dimethyl-4H-imidazole, 5-a7ΖΪ, 47 47 bonsodiazepine or its maleate, characterized in that starting material uses a compound of formula VII or VII 'where Z is grouping