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WO1996009307A1 - Derives de purine et 8-azapurine appropries au traitement therapeutique du sida - Google Patents

Derives de purine et 8-azapurine appropries au traitement therapeutique du sida Download PDF

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Publication number
WO1996009307A1
WO1996009307A1 PCT/EP1995/003791 EP9503791W WO9609307A1 WO 1996009307 A1 WO1996009307 A1 WO 1996009307A1 EP 9503791 W EP9503791 W EP 9503791W WO 9609307 A1 WO9609307 A1 WO 9609307A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
hydrogen
group
reaction
carried out
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1995/003791
Other languages
English (en)
Inventor
Mario Grifantini
Palmarisa Franchetti
Loredana Cappellacci
Paolo La Colla
Anna Giulia Loi
Giovanna Piras
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Istituto Superiore di Sanita ISS
Universita degli Studi di Cagliari
Original Assignee
Istituto Superiore di Sanita ISS
Universita degli Studi di Cagliari
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Istituto Superiore di Sanita ISS, Universita degli Studi di Cagliari filed Critical Istituto Superiore di Sanita ISS
Priority to AU37422/95A priority Critical patent/AU3742295A/en
Publication of WO1996009307A1 publication Critical patent/WO1996009307A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • HIV human immunodeficiency virus
  • RT reverse transcriptase
  • viral protease represents two particularly promising strategies.
  • Azidothymide has been the first drug to be used for the treatment of AIDS and, more recently, dideoxyinosine (ddl) has been licenced for the treatment of patients who show intolerance to AZT.
  • ddC and d4T are the other two drugs at present used in the clinic.
  • the above compounds also inhibit the mammalian DNA polymerases ( ⁇ , ⁇ , ⁇ and ⁇ ) and often show significant toxic side-effects.
  • the emergence of drug- resistant strains is a further problem linked to their use.
  • PMEG is one of the most powerful wide spectrum antiviral agents known up to now. However, due to its cytotoxicity, it has not been possible to use it in the clinic. The search for drugs equally powerful, but endowed with a better selectivity index is therefore important.
  • R 1 is an amino group or hydrogen.
  • R 2 is an halogen or a OR 5 or NHR 5 group where R 5 is hydrogen or an alkyl- carbonyl group,
  • the present invention refers also to pharmaceutical compositions containing at least one derivative (I) or one of its pharmacologically acceptable salts or esters and to the relative therapeutic method. Finally the present invention refers also to a process for the preparation of the derivatives having formula (I). DETAILED DESCRIPTION OF THE INVENTION
  • Z is N or CH
  • R 1 is an amino group or hydrogen
  • R 2 is an halogen or a OR 5 or NHR 5 group where R 5 is hydrogen or an alkyl- carbonyl group
  • the compounds of the invention can be isolated in the form of free acids.
  • the free acid forms can be easily transformed into physiologically acceptable salts by methods known in the art.
  • Such salts include those of ammonium ion. Li + , Na + ; the salts may be monobasic or dibasic.
  • the mesylate having formula (III) is prepared with the method described by K.-L. Yu et al. (J. Med. Chem. 1992. 35. 2958-2969).
  • the reaction of the step a) is carried out in anhydrous dimethyl sulfoxyde, stirring and under nitrogen atmosphere at a temperature equal to 95-100 °C.
  • the molar ratio between the compound (III) and the compound (II) is between 0.8:1 and 1.2:1 and preferably it is 1:1.
  • the mixture is cooled at room temperature and filtered and the filtrate is evaporated to dryness in vacuo.
  • the separation of the step b) is realized submitting the residue obtained by evaporation of the step a) to flash cromatography on silica gel eluting with a mixture of solvents such as CHCl 3 -MeOH
  • the reaction of the step c) is carried out in anhydrous acetonitrile at a temperature equal to 25-30 oC.
  • the molar ratio between bromotrimethylsilane and the compound (V) is between 15:1 and 8:1 and preferably it is 10:1. Then the product (I) is separated from the reaction mixture by known technique operations.
  • the N8 substituted derivative (0.55 g. 20% ) (IVb) has been separated as first fraction as an oily product by chromatography on a silica gel column eluting with a mixture of CHCl 3 -MeOH-NH 4 OH (90:9:1).
  • compound (IX) is catalytically hydrogenated and then converted into compound (V) by nitrosation in acidic medium.
