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WO1996007409A1 - Alcaloides et leurs agents antiviraux - Google Patents

Alcaloides et leurs agents antiviraux Download PDF

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Publication number
WO1996007409A1
WO1996007409A1 PCT/GB1995/002091 GB9502091W WO9607409A1 WO 1996007409 A1 WO1996007409 A1 WO 1996007409A1 GB 9502091 W GB9502091 W GB 9502091W WO 9607409 A1 WO9607409 A1 WO 9607409A1
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WO
WIPO (PCT)
Prior art keywords
spectrum
alkaloids
compounds
methanol
tms
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/GB1995/002091
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English (en)
Inventor
Peter John Houghton
Tibebe Zewdie Woldermarian
Naheed Mahmood
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Kings College London
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Kings College London
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Filing date
Publication date
Application filed by Kings College London filed Critical Kings College London
Priority to AU33952/95A priority Critical patent/AU3395295A/en
Publication of WO1996007409A1 publication Critical patent/WO1996007409A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems

Definitions

  • the present invention relates to chromone alkaloids isolated from the root, stem and root -bark of Schumanniophyton magnificum and S. problematicum, which are trees found in West Central Africa.
  • the present invention also relates to analogues of the alkaloids and to therapeutic uses of the alkaloids and their analogues.
  • the invention relates to use of the alkaloids and their analogues in the prophylaxis and treatment of infection by human immunodeficiency virus (HIV), which is believed to be the aetiological agent in human acquired immunodeficiency syndrome (AIDS), and herpes simplex virus (HSV).
  • HBV human immunodeficiency virus
  • AIDS human acquired immunodeficiency syndrome
  • HSV herpes simplex virus
  • Chromone alkaloids were first isolated from S. problematicum by Schlittler et al. (Tetrahedron Letts., 2911-2914 (1978)), who reported three alkaloids, schumanniophytine (1) and two unnamed piperidin-2-ones (2a) and (2b):
  • Rohitukine (5) has also been isolated from other plants belonging to the family Meliaceae. Rohitukine (5) and a number of derivatives thereof are reported (United States Patents 4,603,137 and 4,900,727 and Australian Patent Application AU-A-43841/89) to exhibit anti-inflammatory, analgesic, immuno-suppressive and anti-tumour activity.
  • HIV is believed to be the aetiological agent in AIDS.
  • Barre-Sinoussi et al . Science, 220, 868-870, (1983); Gallo et al . , Science, 224, 500-503, (1984)
  • chemical compounds such as AZT (zidovudine)
  • Such compounds however, often exhibit problems with toxicity and other undesirable side effects in individual patients.
  • Schumanniophyton alkaloids and derivatives thereof are effective viral inhibitors whilst exhibiting low toxicity.
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 may be the same or different and are selected from the group comprising hydrogen, hydroxy and substituted alkyl, alkoxy, alkoyloxy, aryl, aryloxy and aryloyloxy groups;
  • R 3 is selected from the group comprising hydrogen, carbohydrates and oligosaccharides, and substituted or unsubstituted alkyl, alkoyl, aryl and aryloyl groups;
  • R 9 is an alkyl group
  • X is selected from -CH 2 - and - C (O) - ;
  • Y is selected from -CHR 10 - and - C (O) - ;
  • Z is selected from N and O;
  • n is selected from 0, 1 and 2;
  • R 10 is selected from the group comprising hydrogen, hydroxy, carbohydrates and oligosaccharides, and substituted or unsubstituted alkyl, alkoxy, alkoyloxy, aryl, aryloxy and aryloyloxy groups;
  • the viral infection comprises HIV or HSV infection.
  • Pharmaceutically acceptable derivative means any pharmaceutically acceptable salt or addition compound or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) the parent compound or an anti-virally active metabolite or residue thereof.
  • Pharmaceutically acceptable salts include, for example, the hydrochloride, hydrobromide, sulphate, phosphate, acetate, oxalate, tartrate, citrate, maleate or fumarate.
  • Pharmaceutically acceptable addition compounds include, for example, quaternary amines and esters of the compounds.
  • alkyl group means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical.
  • the alkyl group is preferably C 3 to C 12 , more preferably C 5 to C 10 , more preferably C 5 to C 7 .
  • the alkyl group is preferably C 1 to C 10 , more preferably C 1 to C 6 , more preferably methyl.
  • aryl group means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, preferably one, heteratom, such as pyridyl, pyrrolyl, furanyl and thiophenyl.
  • the aryl group comprises phenyl.
  • the alkyl and aryl groups may be substituted or unsubstituted, preferably unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent.
