WO1995007910A1 - Derives d'indole presentant une action antivirale - Google Patents

Derives d'indole presentant une action antivirale Download PDF

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Publication number
WO1995007910A1
WO1995007910A1 PCT/GB1994/002016 GB9402016W WO9507910A1 WO 1995007910 A1 WO1995007910 A1 WO 1995007910A1 GB 9402016 W GB9402016 W GB 9402016W WO 9507910 A1 WO9507910 A1 WO 9507910A1
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formula
compound
preparation
reacting
compounds
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PCT/GB1994/002016
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English (en)
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Martin John Slater
George Stuart Cockerill
John Edward Robinson
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The Wellcome Foundation Limited
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Priority to AU76212/94A priority Critical patent/AU7621294A/en
Publication of WO1995007910A1 publication Critical patent/WO1995007910A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

Definitions

  • the present invention relates to certain novel indole derivatives, salts, esters and physiologically functional derivatives thereof, to their use in medical therapy and in particular to their use in the manufacture of a medicament for the treatment or prophylaxis of viral infections, and to pharmaceutical formulations thereof.
  • herpes simplex virus types 1 and 2 HSV 1
  • HSV 2 herpes simplex virus types 1 and 2
  • VZV varicella zoster virus
  • CMV cytomegalovirus
  • EBV Epstein-Barr virus
  • HHV6 Human Herpes Virus 6
  • HHV7 Human Herpes Virus 7
  • HSV infection is often characterised by extensive and debilitating lesions of the skin, mouth and/or genitals. Primary infections may be subclinical although tend to be more severe than infections in individuals previously exposed to the virus. Ocular infection by HSV can lead to keratitis or cataracts thereby endangering the host's sight. Infection in the newborn, in immunocompromised patients including Acquired Immune Deficiency Syndrome (AIDS) patients or penetration of the infection into the central nervous system can prove fatal.
  • AIDS Acquired Immune Deficiency Syndrome
  • VZV is a herpes virus which causes chickenpox and shingles.
  • Chickenpox is the primary disease produced in a host without immunity and in young children is usually a mild illness characterised by a vesicular rash and fever.
  • Shingles or zoster is the recurrent form of the disease which occurs in adults who were previously infected with VZV.
  • the clinical manifestions of shingles are characterised by neuralgia and a vesicular skin rash that is unilateral and dermatomal in distribution. Spread of inflammation may lead to paralysis or convulsions. Coma can occur if the meninges becomes affected. In immunodeficient patients VZV may disseminate causing serious or even fatal illness.
  • VZV is of serious concern in patients receiving immunosuppressive drugs for transplant purposes or for treatment of malignant neoplasia and is a serious complication of AIDS patients due to their impaired immune system.
  • infection with CMV leads to a lifelong association of virus and host and, following a primary infection, virus may be shed for a number of years.
  • Congenital infection following infection of the mother during pregnancy may give rise to clinical effects such as death or gross disease (microcephaly, hepatosplenomegaly, jaundice, mental retardation), retinitis leading to blindness or, in less severe forms, failure to thrive, and susceptibility to chest and ear infections.
  • CMV infection in patients who are immunocompromised for example as a result of malignancy treatment with immunosuppressive drugs following transplantation or infection with Human Immunodeficiency virus (HIV) may give rise to retinitis, pneumonitis, gastrointestinal disorders and neurological diseases.
  • HIV Human Immunodeficiency virus
  • EBV infectious mononucleosis
  • diseases include lymphoproliferative disease which frequently occurs in people with congenital or acquired cellular immune deficiency, X-linked lymphoproliferative disease which occurs mainly in young boys, EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngeal carcinoma, Burkitt lymphoma, non-Hodgkin ⁇ -cell lymphoma, immunoblastic lymphoma, thymomas and oral hairy leukoplakia.
  • EBV infections have also been found in association with a variety of epithelial-cell-derived tumours of the upper and a lowe respiratory tracts including the lung.
  • HHV-6 has been shown to be a causative agent of infantum subitum in children and of kidney rejection and interstitial pneumonia in kidney and bone marrow transplant patients respectively and may be associated with other diseases. There is also evidence of repression of stem cell counts in bone marrow transplant patients. HHV-7 is of undetermined disease aetiology.
  • Hepatitis B Virus is a viral pathogen of world-wide major importance.
  • the virus is aetiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world's liver cancer.
  • Clinical effects of infection with HBV range from headache, fever, malaise, nausea, vomiting, anorexia and abdominal pains.
  • Replication of the virus is usually controlled by the immune response, with a course of recovery lasting weeks or months in humans, but infection may be more severe leading to persistent chronic liver disease as outlined above.
  • Papillomaviruses are widespread in nature and infect most vertebrate species including humans.
  • HPVs human papillomaviruses
  • HPVs human papillomaviruses
  • exophytic genital warts or condyloma which occur on the penis, vulva or in the perianal region are highly associated with infection by HPV types 6 and 11.