  • step a) The reaction of step a) is carried out in dimethylformamide, under nitrogen atmosphere at 80 °C.
  • the molar ratio between compound (III) and sodium azide is 1:10.
  • the solvent is then removed by evaporation, the residue is treated with water and extracted with chloroform.
  • Compound (VI) is obtained pure after evaporation of the organic solvent.
  • step b) The reaction of step b) is carried out in methanol over palladium on carbon under hydrogen atmosphere at 40 psi .
  • the molar ratio between compound (VI) and catalyst is 30:1.
  • compound VII is obtained enough pure by evaporation of the organic solvent.
  • step c) is executed by reaction of (VII) with compound (VIII) in a dipolar aprotic solvent, such as dimethylformamide in the presence of trietylamine at room temperature.
  • a dipolar aprotic solvent such as dimethylformamide
  • the derivative (IX) is purified by flash chromatography on silica gel eluting with a mixture of solvents such as CHCl 3 -MeOH (95:5).
  • the first reaction of step d) is executed in methanol by catalytic hydrogenation (Raney nickel at a hydrogen pressure of 50 psi).
  • the molar ratio between (IX) and catalyst ranges from 8:1 to 2:1 and preferentially is 4:1.
  • To the reaction mixture is then added acetic acid in deoxygenated water (40:10).
  • To this mixture stirred and cooled at 0°C sodium sodium nitrite in deoxygenated water is added.
  • Compound (V) is obtained by extraction of the mixture with chloroform.
  • the cytotoxicity of the compounds is expressed as the concentration necessary to reduce of the viability of normal MT-4 cells by 50% (CC50).
  • the activity is expressed as the concentration required to protect 50% of the MT-4 cells from the virus-induced cytopathogenic effect (EC50).
  • the MT-4 cells have been cultured in RPMI 1640 additioned of fetal calf serum (FCS) at 10%, penicillin 100 U/ml and streptomycin 100 ⁇ g/ml. The cultures have been incubated at 37 °C in a 5% CO 2 atmosphere and have been periodically checked for the absence of mycoplasmas contamination.
  • FCS fetal calf serum
  • the experimental protocols used for the evaluation of cytotoxicity and antiviral activity are based on the MTT colorimetric method, owing to its easy execution and to the quickness of the answer.
  • the MTT is a tetrazolium salt which is transformed by the mitochondrial succinate dehydrogenase enzyme to formazane which is a product having blue colour.
  • the amount of formazane produced is directly proportional to the number of living cells.
  • the produced amount of formazane has been then measured at the spectrophotometer by optical density reading at 570 nm.
  • the MT-4 cells seeded at a density equal to 1 x 10 cells/ml have been acutely infected with type 1 HIV (strain IIIB) and with type 2 HIV (strain CBL20) at an infection multiplicity (m.o.i.) of 0.01. After 1 hour of incubation at 20 °C and subsequent removal of the inoculum, the cells have been washed for three times and then suspended again at a density equal to 1 x 10 5 cells/ml, in absence or presence of the compounds under examination. After 4 days of incubation at 37 °C, the cellular viability has been determined by the above described MTT method.
  • the derivatives having formula (I) according to the present invention and their pharmacologically acceptable salts may be used with success, alone or in associations with other antivirals or in pharmaceutical compositions, in the therapy of the HIV virus infections.
  • Said combinations comprise at least a derivative having formula (I) together with AZT and/or ddl and/or ddC.
  • compositions comprise a pharmaceutically effective dose of at least a derivative having formula (I) or of one of its pharmaceutically acceptable salts in mixture with pharmaceutically acceptable diluents and/or excipients.
  • compositions may be prepared in formulations suitable to the administration by oral or by parenteral way.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit des nouveaux dérivés de purine et 8-azapurine, leur procédé de préparation ainsi que leur utilisation dans le traitement des infections à virus VIH, seuls ou associés à l'AZT et/ou au ddI et/ou au ddC.
PCT/EP1995/003791 1994-09-23 1995-09-25 Derives de purine et 8-azapurine appropries au traitement therapeutique du sida Ceased WO1996009307A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37422/95A AU3742295A (en) 1994-09-23 1995-09-25 Purine and 8-azapurine derivatives suitable to the therapeutic treatment of aids

