CA2106387A1 - Benzodiazepinones - Google Patents

Abstract

Novel benzodiazepinones of formula (I) wherein X is Cl or CH3, and compositions containing same for alleviation of viral infections, including HIV infections.

Description

2 ~ a 6 3 8 7 PCr/EP93/00352 Benzodiazepinones and medlclnes conta1n~n~ them The present invention relates to benzodiazepinones of formula XJ~N

N--NH
wherein X is ~1 or C~3, and pharmaceutically acceptable salts.

Objects of the present invention are Ihe above compounds per se and for use as a therapeutically active agent, especially for the o treatment or prophylaxis of viral infeetions, particularly of retroviral infections, sueh as HIV 1 and/or HIV 2 infections, or for protecting cells against such i~fecdons;
furthcr a process for the manufacture of these compounds and ~
medicaments containing one of such compounds and, optionally, a -15 second antiviral agent, cspecially a reversc transcripusc inhibitor, sueh as ddC, AZI or ddI, TIBO derivatiws, trieyelie diazepinones, a HIV-protease inhibitor, a-, ~- and/or y-interferon, interleukin-2 and/or GM-CSF, and the use of these eompounds for the manufaeture of medicaments 20 espeeially for the treatment or prophylaxis of viral infeetions, partieularly of retroviral infeetions, such as HIV 1 and/or ~IV 2 infcctions, or for proteeting cells against sueh infections.
All the tautomerie and stereoisomerie forrns of the eompounds of formula I are ineluded in the seope of this invention.
2S- Pharmaeeutieally aeeeptable salts may be those with organie acits, e.g. Iaetie, aeetie, malie or p-toluenesulfonie acid; or salts with mineral aeids, sueh as hydroehlorie or sulfuric aeid.
Mé/8.2.93 -..: ~:, ....
:,., :,, SUBSTITUTE SHEET
.:', ` ` . ' wos3/l70l0 ~ ~ 6~7 - 2 - Pcr/EPg3/oo3s2 The compounds of the invention can be prepared in a manner known per se, e.g. as described in US 3405122, 3398159, 3407211 and 3400128; in J. Org. Chem. 41, 1976, 2720; 35, 1970, 2455 and 46, 1981, 839; in Acta Chem. Scan. B 31, 1977, 701, in J. Heterocyclic 5 Chem. 12, 1975, 49 and 25, 1988, 1293; in Synthesis 1988, 767- in Syn. Commun. 15, 1985, 1271 and J.A.C.S. 100, 1978, 4842.

Thus the compounds of the invention c~n be prepared by cyclizing a compound of formula XJ~o V

N--NH
wherein X is as above, - ~;by acid-catalysis.
lS
This cyclization can be performed by heating the compound V
with an acid, such as pivalic acid, in a solvent, such as toluene and THF, or in n-butanol, at a temperature up to reflux temperature. - -The amines V can be prepared via the corresponding bromides IV

N J~ Br ~ IV ~

N--NRs 2S starting from ketones of formula III

SUBSTITUTE SHEET

... - , ,.. - . , .. .. ,, . , :. . . . ~ ;.. : .

wo 93/17010 3~ 1 0 6 3 8 7 Pcr/EP93/003s2 ,~ NR3R~
x~ III
~ ~ .
N--NRs wherein X is as above and R3, R4 and R5 are H or a N-protecting s group.

Suitable N-protecting groups include triphenylmethyl, acyl, trialkylsilyl, alkyldiarylsilyl, ethoxymethyl, (dialkylamiDo)methyl, t-butoxycarbonyl and phenoxycarbonyl. A preferred method for 10 performing the reaction III ~ IV ) V involves bromoacetylation of a ketone III to the bromide IV, followed by ammonolysis to the amine V.