  • juvenile and adult onset laryngeal papillomas are associated with infection by HPV types 6 and 11.
  • HPV types 16 and 18 and other related HPVs such as 31,33,35 and 39
  • HPV types 16 and 18 and other related HPVs such as 31,33,35 and 39
  • HPV types 16 and 18 and other related HPVs such as 31,33,35 and 39
  • HPV types 1 to 4 HPV types 1 to 4.
  • Retroviruses form a sub-group of RNA viruses which, in order to replicate, must first 'reverse transcribe' the RNA of their genome into DNA ('transcription' conventionally describes the synthesis of RNA from DNA). Once in the form of DNA, the viral genome may be incorporated into the host cell genome, allowing it to take advantage of the host cell's transcription/translation machinery for the purposes of replication. Once incorporated, the viral DNA is virtually indistinguishable from the host's DNA and, in this state, the virus may persist for the life of the cell.
  • a species of retrovirus, HIV 1 and 2 has been reproducibly isolated from humans with AIDS or with the symptoms that frequently precede AIDS.
  • AIDS is an immunosuppressive or immunodestructive disease that predisposes subjects to fatal opportunistic infections.
  • Characteristically, ADDS is associated with a progressive depletion of T-cells, especially the helper-inducer subset bearing the OKT surface marker.
  • HIV is cytopathic and appears to preferentially infect and destroy T-cells bearing the OKT marker and it is now generally recognised that HIV is the aetiological agent of AIDS.
  • AIDS-related complex ARC
  • PDL progressive generalised lymphadenopathy
  • Karposi's sarcoma thrombocytopenic purpura
  • AIDS-related neurological conditions such as multiple sclerosis or topical paraparesis
  • anti-HIV antibody-positive conditions including such conditions in asymptomatic patients.
  • RNA virus which has been recognised as the causative agent of an increasingly serious international health problem is the non-A, non-B hepatitis. At least 80% of cases of chronic post-transfusional non-A, non-B hepatitis have been shown to be due to the virus now identified as hepatitis C and this virus probably accounts for virtually all cases of post-transfusional hepatitis in clinical settings where blood products are screened for hepatitis B.
  • Coxsackie viruses belong to the enterovirus genus. They have a single stranded RNA genome contained in an icosachedral nucleocapsid. Coxsackie virus infection is increasingly recognised as a cause of primary myocardial disease in adults and children. Coxsackie infection is also associated with meningitis, pleurodynia, herpangia, hand-feet and mouth disease, respiratory disease, eye disease, diabetes and post-viral fatigue syndrome. In the latter case viral RNA has been detected in the muscle and in menocytes.
  • European Patent Specification 0 328 000 describes certain indolecarbazole derivatives and indicates thafthese compounds can be used for the treatment of heart and blood vessel diseases, such as thrombosis, arteriosclerosis and hypertension, inflammatoiy processes, allergies, cancers and certain degenerative damage to the central nervous system.
  • Maleimide derivatives having similar suggested properties are described in European Patent Specification 0 391 060.
  • US patent 5,043,335 describes certain indolecarbazole derivatives and their use in the treatment of heart and blood vessel diseases such as thrombosis, arteriosclerosis and hypertension.
  • PCT specification number 9300571 describes certain indolecarbazole derivatives and their use in the treatment or prophylaxis of viral infections.
  • indole derivatives which have been found suitable for use in the treatment or prophylaxis of viral infections, for example retrovirus, herpes virus, hepatitis virus, influenza virus, papillomavirus, coxsackie virus and hepatitis C virus infections.
  • retrovirus herpes virus
  • hepatitis virus influenza virus
  • papillomavirus papillomavirus
  • coxsackie virus hepatitis C virus infections
  • the compounds of the invention are used in the treatment or prophylaxis of CMV infections.
  • R 1 represents:-
  • R 10 is C 1-6 alkyl, C 3-7 cycloalkyl, aryl (for example phenyl), arylalkyl (for example benzyl), C 1-6 alkenyl, or H];
  • R 11 and R 12 which may be the same or different, each represent H, COR 10 (where R 10 is hereinbefore defined), C 1-6 alkyl, C 3-7 cycloalkyl, aryl, arylalkyl, or R 11 and R 12 together with the N atom to which they are attached form a 3-,4-,5- or 6- membered heterocyclic ring (for example piperidine, pyrrolidine) in which from 1 to 3 carbon atom(s) are replaced by hereroatom(s) independently selected from O, N and S (for example morpholino, piperazine) which ring may, where possible, be partially or completely unsaturated];
  • COR 10 where R 10 is hereinbefore defined
  • C 1-6 alkyl, C 3-7 cycloalkyl, aryl, arylalkyl, or R 11 and R 12 together with the N atom to which they are attached form a 3-,4-,5- or 6- membered heterocyclic ring (for example piperidine,
  • R 2 and R 3 which may be the same or different, are each independently selected from:-
  • R 6 and R 7 which may be the same or different, each represents one or more ring substituent(s) selected from:-
  • -C 1-6 alkyl optionally substituted by OR 10 (where R 10 is hereinbefore defined), halogen, (for example trifluoromethyl), or NR 11 R 12 (where R 11 and R 12 are as defined above);
  • R 8 and R 9 which may be the same or different, each together with the carbon atoms to which they are attached form an unsaturated 6-membered carbocyclic, preferably an aromatic, ring in which from 1 to 3 carbon atom(s) may be replaced by nitrogen atom(s), providing that at least one ring structure contains at least one nitrogen atom, which may optionally be substituted with an oxide group;
  • Preferred compounds of formula (I) include those wherein both R 8 and R 9 form a 6-membered aromatic ring in which one carbon atom is replaced by a nitrogen atom in each ring system and ideally each nitrogen atom of each ring system is in the 1 and 11 positions respectively and in which each of the nitrogen atoms may optionally be substituted with an oxide group.