  • Substituents may include halogen atoms; oxygen containing groups such as oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkoyl, alkoyloxy; nitrogen containing groups such as amino, alkylamino, dialkylamino, cyano, azide and nitro; sulphur containing groups such as thiol, alkylthiol, sulphonyl and sulphoxide; heterocyclic groups containing one or more, preferably one, heteroatom, such as thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl
  • alkoxy means alkyl-0-.
  • alkoyloxy means alkyl -C(O)-O-.
  • aryloxy means aryl-O-.
  • aryloyloxy means aryl -C(O)-O-.
  • Carbohydrates and oligosaccharides preferably comprise carbohydrates and oligosaccharides that improve the bioavailability of the compound, such as mono- up to penta- saccharides comprising, for example, glucose, glucuronic acid or rhamnose or their derivatives.
  • R 1 is methyl or substituted or unsubstituted phenyl. More preferably, R 1 is methyl or unsubstituted phenyl, preferably methyl.
  • R 2 is hydroxy or alkoyloxy. More preferably, R 2 is hydroxy.
  • R 3 is hydrogen or alkyl. More preferably, R 3 is hydrogen.
  • R 4 is hydrogen
  • R 5 is hydroxy or alkoyloxy. More preferably, R 5 is hydroxy.
  • R 6 is hydroxy or alkoyloxy. More preferably, R 6 is hydroxy. Preferably, R 7 is hydroxy or alkoyloxy.
  • R 8 is hydrogen.
  • R 10 is hydroxy or alkoyloxy. More preferably, R 10 is hydroxy.
  • x is preferably -C(O)-.
  • X is preferably -CH 2 -.
  • Y is -CHR 10 -
  • Z is O.
  • n 1
  • R 4 , R 5 and R 8 are hydrogen and Y is -CHR 10 -.
  • the compound is selected from the group comprising formulae I, II, III and IV, more preferably I and III, more preferably I.
  • the compound is selected from the group comprising
  • the compounds of the present invention exist in various diastereomeric and enantiomeric forms as a result of asymmetric centres in the compounds.
  • the present invention incudes different diastereomers and enantiomers in isolation from each other, as well as mixtures.
  • the compounds of the present invention may be synthesised by conventional synthetic organic chemistry or may be prepared by isolation of the natural product from the root, stem or root-bark of S. magnificum or S. problematicum (Flora of West Tropical Africa, 2nd edition, (1963), ed. N. Hepper, volume II, pages 104-105 and 116, J. Hutchinson and J.M. Dalziel, pub. Crown Agents.) followed, where appropriate, by derivatisation using conventional synthetic organic chemistry.
  • a further aspect of the present invention provides use of a schumanniophyton alkaloid or derivative thereof in the manufacture of a medicament for the treatment or prophylaxis of viral infection.
  • a schumanniophyton alkaloid comprises an alkaloid isolatable from S . magnifi cum or S . spa ti cum .
  • Derivatives thereof comprise alkaloids bearing alkyl, alkoxy, alkoyloxy, aryl, aryloxy and aryloyloxy substituents as defined hereinbefore.
  • R 1 -R 5 , X, Y, Z and n are as defined above,
  • R 1 is methyl
  • R 3 is hydrogen or methyl
  • R 4 is hydrogen
  • R 5 is hydrogen
  • X is -C(O)-
  • Y is
  • R 10 is OH or OAc, Z is 0 and n is 1, then R 2 is not the same as R 10 ;
  • R 1 -R 5 , R 9 , Y, Z and n are as defined above;
  • R 1 -R 5 , X, Z and n are as defined above,
  • R 1 is methyl
  • R 3 is hydrogen cr methyl
  • R 4 is hydrogen
  • X is -C(O)-
  • Z is 0 and n is 1, then R 2 is not OH or OAc;
  • R 1 -R 7 , X, Z and n are as defined above,
  • R 1 , R 2 , R 4 , R 5 and Z are as defined above,
  • R 1 is methyl, R 4 and R 5 are hydrogen and Z is 0, then R 2 is not OH or OAc;
  • R 1 , R 2 , R 4 , R 8 and Z are as defined above,
  • R 1 is methyl
  • R 4 and R 8 are hydrogen and Z is 0 then R 2 is not OH or OAc.
  • a pharmaceutical composition for use in the treatment or prophylaxis of viral infection comprising a compound as hereinbefore defined in combination with a pharmaceutically acceptable excipient.
  • the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal and topical administration.
  • the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
  • Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl- pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • suspending agents such as cellulose derivatives, sodium alginate, polyvinyl- pyrrolidone and gum tragacanth
  • a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • a process for the production of a pharmaceutical composition comprising the step of combining a compound as hereinbefore defined with a pharmaceutically acceptable excipient.
  • a method of treatment or prophylaxis of viral infection comprising administering to a patient in need of such treatment or prophylaxis an effective dose of a compound as hereinbefore defined.
  • the chloroform layer was washed with 2 x 150mL water and then taken to dryness. 2.5g of the residue was adsorbed on to silica gel for Flash chromatography and fractionated on a silica column 1.5 x 25 cm. The following eluting solvents were used and 5ml aliquots collected.
  • the compounds are eluted in the following order. (Details of the R f values, colour reactions and spectroscopic characteristics are given below).