The ketones III can bc prepared by reacting a metallo~
lS heterocycle of formula VI -. ~ -, ~: whcre Z is the same R5 substituted pyrazolyl group as in the compounds of formulae III and IV above, except that one or both hydrogens on the C-atoms in this pyrazolyl group may be - rcplaccd by an unrcactive blocking group; and R6 is a metal or a :~ metallic halide group, such as MgBr, MgCI, Li, Na or Sn, .
with an aromatic compound of formula VII

NR~R9 ~ il' VII
X '--where R7 is formyl or a functional derivative of a carboxylic acid~ ;
such as cyano, ester, amide or acyl chloride, X is as above and R8 ,' , ~ . :

~ SUBSTITUTE SHEE~ -:

WO 93/17010 2 ~ G 3 3 7 Pcr/Ep93/003S2 -;

and R9 are H, O, acyl, trialkylsilyl, alkyldiarylsilyl or t-butoxy-carbonyl.

In formula VI above, preferable unreactive blocking groups s include halogen, S-lower alkyl, S-aryl, trialkylsilyl and alkyldiarysilyl.
When R7 is formyl, an alcohol of forrnula VIII is genera~ed -~o Nf~R9 ~ .
¦I VIII
~,OH

:
~vhere X. Z, R8, and R9 are as defined above.

When R7 in formula VII is other than formyl, a ketone of formula IX is obtained ~ NR~R9 xJ~o IX
Z : -where X, Z, R8 and R9 are as defined above.

The conversion of VIII to lX can be accomplished by oxidation a:,~, e.g. catalytic oxydation or reaction with active rnaganese dioxide.

Compound IX is then converud to the desired compound of formula III using conventional methods, e.g, as described in the ~ 2S E~camples.

- Similarly, a compound of formula VI is reacted with a compound, of formula X

,. ' : ~.

' F
~ -~ SUBSTITUTE SHEET

wo 93/17010 ,~ Pcr/Ep93/oo3s2 - S -210b~ l ~N~,CH3 X~O
O
where X is as above, to generate the desired ketone IX wherein R8 is H and R9 is acetyl.
The compounds I and their salts have useful antiviral, especially anti-retroviral activity, particularly ~gainst HIV, the virus implicated in the development of AIDS and related diseases such as ARC (AIDS
related complex). These compounds also inhibit HIV replication by lo inhibiting such important HIV viral functions as TAT (transactivating transcriptional) activity.

The compounds of formula I were tested for anti-HIV-TAT
activity in an assay comprising the following steps:
IS (a) putting botb, the expression of thc Secreted Alkaline Phosphatase (SeAP) gene and the viral transactiYator TAT gene under the control of the HIV promoter LTR responsive to the acdon of the HIV transactivator TAT;
(b) transfecting cultured mammalian cells with plasmids which ;
20 contain the gene constructs of (a) above and cause cellular production of the transactivating factor~ TAT and SeAP;
(c) adding the agent to be tested, here the compounds of formula I; and determining the amount of SeAP produced, by measuring SeAP ~ - -enzymatic activity, wbereby inhibition of SeAP production correlates 25 with the anti-TAT inhibition activity.
In this assay, the inhibition of SeAP positively correlates with anti-TAT activity. The greater the ability of an agent to inhibit SeAP, ~ ;
the greatcr is its anti-TAT activity.
Specifically, with respect to the results reported below, the anti~
30 HIV-TAT assay was run as follows:

-~.
SUBSTITUTE SHEET
... ..

WO 93/17010 ~ 1 ~) 6 3 ~ 7 PCr/EP93/00352 At 24 hours post transfection 1. 10, ~5 and 50 ~M of a ~est compound of formula I was added to the culture media of COS cells transfected with two plasmids, one containing the reporter gene which codes for SeAP under control of HIV-LTR. and the other 5 containing the HIV-TAT gene also under control of HIV-LTR. The alkaline phosphatase activity of the media was assayed 48 hours after addition of test compound with a colorimetric assay using p-nitrophenylphosphate as the substrate. The anti-TAT activity is measured by the percent inhibition of SeAP gene expression under 10 the control of HIV-LTR versus the percent inhibition of SeAP gene under RSV-LTR, which does not respond tQ TAT.
The results in the Table below show that the compounds of formula I are specific inhibitors of HIV-TAT-regulated gene expression without non-specific cytotoxic effects.
IS The specificity of the compounds of forrnula I as TAT inhibitors was demonstrated with a parallel assay in which the SeAP gene expression is put under control of the Rous sarcoma virus (RSV)-LTR
which does no~ respond to TAT. This assay thus eliminates the possibility that the compounds of formula I are either general 20 cytotoxic agents or inhibit the acdvity of SeAP.
The anti-HIV-TAT activities of the test compounds were determined by measuring the amount of alkaline phosphatase in the supernatant media of cul~ures of cells in which SeAP gene expression was under the control of the HIV LTR promoter. The specific 25 inhibitory activities of the test compounds were calculated according to the formula:
100 [( 1 -A/B) - ( I -C/D)]
wherc A and B are the alkaline phosphatase activites produced by HIV-LTR/SeAP in the presence and absence, respectively, of tes~
30 compound, and C and D are the alk~line phosphatase activities produced by RSV-LTR/SeAP in the presence and absence, respectively, of test compound. The concentrations tested ranged from SUBSTITUTE SHEET