  • R 8 and R 9 form a 6-membered aromatic ring in which only one ring system has one carbon atom replaced by a nitrogen atom ideally either in the 1 or 11 position respectively and in which the nitrogen atom may optionally be substituted with an oxide group .
  • Particularly preferred compounds of formula (I) include:
  • alkyl as a group or part of a group means a straight or branched chain alkyl group. Such alkyl groups preferably have 1 to 3 carbon atom(s).
  • aryl as a group or part of a group includes phenyl and naphthyl.
  • heteroaryl includes a 5- or 6-membered aromatic ring where 1 to 3 carbon atom(s) are replaced with heteroatom(s) selected from N, O or S (for example pyridyl, pyrrolyl, thienyl and furyl), optionally fused to an aryl ring (for example quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzothiazolyl), and the term heterocycle includes a 5- or 6-membered carbocyclic ring where 1 to 3 carbon atom(s) are replaced by hetero atom(s) selected from N, O or S (for example morpholine, pyrrolidine, piperidine, piperazine) which may be partially or completely saturated.
  • heteroatom(s) selected from N, O or S
  • the present invention further includes: a) compounds according to the invention for use in medical therapy particularly in the treatment or prophylaxis of a viral infection (such as those set out herebefore) especially CMV infections; b) use of a compound according to the invention in the manufacture of a medicament for use in the treatment or prophylaxis of a viral infection (such as those set our herebefore); c) a method for the treatment of a viral infection (such as those set out herebefore) comprising administering to the subject an antivirally therapeutic amount of a compound of the invention; and d) pharmaceutical formulations comprising a compound of the invention and at least one pharmaceutically acceptable carrier or excipient.
  • Examples of clinical condition caused by viruses which may be treated in accordance with the invention include those referred to above.
  • physiologically functional derivative means any physiologically acceptable salt, ester, or salt of such ester of a compound of formula (I) above or any other compound which upon administration to the recipient, is capable of providing (directly or indirectly) such a compound or an antivirally active metabolite or residue thereof.
  • the compounds may also be used for the treatment or prophylaxis of heart and blood vessel diseases, thrombosis, arteriosclerosis and hypertension, inflammatory processes, allergies, cancer and certain degenerative damage to the central nervous system.
  • Preferred esters in accordance with the invention include carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C 1-4 alkyl, or C 1- 4 alkoxy), or amino; sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); amino acid esters (for example, L-valyl or L-isoleucyl); and mono-, di-, or triphosphate esters.
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
  • Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
  • Any aryl moiety present in such esters advantageously comprises a phenyl group. Any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts of the compounds of formula (I) and physiologically acceptable derivatives thereof include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 + (wherein X is C 1-4 alkyl).
  • an appropriate base such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 + (wherein X is C 1-4 alkyl).
  • Physiologically acceptable salts of a hydrogen atom or an ammo group include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids, and inorganic acids, such as hydrochloric, sulphuric, phosphoric and sulphamic acids.
  • Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + , NH 4 + and NX 4 + (wherein X is a
  • salts of compounds of formula (I) will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base are within the scope of the present invention.
  • Combination therapies according to the present invention comprise the administration of at least one compound of the formula (I) or a physiologically functional derivative thereof and at least one other therapeutic agent.
  • the compound(s) of formula (I) and therapeutic agent(s) may be administered together in a single formulation or separately and, when administered separately, this may occur sequentially in any order or together.
  • the amounts of the compound(s) of formula(I) and therapeutic agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the combination therapy involves the administration of one compound of formula (I) or a physiologically functional derivative thereof and one of the agents mentioned herein below.
  • therapeutic agents include agents that are effective for the treatment of HIV infections or associated conditions such as 3'-azido-3'-deoxythymidine (zidovudine), other 2',3'-dideoxynucleosides such as 2',3'-dideoxycytidine, 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine, carbovir, pentoxifylline, N-acetylcysteine, procysteine, a-trichoxanthin, acyclic nucleosides (for example, acyclovir), 2',3'-didehydrothymidine, protease inhibitors such as N-tert-butyl-dechydro-2-[2(R)-hydroxy-4-phenyl-3-(S)-[[N-(2-quinolycarbonyl)-L-asparginyl]-butyl]-(4aS,78aS)-
  • Further compounds include those disclosed in EP-A-
  • the combination therapy involves the administration of one of the above-mentioned agents and a compound within one of the preferred groups of compounds of formula (I) as described above.