  • 60mg of the alkaloid was dissolved in 1mL pyridine.
  • 60mg dimethylaminopyridine (DMAP) and 120 mg 4-bromo benzoyl chloride (4BrBzCl) were dissolved in 1mL dichloromethane and were added to the alkaloid solution.
  • the solution was made up to 6mL with dichloromethane and kept at 25o for 72 hours.
  • reaction mixture was poured into 20mL 1M NaHCO 3 and extracted with 3 x 10mL CHCl 3 .
  • the chloroform was washed with water and evaporated off under reduced pressure.
  • the residue was examiend on TLC and the products isolated by prep TLC (silica gel/chloroform:methanol 12:1). The mass spectrum and 1 H NMR spectrum of each product was obtained.
  • 60mg alkaloid is mixed with 1 ml pyridine and 2 ml acetic anhydride and kept for 72 hours at 25o.
  • the solvents were evaporated under reduced pressure and the residue acidified with 1M HCl (20mL) and shaken with 3 x 10mL chloroform.
  • the chloroform was evaporated to small volume and the products purified by prep TLC using silica gel/chlcroform:methanol 12:1. The mass spectrum and 1 H NMR spectrum of each product was obtained.
  • 60mg alkaloid is mixed with 1 ml pyridine and 2 ml acetic anhydride and refluxed on a water bath for 3 hours.
  • the solvents were evaporated under reduced pressure and the residue acidified with 1M HCl (20mL) and shaken with 3 x 10mL chloroform.
  • the chloroform was evaporated to small volume and the products purified by prep TLC using silica gel/chloroform:methanol 12:1. The mass spectrum and *H NMR spectrum of each product was obtained.
  • Boron trifluoride/ether reagent is dissolved in dry CH 2 Cl 2 to form 0.27M solution.
  • the alkaloid is added to the mixture which is then kept under nitrogen at 0o.
  • 0.3M epichlorhydrin in CH 2 Cl 2 is added dropwise and the mixture stirred continuously for 7 hours at 0°.
  • Cold 5% aqueous K 2 CO 3 is then added to the mixture and after careful shaking the organic layer is removed, washed with water and the products isolated.
  • the alkaloid is dissolved in dry benzene.
  • p-Toluene sulphonic acid and dry CaCl 2 are added and the mixture refluxed for 3 hours.
  • the benzene is washed with water and the alkaloid products are recovered from the benzene layer.
  • the alkaloid is dissolved in dry CH 2 Cl 2 and equimolar p- toluene sulphonylhydrazine added. The mixture is refluxed at 100° for 30 min and after cooling, sodium borohydride is added. The reaction mixture is washed with water and the products recovered from the organic layer. Exampl e 15
  • the alkaloid is dissolved in water:ethanol 1:1 and 10M NaOH added to make the mixture pH 12. 13.5M ammonia is then added to the mixture which is then refluxed at 100° for 30 min.
  • the pH of the reaction mixture is adjusted to 7 with dilute acid and CH 2 Cl 2 is added to extract the products.
  • Boron trifluoride/ether reagent is dissolved in dry CH 2 Cl 2 to form 0.27M solution.
  • the alkaloid is added to the mixture which is then kept under nitrogen at 0°.
  • 0.3M epichlorhydrin in Ch 2 Cl 2 is added dropwise and the mixture stirred continuously for 7 hours at 0°.
  • LiBH 4 is then added to the mixture which is then stirred at 0° for 3 hours.
  • the anti-HIV activity and toxicity of compounds were assessed in C8166 cells infected with HIV-1 III-B .
  • Cells were grown in RMPI 1640 with 10% fetal calf serum.
  • Forty- thousand cells per microtitre plate well were mixed with 5- fold dilutions of compound prior to addition of 10 CCID 50 (50% cell culture infectious dose) units of virus and incubated for 5-7 days. Formation of syncytia was examined from 2 days post-infection.
  • Gp120 antigen produced at 5-7 days was measured by ELISA, using the lectin GNA (from Galanthus nivalis) to capture the glycoprotein and human anti-HIV serum for detection, as described by Mahmood and Hay, (J. Immunol.
  • the antiviral activity against herpes simplex type I was determined by measuring viral antigen produced in injected Vero or human lung embryonic cells MRC5 as described by Mahmood et al (Antiviral Chem. Cher. ther . 4, 235-240. (1993)). Five fold dilutions of compounds were added to duplicate cells just before adding virus at a multiplicity of infection of 0.01 plaque-forming units per cell. The cells were incubated 16-18h at 37° and then fixed with 3% for 1-2h. Antigen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des alcaloïdes de chromone isolés de la racine, de la tige et de l'écorce de la racine de Schumanniophyton magnificum et de Schummaniophyton problematicum, leurs analogues, ainsi que leur utilisation thérapeutique, afin de traiter des infections virales.
PCT/GB1995/002091 1994-09-07 1995-09-05 Alcaloides et leurs agents antiviraux Ceased WO1996007409A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU33952/95A AU3395295A (en) 1994-09-07 1995-09-05 Alkaloids and their antiviral agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9417969A GB9417969D0 (en) 1994-09-07 1994-09-07 Alkaloids and derivatives thereof
GB9417969.4 1994-09-07