;.. ;, .. ,. , - . . . .. - . , . ....... ~ .;.. , . , . ` :.. , .. . .. ,.... ....- - . ..
, - -- , - ,: ,, ; : ~ , . ~ . . - ., ....................... . , .

..... , - .. . - .. . .. . . . . . , . - .

wo 93/17010 - 7 - 2 :~ ~ 6 3 8 7 pcr/Ep93/oo3s2 1-50 ~M. The results provided are the average of at least three tests.
The test compound was added 24 hours after cells were transfected with the plasmids when SeAP specific mRNA and protein were already present and the protein was very stable. Therefore, 100%
5 inhibition would not be observed with this assay procedure.
Table Product of Anti-HIV-TAT
Example No.
1 High 3 Hi~h 0 With respect to human pa~ients infected with HIV, and patients with symptomatic or asymptomatic HIV infections, an antivirally-effective amount of a compound of forrnula I or a salt thereof is in the range of from about 0.5 to 40 mg/kg, preferably from about 1 to 15 mg/kg, more preferably from about 4 to 10 mg/kg body weight per - -15 day. In unit dosage form, for a 70kg patient, this would be an amount of from about 35 to 2800, prefcrably from about 210 to 3S0 mg per day. This dosagc rnay be administcrcd parcnterally or orally in ODC or morc doses at various intcrYals daily, preferably orally once daily.
The compounds may also be administered with other antiviral I ~-and/or biological response modifiers. For example, the compounds of - formula I may bc administered with known HIV-RT inhibitors such as ddC, AZT, ddI or non-nucleoside RT inhibitors such as TIBO
dcrivativcs or tricyclic diazepinones, or other inhibitors which act 'i!'~',.,'-':': ''"
2S against other HIV proteins such as protease, integrase and RNAaseH, as wcll as with biological modifiers such as a-, ,B- or y-interferon or a combination thcrcof, intcrlcukin-2 and GM-CSF. The dosages of ddC
and AZT used in AIDS or ARC human patients have been published.
When giYen in combined therapy, the other anti-HIV compounds may ~ -30 be giYen at the same time as a compound of formula I or the dosing rnay bc staggered as dcsired. The two (or more) dr,ugs may also be '~
. ' ., .'..

. -'.

~- SUBSTITUTE SHEET :

wo 93/17010 ~'J ~ i 3 ~ 7 - 8 - pcr/Ep93/oo3s2 combined in a composition. Doses of each drug may be less when used in combination than when they are used as a single agent.
It is possible for the compounds of the invention to be administered alone in solution. However, it is preferred that the active s ingredients be administered in a pharmaceutical formulation or composition. These formulations comprise at least one active ingredient together with one or more pharmaceutically acceptable carrier and excipient and may optionally include other therapeutic agents, for example a protease inhibitor. These carriers include those 10 suitable for oral, rectal, nasal, topical, buccal, sublingual, vaginal or parent~ral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
Examples of compositions of the invention are solutions of the active ingredient(s), e.g. in water or saline; capsules, e.g. soft gelatine 1 S capsules; sachets or tablets, each containing a pre-determined amount of the active ingredient, e.g. as granules; solutions or suspensions in an aqueous liquid or in an oil-in-water emulsion or a water-in~oil liquid emulsion. Tablets may include one or more of lactose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium 20 stearate. stearic acid and other excipients, colorants and phannacologically compatible carriers. Formulations suitable for topical administration include lozenges comprising the active ingredient in a flavor, usually sucrose and acacia or tragacanth;
pastilles comprising the active ingredient in an inert basis such as 2S gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising cocoa butter or a salicylate. Formulations suitable for vaginal administration may be 30 presented as pessaries, tampons, creams, gells, pastes, foams or spray formulas. Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions which -~
may contain anti-oxidants, buffers, bacteriostats and solutes which ` render the formulation isotonic with the blood of the intended ' .
, ~ . .
SUBSTITUTE SHEET :; ~