  • compositions containing a compound of the invention may be administered for therapy to a mammal including a human ("the recipient") by any suitable route appropriate to the clinical condition to be treated; suitable routes include oral, rectal, nasal, topical (including buccal, sublingual and transdermal), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal).
  • suitable routes include oral, rectal, nasal, topical (including buccal, sublingual and transdermal), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal).
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the pharmaceutically acceptable carrier(s) or excipient(s).
  • a suitable, effective dose will be in the range of 0.5 to 120 mg per kilogram body weight of the recipient per day, preferably in the range of 1 to 90 mg per kilogram body weight per day and most preferably in the range of 2 to 60 mg per kilogram body weight per day.
  • An optimum dose is about 30 mg per kilogram body weight per day.
  • all weights of active ingredients are calculated as the parent compounds of the compounds according to the invention.
  • the desired dose is preferably presented as two, three, four, five, six, or more sub-doses administered at appropriate intervals throughout the day.
  • sub-doses may be administered in unit dosage forms, for example, containing from 1 to 1500 mg, preferably from 5 to 1000 mg, most preferably from 10 to 700 mg of active ingredient per unit dosage form.
  • the dose may be administered as a continuous infusion.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.25 to about 100 ⁇ M, preferably from about 0.5 to 70 ⁇ M, most preferably from about 1 to about 50 ⁇ M.
  • This may be achieved, for example, by the intravenous injection of a 0.1 to 5% w/v solution of the active ingredient, optionally in saline, or orally administered, for example, as a tablet, capsule, or syrup containing from about 0.5 to about 100 mg/kg of the active ingredient.
  • Desirable blood levels may be maintained by a continuous infusion to provide from about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing from about 0.4 to about 15 mg/kg of the active ingredient.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets; as powders or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved in an adhesive or 3) dispersed in a polymer.
  • a suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%.
  • the active compound may be delivered from the patch by ionophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base or as a water-in-oil base.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Formulations suitable for topical administration in the mouth include lozenges, pastilles and mouth-washes.
  • Formulations for rectal administration may be presented as a suppository or as an enema.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oily solutions and suspensions of the active ingredient.
  • Suitable formulations for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous 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 containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (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 powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a compound of formula (I) or a salt, ester or physiologically functional derivative thereof or a solvate of any thereof may be prepared by the general methods outlined below, these are further features of the invention.
  • the symbols R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , X and Y have the meanings ascribed to them in formula (I) unless otherwise stated (R 10' is an alternative value of R 10 ).
  • the compounds of formula (I) may be prepared by a process which comprises:-
  • (III) is 3-(3-indolyl)-4-(1H-7-aza-indol-3-yl)maleimide
  • X 1 represents an acid anion
  • X or Y is H and the other one is OR 1 0' or SR 10' with an alcohol R 1 0 OH or a thiol R 10 SH;
  • compounds of formula (I) as defined above may be prepared by reacting compounds of formula (II) with a phosphine, for example triphenylphosphine or a phosphite, for example triethylphosphite, .in a suitable solvent such as collidine, lutidine or t-butylbenzene.
  • a phosphine for example triphenylphosphine or a phosphite, for example triethylphosphite, .in a suitable solvent such as collidine, lutidine or t-butylbenzene.
  • compounds of formula (I) as defined above may be prepared by reacting a compound of formula (HI) with an oxidising agent such as DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) in a suitable solvent, such as benzene, toluene, dioxane or xylene, or combinations thereof preferably in the presence of an acid, for example p-toluenesulphonic acid, and at an elevated temperature, preferably in the range of 50-150oC.
  • an oxidising agent such as DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone)
  • a suitable solvent such as benzene, toluene, dioxane or xylene, or combinations thereof preferably in the presence of an acid, for example p-toluenesulphonic acid, and at an elevated temperature, preferably in the range of 50-150oC.
  • cyclisation can be effected using palladium, silver oxide, light optionally with oxygen and preferably with iodine in an inert atmosphere (for example under nitrogen), heat or oxidising agents such as tert-butyl hypochlorite.
  • amine of formula R 1 NH 2 R 1 as previously defined
  • amine salt of formula R 1 NH 3 X 1 X signifies an acid anion such as halide, carboxylate, carbonate or sulphate
  • X signifies an acid anion such as halide, carboxylate, carbonate or sulphate
  • a suitable solvent for example tetrahydrofuran, dimethylformamide, acetic acid or toluene (or combinations thereof), or with hexamethyldisilazane and methanol in a suitable solvent such as tetrahydrofiiran or dimethylformamide.