Publications (1)

Publication Number Publication Date
WO1996007409A1 true WO1996007409A1 (fr) 1996-03-14

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Application Number Title Priority Date Filing Date
PCT/GB1995/002091 Ceased WO1996007409A1 (fr) 1994-09-07 1995-09-05 Alcaloides et leurs agents antiviraux

Country Status (3)

Country Link
AU (1) AU3395295A (fr)
GB (1) GB9417969D0 (fr)
WO (1) WO1996007409A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6660750B2 (en) 2000-02-15 2003-12-09 University Of Iowa Research Foundation Flavopiridol methods and compositions for HIV therapy
US6924376B2 (en) 2002-04-17 2005-08-02 Cytokinetics, Inc. Compounds, compositions and methods
US6949538B2 (en) 2002-07-17 2005-09-27 Cytokinetics, Inc. Compounds, compositions, and methods

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BEUTLER, J.A. ET AL: "Anti-HIV and cytotoxic alkaloids from Buchenavia Capitata", JOURNAL OF NATURAL PRODUCTS, vol. 55, no. 2, pages 207 - 213 *
HOUGHTON P J ET AL: "Antiviral activity of chromone alkaloids from Schumanniophyton magnificum", JOURNAL OF PHARMACY AND PHARMACOLOGY, 46 (SUPPL. 2). 1994. 1061. *
HOUGHTON P J ET AL: "NOVEL CHROMONE ALKALOIDS FROM SCHUMANNIOPHYTON-MAGNIFICUM", PLANTA MED, 0 (1). 1985. 23-27. *
HOUGHTON P J: "REVISION OF STRUCTURES OF SOME SCHUMANNIOPHYTON ALKALOIDS", PLANTA MED, 53 (3). 1987. 264-266. *
HOUGHTON, P. J. ET AL: "Antiviral activity of natural and semi-synthetic chromone alkaloids", ANTIVIRAL RES., 1994, 235-44 *
MAHMOOD, N. ET AL: "Inhibiton of HIV infection by flavanoids", ANTIVIRAL RESEARCH, vol. 22, no. 2-3, pages 189 - 199 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6660750B2 (en) 2000-02-15 2003-12-09 University Of Iowa Research Foundation Flavopiridol methods and compositions for HIV therapy
US6924376B2 (en) 2002-04-17 2005-08-02 Cytokinetics, Inc. Compounds, compositions and methods
US7491746B2 (en) 2002-04-17 2009-02-17 Cytokinetics, Inc. Compounds, compositions and methods
US7629477B2 (en) 2002-04-17 2009-12-08 Cytokinetics, Inc. Compounds, compositions and methods
US7919524B2 (en) 2002-04-17 2011-04-05 Cytokinetics, Inc. Compounds, compositions and methods
US8119678B2 (en) 2002-04-17 2012-02-21 Cytokinetics, Incorporated Compounds, compositions and methods
US8329928B2 (en) 2002-04-17 2012-12-11 Cytokinetics, Incorporated Compounds, compositions and methods
US8633236B2 (en) 2002-04-17 2014-01-21 Cytokinetics, Inc. Compounds, compositions and methods
US6949538B2 (en) 2002-07-17 2005-09-27 Cytokinetics, Inc. Compounds, compositions, and methods

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Publication number Publication date
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GB9417969D0 (en) 1994-10-26

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