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI94A001939 1994-09-23
ITMI941939A IT1270008B (it) 1994-09-23 1994-09-23 Derivati purinici ed 8-azapurinici atti al trattamento terapeutico dell'aids

Publications (1)

Publication Number Publication Date
WO1996009307A1 true WO1996009307A1 (fr) 1996-03-28

Family

ID=11369590

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/003791 Ceased WO1996009307A1 (fr) 1994-09-23 1995-09-25 Derives de purine et 8-azapurine appropries au traitement therapeutique du sida

Country Status (3)

Country Link
AU (1) AU3742295A (fr)
IT (1) IT1270008B (fr)
WO (1) WO1996009307A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006138264A2 (fr) 2005-06-14 2006-12-28 Schering Corporation Inhibiteurs d'aspartyl protease
US7157448B2 (en) 2001-01-19 2007-01-02 Lg Life Sciences Ltd. Acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0269947A1 (fr) * 1986-11-18 1988-06-08 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Dérivés de phosphonométhoxyalkylène-purine et pyrimidine antiviraux
WO1993007157A1 (fr) * 1991-10-11 1993-04-15 Institute Of Organic Chemistry And Biochemistry Ofthe Academy Of Sciences Of The Czech Republic Derives acycliques antiviraux alcenyle et alkynyle de purine et de pyrimidine substitues par phosphonomethoxyalkyle
WO1994003467A2 (fr) * 1992-08-05 1994-02-17 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Analogues de nucleotides enantiomeres antiretroviraux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0269947A1 (fr) * 1986-11-18 1988-06-08 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Dérivés de phosphonométhoxyalkylène-purine et pyrimidine antiviraux
WO1993007157A1 (fr) * 1991-10-11 1993-04-15 Institute Of Organic Chemistry And Biochemistry Ofthe Academy Of Sciences Of The Czech Republic Derives acycliques antiviraux alcenyle et alkynyle de purine et de pyrimidine substitues par phosphonomethoxyalkyle
WO1994003467A2 (fr) * 1992-08-05 1994-02-17 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Analogues de nucleotides enantiomeres antiretroviraux

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7157448B2 (en) 2001-01-19 2007-01-02 Lg Life Sciences Ltd. Acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same
US7605147B2 (en) 2001-01-19 2009-10-20 Lg Life Sciences Ltd. Acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same
US7723319B2 (en) 2001-01-19 2010-05-25 Lg Life Sciences Ltd. Acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same
WO2006138264A2 (fr) 2005-06-14 2006-12-28 Schering Corporation Inhibiteurs d'aspartyl protease
WO2006138264A3 (fr) * 2005-06-14 2007-03-01 Schering Corp Inhibiteurs d'aspartyl protease
JP2008543849A (ja) * 2005-06-14 2008-12-04 シェーリング コーポレイション アスパルチルプロテアーゼ阻害剤
US7868000B2 (en) 2005-06-14 2011-01-11 Schering Corporation Aspartyl protease inhibitors
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10035814B2 (en) 2011-12-22 2018-07-31 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10562926B2 (en) 2011-12-22 2020-02-18 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US11279720B2 (en) 2011-12-22 2022-03-22 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US12398162B2 (en) 2011-12-22 2025-08-26 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors

Also Published As

Publication number Publication date
ITMI941939A0 (it) 1994-09-23
ITMI941939A1 (it) 1996-03-23
IT1270008B (it) 1997-04-16
AU3742295A (en) 1996-04-09

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