  • Compounds of formula (XV) may be prepared by reacting a compound of formula (XVIII) with a compound of formula (XIX) in the presence of a base, such as triethylamine, ethyl diisopropylamine, or pyridine, and optionally in a suitable solvent, such as dichloromethane.
  • a base such as triethylamine, ethyl diisopropylamine, or pyridine
  • a suitable solvent such as dichloromethane.
  • Compounds of formula (XIX) may be prepared by reacting a compound of formula (XVI) with oxalyl chloride or thionyl chloride, optionally in a suitable solvent, for example dichloromethane or toluene, provided that R 3 is a protecting group (for example p-tosyl) when R 9 represents a heterocyclic ring system.
  • a suitable solvent for example dichloromethane or toluene
  • Compounds of formula (XVIII) may be prepared by hydrolysis of a compound of formula (XX) where R 10 is as hereinbefore defined, using acidic (eg. HCl) or basic (eg. NaOH) conditions.
  • acidic e.g. HCl
  • basic e.g. NaOH
  • Compounds of formula (XX) may be prepared by reacting a compound of formula (XXI) with an oxidising agent, such as selenium dioxide or DDQ.
  • an oxidising agent such as selenium dioxide or DDQ.
  • Compounds of formula (III) may also be prepared by reacting a compound of formula (VIII) where V is a halide, OPO(R 10 ) 2 or OCOR 10 (where R 10 is as hereinbefore defined), and preferably where R 2 is a protecting group. with a compound of formula (IX),
  • Z is OR 10 or SR 10 in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine, ethyldiisopropylamine or pyridine, followed by treatment with an acid, such as p-toluenesulphonic acid or hydrochloric acid.
  • a suitable solvent such as dichloromethane
  • an acid such as p-toluenesulphonic acid or hydrochloric acid.
  • the acid treatment may be optionally replaced by treatment with a mixed anhydride (for example trifluoroacetic anhydride) in the presence of a base (for example pyridine, triethylamine).
  • Compounds of formula (X) are available commercially or may be prepared by methods known to a skilled person in the art.
  • Compounds of formula (VIII) where V is OCOR 10 or OPO(R 10 ) 2 may be prepared by reacting a compound of formula (XVIII) with a chloroformate (for example methylchloroformate) or a phosphine chloride (for example diphenylphosphinic chloride) in the presence of a base (for example pyridine, triethylamine).
  • a chloroformate for example methylchloroformate
  • a phosphine chloride for example diphenylphosphinic chloride
  • oxalyl halide for example oxalyl chloride
  • a suitable solvent for example dichloromethane or tetrahydrofuran.
  • Compounds of formula (VIII) where V is a halide and R 8 is a heterocyclic ring system may be prepared by reacting a compound of formula (XVIII) with oxalyl chloride or thionyl chloride optionally in a suitable solvent, for example dichloromethane or toluene, provided that R 2 is a protecting group (such as p-tosyl).
  • Compounds of formula (XI) may be prepared by reacting a compound of formula (XII), wherein L is a leaving group and M is a metal atom, with a compound of formula (XIII) wherein L is a leaving group, in a suitable solvent such as tetrahydrofuran, 1,4- dioxane, diethyl ether, benzene, toluene, or combinations thereof.
  • a suitable solvent such as tetrahydrofuran, 1,4- dioxane, diethyl ether, benzene, toluene, or combinations thereof.
  • compounds of formula (I) as defined above may be prepared by reacting commercially available amines of formula R 1 NH 2 or amine salts of formula R 1 NH 3 X 1 where X represents an acid anion such as halide, acetate, carbonate or sulphate with an anhydride of formula (IV)
  • Compounds of formula (IV) may be prepared by reacting a compound of formula (XV) with an oxidising agent such as DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) in a suitable solvent, such as benzene, toluene, dioxane or xylene, or combinations thereol; preferably in the presence of an acid, for example p-toluenesulphonic acid, and at an elevated temperature, preferably in the range of 50-150oC.
  • cyclisation can be effected using palladium, silver oxide, light (preferably with iodine in an inert atmosphere), heat or oxidising agents such as tert-butyl hypochlorite.
  • Compounds of formula (XV) can also be prepared by reacting a compound of formula (XVI) with a compound of formula (VIII), where R 2 is preferably a protecting group when R 8 is a heterocyclic ring, in the presence of a base, such as triethylamine, ethyl diisopropylamine or pyridine and optionally a suitable solvent, such as dichloromethane.
  • a base such as triethylamine, ethyl diisopropylamine or pyridine
  • a suitable solvent such as dichloromethane.
  • Preferred protecting groups for the pyrrolo nitrogen in compounds of formula (VIII) are tert-butyloxycarbonyl (BOC), p-toluenesulphonyl (tosyl), benzyl, benxyloxymethyl, methoxy and silyl (eg. tert-butyldimethylsily, triisopropyl).
  • R 2 and R 3 where R 2 and/or R 3 are not hydrogen may be performed at any stage of the process.