wo 93/l7010 9 2 ;l 0 6 3 ~ 7 Pcr/Ep93/oo3s2 recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example ampules and vials, and may be stored in a 5 Iyophilized condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared from sterile powder, granules and tablets of the kind previously described.
Examp!e I

a) A mixt~are of 4-bromo(1H)-pyrazole ~50.8 g) (described in U.S.
Patent No. ~,~92,163), 1300 ml of CH2CI2, triphenylmethyl chloride (99,5 g) and Et3N (35.3 g) was stirred at room temperature for 24 5 hours. The solution was then extracted with H2O, dried over MgSO4, filtered and evaporated to give a solid residue. Crystallization with -~ -CH2Cl2/Hexane provided white crystals: mp. 190-192C. A second crop was taken to provide a total of 117.3 g (~4%) of 4-bromo-1-(tri-phenylmethyl)- 1 H-pyrazole.
b) A mixture of 4-bromo-1-(triphenylmethyl)-lH-pyrazole (48 g), Et2O (100 ml) and THF (500 ml) were stirred at -78C under a stream of argon. tBul i (160 ml, 1.7M) was added to the mix~ure, and the resultant solution was stirred for 2.5 hours at -78C. At that time, the 25 solution was added to a solution of 2-methyl-6-chloro-4H-3,1 -benzoxazin-4-one (21 g) in THF (500 ml) which had been cooled to -78C. The mixture was allowed to warm to room temperature overnight, and then quenched with saturated NH4CI solution (350 ml). ~;
After dilution with EtOAc (500 ml), the layers were separated, and the ~ -30 organic layer washed with saturated NaCI solution, dried over MgSO4, -filtered and evaporated. The solid residue was combined with THF
(400 ml), MeOH (350 ml), H20 (250 ml) and 10N NaOH (300 ml), and stirred at reflux temperature for 3 hours. After cooling to room ~ -tcmperature, the organic and aqueous phases were separated. The 3S aqueous phase was extracted with Et2O and the combined organic . . .
. .

.
; .
SUBSTITUTE SHEET ^ 7~

, .,, .. , , .~ ;.. , , . - . - . - . - . , - . , .. : .

wo 93/17010 Pcr/EP93/oo3s2 2~3~ o fractions dried over MgSO4, filtered and evaporated to give a foam.
This material was combined with CH2CI2 (I liter) and stirred overnight. After filtration, the filtrate was evaporated to afford 49 g of a viscous yellow oil.
c) To a stirred mixture of the product of b) above, THF (450 ml), CH2CI2 (450 ml), and lN NaOH (1400 ml) were added dropwise at room temperature. The two-phase mixture was stirred at room temperature for 20 minutes. After separation of the layers, the to a~ueous layer was further extracted with CH2CI The organic layers were dried over MgSO4 and evaporated to dryness. The residue was crystallized from THF (100 ml), and hexane (300 ml) to afford 23.~ g of 2-bromo-4'-chloro-2'-[( 1 -triphenylmethyl)- 1 H-pyrazol-4-yl ] -carbonyl]acetanilide. mp. 1 97-200C.
d) To 1 liter of condensed liquid ammonia in a dry-ice bath was added a solution of the product of c), in THF (200 ml). The mixture was stirred overnight and the ammonia allowed to evaporate.
Residual solvent was distilled off. The dried residue was stirred with 20 EtOAc (450 ml) and H2O (600 ml). The product was collected, washed with water and dried to give 18.3 g of a solid.

