Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals

Definitions

• the present invention relates to benzodiazepinones of formula
• Objects of the present invention are the above compounds per se and for use as a therapeutically 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; further a process for the manufacture of these compounds and medicaments containing one of such compounds and, optionally, a second antiviral agent, especially a reverse transcriptase inhibitor, such as ddC, AZT or ddl, TIBO derivatives, tricyclic diazepinones, a HIV-protease inhibitor, ⁇ -, ⁇ - and/or ⁇ -interferon, interleukin-2 and/or GM-CSF, and the use of these compounds for the manufacture of medicaments 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.
• a second antiviral agent especially a reverse transcriptase inhibitor, such as dd
• Pharmaceutically acceptable salts may be those with organic acids, e.g. lactic, acetic, malic or p-toluenesulfonic acid; or salts with mineral acids, such as hydrochloric or sulfuric acid.
• organic acids e.g. lactic, acetic, malic or p-toluenesulfonic acid
• mineral acids such as hydrochloric or sulfuric acid.
• SUBSTITUTE SHEET 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. Heterocyciic 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.
• 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.
• an acid such as pivalic acid
• a solvent such as toluene and THF
• the amines V can be prepared via the corresponding bromides
• R 3 , R 4 and R 5 are H or a N-protecting group.
• Suitable N-protecting groups include triphenylmethyl, acyl, trialkylsilyl, alkyldiarylsilyl, ethoxymethyl, (dialkylamino)methyl, t- butoxycarbonyl and phenoxycarbonyl.
• a preferred method for performing the reaction III ⁇ IV- ⁇ V involves bromoacetylation of a ketone III to the bromide IV, followed by ammonolysis to the amine V.
• ketones III can be prepared by reacting a metallo- heterocycle of formula VI
• R ⁇ is a metal or a metallic halide group, such as MgBr, MgCl, Li, Na or Sn, with an aromatic compound of formula VII
• R? is formyl or a functional derivative of a carboxylic acid, such as cyano, ester, amide or acyl chloride
• X is as above and R ⁇
• SUBSTITUTE SHEET and R9 are H, O, acyl, trialkylsilyl, alkyldiarylsilyl or t-butoxy- carbonyl.
• preferable unreactive blocking groups include halogen, S-lower alkyl, S-aryl, trialkylsilyl and alkyldiarysilyl.
• the conversion of VIII to IX can be accomplished by oxidation, e.g. catalytic oxydation or reaction with active maganese dioxide.
• the compounds I and their salts have useful antiviral, especially anti-retroviral activity, particularly against 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 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:
• SeAP Phosphatase gene and the viral transactivator TAT gene under the control of the HIV promoter LTR responsive to the action of the HIV transactivator TAT;
• the inhibition of SeAP positively correlates with anti-TAT activity.
• the anti- HIV-TAT assay was run as follows:
• test 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 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 the control of HIV-LTR versus the percent inhibition of SeAP gene under RSV-LTR, which does not respond to TAT.
• the anti-HIV-TAT activities of the test compounds were determined by measuring the amount of alkaline phosphatase in the supernatant media of cultures of cells in which SeAP gene expression was under the control of the HIV LTR promoter.
• the specific inhibitory activities of the test compounds were calculated according to the formula:
• a and B are the alkaline phosphatase activites produced by HIV-LTR/SeAP in the presence and absence, respectively, of test compound
• C and D are the alkaline phosphatase activities produced by RSV-LTR/SeAP in the presence and absence, respectively, of test compound.
• concentrations tested ranged from 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% inhibition would not be observed with this assay procedure.
• an antivirally- effective amount of a compound of formula 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 day. In unit dosage form, for a 70 kg patient, this would be an amount of from about 35 to 2800, preferably from about 210 to 350 mg per day. This dosage may be administered parenterally or orally in one or more doses at various intervals daily, preferably orally once daily.
• the compounds may also be administered with other antiviral and/or biological response modifiers.
• the compounds of formula I may be administered with known HIV-RT inhibitors such as ddC, AZT, ddl or non-nucleoside RT inhibitors such as TIBO derivatives or tricyclic diazepinones, or other inhibitors which act against other HIV proteins such as protease, integrase and RNAaseH, as well as with biological modifiers such as ⁇ -, ⁇ - or ⁇ -interferon or a combination thereof, interleukin-2 and GM-CSF.
• the dosages of ddC and AZT used in AIDS or ARC human patients have been published.
• the other anti-HIV compounds When given in combined therapy, the other anti-HIV compounds may be given at the same time as a compound of formula I or the dosing may be staggered as desired.
• the two (or more) drugs may also be combined in a composition. Doses of each drug may be less when used in combination than when they are used as a single agent.
• the compounds of the invention may be administered alone in solution.
• the active 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 suitable for oral, rectal, nasal, topical, buccal, sublingual, vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
• compositions of the invention are solutions of the active ingredient(s), e.g. in water or saline; capsules, e.g. soft gelatine 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 stearate, stearic acid and other excipients, colorants and pharmacologically 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 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 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 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 lyophilized 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.
• Example le The product of Example le) can also be prepared as follows:
• Example la The product of Example la) (24 g) was combined with THF (400 ml) and Et 2 ⁇ (100 ml) and cooled to -78°C under argon. tBuLi (80 ml, 1.7M) was added dropwise to the mixture, and the resultant solution stirred at -78°C. A solution of 5-chloro-2-nitrobenzaldehyde (11.2 g) in THF (150 ml) was added dropwise to the stirred solution, and the resultant mixture allowed to warm to room temperature overnight. After quenching with saturated NH 4 CI solution, the mixture was diluted with EtOAc, and the layers separated.
• the mixture was diluted with EtOAc and the layers were separated.
• the organic layer was washed with saturated aqueous sodium chloride.
• the aqueous layers were washed with EtOAc.
• the organic layers were combined, dried, filtered, and concentrated.
• the resulting solid was suspended in a mixture of THF (300 ml), methanol (350 ml), water (250 ml) and ION sodium hydroxide (270 ml), and heated at reflux temperature with stirring.
• the mixture was allowed to cool to room temperature, and partitioned between ether and water.
• the organic layers were washed with saturated aqueous sodium chloride, then combined, dried, filtered, and concentrated.
• the residue was suspended in CH 2 CI2 and filtered.
• the filtercake was washed with CH2CI2.
• compositions containing a compound I or a salt thereof as active ingredients as defined above can be prepared in a manner known per se: a) Oral liquid formulation:
• Vegetable oils q.s. to 1.0 ml

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• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 1993
  • 1993-02-13 CA CA002106387A patent/CA2106387A1/en not_active Abandoned
  • 1993-02-13 WO PCT/EP1993/000352 patent/WO1993017010A1/en not_active Application Discontinuation
  • 1993-02-13 JP JP5514505A patent/JPH06501502A/ja active Pending
  • 1993-02-13 EP EP93903968A patent/EP0586632A1/de not_active Withdrawn
  • 1993-02-13 AU AU34972/93A patent/AU3497293A/en not_active Abandoned

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