  • the indole nitrogens may be alkylated or acylated with groups R 2 -L or R 3 -L where R 2 and R 3 are as previously defined with the exception of hydrogen, and L is a suitable leaving group such as halogen or sulphonate ester (eg. trifluoromethanesulphonate).
  • the reaction preferably taking place in the presence of a base (eg. triethylamine), or a metal hydride (eg. sodium hydride), or an alkyl lithium (eg. n-butyl lithium), and in a suitable solvent (such as dimethylformamide, tetrahydrofiiran, dimethylsulphoxide).
  • R 6 and R 7 where R 6 and/or R 7 are not hydrogen, may be performed at any stage, according to methods known in the art of indole chemistry and aromatic chemistry.
  • a halogen atom may be conveniently introduced using N-halosuccinimides or by the use of a halogen (J.Org.Chem (1951) 16, 1198).
  • a nitro group may for example, be introduced using KNO 3 or HNO 3 in the presence of sulphuric acid or using nitronium tetrafluoroborate.
  • Acyl (eg. formyl) or sulphonyl groups may, for example, be introduced by methods described in Chem. Ind. (1981),
  • Compounds of formula (I) may be converted into an ester by reaction with an appropriate esterifying agent, for example, an acid halide or anhydride.
  • an appropriate esterifying agent for example, an acid halide or anhydride.
  • the salt may be formed by reacting the compound of formula (I) in the form of the free base with the appropriate acid.
  • the two reactants are preferably used in equivalent amounts and the reaction may be carried out in a suitable solvent such as an alcohol, for example ethanol, an ester, for example ethyl acetate, or an ether, for example tetrahydrofuran.
  • One salt of a compound of formula (I) may be converted into another salt using standard methods, for example where it is desired to convert a salt of a compound of formula (I) with an acid which is not physiologically acceptable into a salt with a physiologically acceptable acid.
  • An ester or salt may be converted into the parent compound, for example, by hydrolysis.
  • the resulting orange solid was triturated with acetone (20ml) and THF (20ml), the white insoluble material filtered off, and the filtrate evaporated in vacuo.
  • the resulting red/orange solid was heated at 140°C with ammonium acetate (4g) for 60 minutes and the solvents removed in vacuo.
  • the red oil was chromatographed over flash SiO 2 , eluting with hexane/EtOAc (3:1), (2:1), (1:1) and (1:2) to give the compound O as an orange solid.
  • formulations A, B and C are prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of the magnesium stearate and compression.
  • the formulation is prepared by wet granulation of the following ingredients with a solution of povidone followed by addition of the magnesium stearate and compression. mg/tablet
  • a capsule formulation is prepared by admixing the ingredients of Formulation D in Example 3 above and filling into two-part hard gelatin capsule.
  • Capsules are prepared by admixing the above ingredients and filling into two-part hard gelatin capsules.
  • Capsules are prepared by melting the Macrogol 4000 BP, dispersing the active ingredient in the melt and filling the melt into two-part hard gelatin capsules.
  • Capsules are prepared by dispersing the active ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules.
  • the following controlled release capsule formulation is prepared by extruding ingredients (a), (b) and (c) using an extruder, followed by spheronisation of the extrudate and drying. The dried pellets are then coated with the release-controlling membrane (d) and filled into two-piece, hard gelatin capsules. mg/capsule
  • the active ingredient is dissolved in the glycofurol.
  • the benzyl alcohol is then added and dissolved, and water added to 3 ml.
  • the mixture is then filtered through a sterile micropore filter and sealed in sterile amber glass vials 3 ml.
  • the active ingredient is dissolved in a mixture of the glycerol and most of the purified water.
  • An aqueous solution of the sodium benzoate is then added to the solution, followed by addition of the sorbitol solution and finally the flavour.
  • the volume is made up with purified water and mixed well.
  • Witepsol H15 is melted in a steam-jacketed pan, at 45oC maximum.
  • the active ingredient is sifted through a 200 lm sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45oC, the remaining Witepsol H15 is added to the suspension and stirred to ensure a homogenous mix.
  • the entire suspension is passed through a 250 lm stainless steel screen and, with continuous stirring, is allowed to cool to 40oC. At a temperature of 38oC to 40oC, 2.0g of the mixture is filled into suitable, 2 ml plastic moulds. The suppositories are allowed to cool to room temperature.
  • DMEM10 growth medium
  • Monolayers were infected with 100-200pfu of cell-free virus in 0.2ml of DMEM containing 5% fetal bovine serum plus antibiotics (DMEM5) and incubated for 1 hour at 37oC to allow virus adsorption. Following this time, 0.8ml of DMEM5 (with or without inhibitor) was added to each well and cultures were incubated at 37oC for 2-3 days. Monolayers were fixed with 10% formaldehyde solution in PBS and stained with 0.25% crystal violet in order to visualize virus plaques. Individual foci of multinucleated gian cells (plaques) were apparent using this staining procedure. ID 50 values were derived from plots of percent plaque reduction versus inhibitor concentration.
  • Herpes Simplex Virus types 1 (HSV 1) and 2 (HSV 2) were assayed in monolayers of Vero cells in multiwell trays.