e ) A suspension of this material in 1 -butanol (600 ml) containing 300 mg of pivalic acid was heated to reflux temperature for 8 hours.
2S Additional portions of 300 mg each of pivalic acid were added after 3 hours and 5 hours. Volatiles were evaporated, and trituration of the dry residue yielded 6.5 g of product. This was dissolved in MeOH
(600 ml), treated with charcoal, filtered and concentrated. The precipitated product was collected to give 5.25 g of 7-chloro-1,3-30 dihydro-5-(lH-pyrazol-4-yl)-2H-1,4-benzodiazepin-2-one, mp.
289-29 ~ C.

SlJBSTITUTE SHEET

.... . . . . .. .. ... .. . .. . . .. . . .. .. .. . . .. . . .. ... .. .. . .

. ~ . . .... . , - . . j .. .. .... . . . . . .

Example 2 The product of Example le) c~n also be prepared as follows:

5 a) The product of Example la) (24 g) was combined with THF
(400ml) and Et20 (100 ml) and cooled to -7~C under argon. IBuLi (80 ml, 1.7M) was added dropwise to the mixture, and the resultant solution stirred at -î8C. A solution of ~-chloro-2-nitrobenzaldehyde (11.2 g) in THF (150 ml) was added dropwise to the stirred solution, 0 and the resultant mixture allowed to warm to room temperature ~ - -overnight. After quenching with saturaled NH4CI solution, the mixture was diluted with EIOAc, and the layers separated. The organic frac~ion was washed with saturated NaCI solution, dried over MgSO4, filtered and evaporated. Flash column chromatography using a gradient 5 elution system from 10% EtOAc/hexane to 75% EtOAc/hexane provided 20.6 g of a-(5-chloro-2-nitrophenyl)-1-(triphenylmethyl)-lH-pyrazole-4-methanol, MS 495 (M+).

b) A rnixture of tbc protuct of a) above (27.1 g), CHC13 (250 ml) 20 and MnO2 (20 g) was stirred at reflux temperature for three hours. An addidonal aliquot of MnO2 (5 g) was added, and the mixture stirred ~ ~
five hours. After cooling, the mixture was filtercd and evaporated to --pro~ide 26.9 g (5-chloro-2-nitrophenyl) [I-(~riphenylmethyl)-lH- ~ -pyrazole-4-yllmethanone, MS 493 (M+).
- c) A mixture of the product of b) (26.9 g), EtOH (400 ml) and 4N
HCI (100 ml) was combined and stirred at reflux temperature. After neutralization with 30%-NaOH at 0C, the EtOH was evaporated and the resultant aqueous phase extracted with EtOAc. The organic fractions 30 were dried over MgS04, filtered and evaporated. The residue was purified by filtration through silica gel using a gradient elution system from 30% EtOAc/hexane to 100% EtOAc to yield (5-chloro-2-nitro-phenyl)(lH-pyrazol-4-yl)methanone. This was combined with EtOH
ant 10% PdlC and hydrogenated. Flash column chromatography 35 afforded 10 g of (2-amino-5-chlorophenyl)-lH-pyrazol-4-ylmethanone, MS 221 (M+).
' ' : ' -.~, .
` SUBSTITUTE SWEET
~..................................................................... . .

wo s3/t70l0 Pcr/EP93/003s2 ~ ~ Li~3~7 - 12 -d) To a solution of the product of c) (10.5 g) in THF (300 ml) and CH2C12 (300 ml) was added NaHCO3 (25 g) and an ice-water mixture (300 ml). The stirred mixture was treated with 37.2 ml BrCOCH2Br.
5 The two phases were separated, and the aqueous phase extracted with CH2C12. The organic fractions were dried over MgS04, filtered and evaporated. The residue was dissolved in THF (100 ml) and added to liquid NH3 (200 ml), which has been cooled to -78C, and allowed to stir overnight while warming to room tempera~ure. The volatiles were l o evaporated and the residue partitioned between EtOAc and H2O. After separation of the layers, the aqueous fraction was extracted with EtOAc. The organic fraclions were dried over M ,S04, filtered and e~aporated. The residue was combined with l-BuOH (100 ml) and pivalic acid ( îS mg) and the mix~ure hea~ed ~o reflux ~empera~ure.
5 The solvent was removed by evaporation, and the product purified by flash column chromatography (6.5% MeOH/CH2C12) to provide S.S g of 7-chloro-5 -(1 H-pyrazol-4-yl)- 1,3 -dihydro-2H- 1 ,4-benzodiazepin-2-one.
20 - E~