  • the virus strains used were SC16 and 186 for HSV-1 and HSV-2 respectively.
  • Activity of compounds was determined in the plaque reduction assay, in which a cell monolayer was infected with a suspension of the appropriate HSV, and then overlaid with nutrient carboxymethyl cellulose in the form of a gel to ensure that there was no spread of virus throughout the culture.
  • a range of concentrations of compound of known molarity was incorporated in the nutrient carboxymethyl cellulose overlay. Plaque numbers at each concentration is expressed as percentages of the control and a dose-response curve was drawn.
  • HCMV Human cytomegalovirus
  • MRC5 cells human embryonic lung
  • the standard CMV strain AD 169 was used.
  • Activity of compounds is determined in the plaque reduction assay, in which a cell monolayer is infected with a suspension of HCMV, and then overlaid with nutrient carboxymethyl cellulose in the form of a gel to ensure that there is no spread of virus throughout the culture.
  • a range of concentrations of compound of known molarity was incorporated in the nutrient agarose overlay. Plaque numbers at each concentration of drug are expressed as percentage of the control and a dose-response curve is drawn.
  • VZV varicella zoster virus
  • Vero cells grown on 96-well microtiter dishes are exposed to different dilutions of drug, and cell viability determined daily on replicate cultures using uptake of a tetrazolium dye (MTT).
  • MTT tetrazolium dye

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à des composés de la formule (I) dans laquelle R8 et R9 qui peuvent être semblables ou différents, forment chacun avec les atomes de carbone auxquels ils sont attachés, un noyau carbocyclique insaturé à 6 éléments dans lequel on peut remplacer de 1 à 3 atomes de carbone par des atomes d'azote, à condition qu'au moins une structure de noyau contienne au moins un atome d'azote; l'invention se rapporte également à l'utilisation de ces composés dans le traitement ou la prophylaxie des infections virales.
PCT/GB1994/002016 1993-09-17 1994-09-16 Derives d'indole presentant une action antivirale WO1995007910A1 (fr)

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AU76212/94A AU7621294A (en) 1993-09-17 1994-09-16 Antiviral indole derivatives

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GB939319297A GB9319297D0 (en) 1993-09-17 1993-09-17 Indole derivatives
GB9319297.9 1993-09-17

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GB (1) GB9319297D0 (fr)
HU (1) HUT71599A (fr)
IL (1) IL110980A0 (fr)
WO (1) WO1995007910A1 (fr)
ZA (1) ZA947210B (fr)

Cited By (23)

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FR2826653A1 (fr) * 2001-06-29 2003-01-03 Servier Lab Nouveaux derives de pyrido-pyrido-pyrrolo[3,2-g]pyrrolo [3,4-e]-indole et pyrido-pyrrolo[2,3-a]pyrrolo[3,4-c] carbazole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2003027275A1 (fr) 2001-09-27 2003-04-03 Alcon, Inc. Inhibiteurs de la glycogene synthase kinase-3 (gsk-3) pour le traitement du glaucome
WO2003095452A1 (fr) * 2002-05-08 2003-11-20 Janssen Pharmaceutica N.V. Inhibiteurs substitues de la pyrroline kinase
JP2004501097A (ja) * 2000-05-09 2004-01-15 セフアロン・インコーポレーテツド 新規な多環式化合物およびそれらの使用
WO2007065924A1 (fr) 2005-12-09 2007-06-14 Novartis Ag Composés hétérocycliques bicycliques utilisés comme agents anti-inflammatoires
EP1900738A3 (fr) * 2002-05-08 2008-04-09 Janssen Pharmaceutica, N.V. Inhibiteurs substitués de la pyrroline kinase
US7488826B2 (en) 2003-03-27 2009-02-10 Janssen Pharmaceutica N.V. Substituted pyrroline kinase inhibitors
US7504509B2 (en) 2003-12-19 2009-03-17 Plexxikon, Inc. Compounds and methods for development of Ret modulators
US7666878B2 (en) 2004-06-17 2010-02-23 Novartis Ag Pyrrolopyridine derivatives and their use as Crth2 antagonists
WO2011073092A1 (fr) 2009-12-18 2011-06-23 Johannes Gutenberg-Universität Mainz Composés de 3-(indolyl) ou 3-(azaindolyl)-4-arylmaléimide et leur utilisation dans le traitement des tumeurs
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8008320B2 (en) 2004-12-08 2011-08-30 Johannes Gutenberg-Universitatis 3-(indolyl)-4-arylmaleimide derivatives and their use as angiogenesis inhibitors
WO2012084683A1 (fr) 2010-12-23 2012-06-28 Johannes Gutenberg-Universität Mainz 3-(indolyl)- et 3-(azaindolyl)-4-arylmaléimides conjugués et leur utilisation dans le traitement des tumeurs