a) Bromopyrazole (24.0 g) was suspended in dry THF (600 ml) and cooled in dry ice-aeetone bath with stirring under an argon atmosphere. n-Butyllithium (2.5M in hexane, 24 ml) was added drop-25 wise. After 2 hours, the solution was added to 2-methyl-6-methyl-4H-3,1-benzoxazin-4-one (8.76 g) (prepared according to 1. Chem.
Soc.,. 1954, 4676) in THF (500 ml), pre-cooled to -~0C. The reacdon was qucnched after stirring for 20 minutes by addition of 15% NH4CI ' in water (w/v, 300 ml) and allowed to warm to room temperature.
30 The mixture was diluted with EtOAc and the layers were separated.
The organic layer was washed with saturated aqueous sodium chloride. The aqueous laycrs were washed with EtOAc. The organic layers wcre combined, dried, filtered~ and concentrated. The resulting solid was suspended in a mixture of THF (300 ml), methanol (350 ml), 3S water (250 ml) and 10N sodium hydroxide (270 ml), and heated at reflux temperature with stirring. The mixture was allowed to cool to ~ .
. ~
SUBSTITUTE SHEET
. .

wo 93/17010 210 ~ ~ ~3 7 pcr/Eps3/oo352 room temperature, and partitioned be~ween ether and water. The organic layers were washed with s~turated aqueous sodium chloride, then combined, dried, filtered, ~nd concentrated. The residue was suspended in CH2CI2 and filtered. The filtercake was washed with CH2CI2. The filtrate was concentrated and passed through silica gel using EtOAc-CH2Cl2 mixture (1:9 v/v) as eluant. The eluant was concentrated and the residue crystallized from CH2CI2-hexane to give 15.18 g of (2-amino-5-methylphenyl)[l-(triphenylmethyl)-lH-pyrazol-4-yl]methanone. MS Calcd: 443~ 1997; Found: 443, 1990.
b) The product of a) (2.~5 8) was dissolved in a mixture of THF
(150 ml) and ether (150 mi) and cooled in an ice-water bath.
Saturated aqueous sodium carbonate (100 ml) was then added.
Bromoacetyl bromide (4 x 0.67 ml. 30.9 mmol) was added with I s stirring. After 4 hours, the reaction mixture was dilu~ed with water and extracted with EtOAc. The precipitate formed was collected by filtration and dissolved in CH2C12. The EtOAc fraction was combined with the CH2C12 solution and dried, fil~ered, evaporated, and concentrated, and the residue crystallized from CH2C12-hexane to yield 3.33 g Qf 2-bromo-N-~4-methyl-2-[[1-(triphenylmethyl)-lH-pyrazol- :

4-yl]carbonyl]phenyl~acetamide, MS Calcd: 563.1208; Found:
563.1188.
c) The product of b) (2.26 g) was dissolved in CH~Cl2 (100 ml) and 2S cooled in a dry ice-acetone bath. Liquid ammonia (50 ml) was then condensed into the reaction mixture. The resulting solution was stirred and allowed to warm to room temperature~ After addition of .
water and mixing, the layers were separated. The organic layer was extracted with saturated aqueous sodium bicarbonate. The aqueous layers were washed with CH2C12. The CH2Cl2 layers were dried, filtered and concentrated. The residue was recrystallized from CH2C12-hexane to give 1.68 g of 2-amino-N-[4-methyl-2-~[1-(triphenylmethyl)-lH-pyrazol-4-yl~carbonyl]phenyl]acetamide. MS Calcd: 501.'7291; Found:
501.2272.
,', SUBSTITUTE SHEET

............... .. . . . .. ..... . ... ... , .... , . . .. .......... , . ... .- ... . .. .. . -- .
. . .. .. ... . .. .- . - ... . . . . - ~ ... .. ~ .. .... . i .... .. . . .... . . .. . .
., . ., ., . . . ,. ., "., ., . , .. ., - .. ..... . ... . . ...... , .. . . . . - . . - ~ -. ... . - . . ... . ... ...... . ... , .- . . . .:, .. .
- : .:. - . : ,.. -- . -.. - " ,.; - . : ... . . . . .. . .
.. :: - . . , ... . ~ `.. .. . .- -.. . . ... . . .... . . . .. . . ..

WO 93/17010 2 ~ 0 6 3 8 ~ PCT/EP93/003S2 d) A suspension of the product of c) (15.02 g) in nBuOH (300 ml) was heated at reflux with stirring. After cooling to room temperature, the reaction was concentrated to dryness. The residue was suspended in THF and heated to reflux. The resulting suspension was filtered. the 5 filtercake was washed with THF. The filtrate was combined. washed and heated at boiling temperature and concentrated. The resulting mixture was allowed to cool to room tempera~ure and allowed to stand for 3 hours. The product was washed with THF and dried yielding 5.50 g of 1,3-dihydro-7-methyl-5-(lH-pyrazol-4-yl)-2H-l,1-10 benzodiazepin-2-one, mp. 282-289C.

The following galenical compositions containing a compound I or ~
salt thereof as active ingredients as defined above, can be prepared in a manner known per se:
15 a) Oral liquid formulation:
In~çdients .mg/formulation Active ingredi,ent 20.0 mg Methylparaben 20.0 mg Sucrosc q.s.
Flavoring agent q.s.
Citrate buffer q.s.
Purifiod water q.s. 5.0 ml b ) Tablet formulation:
Ingredients me/tablet Active ingredient 20 mg Starch 40 mg Avicel 80 mg Lactose 274 mg Magnesium stearate ~m.
416 mg SUBSTITUTE SHEET : -wo 93/l7010 ~ ; 3 ~ 7 - 15 -Pcr/Eps3/oo352 c) Soft gelatine capsule formulation:
In~redients mg/capsule Active ingredient 20 mg Ethoxylated Fatty acids 500 mg PEG 4000 100 mg Vegetable oils q.s. to 1.0 ml .,. ,~ .. . . ..
.

- SUBSTITUTE SHEET :

.. , .. . .... . . .. . ~

,, ~. .. , .. , .. , ,, .... .,~,, .. , . ..... ,.. , . . .... .. - . . .. ,, .,i ....

.. .. .. ., .. . ... .. ~, . .,;, ,.. ; . - ...

Claims (6)

CLAIMS:

1. Benzodiazepinones of formula I

wherein X is Cl or CH3, and pharmaceutically acceptable salts.

2. 7-Chloro-5-(1H-pyrazol-4-yl)-1,3-dihydro-2H-1,4-benzo-diazepin-2-one.

3. 7-Methyl-5-(1H-pyrazol-4-yl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one.

4. A compound according to claim 1, 2 or 3 for use as a therapeuti-cally active agent, especially for the treatment or prophylaxis of viral infections, particularly of retroviral infections, such as HIV 1 and/or HIV 2 infections, or for protecting cells against such infections.

5. A process for preparing a compound as in claim 1, which comprises cyclizing a compound of formula V

wherein X is as in claim 1, by acid-catalysis.

6. A medicament, especially for the treatment or prophylaxis of viral infections, particularly of retroviral infections, such as HIV I
and/or HIV 2 infections, or for protecting cells against such infections, containing as active pharmaceutical ingredient a compound as in claim 1, 2 or 3, and, optionally, a second antiviral agent, especially a reverse transcriptase inhibitor, such as ddC, AZT, a HIV-protease inhibitor, .alpha.-, .beta.- and/or .gamma.-interferon, interleukin-2 and/or GM-CSF.