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
WO2016008966A1 (fr) 2014-07-17 2016-01-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés pour le traitement de maladies liées à la jonction neuromusculaire
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
WO2016207366A1 (fr) 2015-06-26 2016-12-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques de traitement d'infections virales
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
EP3187495A1 (fr) 2015-12-30 2017-07-05 Johannes Gutenberg-Universität Mainz Composés de 3-(5-fluoroindolyl)-4-arylmaléimide et leur utilisation dans le traitement de tumeurs

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JP2004501097A (ja) * 2000-05-09 2004-01-15 セフアロン・インコーポレーテツド 新規な多環式化合物およびそれらの使用
WO2003002563A1 (fr) * 2001-06-29 2003-01-09 Les Laboratoires Servier Derives de pyrido-pyrido-pyrrolo pyrrolo-indole et pyrido-pyrrolo pyrrolo carbazole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US7001906B2 (en) 2001-06-29 2006-02-21 Les Laboratoires Servier Pyrido-pyrido-pyrrolo pyrrolo-indole and pyrido-pyrrolo pyrrolo carbazole derivatives, method for the production thereof and pharmaceutical compositions containing said derivatives
FR2826653A1 (fr) * 2001-06-29 2003-01-03 Servier Lab Nouveaux derives de pyrido-pyrido-pyrrolo[3,2-g]pyrrolo [3,4-e]-indole et pyrido-pyrrolo[2,3-a]pyrrolo[3,4-c] carbazole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US7598288B2 (en) 2001-09-27 2009-10-06 Alcon, Inc. Inhibitors of glycogen synthase kinase-3 (GSK-3) for treating glaucoma
WO2003027275A1 (fr) 2001-09-27 2003-04-03 Alcon, Inc. Inhibiteurs de la glycogene synthase kinase-3 (gsk-3) pour le traitement du glaucome
EP2281560A1 (fr) 2001-09-27 2011-02-09 Alcon, Inc. Inhibiteurs de la glycogène synthase kinase-3 (GSK-3) pour traiter la neuropathie optique du glaucome
US7781450B2 (en) 2002-05-08 2010-08-24 Janssen Pharmaceutica N.V. Substituted pyrroline kinase inhibitors
US7705015B2 (en) 2002-05-08 2010-04-27 Janssen Pharmaceutica, Nv Substituted pyrroline kinase inhibitors
WO2003095452A1 (fr) * 2002-05-08 2003-11-20 Janssen Pharmaceutica N.V. Inhibiteurs substitues de la pyrroline kinase
US7786135B2 (en) 2002-05-08 2010-08-31 Janssen Pharmaceutica, N.V. Substituted pyrroline kinase inhibitors
US7524858B2 (en) 2002-05-08 2009-04-28 Janssen Pharmaceutica N.V. Substituted pyrroline kinase inhibitors
US7125878B2 (en) 2002-05-08 2006-10-24 Janssen Pharmaceutica Substituted pyrroline kinase inhibitors
EP1900738A3 (fr) * 2002-05-08 2008-04-09 Janssen Pharmaceutica, N.V. Inhibiteurs substitués de la pyrroline kinase
US7488826B2 (en) 2003-03-27 2009-02-10 Janssen Pharmaceutica N.V. Substituted pyrroline kinase inhibitors
US7504509B2 (en) 2003-12-19 2009-03-17 Plexxikon, Inc. Compounds and methods for development of Ret modulators
US7666878B2 (en) 2004-06-17 2010-02-23 Novartis Ag Pyrrolopyridine derivatives and their use as Crth2 antagonists
US9169251B2 (en) 2004-06-17 2015-10-27 Novartis Ag Pyrrolopyridine derivatives and their use as CRTH2 antagonists
US8791256B2 (en) 2004-06-17 2014-07-29 Novartis Ag Pyrrolopyridine derivatives and their use as CRTH2 antagonists
US8470848B2 (en) 2004-06-17 2013-06-25 Novartis Ag Organic compounds
US8455645B2 (en) 2004-06-17 2013-06-04 Novartis Ag Pyrrolopyridine derivatives and their use as CRTH2 antagonists
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8008320B2 (en) 2004-12-08 2011-08-30 Johannes Gutenberg-Universitatis 3-(indolyl)-4-arylmaleimide derivatives and their use as angiogenesis inhibitors
US8431703B2 (en) 2005-12-09 2013-04-30 Novartis Ag Pyrrolopyridine compounds and their use in treating disease
WO2007065924A1 (fr) 2005-12-09 2007-06-14 Novartis Ag Composés hétérocycliques bicycliques utilisés comme agents anti-inflammatoires
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9487515B2 (en) 2006-11-22 2016-11-08 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
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US9695169B2 (en) 2012-05-31 2017-07-04 Plexxikon Inc. Synthesis of heterocyclic compounds
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AU7621294A (en) 1995-04-03
GB9319297D0 (en) 1993-11-03
HU9501809D0 (en) 1995-08-28
HUT71599A (en) 1996-01-29
ZA947210B (en) 1996-03-18
IL110980A0 (en) 1994-11-28

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